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Sample records for groove binding drugs

  1. Minor-Groove Binding Drugs: Where Is the Second Hoechst 33258 Molecule?

    KAUST Repository

    Fornander, Louise H.

    2013-05-16

    Hoechst 33258 binds with high affinity into the minor groove of AT-rich sequences of double-helical DNA. Despite extensive studies of this and analogous DNA binding molecules, there still remains uncertainty concerning the interactions when multiple ligand molecules are accommodated within close distance. Albeit not of direct concern for most biomedical applications, which are at low drug concentrations, interaction studies for higher drug binding are important as they can give fundamental insight into binding mechanisms and specificity, including drug self-stacking interactions that can provide base-sequence specificity. Using circular dichroism (CD), isothermal titration calorimetry (ITC), and proton nuclear magnetic resonance (1H NMR), we examine the binding of Hoechst 33258 to three oligonucleotide duplexes containing AT regions of different lengths: [d(CGCGAATTCGCG)]2 (A2T2), [d(CGCAAATTTGCG)]2 (A3T 3), and [d(CGAAAATTTTCG)]2 (A4T4). We find similar binding geometries in the minor groove for all oligonucleotides when the ligand-to-duplex ratio is less than 1:1. At higher ratios, a second ligand can be accommodated in the minor groove of A4T4 but not A2T2 or A3T3. We conclude that the binding of the second Hoechst to A4T4 is not cooperative and that the molecules are sitting with a small separation apart, one after the other, and not in a sandwich structure as previously proposed. © 2013 American Chemical Society.

  2. Minor-Groove Binding Drugs: Where Is the Second Hoechst 33258 Molecule?

    KAUST Repository

    Fornander, Louise H.; Wu, Lisha; Billeter, Martin; Lincoln, Per; Nordé n, Bengt

    2013-01-01

    Hoechst 33258 binds with high affinity into the minor groove of AT-rich sequences of double-helical DNA. Despite extensive studies of this and analogous DNA binding molecules, there still remains uncertainty concerning the interactions when multiple ligand molecules are accommodated within close distance. Albeit not of direct concern for most biomedical applications, which are at low drug concentrations, interaction studies for higher drug binding are important as they can give fundamental insight into binding mechanisms and specificity, including drug self-stacking interactions that can provide base-sequence specificity. Using circular dichroism (CD), isothermal titration calorimetry (ITC), and proton nuclear magnetic resonance (1H NMR), we examine the binding of Hoechst 33258 to three oligonucleotide duplexes containing AT regions of different lengths: [d(CGCGAATTCGCG)]2 (A2T2), [d(CGCAAATTTGCG)]2 (A3T 3), and [d(CGAAAATTTTCG)]2 (A4T4). We find similar binding geometries in the minor groove for all oligonucleotides when the ligand-to-duplex ratio is less than 1:1. At higher ratios, a second ligand can be accommodated in the minor groove of A4T4 but not A2T2 or A3T3. We conclude that the binding of the second Hoechst to A4T4 is not cooperative and that the molecules are sitting with a small separation apart, one after the other, and not in a sandwich structure as previously proposed. © 2013 American Chemical Society.

  3. Sequence specificity and biological consequences of drugs that bind covalently in the minor groove of DNA

    International Nuclear Information System (INIS)

    Hurley, L.H.; Needham-VanDevanter, D.R.

    1986-01-01

    DNA ligands which bind within the minor groove of DNA exhibit varying degrees of sequence selectivity. Factors which contribute to nucleotide sequence recognition by minor groove ligands have been extensively investigated. Electrostatic interactions, ligand and DNA dehydration energies, hydrophobic interactions and steric factors all play significant roles in sequence selectivity in the minor groove. Interestingly, ligand recognition of nucleotide sequence in the minor groove does not involve significant hydrogen bonding. This is in sharp contrast to cellular enzyme and protein recognition of nucleotide sequence, which is achieved in the major groove via specific hydrogen bond formation between individual bases and the ligand. The ability to read nucleotide sequence via hydrogen bonding allows precise binding of proteins to specific DNA sequences. Minor groove ligands examined to date exhibit a much lower sequence specificity, generally binding to a subset of possible sequences, rather than a single sequence. 19 refs., 7 figs

  4. Using mutagenesis to explore conserved residues in the RNA-binding groove of influenza A virus nucleoprotein for antiviral drug development

    Science.gov (United States)

    Liu, Chia-Lin; Hung, Hui-Chen; Lo, Shou-Chen; Chiang, Ching-Hui; Chen, I.-Jung; Hsu, John T.-A.; Hou, Ming-Hon

    2016-02-01

    Nucleoprotein (NP) is the most abundant type of RNA-binding viral protein in influenza A virus-infected cells and is necessary for viral RNA transcription and replication. Recent studies demonstrated that influenza NP is a valid target for antiviral drug development. The surface of the groove, covered with numerous conserved residues between the head and body domains of influenza A NP, plays a crucial role in RNA binding. To explore the mechanism by which NP binds RNA, we performed a series of site-directed mutagenesis in the RNA-binding groove, followed by surface plasmon resonance (SPR), to characterize the interactions between RNA and NP. Furthermore, a role of Y148 in NP stability and NP-RNA binding was evaluated. The aromatic residue of Y148 was found to stack with a nucleotide base. By interrupting the stacking interaction between Y148 and an RNA base, we identified an influenza virus NP inhibitor, (E, E)-1,7-bis(4-hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5-dione; this inhibitor reduced the NP’s RNA-binding affinity and hindered viral replication. Our findings will be useful for the development of new drugs that disrupt the interaction between RNA and viral NP in the influenza virus.

  5. Binding to the DNA Minor Groove by Heterocyclic Dications: From AT Specific Monomers to GC Recognition with Dimers

    Science.gov (United States)

    Nanjunda, Rupesh; Wilson, W. David

    2012-01-01

    Compounds that bind in the DNA minor groove have provided critical information on DNA molecular recognition, they have found extensive uses in biotechnology and they are providing clinically useful drugs against diseases as diverse as cancer and sleeping sickness. This review focuses on the development of clinically useful heterocyclic diamidine minor groove binders. These compounds have shown us that the classical model for minor groove binding in AT DNA sequences must be expanded in several ways: compounds with nonstandard shapes can bind strongly to the groove, water can be directly incorporated into the minor groove complex in an interfacial interaction, and the compounds can form cooperative stacked dimers to recognize GC and mixed AT/GC base pair sequences. PMID:23255206

  6. Synthesis and characterization of DNA minor groove binding alkylating agents.

    Science.gov (United States)

    Iyer, Prema; Srinivasan, Ajay; Singh, Sreelekha K; Mascara, Gerard P; Zayitova, Sevara; Sidone, Brian; Fouquerel, Elise; Svilar, David; Sobol, Robert W; Bobola, Michael S; Silber, John R; Gold, Barry

    2013-01-18

    Derivatives of methyl 3-(1-methyl-5-(1-methyl-5-(propylcarbamoyl)-1H-pyrrol-3-ylcarbamoyl)-1H-pyrrol-3-ylamino)-3-oxopropane-1-sulfonate (1), a peptide-based DNA minor groove binding methylating agent, were synthesized and characterized. In all cases, the N-terminus was appended with an O-methyl sulfonate ester, while the C-terminus group was varied with nonpolar and polar side chains. In addition, the number of pyrrole rings was varied from 2 (dipeptide) to 3 (tripeptide). The ability of the different analogues to efficiently generate N3-methyladenine was demonstrated as was their selectivity for minor groove (N3-methyladenine) versus major groove (N7-methylguanine) methylation. Induced circular dichroism studies were used to measure the DNA equilibrium binding properties of the stable sulfone analogues; the tripeptide binds with affinity that is >10-fold higher than that of the dipeptide. The toxicities of the compounds were evaluated in alkA/tag glycosylase mutant E. coli and in human WT glioma cells and in cells overexpressing and under-expressing N-methylpurine-DNA glycosylase, which excises N3-methyladenine from DNA. The results show that equilibrium binding correlates with the levels of N3-methyladenine produced and cellular toxicity. The toxicity of 1 was inversely related to the expression of MPG in both the bacterial and mammalian cell lines. The enhanced toxicity parallels the reduced activation of PARP and the diminished rate of formation of aldehyde reactive sites observed in the MPG knockdown cells. It is proposed that unrepaired N3-methyladenine is toxic due to its ability to directly block DNA polymerization.

  7. In and out of the minor groove: interaction of an AT-rich DNA with the drug CD27

    Energy Technology Data Exchange (ETDEWEB)

    Acosta-Reyes, Francisco J. [Universitat Politécnica de Catalunya, Diagonal 647, 08028 Barcelona (Spain); Dardonville, Christophe [Instituto de Química Médica, IQM–CSIC, Juan de la Cierva 3, 28006 Madrid (Spain); Koning, Harry P. de; Natto, Manal [University of Glasgow, 120 University Place, Glasgow G12 8TA, Scotland (United Kingdom); Subirana, Juan A.; Campos, J. Lourdes, E-mail: lourdes.campos@upc.edu [Universitat Politécnica de Catalunya, Diagonal 647, 08028 Barcelona (Spain)

    2014-06-01

    New features of an antiprotozoal DNA minor-groove binding drug, which acts as a cross-linking agent, are presented. It also fills the minor groove of DNA completely and prevents the access of proteins. These features are also expected for other minor-groove binding drugs when associated with suitable DNA targets. The DNA of several pathogens is very rich in AT base pairs. Typical examples include the malaria parasite Plasmodium falciparum and the causative agents of trichomoniasis and trypanosomiases. This fact has prompted studies of drugs which interact with the minor groove of DNA, some of which are used in medical practice. Previous studies have been performed almost exclusively with the AATT sequence. New features should be uncovered through the study of different DNA sequences. In this paper, the crystal structure of the complex of the DNA duplex d(AAAATTTT){sub 2} with the dicationic drug 4, 4′-bis(imidazolinylamino)diphenylamine (CD27) is presented. The drug binds to the minor groove of DNA as expected, but it shows two new features that have not previously been described: (i) the drugs protrude from the DNA and interact with neighbouring molecules, so that they may act as cross-linking agents, and (ii) the drugs completely cover the whole minor groove of DNA and displace bound water. Thus, they may prevent the access to DNA of proteins such as AT-hook proteins. These features are also expected for other minor-groove binding drugs when associated with all-AT DNA. These findings allow a better understanding of this family of compounds and will help in the development of new, more effective drugs. New data on the biological interaction of CD27 with the causative agent of trichomoniasis, Trichomonas vaginalis, are also reported.

  8. In and out of the minor groove: interaction of an AT-rich DNA with the drug CD27

    International Nuclear Information System (INIS)

    Acosta-Reyes, Francisco J.; Dardonville, Christophe; Koning, Harry P. de; Natto, Manal; Subirana, Juan A.; Campos, J. Lourdes

    2014-01-01

    New features of an antiprotozoal DNA minor-groove binding drug, which acts as a cross-linking agent, are presented. It also fills the minor groove of DNA completely and prevents the access of proteins. These features are also expected for other minor-groove binding drugs when associated with suitable DNA targets. The DNA of several pathogens is very rich in AT base pairs. Typical examples include the malaria parasite Plasmodium falciparum and the causative agents of trichomoniasis and trypanosomiases. This fact has prompted studies of drugs which interact with the minor groove of DNA, some of which are used in medical practice. Previous studies have been performed almost exclusively with the AATT sequence. New features should be uncovered through the study of different DNA sequences. In this paper, the crystal structure of the complex of the DNA duplex d(AAAATTTT) 2 with the dicationic drug 4, 4′-bis(imidazolinylamino)diphenylamine (CD27) is presented. The drug binds to the minor groove of DNA as expected, but it shows two new features that have not previously been described: (i) the drugs protrude from the DNA and interact with neighbouring molecules, so that they may act as cross-linking agents, and (ii) the drugs completely cover the whole minor groove of DNA and displace bound water. Thus, they may prevent the access to DNA of proteins such as AT-hook proteins. These features are also expected for other minor-groove binding drugs when associated with all-AT DNA. These findings allow a better understanding of this family of compounds and will help in the development of new, more effective drugs. New data on the biological interaction of CD27 with the causative agent of trichomoniasis, Trichomonas vaginalis, are also reported

  9. NMR studies of DNA oligomers and their interactions with minor groove binding ligands

    Energy Technology Data Exchange (ETDEWEB)

    Fagan, Patricia A. [Univ. of California, Berkeley, CA (United States). Dept. of Chemistry

    1996-05-01

    The cationic peptide ligands distamycin and netropsin bind noncovalently to the minor groove of DNA. The binding site, orientation, stoichiometry, and qualitative affinity of distamycin binding to several short DNA oligomers were investigated by NMR spectroscopy. The oligomers studied contain A,T-rich or I,C-rich binding sites, where I = 2-desaminodeoxyguanosine. I•C base pairs are functional analogs of A•T base pairs in the minor groove. The different behaviors exhibited by distamycin and netropsin binding to various DNA sequences suggested that these ligands are sensitive probes of DNA structure. For sites of five or more base pairs, distamycin can form 1:1 or 2:1 ligand:DNA complexes. Cooperativity in distamycin binding is low in sites such as AAAAA which has narrow minor grooves, and is higher in sites with wider minor grooves such as ATATAT. The distamycin binding and base pair opening lifetimes of I,C-containing DNA oligomers suggest that the I,C minor groove is structurally different from the A,T minor groove. Molecules which direct chemistry to a specific DNA sequence could be used as antiviral compounds, diagnostic probes, or molecular biology tools. The author studied two ligands in which reactive groups were tethered to a distamycin to increase the sequence specificity of the reactive agent.

  10. DNA minor groove binding of small molecules: Experimental and ...

    Indian Academy of Sciences (India)

    Administrator

    Abstract. Eight indole derivatives were studied for their DNA binding ability using fluorescence quenching and molecular docking methods. These indole compounds have structural moieties similar as in few indole alkaloids. Experimental and theoretical studies have suggested that indole derivatives bind in the minor ...

  11. Two 1 : 1 binding modes for distamycin in the minor groove of d(GGCCAATTGG)

    Czech Academy of Sciences Publication Activity Database

    Uytterhoeven, K.; Šponer, Jiří; Van Meervelt, L.

    2002-01-01

    Roč. 269, č. 12 (2002), s. 2868-2877 ISSN 0014-2956 R&D Projects: GA MŠk LN00A016 Keywords : distamycin * drug-DNA complex * minor groove binder Subject RIV: BO - Biophysics Impact factor: 2.999, year: 2002

  12. Configurational entropy change of netropsin and distamycin upon DNA minor-groove binding.

    Science.gov (United States)

    Dolenc, Jozica; Baron, Riccardo; Oostenbrink, Chris; Koller, Joze; van Gunsteren, Wilfred F

    2006-08-15

    Binding of a small molecule to a macromolecular target reduces its conformational freedom, resulting in a negative entropy change that opposes the binding. The goal of this study is to estimate the configurational entropy change of two minor-groove-binding ligands, netropsin and distamycin, upon binding to the DNA duplex d(CGCGAAAAACGCG).d(CGCGTTTTTCGCG). Configurational entropy upper bounds based on 10-ns molecular dynamics simulations of netropsin and distamycin in solution and in complex with DNA in solution were estimated using the covariance matrix of atom-positional fluctuations. The results suggest that netropsin and distamycin lose a significant amount of configurational entropy upon binding to the DNA minor groove. The estimated changes in configurational entropy for netropsin and distamycin are -127 J K(-1) mol(-1) and -104 J K(-1) mol(-1), respectively. Estimates of the configurational entropy contributions of parts of the ligands are presented, showing that the loss of configurational entropy is comparatively more pronounced for the flexible tails than for the relatively rigid central body.

  13. Impact of pyrrolidine-bispyrrole DNA minor groove binding agents and chirality on global proteomic profile in Escherichia Coli.

    Science.gov (United States)

    Yang, Ya-Ting; Lin, Chun-Yu; Jeng, Jingyueh; Ong, Chi-Wi

    2013-05-23

    There is great interest in the design of small molecules that selectively target minor grooves of duplex DNA for controlling specific gene expression implicated in a disease. The design of chiral small molecules for rational drug design has attracted increasing attention due to the chirality of DNA. Yet, there is limited research on the chirality effect of minor groove binders on DNA interaction, especially at the protein expression level. This paper is an attempt to illustrate that DNA binding affinity might not provide a full picture on the biological activities. Drug interacting at the genomic level can be translated to the proteomic level. Here we have illustrated that although the chiral bispyrrole-pyrrolidine-oligoamides, PySSPy and PyRSPy, showed low binding affinity to DNA, their influence at the proteomic level is significant. More importantly, the chirality also plays a role. Two-dimensional proteomic profile to identify the differentially expressed protein in Escherichia coli DH5α (E coli DH5α) were investigated. E coli DH5α incubated with the chiral PySSPy and PyRSPy, diastereomeric at the pyrrolidine ring, showed differential expression of eighteen proteins as observed through two dimensional proteomic profiling. These eighteen proteins identified by MALDI_TOF/TOF MS include antioxidant defense, DNA protection, protein synthesis, chaperone, and stress response proteins. No statistically significant toxicity was observed at the tested drug concentrations as measured via MTT assay. The current results showed that the chiral PySSPy and PyRSPy impact on the proteomic profiling of E coli DH5α, implicating the importance of drug chirality on biological activities at the molecular level.

  14. Methylene blue binding to DNA with alternating AT base sequence: minor groove binding is favored over intercalation.

    Science.gov (United States)

    Rohs, Remo; Sklenar, Heinz

    2004-04-01

    The results presented in this paper on methylene blue (MB) binding to DNA with AT alternating base sequence complement the data obtained in two former modeling studies of MB binding to GC alternating DNA. In the light of the large amount of experimental data for both systems, this theoretical study is focused on a detailed energetic analysis and comparison in order to understand their different behavior. Since experimental high-resolution structures of the complexes are not available, the analysis is based on energy minimized structural models of the complexes in different binding modes. For both sequences, four different intercalation structures and two models for MB binding in the minor and major groove have been proposed. Solvent electrostatic effects were included in the energetic analysis by using electrostatic continuum theory, and the dependence of MB binding on salt concentration was investigated by solving the non-linear Poisson-Boltzmann equation. We find that the relative stability of the different complexes is similar for the two sequences, in agreement with the interpretation of spectroscopic data. Subtle differences, however, are seen in energy decompositions and can be attributed to the change from symmetric 5'-YpR-3' intercalation to minor groove binding with increasing salt concentration, which is experimentally observed for the AT sequence at lower salt concentration than for the GC sequence. According to our results, this difference is due to the significantly lower non-electrostatic energy for the minor groove complex with AT alternating DNA, whereas the slightly lower binding energy to this sequence is caused by a higher deformation energy of DNA. The energetic data are in agreement with the conclusions derived from different spectroscopic studies and can also be structurally interpreted on the basis of the modeled complexes. The simple static modeling technique and the neglect of entropy terms and of non-electrostatic solute

  15. Elucidation of the sequence selective binding mode of the DNA minor groove binder adozelesin, by high-field 1H NMR and restrained molecular dynamics

    International Nuclear Information System (INIS)

    Cameron, L.

    1999-01-01

    Adozelesin (formerly U73-975, The Upjohn Co.) is a covalent, minor-groove binding analogue of the antitumour antibiotic (+)CC-1065. Adozelesin consists of a cyclopropapyrroloindole alkylating sub-unit identical to (+)CC-1065, plus indole and benzofuran sub-units which replace the more complex pyrroloindole B and C sub-units, respectively, of (+)CC-1065. Adozelesin is a clinically important drug candidate, since it does not contain the ethylene bridge moieties on the B and C sub-units which are thought to be responsible for the unusual delayed hepatotoxicity exhibited by (+)CC-1065. Sequencing techniques identified two consensus sequences for adozelesin binding as p(dA) and 5'(T/A)(T/A)T-A*(C/G)G. This suggests that adozelesin spans a total of five base-pairs and shows a preference for A=T base-pair rich sequences, thus avoiding steric crowding around the exocyclic NH 2 of guanine and a wide minor groove. In this project, the covalent modification of two DNA sequences, i.e. 5'd(CGTAAGCGCTTA*CG) 2 and 5'-d(CGAAAAA*CGG)· 5'-d(CCGTTTTTCG), by adozelesin was examined by high-field NMR and restrained molecular mechanics and dynamics. Previous studies of minor groove binding drugs, using techniques as diverse as NMR, X-ray crystallography and molecular modelling, indicate that the incorporation of a guanine into the consensus sequence sterically hinders binding and, more importantly, produces a wider minor groove which is a 'slack' fit for the ligand. The aim of this investigation was to provide an insight into the sequence selective binding of adozelesin to 5'-AAAAA*CG and 5'-GCTTA*CG. The 1 H NMR data revealed that, in both cases, β-helical structure and Watson-Crick base-pairing was maintained on adduct formation. The 5'-GCTTA*CG adduct displayed significant distortion of the guanine base on the non-covalently modified strand. This distortion resulted from an amalgamation of two factors. Firstly, the presence of a strong hydrogen-bond between the amide linker of the

  16. Binding to the minor groove of the double-strand, tau protein prevents DNA from damage by peroxidation.

    Science.gov (United States)

    Wei, Yan; Qu, Mei-Hua; Wang, Xing-Sheng; Chen, Lan; Wang, Dong-Liang; Liu, Ying; Hua, Qian; He, Rong-Qiao

    2008-07-02

    Tau, an important microtubule associated protein, has been found to bind to DNA, and to be localized in the nuclei of both neurons and some non-neuronal cells. Here, using electrophoretic mobility shifting assay (EMSA) in the presence of DNA with different chain-lengths, we observed that tau protein favored binding to a 13 bp or a longer polynucleotide. The results from atomic force microscopy also showed that tau protein preferred a 13 bp polynucleotide to a 12 bp or shorter polynucleotide. In a competitive assay, a minor groove binder distamycin A was able to replace the bound tau from the DNA double helix, indicating that tau protein binds to the minor groove. Tau protein was able to protect the double-strand from digestion in the presence of DNase I that was bound to the minor groove. On the other hand, a major groove binder methyl green as a negative competitor exhibited little effect on the retardation of tau-DNA complex in EMSA. This further indicates the DNA minor groove as the binding site for tau protein. EMSA with truncated tau proteins showed that both the proline-rich domain (PRD) and the microtubule-binding domain (MTBD) contributed to the interaction with DNA; that is to say, both PRD and MTBD bound to the minor groove of DNA and bent the double-strand, as observed by electron microscopy. To investigate whether tau protein is able to prevent DNA from the impairment by hydroxyl free radical, the chemiluminescence emitted by the phen-Cu/H(2)O(2)/ascorbate was measured. The emission intensity of the luminescence was markedly decreased when tau protein was present, suggesting a significant protection of DNA from the damage in the presence of hydroxyl free radical.

  17. A monofunctional platinum complex coordinated to a rhodium metalloinsertor selectively binds mismatched DNA in the minor groove.

    Science.gov (United States)

    Weidmann, Alyson G; Barton, Jacqueline K

    2015-10-05

    We report the synthesis and characterization of a bimetallic complex derived from a new family of potent and selective metalloinsertors containing an unusual Rh-O axial coordination. This complex incorporates a monofunctional platinum center containing only one labile site for coordination to DNA, rather than two, and coordinates DNA nonclassically through adduct formation in the minor groove. This conjugate displays bifunctional, interdependent binding of mismatched DNA via metalloinsertion at a mismatch as well as covalent platinum binding. DNA sequencing experiments revealed that the preferred site of platinum coordination is not the traditional N7-guanine site in the major groove, but rather N3-adenine in the minor groove. The complex also displays enhanced cytotoxicity in mismatch repair-deficient and mismatch repair-proficient human colorectal carcinoma cell lines compared to the chemotherapeutic cisplatin, and it triggers cell death via an apoptotic pathway, rather than the necrotic pathway induced by rhodium metalloinsertors.

  18. Quantitative structure of a complex between a minor-groove-specific drug and a bent DNA decamer duplex: Use of 2D NMR data and NOESY constrained energy minimization

    International Nuclear Information System (INIS)

    Sarma, M.H.; Gupta, G.; Garcia, A.E.; Umemoto, K.; Sarma, R.H.

    1990-01-01

    Two-dimensional nuclear magnetic resonance (2D NMR) studies on d(GA4T4C)2 and d(GT4A4C)2 showed that A.T pairs are propeller twisted. As a result, A/T tracts form a straight rigid structural block with an array of bifurcated inter base pair H bonds in the major groove. It was demonstrated (previous paper) that replacement of methyl group by hydrogen (changing from T to U) in the major groove does not disrupt the array of bifurcated H bonds in the major groove. In this article, we summarize results of 2D NMR and molecular mechanic studies on the effect of a minor-groove-binding A.T-specific drug on the structure d(GA4T4C)2. A distamycin analogue (Dst2) was used for this study. It is shown that Dst2 binds to the minor groove of d(GA4T4C)2 mainly driven by van der Waals interaction between A.T pairs and the drug; as a consequence, an array of bifurcated H bonds can be formed in the minor groove between amide/amino protons of Dst2 and A.T pairs of DNA. NOESY data suggest that Dst2 predominantly binds at the central 5 A.T pairs. NOESY data also reveal that, upon drug binding, d(GA4T4C)2 does not undergo any significant change in conformation from the free state; i.e., propeller-twisted A.T pairs are still present in DNA and hence the array of bifurcated H bonds must be preserved in the major groove. NOESY data for the A5-T6 sequence also indicate that there is little change in junction stereochemistry upon drug binding

  19. Protein Recognition in Drug-Induced DNA Alkylation: When the Moonlight Protein GAPDH Meets S23906-1/DNA Minor Groove Adducts.

    Science.gov (United States)

    Savreux-Lenglet, Gaëlle; Depauw, Sabine; David-Cordonnier, Marie-Hélène

    2015-11-05

    DNA alkylating drugs have been used in clinics for more than seventy years. The diversity of their mechanism of action (major/minor groove; mono-/bis-alkylation; intra-/inter-strand crosslinks; DNA stabilization/destabilization, etc.) has undoubtedly major consequences on the cellular response to treatment. The aim of this review is to highlight the variety of established protein recognition of DNA adducts to then particularly focus on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) function in DNA adduct interaction with illustration using original experiments performed with S23906-1/DNA adduct. The introduction of this review is a state of the art of protein/DNA adducts recognition, depending on the major or minor groove orientation of the DNA bonding as well as on the molecular consequences in terms of double-stranded DNA maintenance. It reviews the implication of proteins from both DNA repair, transcription, replication and chromatin maintenance in selective DNA adduct recognition. The main section of the manuscript is focusing on the implication of the moonlighting protein GAPDH in DNA adduct recognition with the model of the peculiar DNA minor groove alkylating and destabilizing drug S23906-1. The mechanism of action of S23906-1 alkylating drug and the large variety of GAPDH cellular functions are presented prior to focus on GAPDH direct binding to S23906-1 adducts.

  20. Behavior of solvent-exposed hydrophobic groove in the anti-apoptotic Bcl-XL protein: clues for its ability to bind diverse BH3 ligands from MD simulations.

    Directory of Open Access Journals (Sweden)

    Dilraj Lama

    Full Text Available Bcl-XL is a member of Bcl-2 family of proteins involved in the regulation of intrinsic pathway of apoptosis. Its overexpression in many human cancers makes it an important target for anti-cancer drugs. Bcl-XL interacts with the BH3 domain of several pro-apoptotic Bcl-2 partners. This helical bundle protein has a pronounced hydrophobic groove which acts as a binding region for the BH3 domains. Eight independent molecular dynamics simulations of the apo/holo forms of Bcl-XL were carried out to investigate the behavior of solvent-exposed hydrophobic groove. The simulations used either a twin-range cut-off or particle mesh Ewald (PME scheme to treat long-range interactions. Destabilization of the BH3 domain-containing helix H2 was observed in all four twin-range cut-off simulations. Most of the other major helices remained stable. The unwinding of H2 can be related to the ability of Bcl-XL to bind diverse BH3 ligands. The loss of helical character can also be linked to the formation of homo- or hetero-dimers in Bcl-2 proteins. Several experimental studies have suggested that exposure of BH3 domain is a crucial event before they form dimers. Thus unwinding of H2 seems to be functionally very important. The four PME simulations, however, revealed a stable helix H2. It is possible that the H2 unfolding might occur in PME simulations at longer time scales. Hydrophobic residues in the hydrophobic groove are involved in stable interactions among themselves. The solvent accessible surface areas of bulky hydrophobic residues in the groove are significantly buried by the loop LB connecting the helix H2 and subsequent helix. These observations help to understand how the hydrophobic patch in Bcl-XL remains stable in the solvent-exposed state. We suggest that both the destabilization of helix H2 and the conformational heterogeneity of loop LB are important factors for binding of diverse ligands in the hydrophobic groove of Bcl-XL.

  1. Drug binding properties of neonatal albumin

    DEFF Research Database (Denmark)

    Brodersen, R; Honoré, B

    1989-01-01

    Neonatal and adult albumin was isolated by gel chromatography on Sephacryl S-300, from adult and umbilical cord serum, respectively. Binding of monoacetyl-diamino-diphenyl sulfone, warfarin, sulfamethizole, and diazepam was studied by means of equilibrium dialysis and the binding data were analyzed...... by the method of several acceptable fitted curves. It was found that the binding affinity to neonatal albumin is less than to adult albumin for monoacetyl-diamino-diphenyl sulfone and warfarin. Sulfamethizole binding to the neonatal protein is similarly reduced when more than one molecule of the drug is bound...

  2. Dendrimers bind antioxidant polyphenols and cisplatin drug.

    Directory of Open Access Journals (Sweden)

    Amine Abderrezak

    Full Text Available Synthetic polymers of a specific shape and size play major role in drug delivery systems. Dendrimers are unique synthetic macromolecules of nanometer dimensions with a highly branched structure and globular shape with potential applications in gene and drug delivery. We examine the interaction of several dendrimers of different compositions mPEG-PAMAM (G3, mPEG-PAMAM (G4 and PAMAM (G4 with hydrophilic and hydrophobic drugs cisplatin, resveratrol, genistein and curcumin at physiological conditions. FTIR and UV-visible spectroscopic methods as well as molecular modeling were used to analyse drug binding mode, the binding constant and the effects of drug complexation on dendrimer stability and conformation. Structural analysis showed that cisplatin binds dendrimers in hydrophilic mode via Pt cation and polymer terminal NH(2 groups, while curcumin, genistein and resveratrol are located mainly in the cavities binding through both hydrophobic and hydrophilic contacts. The overall binding constants of durg-dendrimers are ranging from 10(2 M(-1 to 10(3 M(-1. The affinity of dendrimer binding was PAMAM-G4>mPEG-PAMAM-G4>mPEG-PAMAM-G3, while the order of drug-polymer stability was curcumin>cisplatin>genistein>resveratrol. Molecular modeling showed larger stability for genisten-PAMAM-G4 (ΔG = -4.75 kcal/mol than curcumin-PAMAM-G4 ((ΔG = -4.53 kcal/mol and resveratrol-PAMAM-G4 ((ΔG = -4.39 kcal/mol. Dendrimers might act as carriers to transport hydrophobic and hydrophilic drugs.

  3. Direction of Intercalation of a bis-Ru(II) Complex to DNA Probed by a Minor Groove Binding Molecule 4',6-Diamidino-2-phenylindole

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Yoon Jung; Kim, Raeyeong; Chitrapriya, Nataraj; Kim, Seog K.; Bae, Inho [Yeungnam Univ., Gyeongsan (Korea, Republic of)

    2013-10-15

    Direction of intercalation to DNA of the planar dipyrido[3,2-a:2',3'-c]phenazine ligands (dppz) of a bis-Ru(II) complex namely, [Ru(1,10-phenanthroline){sub 2}dipyrido[3,2-a:2',3'-c]phenazine]{sup 2+} linkered by a 1,3-bis(4-pyridyl)propane, was investigated by probing the behavior of 4',6-diamidino-2-phenylindole (DAPI) that bound deep in the minor groove. Bis-intercalation of DPPZ resulted in a little blue shift and hyperchromism in DAPI absorption band, and a large decrease in DAPI fluorescence intensity which accompanied by an increase in the dppz emission intensity. Diminishing the intensity of the positive induced circular dichroism (CD) and linear dichroism (LD) were also observed. These spectral changes indicated that insertion of dppz ligand caused the change of the binding mode of DAPI, which probably moved to the exterior of DNA from the minor groove and interacted with the phospghate groups of DNA by electrostatic interaction. At the surface of DNA, DAPI binds at the phosphate groups of DNA by electrostatic attraction. Consequently, this observation indicated that the dppz ligand intercalated from the minor groove.

  4. Structures of the human Pals1 PDZ domain with and without ligand suggest gated access of Crb to the PDZ peptide-binding groove

    Energy Technology Data Exchange (ETDEWEB)

    Ivanova, Marina E.; Fletcher, Georgina C.; O’Reilly, Nicola; Purkiss, Andrew G.; Thompson, Barry J. [Cancer Research UK, 44 Lincoln’s Inn Fields, London WC2A 3LY (United Kingdom); McDonald, Neil Q., E-mail: neil.mcdonald@cancer.org.uk [Cancer Research UK, 44 Lincoln’s Inn Fields, London WC2A 3LY (United Kingdom); Birkbeck College, University of London, Malet Street, London WC1E 7HX (United Kingdom)

    2015-03-01

    This study characterizes the interaction between the carboxy-terminal (ERLI) motif of the essential polarity protein Crb and the Pals1/Stardust PDZ-domain protein. Structures of human Pals1 PDZ with and without a Crb peptide are described, explaining the highly conserved nature of the ERLI motif and revealing a sterically blocked peptide-binding groove in the absence of ligand. Many components of epithelial polarity protein complexes possess PDZ domains that are required for protein interaction and recruitment to the apical plasma membrane. Apical localization of the Crumbs (Crb) transmembrane protein requires a PDZ-mediated interaction with Pals1 (protein-associated with Lin7, Stardust, MPP5), a member of the p55 family of membrane-associated guanylate kinases (MAGUKs). This study describes the molecular interaction between the Crb carboxy-terminal motif (ERLI), which is required for Drosophila cell polarity, and the Pals1 PDZ domain using crystallography and fluorescence polarization. Only the last four Crb residues contribute to Pals1 PDZ-domain binding affinity, with specificity contributed by conserved charged interactions. Comparison of the Crb-bound Pals1 PDZ structure with an apo Pals1 structure reveals a key Phe side chain that gates access to the PDZ peptide-binding groove. Removal of this side chain enhances the binding affinity by more than fivefold, suggesting that access of Crb to Pals1 may be regulated by intradomain contacts or by protein–protein interaction.

  5. Photosensitization by iodinated DNA minor groove binding ligands: Evaluation of DNA double-strand break induction and repair.

    Science.gov (United States)

    Briggs, Benjamin; Ververis, Katherine; Rodd, Annabelle L; Foong, Laura J L; Silva, Fernando M Da; Karagiannis, Tom C

    2011-05-03

    Iodinated DNA minor groove binding bibenzimidazoles represent a unique class of UVA photosensitizer and their extreme photopotency has been previously characterized. Earlier studies have included a comparison of three isomers, referred to as ortho-, meta- and para-iodoHoechst, which differ only in the location of the iodine substituent in the phenyl ring of the bibenzimidazole. DNA breakage and clonogenic survival studies in human erythroleukemic K562 cells have highlighted the higher photo-efficiency of the ortho-isomer (subsequently designated UV(A)Sens) compared to the meta- and para-isomers. In this study, the aim was to compare the induction and repair of DNA double-strand breaks induced by the three isomers in K562 cells. Further, we examined the effects of the prototypical broad-spectrum histone deacetylase inhibitor, Trichostatin A, on ortho-iodoHoechst/UVA-induced double-strand breaks in K562 cells. Using γH2AX as a molecular marker of the DNA lesions, our findings indicate a disparity in the induction and particularly, in the repair kinetics of double-strand breaks for the three isomers. The accumulation of γH2AX foci induced by the meta- and para-isomers returned to background levels within 24 and 48 h, respectively; the number of γH2AX foci induced by ortho-iodoHoechst remained elevated even after incubation for 96 h post-irradiation. These findings provide further evidence that the extreme photopotency of ortho-iodoHoechst is due to not only to the high quantum yield of dehalogenation, but also to the severity of the DNA lesions which are not readily repaired. Finally, our findings which indicate that Trichostatin A has a remarkable potentiating effect on ortho-iodoHoechst/UVA-induced DNA lesions are encouraging, particularly in the context of cutaneous T-cell lymphoma, for which a histone deacetylase inhibitor is already approved for therapy. This finding prompts further evaluation of the potential of combination therapies. Copyright © 2011

  6. The rem mutations in the ATP-binding groove of the Rad3/XPD helicase lead to Xeroderma pigmentosum-Cockayne syndrome-like phenotypes.

    Science.gov (United States)

    Herrera-Moyano, Emilia; Moriel-Carretero, María; Montelone, Beth A; Aguilera, Andrés

    2014-12-01

    The eukaryotic TFIIH complex is involved in Nucleotide Excision Repair and transcription initiation. We analyzed three yeast mutations of the Rad3/XPD helicase of TFIIH known as rem (recombination and mutation phenotypes). We found that, in these mutants, incomplete NER reactions lead to replication fork breaking and the subsequent engagement of the homologous recombination machinery to restore them. Nevertheless, the penetrance varies among mutants, giving rise to a phenotype gradient. Interestingly, the mutations analyzed reside at the ATP-binding groove of Rad3 and in vivo experiments reveal a gain of DNA affinity upon damage of the mutant Rad3 proteins. Since mutations at the ATP-binding groove of XPD in humans are present in the Xeroderma pigmentosum-Cockayne Syndrome (XP-CS), we recreated rem mutations in human cells, and found that these are XP-CS-like. We propose that the balance between the loss of helicase activity and the gain of DNA affinity controls the capacity of TFIIH to open DNA during NER, and its persistence at both DNA lesions and promoters. This conditions NER efficiency and transcription resumption after damage, which in human cells would explain the XP-CS phenotype, opening new perspectives to understand the molecular basis of the role of XPD in human disease.

  7. Trabectedin – the DNA minor groove binder

    Directory of Open Access Journals (Sweden)

    G. A. Belitsky

    2015-01-01

    Full Text Available Trabectedin (ET-743, Yondelis is an alkaloid that was originally isolated from the Caribbean Sea squirt, Ecteinascidia turbinata and is now produced synthetically. Its chemical structure consists in three fused tetrahydroisoquinoline rings. Two of them, A and B, binds covalently to guanine residues in the minor groove of the DNA double helix to bend the molecule toward the major groove and the third ring C protrudes from the DNA duplex, apparently allowing interactions with several nuclear proteins. Binding to the minor groove of DNA, trabectedin trigger a cascade of events that interfere with several transcription factors, DNA binding proteins, and DNA repair pathways in particular nucleotide excision repair. It acts both as a DNA-alkylating drug and topoisomerase poison. Trabectedin-DNA adduct traps the nucleotide excision repair proteins repairing the DNA damage in transcribing genes and induces DNA strand breaks. Cells deficient in homologous recombination pathway which repairs these double-strand breaks show increased sensitivity to trabectedin. The most sensitive of them were myxoid liposarcomas. Trabectedin is also effective in chemotherapy-experienced patients with advanced, recurrent liposarcoma or leiomyosarcoma as well as in women with ovarian cancer and breast cancer with BRCAness phenotype. Besides of tumor cells Trabectedin inhibits inflammatory cells by affecting directly monocytes and tumorassociated macrophages and indirectly by inhibiting production of inflammatory mediators, the cytokines and chemokines. It inhibits also the MDR-1 gene, which is responsible for the resistance of cancer cells to chemotherapeutic agents and strikes tumor angiogenesis.

  8. Sensitive detection of African swine fever virus using real-time PCR with a 5' conjugated minor groove binding probe

    DEFF Research Database (Denmark)

    McKillan, John; McMenamy, Michael; Hjertner, Bernt

    2010-01-01

    sensitive than the conventional PCR recommended by the OIE. Linear range was ten logs from 2 × 101 to 2 × 1010. The assay is rapid with an amplification time just over 2 h. The development of this assay provides a useful tool for the specific diagnosis of ASF in statutory or emergency testing programs......The design of a 5′ conjugated minor groove binder (MGB) probe real-time PCR assay is described for the rapid, sensitive and specific detection of African swine fever virus (ASFV) DNA. The assay is designed against the 9GL region and is capable of detecting 20 copies of a DNA standard. It does...

  9. Anticancer drug mithramycin interacts with core histones: An additional mode of action of the DNA groove binder

    Directory of Open Access Journals (Sweden)

    Amrita Banerjee

    2014-01-01

    Full Text Available Mithramycin (MTR is a clinically approved DNA-binding antitumor antibiotic currently in Phase 2 clinical trials at National Institutes of Health for treatment of osteosarcoma. In view of the resurgence in the studies of this generic antibiotic as a human medicine, we have examined the binding properties of MTR with the integral component of chromatin – histone proteins – as a part of our broad objective to classify DNA-binding molecules in terms of their ability to bind chromosomal DNA alone (single binding mode or both histones and chromosomal DNA (dual binding mode. The present report shows that besides DNA, MTR also binds to core histones present in chromatin and thus possesses the property of dual binding in the chromatin context. In contrast to the MTR–DNA interaction, association of MTR with histones does not require obligatory presence of bivalent metal ion like Mg2+. As a consequence of its ability to interact with core histones, MTR inhibits histone H3 acetylation at lysine 18, an important signature of active chromatin, in vitro and ex vivo. Reanalysis of microarray data of Ewing sarcoma cell lines shows that upon MTR treatment there is a significant down regulation of genes, possibly implicating a repression of H3K18Ac-enriched genes apart from DNA-binding transcription factors. Association of MTR with core histones and its ability to alter post-translational modification of histone H3 clearly indicates an additional mode of action of this anticancer drug that could be implicated in novel therapeutic strategies.

  10. Selenium nanoparticles synthesized in aqueous extract of Allium sativum perturbs the structural integrity of Calf thymus DNA through intercalation and groove binding

    International Nuclear Information System (INIS)

    Ezhuthupurakkal, Preedia Babu; Polaki, Lokeswara Rao; Suyavaran, Arumugam; Subastri, Ariraman; Sujatha, Venugopal; Thirunavukkarasu, Chinnasamy

    2017-01-01

    Biomedical application of selenium nanoparticles (SeNPs) demands the eco-friendly composite for synthesis of SeNPs. The present study reports an aqueous extract of Allium sativum (AqEAS) plug-up the current need. Modern spectroscopic, microscopic and gravimetric techniques were employed to characterize the synthesized nanoparticles. Characterization studies revealed the formation of crystalline spherical shaped SeNPs. FTIR spectrum brings out the presence of different functional groups in AqEAS, which influence the SeNPs formation and stabilization. Furthermore the different aspects of the interaction between SeNPs and CT-DNA were scrutinized by various spectroscopic and cyclic voltametric studies. The results reveals the intercalation and groove binding mode of interaction of SeNPs with stacked base pair of CT-DNA. The Stern–Volmer quenching constant (K SV ) were found to be 7.02 × 10 6 Mˉ 1 (ethidium bromide), 4.22 × 10 6 Mˉ 1 (acridine orange) and 7.6 × 10 6 Mˉ 1 (Hoechst) indicating strong binding of SeNPs with CT–DNA. The SeNPs - CT-DNA interactions were directly visualized by atomic force microscopy. The present study unveils the cost effective, innocuous, highly stable SeNPs intricate mechanism of DNA interaction, which will be a milestone in DNA targeted chemotherapy. - Graphical abstract: Highly stable, innocuous, biocompatible SeNPs nanoparticle has been synthesized using Allium sativum (garlic) extract as reductant. The purity and crystallinity were characterized, further divulge the base pare interaction with Calf –Thymus DNA through various spectroscopic methods and atomic force microscopy. Display Omitted - Highlights: • Synthesis of SeNPs in aqueous extract of Allium sativum. • Characterization of synthesized SeNPs using high throughput techniques. • SeNPs directly interact with CT-DNA through intercalation and groove binding.

  11. Selenium nanoparticles synthesized in aqueous extract of Allium sativum perturbs the structural integrity of Calf thymus DNA through intercalation and groove binding

    Energy Technology Data Exchange (ETDEWEB)

    Ezhuthupurakkal, Preedia Babu; Polaki, Lokeswara Rao; Suyavaran, Arumugam; Subastri, Ariraman [Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry 605 014 (India); Sujatha, Venugopal [Department of Chemistry, Periyar University, Salem 636011 (India); Thirunavukkarasu, Chinnasamy, E-mail: tchinnasamy@hotmail.com [Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry 605 014 (India)

    2017-05-01

    Biomedical application of selenium nanoparticles (SeNPs) demands the eco-friendly composite for synthesis of SeNPs. The present study reports an aqueous extract of Allium sativum (AqEAS) plug-up the current need. Modern spectroscopic, microscopic and gravimetric techniques were employed to characterize the synthesized nanoparticles. Characterization studies revealed the formation of crystalline spherical shaped SeNPs. FTIR spectrum brings out the presence of different functional groups in AqEAS, which influence the SeNPs formation and stabilization. Furthermore the different aspects of the interaction between SeNPs and CT-DNA were scrutinized by various spectroscopic and cyclic voltametric studies. The results reveals the intercalation and groove binding mode of interaction of SeNPs with stacked base pair of CT-DNA. The Stern–Volmer quenching constant (K{sub SV}) were found to be 7.02 × 10{sup 6} Mˉ{sup 1} (ethidium bromide), 4.22 × 10{sup 6} Mˉ{sup 1} (acridine orange) and 7.6 × 10{sup 6} Mˉ{sup 1} (Hoechst) indicating strong binding of SeNPs with CT–DNA. The SeNPs - CT-DNA interactions were directly visualized by atomic force microscopy. The present study unveils the cost effective, innocuous, highly stable SeNPs intricate mechanism of DNA interaction, which will be a milestone in DNA targeted chemotherapy. - Graphical abstract: Highly stable, innocuous, biocompatible SeNPs nanoparticle has been synthesized using Allium sativum (garlic) extract as reductant. The purity and crystallinity were characterized, further divulge the base pare interaction with Calf –Thymus DNA through various spectroscopic methods and atomic force microscopy. Display Omitted - Highlights: • Synthesis of SeNPs in aqueous extract of Allium sativum. • Characterization of synthesized SeNPs using high throughput techniques. • SeNPs directly interact with CT-DNA through intercalation and groove binding.

  12. Binding of the antitumor drug nogalamycin and its derivatives to DNA: Structural comparison

    International Nuclear Information System (INIS)

    Gao, Yi-Gui; Liaw, Yen-Chywan; Robinson, H.; Wang, A. H.-J.

    1990-01-01

    The three-dimensional molecular structures of the complexes between a novel antitumor drug nogalamycin and its derivative U-58872 with a modified DNA hexamer d[m 5 CGT(pS)Am 5 CG] have been determined at 1.7- and 1.8-angstrom resolution, respectively, by X-ray diffraction analyses. Both structures (in space group P6 1 ) have been refined with constrained refinement procedure to final R factors of 0.208 (3386 reflections) and 0.196 (2143 reflections). In both complexes, two nogalamycins bind to the DNA hexamer double helix in a 2:1 ratio with the elongated aglycon chromophore intercalated between the CpG steps at both ends of the helix. The aglycon chromophore spans across the GC Watson-Crick base pairs with its nogalose lying in the minor groove and the aminoglucose lying in the major groove of the distorted B-DNA double helix. Most of the sugars remain in the C2'-endo pucker family, except three deoxycytidine residues (terminal C1, C7, and internal C5). All nucleotides are in the anti conformation. Specific hydrogen bonds are found in the complex between the drug and guanine-cytosine bases in both grooves of the helix. One hydroxyl group of the aminoglucose donates a hydrogen bond to the N7 of guanine, while the other receives a hydrogen bond from the N4 amino group of cytosine. The orientation of these two hydrogen bonds suggests that nogalamycin prefers a GC base pair with its aglycon chromophore intercalating at the 5'-side of a guanine (between NpG), or at the 3'-side of a cytosine (between CpN) with the sugars pointing toward the GC base pair. The binding of nogalamycin to DNA requires that the base pairs in DNA open up transiently to allow the bulky sugars to go through, suggesting that nogalamycin prefers GC sequences embedded in a stretch of AT sequences

  13. Cellular uptake, nuclear localization and cytotoxicity of 125I-labelled DNA minor groove binding ligands in K562, human erythroleukaemia cells

    International Nuclear Information System (INIS)

    Karagiannis, T.C.; Lobachevsky, P.N.; Martin, R.F.

    2000-01-01

    Full text: Iodine-125 decays by orbital electron capture and internal conversion resulting in the emission of numerous Auger electrons which produce a highly localised radiochemical damage in the immediate vicinity of the site of decay. Given the requirement to deliver 125 I to the nuclear DNA, a minor groove binding bibenzimidazole, 125 I-iodoHoechst 33258 was investigated. It has been noted that this analogue may be prone to de-iodination in vitro and in vivo, given the presence of an orthoiodophenol moiety which is analogous to that in thyroxins. Therefore, an 125 I -iodoHoechst analogue without the hydroxyl group was also studied. The 125 I -iodoHoechst 33258 analogue was prepared by direct iodination of Hoechst 33258 and 125 I iodoHoechst was prepared by demetallation of a trimethylstannyl precursor. DNA binding studies indicated that both iodo-analogues bind to calf thymus DNA, K D = 89 ± 30nM, n = 0.018 bp - 1 for iodoHoechst 33258 and K D = 121 ± 31nM, n = 0.024 bp -1 for iodoHoechst. Similarly, nuclear localization following incubation with 5μM of either ligand at 37 deg C was observed in K562 cells by fluorescence microscopy. Flow cytometry was used to investigate the kinetics of drug uptake and efflux in K562 cells. The results indicated that when 10 6 cells were incubated with 5μM ligand at 37 deg C, the uptake reached a plateau at approximately 43 minutes for iodoHoechst 33258 and approximately 52 minutes for iodoHoechst. Ligand efflux results indicated two-phase kinetics. The initial phase which involves 50-60% of drug was characterised by a half-life time (t 1/2 ) of 55.4 minutes for efflux of iodoHoechst 33258 and a t 1/2 of 10.3 minutes for efflux of iodoHoechst, at 37 deg C. Furthermore, the results suggested that the DNA binding sites in a 10 6 cell/ml suspension were saturated by incubation with 3μM iodoHoechst 33258 and 5μM iodoHoechst. In the initial cytotoxicity experiments using 125 I-iodoHoechst 33258, K562 cells were incubated for 1

  14. Clinical relevance of drug binding to plasma proteins

    Science.gov (United States)

    Ascenzi, Paolo; Fanali, Gabriella; Fasano, Mauro; Pallottini, Valentina; Trezza, Viviana

    2014-12-01

    Binding to plasma proteins highly influences drug efficacy, distribution, and disposition. Serum albumin, the most abundant protein in plasma, is a monomeric multi-domain macromolecule that displays an extraordinary ligand binding capacity, providing a depot and carrier for many endogenous and exogenous compounds, such as fatty acids and most acidic drugs. α-1-Acid glycoprotein, the second main plasma protein, is a glycoprotein physiologically involved in the acute phase reaction and is the main carrier for basic and neutral drugs. High- and low-density lipoproteins play a limited role in drug binding and are natural drug delivery system only for few lipophilic drugs or lipid-based formulations. Several factors influence drug binding to plasma proteins, such as pathological conditions, concurrent administration of drugs, sex, and age. Any of these factors, in turn, influences drug efficacy and toxicity. Here, biochemical, biomedical, and biotechnological aspects of drug binding to plasma proteins are reviewed.

  15. Curcumin stably interacts with DNA hairpin through minor groove binding and demonstrates enhanced cytotoxicity in combination with FdU nucleotides.

    Science.gov (United States)

    Ghosh, Supratim; Mallick, Sumana; Das, Upasana; Verma, Ajay; Pal, Uttam; Chatterjee, Sabyasachi; Nandy, Abhishek; Saha, Krishna D; Maiti, Nakul Chandra; Baishya, Bikash; Suresh Kumar, G; Gmeiner, William H

    2018-03-01

    We report, based on biophysical studies and molecular mechanical calculations that curcumin binds DNA hairpin in the minor groove adjacent to the loop region forming a stable complex. UV-Vis and fluorescence spectroscopy indicated interaction of curcumin with DNA hairpin. In this novel binding motif, two ɣ H of curcumin heptadiene chain are closely positioned to the A 16 -H8 and A 17 -H8, while G 12 -H8 is located in the close proximity of curcumin α H. Molecular dynamics (MD) simulations suggest, the complex is stabilized by noncovalent forces including; π-π stacking, H-bonding and hydrophobic interactions. Nuclear magnetic resonance (NMR) spectroscopy in combination with molecular dynamics simulations indicated curcumin is bound in the minor groove, while circular dichroism (CD) spectra suggested minute enhancement in base stacking and a little change in DNA helicity, without significant conformational change of DNA hairpin structure. The DNA:curcumin complex formed with FdU nucleotides rather than Thymidine, demonstrated enhanced cytotoxicity towards oral cancer cells relative to the only FdU substituted hairpin. Fluorescence co-localization demonstrated stability of the complex in biologically relevant conditions, including its cellular uptake. Acridine orange/EtBr staining further confirmed the enhanced cytotoxic effects of the complex, suggesting apoptosis as mode of cell death. Thus, curcumin can be noncovalently complexed to small DNA hairpin for cellular delivery and the complex showed increased cytotoxicity in combination with FdU nucleotides, demonstrating its potential for advanced cancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Selenium nanoparticles synthesized in aqueous extract of Allium sativum perturbs the structural integrity of Calf thymus DNA through intercalation and groove binding.

    Science.gov (United States)

    Ezhuthupurakkal, Preedia Babu; Polaki, Lokeswara Rao; Suyavaran, Arumugam; Subastri, Ariraman; Sujatha, Venugopal; Thirunavukkarasu, Chinnasamy

    2017-05-01

    Biomedical application of selenium nanoparticles (SeNPs) demands the eco-friendly composite for synthesis of SeNPs. The present study reports an aqueous extract of Allium sativum (AqEAS) plug-up the current need. Modern spectroscopic, microscopic and gravimetric techniques were employed to characterize the synthesized nanoparticles. Characterization studies revealed the formation of crystalline spherical shaped SeNPs. FTIR spectrum brings out the presence of different functional groups in AqEAS, which influence the SeNPs formation and stabilization. Furthermore the different aspects of the interaction between SeNPs and CT-DNA were scrutinized by various spectroscopic and cyclic voltametric studies. The results reveals the intercalation and groove binding mode of interaction of SeNPs with stacked base pair of CT-DNA. The Stern-Volmer quenching constant (K SV ) were found to be 7.02×10 6 M- 1 (ethidium bromide), 4.22×10 6 M- 1 (acridine orange) and 7.6×10 6 M- 1 (Hoechst) indicating strong binding of SeNPs with CT-DNA. The SeNPs - CT-DNA interactions were directly visualized by atomic force microscopy. The present study unveils the cost effective, innocuous, highly stable SeNPs intricate mechanism of DNA interaction, which will be a milestone in DNA targeted chemotherapy. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Role of minor groove width and hydration pattern on amsacrine interaction with DNA.

    Directory of Open Access Journals (Sweden)

    Deepak K Jangir

    Full Text Available Amsacrine is an anilinoacridine derivative anticancer drug, used to treat a wide variety of malignancies. In cells, amsacrine poisons topoisomerase 2 by stabilizing DNA-drug-enzyme ternary complex. Presence of amsacrine increases the steady-state concentration of these ternary complexes which in turn hampers DNA replication and results in subsequent cell death. Due to reversible binding and rapid slip-out of amsacrine from DNA duplex, structural data is not available on amsacrine-DNA complexes. In the present work, we designed five oligonucleotide duplexes, differing in their minor groove widths and hydration pattern, and examined their binding with amsacrine using attenuated total reflection Fourier transform infrared (ATR-FTIR spectroscopy. Complexes of amsacrine with calf thymus DNA were also evaluated for a comparison. Our results demonstrate for the first time that amsacrine is not a simple intercalator; rather mixed type of DNA binding (intercalation and minor groove takes place between amsacrine and DNA. Further, this binding is highly sensitive towards the geometries and hydration patterns of different minor grooves present in the DNA. This study shows that ligand binding to DNA could be very sensitive to DNA base composition and DNA groove structures. Results demonstrated here could have implication for understanding cytotoxic mechanism of aminoacridine based anticancer drugs and provide directions to modify these drugs for better efficacy and few side-effects.

  18. Deciphering the Arginine-binding preferences at the substrate-binding groove of Ser/Thr kinases by computational surface mapping.

    Directory of Open Access Journals (Sweden)

    Avraham Ben-Shimon

    2011-11-01

    Full Text Available Protein kinases are key signaling enzymes that catalyze the transfer of γ-phosphate from an ATP molecule to a phospho-accepting residue in the substrate. Unraveling the molecular features that govern the preference of kinases for particular residues flanking the phosphoacceptor is important for understanding kinase specificities toward their substrates and for designing substrate-like peptidic inhibitors. We applied ANCHORSmap, a new fragment-based computational approach for mapping amino acid side chains on protein surfaces, to predict and characterize the preference of kinases toward Arginine binding. We focus on positions P-2 and P-5, commonly occupied by Arginine (Arg in substrates of basophilic Ser/Thr kinases. The method accurately identified all the P-2/P-5 Arg binding sites previously determined by X-ray crystallography and produced Arg preferences that corresponded to those experimentally found by peptide arrays. The predicted Arg-binding positions and their associated pockets were analyzed in terms of shape, physicochemical properties, amino acid composition, and in-silico mutagenesis, providing structural rationalization for previously unexplained trends in kinase preferences toward Arg moieties. This methodology sheds light on several kinases that were described in the literature as having non-trivial preferences for Arg, and provides some surprising departures from the prevailing views regarding residues that determine kinase specificity toward Arg. In particular, we found that the preference for a P-5 Arg is not necessarily governed by the 170/230 acidic pair, as was previously assumed, but by several different pairs of acidic residues, selected from positions 133, 169, and 230 (PKA numbering. The acidic residue at position 230 serves as a pivotal element in recognizing Arg from both the P-2 and P-5 positions.

  19. Major groove binding track residues of the connection subdomain of human immunodeficiency virus type 1 reverse transcriptase enhance cDNA synthesis at high temperatures.

    Science.gov (United States)

    Matamoros, Tania; Barrioluengo, Verónica; Abia, David; Menéndez-Arias, Luis

    2013-12-23

    At high temperatures, RNA denaturation can improve the efficiency and specificity of reverse transcription. Refined structures and molecular models of HIV-1 reverse transcriptases (RTs) from phylogenetically distant clades (i.e., group M subtype B and group O) revealed a major interaction between the template-primer and the Arg³⁵⁸-Gly³⁵⁹-Ala³⁶⁰ triad in the large subunit of HIV-1M/B RT. However, fewer contacts were predicted for the equivalent Lys³⁵⁸-Ala³⁵⁹-Ser³⁶⁰ triad of HIV-1O RT and the nucleic acid. An engineered HIV-1O K358R/A359G/S360A RT showed increased cDNA synthesis efficiency above 68 °C, as determined by qualitative and quantitative reverse transcription polymerase chain reactions. In comparison with wild-type HIV-1O RT, the mutant enzyme showed higher thermal stability but retained wild-type RNase H activity. Mutations that increased the accuracy of HIV-1M/B RTs were tested in combination with the K358R/A359G/S360A triple mutation. Some of them (e.g., F61A, K65R, K65R/V75I, and V148I) had a negative effect on reverse transcription efficiency above 65 °C. RTs with improved DNA binding affinities also showed higher cDNA synthesis efficiencies at elevated temperatures. Two of the most thermostable RTs (i.e., mutants T69SSG/K358R/A359G/S360A and K358R/A359G/S360A/E478Q) showed moderately increased fidelity in forward mutation assays. Our results demonstrate that the triad of Arg³⁵⁸, Gly³⁵⁹, and Ala³⁶⁰ in the major groove binding track of HIV-1 RT is a major target for RT stabilization, and most relevant for improving reverse transcription efficiency at high temperatures.

  20. Methodological aspects on drug receptor binding analysis

    International Nuclear Information System (INIS)

    Wahlstroem, A.

    1978-01-01

    Although drug receptors occur in relatively low concentrations, they can be visualized by the use of appropriate radioindicators. In most cases the procedure is rapid and can reach a high degree of accuracy. Specificity of the interaction is studied by competition analysis. The necessity of using several radioindicators to define a receptor population is emphasized. It may be possible to define isoreceptors and drugs with selectivity for one isoreceptor. (Author)

  1. Quantifying drug-protein binding in vivo

    International Nuclear Information System (INIS)

    Buchholz, B; Bench, G; Keating III, G; Palmblad, M; Vogel, J; Grant, P G; Hillegonds, D

    2004-01-01

    Accelerator mass spectrometry (AMS) provides precise quantitation of isotope labeled compounds that are bound to biological macromolecules such as DNA or proteins. The sensitivity is high enough to allow for sub-pharmacological (''micro-'') dosing to determine macromolecular targets without inducing toxicities or altering the system under study, whether it is healthy or diseased. We demonstrated an application of AMS in quantifying the physiologic effects of one dosed chemical compound upon the binding level of another compound in vivo at sub-toxic doses [4].We are using tissues left from this study to develop protocols for quantifying specific binding to isolated and identified proteins. We also developed a new technique to quantify nanogram to milligram amounts of isolated protein at precisions that are comparable to those for quantifying the bound compound by AMS

  2. Grooved cold moderator tests

    International Nuclear Information System (INIS)

    Inoue, K.; Kiyanagi, Y.; Iwasa, H.; Watanabe, N.; Ikeda, S.; Carpenter, J.M.; Ishikawa, Y.

    1983-01-01

    We performed some grooved cold moderator experiments for methane at 20 K by using the Hokkaido University linac to obtain information to be used in the planning of the KENS-I' project. Cold neutron gains, spatial distribution of emitted beams and time distribution of the neutrons in the grooved cold moderator were measured. Furthermore, we assessed the effects of the grooved cold moderator on the performances of the spectrometers presently installed at the KENS-I cold source. We concluded that the grooved cold moderator benefited appreciably the performances of the spectrometers

  3. Endosonography of groove pancreatitis

    NARCIS (Netherlands)

    Tio, T. L.; Luiken, G. J.; Tytgat, G. N.

    1991-01-01

    Groove pancreatitis is a rare form of chronic pancreatitis. Distinction between pancreatitis and pancreatic carcinoma is often difficult. Two cases of groove pancreatitis diagnosed by endosonography are described. A hypoechoic pattern between the duodenal wall and pancreas was clearly imaged in both

  4. Resistance to minor groove binders.

    Science.gov (United States)

    Colmegna, Benedetta; Uboldi, Sarah; Erba, Eugenio; D'Incalci, Maurizio

    2014-03-01

    In this paper multiple resistance mechanisms to minor groove binders (MGBs) are overviewed. MGBs with antitumor properties are natural products or their derivatives and, as expected, they are all substrates of P-glycoprotein (P-gp). However, a moderate expression of P-gp does not appear to reduce the sensitivity to trabectedin, the only MGB so far approved for clinical use. Resistance to this drug is often related to transcriptional mechanisms and to DNA repair pathways, particularly defects in transcription-coupled nucleotide excision repair (TC-NER). Therefore tumors resistant to trabectedin may become hypersensitive to UV rays and other DNA damaging agents acting in the major groove, such as Platinum (Pt) complexes. If this is confirmed in clinic, that will provide the rationale to combine trabectedin sequentially with Pt derivates.

  5. First branchial groove anomaly.

    Science.gov (United States)

    Kumar, M; Hickey, S; Joseph, G

    2000-06-01

    First branchial groove anomalies are very rare. We report a case of a first branchial groove anomaly presented as an infected cyst in an 11-month-old child. Management of such lesions is complicated because of their close association with the facial nerve. Surgical management must include identification and protection of the facial nerve. Embryology and facial nerve disposition in relation to the anomaly are reviewed.

  6. Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients.

    Science.gov (United States)

    de Witte, Wilhelmus E A; Wong, Yin Cheong; Nederpelt, Indira; Heitman, Laura H; Danhof, Meindert; van der Graaf, Piet H; Gilissen, Ron A H J; de Lange, Elizabeth C M

    2016-01-01

    Drug-target binding kinetics are major determinants of the time course of drug action for several drugs, as clearly described for the irreversible binders omeprazole and aspirin. This supports the increasing interest to incorporate newly developed high-throughput assays for drug-target binding kinetics in drug discovery. A meaningful application of in vitro drug-target binding kinetics in drug discovery requires insight into the relation between in vivo drug effect and in vitro measured drug-target binding kinetics. In this review, the authors discuss both the relation between in vitro and in vivo measured binding kinetics and the relation between in vivo binding kinetics, target occupancy and effect profiles. More scientific evidence is required for the rational selection and development of drug-candidates on the basis of in vitro estimates of drug-target binding kinetics. To elucidate the value of in vitro binding kinetics measurements, it is necessary to obtain information on system-specific properties which influence the kinetics of target occupancy and drug effect. Mathematical integration of this information enables the identification of drug-specific properties which lead to optimal target occupancy and drug effect in patients.

  7. The influence of drug distribution and drug-target binding on target occupancy : The rate-limiting step approximation

    NARCIS (Netherlands)

    Witte, de W.E.A.; Vauquelin, G.; Graaf, van der P.H.; Lange, de E.C.M.

    2017-01-01

    The influence of drug-target binding kinetics on target occupancy can be influenced by drug distribution and diffusion around the target, often referred to as "rebinding" or "diffusion-limited binding". This gives rise to a decreased decline of the drug-target complex concentration as a result of a

  8. Fluoroquinolone-gyrase-DNA complexes: two modes of drug binding.

    Science.gov (United States)

    Mustaev, Arkady; Malik, Muhammad; Zhao, Xilin; Kurepina, Natalia; Luan, Gan; Oppegard, Lisa M; Hiasa, Hiroshi; Marks, Kevin R; Kerns, Robert J; Berger, James M; Drlica, Karl

    2014-05-02

    DNA gyrase and topoisomerase IV control bacterial DNA topology by breaking DNA, passing duplex DNA through the break, and then resealing the break. This process is subject to reversible corruption by fluoroquinolones, antibacterials that form drug-enzyme-DNA complexes in which the DNA is broken. The complexes, called cleaved complexes because of the presence of DNA breaks, have been crystallized and found to have the fluoroquinolone C-7 ring system facing the GyrB/ParE subunits. As expected from x-ray crystallography, a thiol-reactive, C-7-modified chloroacetyl derivative of ciprofloxacin (Cip-AcCl) formed cross-linked cleaved complexes with mutant GyrB-Cys(466) gyrase as evidenced by resistance to reversal by both EDTA and thermal treatments. Surprisingly, cross-linking was also readily seen with complexes formed by mutant GyrA-G81C gyrase, thereby revealing a novel drug-gyrase interaction not observed in crystal structures. The cross-link between fluoroquinolone and GyrA-G81C gyrase correlated with exceptional bacteriostatic activity for Cip-AcCl with a quinolone-resistant GyrA-G81C variant of Escherichia coli and its Mycobacterium smegmatis equivalent (GyrA-G89C). Cip-AcCl-mediated, irreversible inhibition of DNA replication provided further evidence for a GyrA-drug cross-link. Collectively these data establish the existence of interactions between the fluoroquinolone C-7 ring and both GyrA and GyrB. Because the GyrA-Gly(81) and GyrB-Glu(466) residues are far apart (17 Å) in the crystal structure of cleaved complexes, two modes of quinolone binding must exist. The presence of two binding modes raises the possibility that multiple quinolone-enzyme-DNA complexes can form, a discovery that opens new avenues for exploring and exploiting relationships between drug structure and activity with type II DNA topoisomerases.

  9. 3-D Image Analysis of Fluorescent Drug Binding

    Directory of Open Access Journals (Sweden)

    M. Raquel Miquel

    2005-01-01

    Full Text Available Fluorescent ligands provide the means of studying receptors in whole tissues using confocal laser scanning microscopy and have advantages over antibody- or non-fluorescence-based method. Confocal microscopy provides large volumes of images to be measured. Histogram analysis of 3-D image volumes is proposed as a method of graphically displaying large amounts of volumetric image data to be quickly analyzed and compared. The fluorescent ligand BODIPY FL-prazosin (QAPB was used in mouse aorta. Histogram analysis reports the amount of ligand-receptor binding under different conditions and the technique is sensitive enough to detect changes in receptor availability after antagonist incubation or genetic manipulations. QAPB binding was concentration dependent, causing concentration-related rightward shifts in the histogram. In the presence of 10 μM phenoxybenzamine (blocking agent, the QAPB (50 nM histogram overlaps the autofluorescence curve. The histogram obtained for the 1D knockout aorta lay to the left of that of control and 1B knockout aorta, indicating a reduction in 1D receptors. We have shown, for the first time, that it is possible to graphically display binding of a fluorescent drug to a biological tissue. Although our application is specific to adrenergic receptors, the general method could be applied to any volumetric, fluorescence-image-based assay.

  10. Exploring the binding sites and binding mechanism for hydrotrope encapsulated griseofulvin drug on γ-tubulin protein.

    Directory of Open Access Journals (Sweden)

    Shubhadip Das

    Full Text Available The protein γ-tubulin plays an important role in centrosomal clustering and this makes it an attractive therapeutic target for treating cancers. Griseofulvin, an antifungal drug, has recently been used to inhibit proliferation of various types of cancer cells. It can also affect the microtubule dynamics by targeting the γ-tubulin protein. So far, the binding pockets of γ-tubulin protein are not properly identified and the exact mechanism by which the drug binds to it is an area of intense speculation and research. The aim of the present study is to investigate the binding mechanism and binding affinity of griseofulvin on γ-tubulin protein using classical molecular dynamics simulations. Since the drug griseofulvin is sparingly soluble in water, here we also present a promising approach for formulating and achieving delivery of hydrophobic griseofulvin drug via hydrotrope sodium cumene sulfonate (SCS cluster. We observe that the binding pockets of γ-tubulin protein are mainly formed by the H8, H9 helices and S7, S8, S14 strands and the hydrophobic interactions between the drug and γ-tubulin protein drive the binding process. The release of the drug griseofulvin from the SCS cluster is confirmed by the coordination number analysis. We also find hydrotrope-induced alteration of the binding sites of γ-tubulin protein and the weakening of the drug-protein interactions.

  11. Target-mediated drug disposition model for drugs with two binding sites that bind to a target with one binding site.

    Science.gov (United States)

    Gibiansky, Leonid; Gibiansky, Ekaterina

    2017-10-01

    The paper extended the TMDD model to drugs with two identical binding sites (2-1 TMDD). The quasi-steady-state (2-1 QSS), quasi-equilibrium (2-1 QE), irreversible binding (2-1 IB), and Michaelis-Menten (2-1 MM) approximations of the model were derived. Using simulations, the 2-1 QSS approximation was compared with the full 2-1 TMDD model. As expected and similarly to the standard TMDD for monoclonal antibodies (mAb), 2-1 QSS predictions were nearly identical to 2-1 TMDD predictions, except for times of fast changes following initiation of dosing, when equilibrium has not yet been reached. To illustrate properties of new equations and approximations, several variations of population PK data for mAbs with soluble (slow elimination of the complex) or membrane-bound (fast elimination of the complex) targets were simulated from a full 2-1 TMDD model and fitted to 2-1 TMDD models, to its approximations, and to the standard (1-1) QSS model. For a mAb with a soluble target, it was demonstrated that the 2-1 QSS model provided nearly identical description of the observed (simulated) free drug and total target concentrations, although there was some minor bias in predictions of unobserved free target concentrations. The standard QSS approximation also provided a good description of the observed data, but was not able to distinguish between free drug concentrations (with no target attached and both binding site free) and partially bound drug concentrations (with one of the binding sites occupied by the target). For a mAb with a membrane-bound target, the 2-1 MM approximation adequately described the data. The 2-1 QSS approximation converged 10 times faster than the full 2-1 TMDD, and its run time was comparable with the standard QSS model.

  12. Programmable Oligomers Targeting 5′-GGGG-3′ in the Minor Groove of DNA and NF-κB Binding Inhibition

    Science.gov (United States)

    Chenoweth, David M.; Poposki, Julie A.; Marques, Michael A.; Dervan, Peter B.

    2009-01-01

    A series of hairpin oligomers containing benzimidazole (Bi) and imidazopyridine (Ip) rings were synthesized and screened to target 5′-WGGGGW-3′, a core sequence in the DNA binding site of NF-κB, a prolific transcription factor important in biology and disease. Five Bi and Ip containing oligomers bound to the 5′-WGGGGW-3′ site with high affinity. One of the oligomers (Im-Im-Im-Im-γ-PyBi-PyBi-β-Dp) was able to inhibit DNA binding by the transcription factor NF-κB. PMID:17095230

  13. Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients.

    NARCIS (Netherlands)

    Witte, W.E.; Wong, Y.C.; Nederpelt, I.; Heitman, L.H.; Danhof, M.; Graaf, van der P.H.; Gilissen, R.A.; de, Lange E.C.

    2016-01-01

    INTRODUCTION Drug-target binding kinetics are major determinants of the time course of drug action for several drugs, as clearly described for the irreversible binders omeprazole and aspirin. This supports the increasing interest to incorporate newly developed high-throughput assays for drug-target

  14. Impact of germline and somatic missense variations on drug binding sites.

    Science.gov (United States)

    Yan, C; Pattabiraman, N; Goecks, J; Lam, P; Nayak, A; Pan, Y; Torcivia-Rodriguez, J; Voskanian, A; Wan, Q; Mazumder, R

    2017-03-01

    Advancements in next-generation sequencing (NGS) technologies are generating a vast amount of data. This exacerbates the current challenge of translating NGS data into actionable clinical interpretations. We have comprehensively combined germline and somatic nonsynonymous single-nucleotide variations (nsSNVs) that affect drug binding sites in order to investigate their prevalence. The integrated data thus generated in conjunction with exome or whole-genome sequencing can be used to identify patients who may not respond to a specific drug because of alterations in drug binding efficacy due to nsSNVs in the target protein's gene. To identify the nsSNVs that may affect drug binding, protein-drug complex structures were retrieved from Protein Data Bank (PDB) followed by identification of amino acids in the protein-drug binding sites using an occluded surface method. Then, the germline and somatic mutations were mapped to these amino acids to identify which of these alter protein-drug binding sites. Using this method we identified 12 993 amino acid-drug binding sites across 253 unique proteins bound to 235 unique drugs. The integration of amino acid-drug binding sites data with both germline and somatic nsSNVs data sets revealed 3133 nsSNVs affecting amino acid-drug binding sites. In addition, a comprehensive drug target discovery was conducted based on protein structure similarity and conservation of amino acid-drug binding sites. Using this method, 81 paralogs were identified that could serve as alternative drug targets. In addition, non-human mammalian proteins bound to drugs were used to identify 142 homologs in humans that can potentially bind to drugs. In the current protein-drug pairs that contain somatic mutations within their binding site, we identified 85 proteins with significant differential gene expression changes associated with specific cancer types. Information on protein-drug binding predicted drug target proteins and prevalence of both somatic and

  15. Melanin binding study of clinical drugs with cassette dosing and rapid equilibrium dialysis inserts

    OpenAIRE

    Pelkonen L; Tengvall-Unadike U; Ruponen M; Kidron H; del Amo EM; Reinisalo M; Urtti A

    2017-01-01

    Melanin pigment is a negatively charged polymer found in pigmented human tissues. In the eye, iris, ciliary body, choroid and retinal pigment epithelium (RPE) are heavily pigmented. Several drug molecules are known to bind to melanin, but larger sets of drugs have not been compared often in similar test conditions. In this study, we introduce a powerful tool for screening of melanin binding. The binding of a set of 34 compounds to isolated porcine RPE melanin was determined by cassette (n-in-...

  16. Mathematical description of drug-target interactions: application to biologics that bind to targets with two binding sites.

    Science.gov (United States)

    Gibiansky, Leonid; Gibiansky, Ekaterina

    2018-02-01

    The emerging discipline of mathematical pharmacology occupies the space between advanced pharmacometrics and systems biology. A characteristic feature of the approach is application of advance mathematical methods to study the behavior of biological systems as described by mathematical (most often differential) equations. One of the early application of mathematical pharmacology (that was not called this name at the time) was formulation and investigation of the target-mediated drug disposition (TMDD) model and its approximations. The model was shown to be remarkably successful, not only in describing the observed data for drug-target interactions, but also in advancing the qualitative and quantitative understanding of those interactions and their role in pharmacokinetic and pharmacodynamic properties of biologics. The TMDD model in its original formulation describes the interaction of the drug that has one binding site with the target that also has only one binding site. Following the framework developed earlier for drugs with one-to-one binding, this work aims to describe a rigorous approach for working with similar systems and to apply it to drugs that bind to targets with two binding sites. The quasi-steady-state, quasi-equilibrium, irreversible binding, and Michaelis-Menten approximations of the model are also derived. These equations can be used, in particular, to predict concentrations of the partially bound target (RC). This could be clinically important if RC remains active and has slow internalization rate. In this case, introduction of the drug aimed to suppress target activity may lead to the opposite effect due to RC accumulation.

  17. Crystal structure of equine serum albumin in complex with cetirizine reveals a novel drug binding site.

    Science.gov (United States)

    Handing, Katarzyna B; Shabalin, Ivan G; Szlachta, Karol; Majorek, Karolina A; Minor, Wladek

    2016-03-01

    Serum albumin (SA) is the main transporter of drugs in mammalian blood plasma. Here, we report the first crystal structure of equine serum albumin (ESA) in complex with antihistamine drug cetirizine at a resolution of 2.1Å. Cetirizine is bound in two sites--a novel drug binding site (CBS1) and the fatty acid binding site 6 (CBS2). Both sites differ from those that have been proposed in multiple reports based on equilibrium dialysis and fluorescence studies for mammalian albumins as cetirizine binding sites. We show that the residues forming the binding pockets in ESA are highly conserved in human serum albumin (HSA), and suggest that binding of cetirizine to HSA will be similar. In support of that hypothesis, we show that the dissociation constants for cetirizine binding to CBS2 in ESA and HSA are identical using tryptophan fluorescence quenching. Presence of lysine and arginine residues that have been previously reported to undergo nonenzymatic glycosylation in CBS1 and CBS2 suggests that cetirizine transport in patients with diabetes could be altered. A review of all available SA structures from the PDB shows that in addition to the novel drug binding site we present here (CBS1), there are two pockets on SA capable of binding drugs that do not overlap with fatty acid binding sites and have not been discussed in published reviews. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Calorimetric investigation of diclofenac drug binding to a panel of moderately glycated serum albumins.

    Science.gov (United States)

    Indurthi, Venkata S K; Leclerc, Estelle; Vetter, Stefan W

    2014-08-01

    Glycation alters the drug binding properties of serum proteins and could affect free drug concentrations in diabetic patients with elevated glycation levels. We investigated the effect of bovine serum albumin glycation by eight physiologically relevant glycation reagents (glucose, ribose, carboxymethyllysine, acetoin, methylglyoxal, glyceraldehyde, diacetyl and glycolaldehyde) on diclofenac drug binding. We used this non-steroidal anti-inflammatory drug diclofenac as a paradigm for acidic drugs with high serum binding and because of its potential cardiovascular risks in diabetic patients. Isothermal titration calorimetry showed that glycation reduced the binding affinity Ka of serum albumin and diclofenac 2 to 6-fold by reducing structural rigidity of albumin. Glycation affected the number of drug binding sites in a glycation reagent dependent manner and lead to a 25% decrease for most reagent, expect for ribose, with decreased by 60% and for the CML-modification, increased the number of binding sites by 60%. Using isothermal titration calorimetry and differential scanning calorimetry we derived the complete thermodynamic characterization of diclofenac binding to all glycated BSA samples. Our results suggest that glycation in diabetic patients could significantly alter the pharmacokinetics of the widely used over-the-counter NSDAI drug diclofenac and with possibly negative implications for patients. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. EDM Electrode for Internal Grooves

    Science.gov (United States)

    Ramani, V.; Werner, A.

    1985-01-01

    Electroerosive process inexpensive alternative to broaching. Hollow brass electrodes, soldered at one end to stainless-steel holding ring, held in grooves in mandrel. These electrodes used to machine grooves electrically in stainless-steel tube three-eights inch (9.5 millimeters) in diameter. Tool used on tubes already in place in equipment.

  20. Druggable pockets and binding site centric chemical space: a paradigm shift in drug discovery.

    Science.gov (United States)

    Pérot, Stéphanie; Sperandio, Olivier; Miteva, Maria A; Camproux, Anne-Claude; Villoutreix, Bruno O

    2010-08-01

    Detection, comparison and analyses of binding pockets are pivotal to structure-based drug design endeavors, from hit identification, screening of exosites and de-orphanization of protein functions to the anticipation of specific and non-specific binding to off- and anti-targets. Here, we analyze protein-ligand complexes and discuss methods that assist binding site identification, prediction of druggability and binding site comparison. The full potential of pockets is yet to be harnessed, and we envision that better understanding of the pocket space will have far-reaching implications in the field of drug discovery, such as the design of pocket-specific compound libraries and scoring functions.

  1. Room to Groove?

    DEFF Research Database (Denmark)

    Seabrooke, Leonard

    . As long as they stay within the parameters of legitimate financial practice to signal institutional isomorphism, the `groove', creditors may well allow borrowers room for change in self-determined ways. This paper maps out the historical and conceptual terrain concerning civilizing ideas about...... the legitimacy of financial practices within global capital markets, and investigates relationships between Western `civilizers' and Emerging Market Economies during the last two periods of financial globalization, the late-nineteenth/ early-twentieth centuries and the late-twentieth century.......The use of a `standard of civilization', a preferred form of socio-political organization, in global capital markets presents both constraints and opportunities for creditors and borrowers. When imposed, civilizing standards may change how a borrower would prefer to conduct their affairs. Creditors...

  2. Missing Fragments: Detecting Cooperative Binding in Fragment-Based Drug Design

    Science.gov (United States)

    2012-01-01

    The aim of fragment-based drug design (FBDD) is to identify molecular fragments that bind to alternate subsites within a given binding pocket leading to cooperative binding when linked. In this study, the binding of fragments to human phenylethanolamine N-methyltransferase is used to illustrate how (a) current protocols may fail to detect fragments that bind cooperatively, (b) theoretical approaches can be used to validate potential hits, and (c) apparent false positives obtained when screening against cocktails of fragments may in fact indicate promising leads. PMID:24900472

  3. Binding thermodynamics discriminates fragments from druglike compounds: a thermodynamic description of fragment-based drug discovery.

    Science.gov (United States)

    Williams, Glyn; Ferenczy, György G; Ulander, Johan; Keserű, György M

    2017-04-01

    Small is beautiful - reducing the size and complexity of chemical starting points for drug design allows better sampling of chemical space, reveals the most energetically important interactions within protein-binding sites and can lead to improvements in the physicochemical properties of the final drug. The impact of fragment-based drug discovery (FBDD) on recent drug discovery projects and our improved knowledge of the structural and thermodynamic details of ligand binding has prompted us to explore the relationships between ligand-binding thermodynamics and FBDD. Information on binding thermodynamics can give insights into the contributions to protein-ligand interactions and could therefore be used to prioritise compounds with a high degree of specificity in forming key interactions. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Olfactory groove meningiomas.

    Science.gov (United States)

    Hentschel, Stephen J; DeMonte, Franco

    2003-06-15

    Olfactory groove meningiomas (OGMs) arise over the cribriform plate and may reach very large sizes prior to presentation. They can be differentiated from tuberculum sellae meningiomas because OGMs arise more anterior in the skull base and displace the optic nerve and chiasm inferiorly rather than superiorly. The authors searched the neurosurgery database at the M. D. Anderson Cancer Center for cases of OGM treated between 1993 and 2003. The records of these patients were then reviewed retrospectively for details regarding clinical presentation, imaging findings, surgical results and complications, and follow-up status. Thirteen patients, (12 women and one man, mean age 56 years) harbored OGMs (mean size 5.7 cm). All patients underwent bifrontal craniotomies and biorbital osteotomies. There were 11 complete resections (including the hyperostotic bone and dura of the cribriform plate and any extension into the ethmoid sinuses) and two subtotal resections with minimal residual tumor left in patients with recurrent lesions. No complication directly due to the surgery occurred in any patient. There were no recurrences in a mean follow-up period of 2 years (range 0-5 years). With current microsurgical techniques, the results of OGM resection are excellent, with a high rate of total resection and a low incidence of complications. All hyperostotic bone should be removed with the dura of the anterior skull base to minimize the risk of recurrence.

  5. The role of water in the thermodynamics of drug binding to cyclodextrin

    Energy Technology Data Exchange (ETDEWEB)

    Todorova, Niya A. [Center for Advanced Research in Biotechnology, National Institute of Standards and Technology, 9600 Gudelsky Drive, Rockville, MD 20850 (United States); Schwarz, Frederick P. [Center for Advanced Research in Biotechnology, National Institute of Standards and Technology, 9600 Gudelsky Drive, Rockville, MD 20850 (United States)]. E-mail: fred@carb.nist.gov

    2007-07-15

    The thermodynamic parameters, {delta}{sub B} G {sup 0}, {delta}{sub B} H {sup 0}, {delta}{sub B} S {sup 0}, and {delta}{sub B} C {sub p}, of the drugs flurbiprofen (FLP), nabumetone (NAB), and naproxen (NPX) binding to {beta}-cyclodextrin ({beta}CD) and to {gamma}-cyclodextrin ({gamma}CD) in 0.10 M sodium phosphate buffer were determined from isothermal titration calorimetry (ITC) measurements over the temperature range from 293.15 K to 313.15 K. The heat capacity changes for the binding reactions ranged from -(362 {+-} 48) J . mol{sup -1} . K{sup -1} for FLP and -(238 {+-} 90) J . mol{sup -1} . K{sup -1} for NAB binding in the {beta}CD cavity to 0 for FLP and -(25.1 {+-} 9.2) J . mol{sup -1} . K{sup -1} for NPX binding in the larger {gamma}CD cavity, implying that the structure of water is reorganized in the {beta}CD binding reactions but not reorganized in the {gamma}CD binding reactions. Comparison of the fluorescence enhancements of FLP and NAB upon transferring from the aqueous buffer to isopropanol with the maximum fluorescence enhancements observed for their {beta}CD binding reactions indicated that some localized water was retained in the FLP-{beta}CD complex and almost none in the NAB-{beta}CD complex. No fluorescence change occurs with drug binding in the larger {gamma}CD cavity, indicating the retention of the bulk water environment in the drug-{gamma}CD complex. Since the specific drug binding interactions are essentially the same for {beta}CD and {gamma}CD, these differences in the retention of bulk water may account for the enthalpically driven nature of the {beta}CD binding reactions and the entropically driven nature of the {gamma}CD binding reactions.

  6. Shared peptide binding of HLA Class I and II alleles associate with cutaneous nevirapine hypersensitivity and identify novel risk alleles

    DEFF Research Database (Denmark)

    Pavlos, Rebecca; McKinnon, Elizabeth J.; Ostrov, David A.

    2017-01-01

    Genes of the human leukocyte antigen (HLA) system encode cell-surface proteins involved in regulation of immune responses, and the way drugs interact with the HLA peptide binding groove is important in the immunopathogenesis of T-cell mediated drug hypersensitivity syndromes. Nevirapine (NVP), is...

  7. Determination of binding affinities of some approved drugs to ...

    African Journals Online (AJOL)

    Ascaris MRFR was obtained as pdb file (3vra) from the Protein Data Bank and further prepared for docking simulations using both Chimera v. 1.8.1 and AutoDock tools v. 1.5.6. In order to validate the docking protocol, the binding of atpenin, an experimental anthelmintic compound, to MRFR was successfully reproduced in ...

  8. DNA minor groove alkylating agents.

    Science.gov (United States)

    Denny, W A

    2001-04-01

    Recent work on a number of different classes of anticancer agents that alkylate DNA in the minor groove is reviewed. There has been much work with nitrogen mustards, where attachment of the mustard unit to carrier molecules can change the normal patterns of both regio- and sequence-selectivity, from reaction primarily at most guanine N7 sites in the major groove to a few adenine N3 sites at the 3'-end of poly(A/T) sequences in the minor groove. Carrier molecules discussed for mustards are intercalators, polypyrroles, polyimidazoles, bis(benzimidazoles), polybenzamides and anilinoquinolinium salts. In contrast, similar targeting of pyrrolizidine alkylators by a variety of carriers has little effect of their patterns of alkylation (at the 2-amino group of guanine). Recent work on the pyrrolobenzodiazepine and cyclopropaindolone classes of natural product minor groove binders is also reviewed.

  9. ANALYSIS OF DRUG-PROTEIN BINDING BY ULTRAFAST AFFINITY CHROMATOGRAPHY USING IMMOBILIZED HUMAN SERUM ALBUMIN

    Science.gov (United States)

    Mallik, Rangan; Yoo, Michelle J.; Briscoe, Chad J.; Hage, David S.

    2010-01-01

    Human serum albumin (HSA) was explored for use as a stationary phase and ligand in affinity microcolumns for the ultrafast extraction of free drug fractions and the use of this information for the analysis of drug-protein binding. Warfarin, imipramine, and ibuprofen were used as model analytes in this study. It was found that greater than 95% extraction of all these drugs could be achieved in as little as 250 ms on HSA microcolumns. The retained drug fraction was then eluted from the same column under isocratic conditions, giving elution in less than 40 s when working at 4.5 mL/min. The chromatographic behavior of this system gave a good fit with that predicted by computer simulations based on a reversible, saturable model for the binding of an injected drug with immobilized HSA. The free fractions measured by this method were found to be comparable to those determined by ultrafiltration, and equilibrium constants estimated by this approach gave good agreement with literature values. Advantages of this method include its speed and the relatively low cost of microcolumns that contain HSA. The ability of HSA to bind many types of drugs also creates the possibility of using the same affinity microcolumn to study and measure the free fractions for a variety of pharmaceutical agents. These properties make this technique appealing for use in drug binding studies and in the high-throughput screening of new drug candidates. PMID:20227701

  10. Lysozyme binding ability toward psychoactive stimulant drugs: Modulatory effect of colloidal metal nanoparticles.

    Science.gov (United States)

    Sonu, Vikash K; Islam, Mullah Muhaiminul; Rohman, Mostofa Ataur; Mitra, Sivaprasad

    2016-10-01

    The interaction and binding behavior of the well-known psychoactive stimulant drugs theophylline (THP) and theobromine (THB) with lysozyme (LYS) was monitored by in-vitro fluorescence titration and molecular docking calculations under physiological condition. The quenching of protein fluorescence on addition of the drugs is due to the formation of protein-drug complex in the ground state in both the cases. However, the binding interaction is almost three orders of magnitude stronger in THP, which involves mostly hydrogen bonding interaction in comparison with THB where hydrophobic binding plays the predominant role. The mechanism of fluorescence quenching (static type) remains same also in presence of gold and silver nanoparticles (NPs); however, the binding capacity of LYS with the drugs changes drastically in comparison with that in aqueous buffer medium. While the binding affinity of LYS to THB increases ca. 100 times in presence of both the NPs, it is seen to decrease drastically (by almost 1000 fold) for THP. This significant modulation in binding behavior indicates that the drug transportation capacity of LYS can be controlled significantly with the formation protein-NP noncovalent assembly system as an efficient delivery channel. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Optics of multiple grooves in metal

    DEFF Research Database (Denmark)

    Skjølstrup, Enok Johannes Haahr; Søndergaard, Thomas; Pedersen, Kjeld

    2017-01-01

    This paper studies theoretically how the optics of multiple grooves in a metal change as the number of grooves is increased gradually from a single groove to innitely many arranged in a periodic array. In the case of a single groove the out-of-plane scattering (OUP) cross section at resonance can...

  12. Optics of multiple grooves in metal

    DEFF Research Database (Denmark)

    Skjølstrup, Enok Johannes Haahr; Søndergaard, Thomas; Pedersen, Kjeld

    2017-01-01

    This paper theoretically studies how the optics of multiple grooves in a metal change as the number of grooves gradually increased from a single groove to infinitely many arranged in a periodic array. In the case of a single groove, the out-of-plane scattering (OUP) cross section at resonance can...

  13. Human serum albumin unfolding pathway upon drug binding: A thermodynamic and spectroscopic description

    International Nuclear Information System (INIS)

    Cheema, Mohammad Arif; Taboada, Pablo; Barbosa, Silvia; Juarez, Josue; Gutierrez-Pichel, Manuel; Siddiq, Mohammad; Mosquera, Victor

    2009-01-01

    The interest on phenothiazine drugs has been increased during last years due to their proved utility in the treatment of several diseases and biomolecular processes. In the present work, the binding of the amphiphilic phenothiazines promazine and thioridazine hydrochlorides to the carrier protein human serum albumin (HSA) has been examined by ζ-potential, isothermal titration calorimetry (ITC), fluorescence and circular dichorism (CD) spectroscopies, and dynamic light scattering (DLS) at physiological pH with the aim of analyzing the role of the different interactions in the drug complexation process with this protein. The ζ-potential results were used to check the existence of complexation. This is confirmed by a progressive screening of the protein charge up to a reversal point as a consequence of drug binding. On the other hand, binding causes alterations on the tertiary and secondary structures of the protein, which were observed by fluorescence and CD spectroscopies, involving a two-step, three-state transition. The thermodynamics of the binding process was derived from ITC results. The binding enthalpies were negative, which reveal the existence of electrostatic interactions between protein and drug molecules. In addition, increases in entropy are consistent with the predominance of hydrophobic interactions. Two different classes of binding sites were detected, viz. Binding to the first class of binding sites is dominated by an enthalpic contribution due to electrostatic interactions whereas binding to a second class of binding sites is dominated by hydrophobic bonding. In the light of these results, protein conformational change resembles the acid-induced denaturation of HSA with accumulation of an intermediate state. Binding isotherms were derived from microcalorimetric results by using a theoretical model based on the Langmuir isotherm. On the other hand, the population distribution of the different species in solution and their sizes were determined

  14. Human serum albumin unfolding pathway upon drug binding: A thermodynamic and spectroscopic description

    Energy Technology Data Exchange (ETDEWEB)

    Cheema, Mohammad Arif [Grupo de Fisica de Coloides y Polimeros, Departamento de Fisica de la Materia Condensada, Facultad de Fisica, Universidad de Santiago de Compostela, E-15782, Santiago de Compostela (Spain); Department of Chemistry, Quaid-i-Azam University, Islamabad 45320 (Pakistan); Taboada, Pablo [Grupo de Fisica de Coloides y Polimeros, Departamento de Fisica de la Materia Condensada, Facultad de Fisica, Universidad de Santiago de Compostela, E-15782, Santiago de Compostela (Spain); Department of Chemistry, Quaid-i-Azam University, Islamabad 45320 (Pakistan)], E-mail: pablo.taboada@usc.es; Barbosa, Silvia; Juarez, Josue; Gutierrez-Pichel, Manuel [Grupo de Fisica de Coloides y Polimeros, Departamento de Fisica de la Materia Condensada, Facultad de Fisica, Universidad de Santiago de Compostela, E-15782, Santiago de Compostela (Spain); Department of Chemistry, Quaid-i-Azam University, Islamabad 45320 (Pakistan); Siddiq, Mohammad [Department of Chemistry, Quaid-i-Azam University, Islamabad 45320 (Pakistan); Mosquera, Victor [Grupo de Fisica de Coloides y Polimeros, Departamento de Fisica de la Materia Condensada, Facultad de Fisica, Universidad de Santiago de Compostela, E-15782, Santiago de Compostela (Spain); Department of Chemistry, Quaid-i-Azam University, Islamabad 45320 (Pakistan)

    2009-04-15

    The interest on phenothiazine drugs has been increased during last years due to their proved utility in the treatment of several diseases and biomolecular processes. In the present work, the binding of the amphiphilic phenothiazines promazine and thioridazine hydrochlorides to the carrier protein human serum albumin (HSA) has been examined by {zeta}-potential, isothermal titration calorimetry (ITC), fluorescence and circular dichorism (CD) spectroscopies, and dynamic light scattering (DLS) at physiological pH with the aim of analyzing the role of the different interactions in the drug complexation process with this protein. The {zeta}-potential results were used to check the existence of complexation. This is confirmed by a progressive screening of the protein charge up to a reversal point as a consequence of drug binding. On the other hand, binding causes alterations on the tertiary and secondary structures of the protein, which were observed by fluorescence and CD spectroscopies, involving a two-step, three-state transition. The thermodynamics of the binding process was derived from ITC results. The binding enthalpies were negative, which reveal the existence of electrostatic interactions between protein and drug molecules. In addition, increases in entropy are consistent with the predominance of hydrophobic interactions. Two different classes of binding sites were detected, viz. Binding to the first class of binding sites is dominated by an enthalpic contribution due to electrostatic interactions whereas binding to a second class of binding sites is dominated by hydrophobic bonding. In the light of these results, protein conformational change resembles the acid-induced denaturation of HSA with accumulation of an intermediate state. Binding isotherms were derived from microcalorimetric results by using a theoretical model based on the Langmuir isotherm. On the other hand, the population distribution of the different species in solution and their sizes were

  15. [Integration of pharmacokinetics and pharmacodynamics based on the in vivo analysis of drug-receptor binding].

    Science.gov (United States)

    Yamada, Shizuo

    2015-01-01

      As I was deeply interested in the effects of drugs on the human body, I chose pharmacology as the subject of special study when I became a 4th year student at Shizuoka College of Pharmacy. I studied abroad as a postdoctoral fellow for two years, from 1978, under the tutelage of Professor Henry I. Yamamura (pharmacology) in the College of Medicine at the University of Arizona, USA. He taught me a variety of valuable skills such as the radioreceptor binding assay, which represented the most advanced technology developed in the US at that time. After returning home, I engaged in clarifying receptor abnormalities in pathological conditions, as well as in drug action mechanisms, by making the best use of this radioreceptor binding assay. In 1989, following the founding of the University of Shizuoka, I was invited by Professor Ryohei Kimura to join the Department of Pharmacokinetics. This switch in discipline provided a good opportunity for me to broaden my perspectives in pharmaceutical sciences. I worked on evaluating drug-receptor binding in vivo as a combined index for pharmacokinetics and pharmacological effect manifestation, with the aim of bridging pharmacology and pharmacokinetics. In fact, by focusing on data from in vivo receptor binding, it became possible to clearly rationalize the important consideration of drug dose-concentration-action relationships, and to study quantitative and kinetic analyses of relationships among pharmacokinetics, receptor binding and pharmacological effects. Based on this concept, I was able to demonstrate the utility of dynamic analyses of drug-receptor binding in drug discovery, drug fostering, and the proper use of pharmacokinetics with regard to many drugs.

  16. Characterization of the interaction forces in a drug carrier complex of doxorubicin with a drug-binding peptide.

    Science.gov (United States)

    Gocheva, Gergana; Ilieva, Nina; Peneva, Kalina; Ivanova, Anela

    2018-04-01

    Polypeptide-based materials are used as building blocks for drug delivery systems aimed at toxicity decrease in chemotherapeutics. A molecular-level approach is adopted for investigating the non-covalent interactions between doxorubicin and a recently synthesized drug-binging peptide as a key part of a system for delivery to neoplastic cells. Molecular dynamics simulations in aqueous solution at room and body temperature are applied to investigate the structure and the binding modes within the drug-peptide complex. The tryptophans are outlined as the main chemotherapeutic adsorption sites, and the importance of their placement in the peptide sequence is highlighted. The drug-peptide binging energy is evaluated by density functional theory calculations. Principal component analysis reveals comparable importance of several types of interaction for the binding strength. π-Stacking is dominant, but other factors are also significant: intercalation, peptide backbone stacking, electrostatics, dispersion, and solvation. Intra- and intermolecular H-bonding also stabilizes the complexes. The influence of solvent molecules on the binding energy is mild. The obtained data characterize the drug-to-peptide attachment as a mainly attractive collective process with interactions spanning a broad range of values. These results explain with atomistic detail the experimentally registered doxorubicin-binging ability of the peptide and outline the complex as a prospective carrying unit that can be employed in design of drug delivery systems. © 2017 John Wiley & Sons A/S.

  17. Effect of anticonvulsant drugs on (35S)t-butylbicyclophosphorothionate binding in vitro and ex vivo

    International Nuclear Information System (INIS)

    Pitkaenen, A.; Riekkinen, P.J.; Saano, V.; Tuomisto, L.

    1987-01-01

    Using several concentrations of eight anticonvulsant drugs in clinical use (carbamazepine, clonazepam, phenytoin, phenobarbital, ethosuximide, primidone, sodium valproate, and D,L-γ-vinyl GABA), we studied their abilities in vitro to displace ( 35 S)t-butylbicyclophosphorothionate ( 35 S-TBPS) from its binding site in a homogenate of rat brain. Thereafter ethosuximide (150 mg/kg), phenobarbital (30 mg/kg), clonazepam (0.3 mg/kg), or phenytoin (100 mg/kg) was injected intraperitoneally into rats for 16-20 days; and the effect of drug administration on 35 S-TBPS binding was studied in the cortex and hippocampus ex vivo. Phenobarbital (100 μM, P 35 S-TBPS binding in vitro by 10-16%. After drug administration of phenobarbital (concentration in plasma 168 μM), the number of binding sites decreased and the binding affinity (p 35 S-TBPS binding in vitro at the concentration analogous to therapeutic plasma levels or ex vivo at the dose used. These results suggest that the use of phenobarbital may modulate the TBPS binding site, but the role of the present findings in the anticonvulsant action of phenobarbital needs to be further studied. (author)

  18. Structure of a Pheromone Receptor-Associated Mhc Molecule With An Open And Empty Groove

    Energy Technology Data Exchange (ETDEWEB)

    Olson, R.; Huey-Tubman, K.E.; Dulac, C.; Bjorkman, P.J.; /Caltech /Harvard U.

    2006-10-06

    Neurons in the murine vomeronasal organ (VNO) express a family of class Ib major histocompatibility complex (MHC) proteins (M10s) that interact with the V2R class of VNO receptors. This interaction may play a direct role in the detection of pheromonal cues that initiate reproductive and territorial behaviors. The crystal structure of M10.5, an M10 family member, is similar to that of classical MHC molecules. However, the M10.5 counterpart of the MHC peptide-binding groove is open and unoccupied, revealing the first structure of an empty class I MHC molecule. Similar to empty MHC molecules, but unlike peptide-filled MHC proteins and non-peptide-binding MHC homologs, M10.5 is thermally unstable, suggesting that its groove is normally occupied. However, M10.5 does not bind endogenous peptides when expressed in mammalian cells or when offered a mixture of class I-binding peptides. The F pocket side of the M10.5 groove is open, suggesting that ligands larger than 8-10-mer class I-binding peptides could fit by extending out of the groove. Moreover, variable residues point up from the groove helices, rather than toward the groove as in classical MHC structures. These data suggest that M10s are unlikely to provide specific recognition of class I MHC-binding peptides, but are consistent with binding to other ligands, including proteins such as the V2Rs.

  19. Structure of a pheromone receptor-associated MHC molecule with an open and empty groove.

    Directory of Open Access Journals (Sweden)

    2005-08-01

    Full Text Available Neurons in the murine vomeronasal organ (VNO express a family of class Ib major histocompatibility complex (MHC proteins (M10s that interact with the V2R class of VNO receptors. This interaction may play a direct role in the detection of pheromonal cues that initiate reproductive and territorial behaviors. The crystal structure of M10.5, an M10 family member, is similar to that of classical MHC molecules. However, the M10.5 counterpart of the MHC peptide-binding groove is open and unoccupied, revealing the first structure of an empty class I MHC molecule. Similar to empty MHC molecules, but unlike peptide-filled MHC proteins and non-peptide-binding MHC homologs, M10.5 is thermally unstable, suggesting that its groove is normally occupied. However, M10.5 does not bind endogenous peptides when expressed in mammalian cells or when offered a mixture of class I-binding peptides. The F pocket side of the M10.5 groove is open, suggesting that ligands larger than 8-10-mer class I-binding peptides could fit by extending out of the groove. Moreover, variable residues point up from the groove helices, rather than toward the groove as in classical MHC structures. These data suggest that M10s are unlikely to provide specific recognition of class I MHC-binding peptides, but are consistent with binding to other ligands, including proteins such as the V2Rs.

  20. Long chain fatty acids alter the interactive binding of ligands to the two principal drug binding sites of human serum albumin.

    Directory of Open Access Journals (Sweden)

    Keishi Yamasaki

    Full Text Available A wide variety of drugs bind to human serum albumin (HSA at its two principal sites, namely site I and site II. A number of reports indicate that drug binding to these two binding sites are not completely independent, and that interactions between ligands of these two discrete sites can play a role. In this study, the effect of the binding of long-chain fatty acids on the interactive binding between dansyl-L-asparagine (DNSA; site I ligand and ibuprofen (site II ligand at pH6.5 was examined. Binding experiments showed that the binding of sodium oleate (Ole to HSA induces conformational changes in the molecule, which, in turn, changes the individual binding of DNSA and ibuprofen, as well as the mode of interaction between these two ligands from a 'competitive-like' allosteric interaction in the case of the defatted HSA conformer to a 'nearly independent' binding in the case of non-defatted HSA conformer. Circular dichroism measurements indicated that ibuprofen and Ole are likely to modify the spatial orientation of DNSA at its binding site. Docking simulations suggest that the long-distance electric repulsion between DNSA and ibuprofen on defatted HSA contributes to a 'competitive-like' allosteric interaction, whereas extending the distance between ligands and/or increasing the flexibility or size of the DNSA binding site in fatted HSA evokes a change in the interaction mode to 'nearly independent' binding. The present findings provide further insights into the structural dynamics of HSA upon the binding of fatty acids, and its effects on drug binding and drug-drug interactions that occur on HSA.

  1. Binding kinetics of five drugs to beta2-adrenoceptor using peak profiling method and nonlinear chromatography.

    Science.gov (United States)

    Liang, Yuan; Wang, Jing; Fei, Fuhuan; Sun, Huanmei; Liu, Ting; Li, Qian; Zhao, Xinfeng; Zheng, Xiaohui

    2018-02-23

    Investigations of drug-protein interactions have advanced our knowledge of ways to design more rational drugs. In addition to extensive thermodynamic studies, ongoing works are needed to enhance the exploration of drug-protein binding kinetics. In this work, the beta2-adrenoceptor (β 2 -AR) was immobilized on N, N'-carbonyldiimidazole activated amino polystyrene microspheres to prepare an affinity column (4.6 mm × 5.0 cm, 8 μm). The β 2 -AR column was utilized to determine the binding kinetics of five drugs to the receptor. Introducing peak profiling method into this receptor chromatographic analysis, we determined the dissociation rate constants (k d ) of salbutamol, terbutaline, methoxyphenamine, isoprenaline hydrochloride and ephedrine hydrochloride to β 2 -AR to be 15 (±1), 22 (±1), 3.3 (±0.2), 2.3 (±0.2) and 2.1 (±0.1) s -1 , respectively. The employment of nonlinear chromatography (NLC) in this case exhibited the same rank order of k d values for the five drugs bound to β 2 -AR. We confirmed that both the peak profiling method and NLC were capable of routine measurement of receptor-drug binding kinetics. Compared with the peak profiling method, NLC was advantageous in the simultaneous assessment of the kinetic and apparent thermodynamic parameters. It will become a powerful method for high throughput drug-receptor interaction analysis. Copyright © 2018 Elsevier B.V. All rights reserved.

  2. Optics of multiple ultrasharp grooves in metal

    DEFF Research Database (Denmark)

    Skjølstrup, Enok Johannes Haahr; Søndergaard, Thomas

    2017-01-01

    . When the multiple-groove array is illuminated by a plane wave the out-of-plane scattering is found to be extraordinarily large compared with the expected maximum from a geometric-optics estimate even for array widths of many wavelengths. The out-of-plane scattering is even higher per groove compared......The optics of multiple ultrasharp sub-wavelength grooves in metal is studied theoretically. Focus is on the transition from a single groove, where the scattering cross section is significant and can exceed the groove width, to infinitely many grooves in a periodic array with very low reflectance...

  3. Altered drug binding to serum proteins in pregnant women: therapeutic relevance.

    OpenAIRE

    Perucca, E; Ruprah, M; Richens, A

    1981-01-01

    The binding of diazepam, phenytoin and valproic acid to serum proteins in vitro has been compared in pregnant women of different gestational ages and in controls. The unbound fraction of each of three drugs was elevated during pregnancy (particularly during the last 8 weeks) probably due, at least in part, to a fall in serum albumin concentration. These findings may provide a partial explanation for the increase in the clearance of certain drugs during pregnancy and need to be taken into acco...

  4. Development of Drug Loaded Nanoparticles Binding to Hydroxyapatite Based on a Bisphosphonate Modified Nonionic Surfactant

    Directory of Open Access Journals (Sweden)

    Jiabin Zhang

    2015-01-01

    Full Text Available This study aimed at development of drug loaded nanoparticles which could bind to hydroxyapatite (HA to construct drug or growth factor releasing bone graft substitutes. To this end, the terminal hydroxyl group of a nonionic surfactant Brij 78 (polyoxyethylene (20 stearyl ether was first modified with pamidronate (Pa. Using Pa-Brij 78 as both a surfactant and an affinity ligand to HA, three different Pa surface functionalized nanoparticles were prepared, named as solid lipid nanoparticles (Pa-SNPs, nanoemulsions (Pa-NEMs, and PLGA nanoparticles (Pa-PNPs. A model drug curcumin was successfully encapsulated in the three nanoparticles. The sizes of Pa-NEM and Pa-PNP were around 150 nm and the size of Pa-SNP was around 90 nm with polydispersity indexes (PDIs less than 0.20. Drug encapsulation efficiencies of the three nanoparticles were all greater than 85%. Furthermore, the order of binding affinity of the nanoparticles to HA was Pa-PNP>Pa-NEM=Pa-SNP. After lyophilization, the sizes of the three nanoparticles were increased about 0.5–2.0-fold but their binding affinities to HA were almost the same as the fresh prepared nanoparticles. In conclusion, a Pa-modified Brij 78 was synthesized and used for fabrication of a series of drug loaded nanoparticles to construct drug-eluting HA-based bone graft substitutes.

  5. HIV-1 binding and neutralizing antibodies of injecting drug users

    Directory of Open Access Journals (Sweden)

    E.P. Ouverney

    2005-09-01

    Full Text Available Previous studies have demonstrated a stronger seroreactivity against some synthetic peptides responsible for inducing neutralizing antibodies in injecting drug users (IDU compared to that of individuals sexually infected with HIV-1 (S, but the effectiveness in terms of the neutralizing ability of these antibodies has not been evaluated. Our objective was to study the humoral immune response of IDU by determining the specificity of their antibodies and the presence of neutralizing antibodies. The neutralization capacity against the HIV-1 isolate MN (genotype B, the primary HIV-1 isolate 95BRRJ021 (genotype F, and the seroreactivity with peptides known to induce neutralizing antibodies, from the V2 and V3 loops of different HIV-1 subtypes, were analyzed. Seroreactivity indicates that IDU plasma are more likely to recognize a broader range of peptides than S plasma, with significantly higher titers, especially of V3 peptides. Similar neutralization frequencies of the MN isolate were observed in plasma of the IDU (16/47 and S (20/60 groups in the 1:10 dilution. The neutralization of the 95BRRJ021 isolate was more frequently observed for plasma from the S group (15/23 than from the IDU group (15/47, P = 0.0108. No correlation between neutralization and seroreactivity with the peptides tested was observed. These results suggest that an important factor responsible for the extensive and broad humoral immune response observed in IDU is their infection route. There was very little difference in neutralizing antibody response between the IDU and S groups despite their differences in seroreactivity and health status.

  6. Metabolism of ATP-binding cassette drug transporter inhibitors: complicating factor for multidrug resistance.

    NARCIS (Netherlands)

    Cnubben, N.H.; Wortelboer, H.M.; Zanden, J.J. van; Rietjens, I.M.; Bladeren, P.J. van

    2005-01-01

    Membrane transport proteins belonging to the ATP-binding cassette (ABC) family of transport proteins play a central role in the defence of organisms against toxic compounds, including anticancer drugs. However, for compounds that are designed to display a toxic effect, this defence system diminishes

  7. Oligomycin frames a common drug-binding site in the ATP synthase

    Energy Technology Data Exchange (ETDEWEB)

    Symersky, Jindrich; Osowski, Daniel; Walters, D. Eric; Mueller, David M. (Rosalind)

    2015-12-01

    We report the high-resolution (1.9 {angstrom}) crystal structure of oligomycin bound to the subunit c10 ring of the yeast mitochondrial ATP synthase. Oligomycin binds to the surface of the c10 ring making contact with two neighboring molecules at a position that explains the inhibitory effect on ATP synthesis. The carboxyl side chain of Glu59, which is essential for proton translocation, forms an H-bond with oligomycin via a bridging water molecule but is otherwise shielded from the aqueous environment. The remaining contacts between oligomycin and subunit c are primarily hydrophobic. The amino acid residues that form the oligomycin-binding site are 100% conserved between human and yeast but are widely different from those in bacterial homologs, thus explaining the differential sensitivity to oligomycin. Prior genetics studies suggest that the oligomycin-binding site overlaps with the binding site of other antibiotics, including those effective against Mycobacterium tuberculosis, and thereby frames a common 'drug-binding site.' We anticipate that this drug-binding site will serve as an effective target for new antibiotics developed by rational design.

  8. Distribution of primaquine in human blood: Drug-binding to alpha 1-glycoprotein

    International Nuclear Information System (INIS)

    Kennedy, E.; Frischer, H.

    1990-01-01

    To clarify the distribution of the antimalarial primaquine in human blood, we measured the drug separately in the liquid, cellular, and ultrafiltrate phases. Washed red cells resuspended at a hematocrit of 0.4 were exposed to a submaximal therapeutic level of 250 ng/ml of carbon 14-labeled primaquine. The tracer was recovered quantitatively in separated plasma and red cells. Over 75% of the total labeled drug was found in red cells suspended in saline solution, but only 10% to 30% in red cells suspended in plasma. The plasma effect was not mediated by albumin. Studies with alpha 1-acid glycoprotein (AGP), tris(2-butoxyethyl)phosphate, an agent that displaces AGP-bound drugs, and cord blood known to have decreased AGP established that primaquine binds to physiologic amounts of the glycoprotein in plasma. Red cell primaquine concentration increased linearly as AGP level fell and as the free drug fraction rose. We suggest that clinical blood levels of primaquine include the red cell fraction or whole blood level because (1) erythrocytic primaquine is a sizable and highly variable component of the total drug in blood; (2) this component reflects directly the free drug in plasma, and inversely the extent of binding to AGP; (3) the amount of free primaquine may influence drug transport into specific tissues in vivo; and (4) fluctuations of AGP, an acute-phase reactant that increases greatly in patients with malaria and other infections, markedly affect the partition of primaquine in blood. Because AGP binds many basic drugs, unrecognized primaquine-drug interactions may exist

  9. Structural analysis of protein-ligand interactions: the binding of endogenous compounds and of synthetic drugs.

    Science.gov (United States)

    Gallina, Anna M; Bork, Peer; Bordo, Domenico

    2014-02-01

    The large number of macromolecular structures deposited with the Protein Data Bank (PDB) describing complexes between proteins and either physiological compounds or synthetic drugs made it possible a systematic analysis of the interactions occurring between proteins and their ligands. In this work, the binding pockets of about 4000 PDB protein-ligand complexes were investigated and amino acid and interaction types were analyzed. The residues observed with lowest frequency in protein sequences, Trp, His, Met, Tyr, and Phe, turned out to be the most abundant in binding pockets. Significant differences between drug-like and physiological compounds were found. On average, physiological compounds establish with respect to drugs about twice as many hydrogen bonds with protein atoms, whereas drugs rely more on hydrophobic interactions to establish target selectivity. The large number of PDB structures describing homologous proteins in complex with the same ligand made it possible to analyze the conservation of binding pocket residues among homologous protein structures bound to the same ligand, showing that Gly, Glu, Arg, Asp, His, and Thr are more conserved than other amino acids. Also in the cases in which the same ligand is bound to unrelated proteins, the binding pockets showed significant conservation in the residue types. In this case, the probability of co-occurrence of the same amino acid type in the binding pockets could be up to thirteen times higher than that expected on a random basis. The trends identified in this study may provide an useful guideline in the process of drug design and lead optimization. Copyright © 2014 John Wiley & Sons, Ltd.

  10. DNA and protein binding, double-strand DNA cleavage and cytotoxicity of mixed ligand copper(II) complexes of the antibacterial drug nalidixic acid.

    Science.gov (United States)

    Loganathan, Rangasamy; Ganeshpandian, Mani; Bhuvanesh, Nattamai S P; Palaniandavar, Mallayan; Muruganantham, Amsaveni; Ghosh, Swapan K; Riyasdeen, Anvarbatcha; Akbarsha, Mohammad Abdulkader

    2017-09-01

    The water soluble mixed ligand complexes [Cu(nal)(diimine)(H 2 O)](ClO 4 ) 1-4, where H(nal) is nalidixic acid and diimine is 2,2'-bipyridine (1), 1,10-phenanthroline (2), 5,6-dimethyl-1,10-phenanthroline (3), and 3,4,7,8-tetramethyl-1,10-phenanthroline (4), have been isolated. The coordination geometry around Cu(II) in 1 and that in the Density Functional Theory optimized structures of 1-4 has been assessed as square pyramidal. The trend in DNA binding constants (K b ) determined using absorption spectral titration (K b : 1, 0.79±0.1base pair. In contrast, 3 and 4 are involved in intimate hydrophobic interaction with DNA through the methyl substituents on phen ring, which is supported by viscosity and protein binding studies. DNA docking studies imply that 4 is involved preferentially in DNA major groove binding while 1-3 in minor groove binding and that all the complexes, upon removing the axially coordinated water molecule, bind in the major groove. Interestingly, 3 and 4 display prominent double-strand DNA cleavage while 1 and 2 effect only single-strand DNA cleavage in the absence of an activator. The complexes 3 and 4 show cytotoxicity higher than 1 and 2 against human breast cancer cell lines (MCF-7). The complex 4 induces apoptotic mode of cell death in cancer cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Differential binding of prohibitin-2 to estrogen receptor α and to drug-resistant ERα mutants

    Energy Technology Data Exchange (ETDEWEB)

    Chigira, Takeru, E-mail: 8120661875@mail.ecc.u-tokyo.ac.jp [Department of Chemistry and Biotechnology, School of Engineering, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639 (Japan); Nagatoishi, Satoru, E-mail: nagatoishi@bioeng.t.u-tokyo.ac.jp [Department of Bioengineering, School of Engineering, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8654 (Japan); Tsumoto, Kouhei, E-mail: tsumoto@bioeng.t.u-tokyo.ac.jp [Department of Chemistry and Biotechnology, School of Engineering, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639 (Japan); Department of Bioengineering, School of Engineering, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8654 (Japan)

    2015-08-07

    Endocrine resistance is one of the most challenging problems in estrogen receptor alpha (ERα)-positive breast cancer. The transcriptional activity of ERα is controlled by several coregulators, including prohibitin-2 (PHB2). Because of its ability to repress the transcriptional activity of activated ERα, PHB2 is a promising antiproliferative agent. In this study, were analyzed the interaction of PHB2 with ERα and three mutants (Y537S, D538G, and E380Q) that are frequently associated with a lack of sensitivity to hormonal treatments, to help advance novel drug discovery. PHB2 bound to ERα wild-type (WT), Y537S, and D538G, but did not bind to E380Q. The binding thermodynamics of Y537S and D538G to PHB2 were favorably altered entropically compared with those of WT to PHB2. Our results show that PHB2 binds to the ligand binding domain of ERα with a conformational change in the helix 12 of ERα. - Highlights: • Molten globule-likeness of an ERα repressor Prohibitin-2 (PHB2) is identified. • The thermodynamics is validated for the interaction between ERα and PHB2. • PHB2 binds to Y537S and D538G mutants of ERα commonly found in breast cancer. • ERα WT and mutants showed different thermodynamic parameters in the binding to PHB2. • ERα binds to PHB2 with conformational change involving packing of helix 12.

  12. Understanding the physical and chemical nature of the warfarin drug binding site in human serum albumin: experimental and theoretical studies.

    Science.gov (United States)

    Abou-Zied, Osama K

    2015-01-01

    Human serum albumin (HSA) is one of the major carrier proteins in the body and constitutes approximately half of the protein found in blood plasma. It plays an important role in lipid metabolism, and its ability to reversibly bind a large variety of pharmaceutical compounds makes it a crucial determinant of drug pharmacokinetics and pharmacodynamics. This review deals with one of the protein's major binding sites "Sudlow I" which includes a binding pocket for the drug warfarin (WAR). The binding nature of this important site can be characterized by measuring the spectroscopic changes when a ligand is bound. Using several drugs, including WAR, and other drug-like molecules as ligands, the results emphasize the nature of Sudlow I as a flexible binding site, capable of binding a variety of ligands by adapting its binding pockets. The high affinity of the WAR pocket for binding versatile molecular structures stems from the flexibility of the amino acids forming the pocket. The binding site is shown to have an ionization ability which is important to consider when using drugs that are known to bind in Sudlow I. Several studies point to the important role of water molecules trapped inside the binding site in molecular recognition and ligand binding. Water inside the protein's cavity is crucial in maintaining the balance between the hydrophobic and hydrophilic nature of the binding site. Upon the unfolding and refolding of HSA, more water molecules are trapped inside the binding site which cause some swelling that prevents a full recovery from the denatured state. Better understanding of the mechanism of binding in macromolecules such as HSA and other proteins can be achieved by combining experimental and theoretical studies which produce significant synergies in studying complex biochemical phenomena.

  13. Binding of several anti-tumor drugs to bovine serum albumin: Fluorescence study

    Energy Technology Data Exchange (ETDEWEB)

    Bi Shuyun [College of Chemistry, Changchun Normal University, Changchun 130032 (China)], E-mail: sy_bi@sina.com; Sun Yantao [College of Chemistry, Jilin University, Changchun 130023 (China); College of Chemistry, Jilin Normal University, Siping 136000 (China); Qiao Chunyu; Zhang Hanqi [College of Chemistry, Jilin University, Changchun 130023 (China); Liu Chunming [College of Chemistry, Changchun Normal University, Changchun 130032 (China)

    2009-05-15

    The interactions of mitomycin C (MMC), fluorouracil (FU), mercaptopurine (MP) and doxorubicin hydrochloride (DXR) with bovine serum albumin (BSA) were studied by spectroscopic method. Quenching of fluorescence of serum albumin by these drugs was found to be a static quenching process. The binding constants (K{sub A}) were 9.66x10{sup 3}, 2.08x10{sup 3}, 8.20x10{sup 2} and 7.50x10{sup 3} L mol{sup -1} for MMC-, FU-, MP- and DXR-BSA, respectively, at pH 7.4 Britton-Robinson buffer at 28 deg. C. The thermodynamic functions such as enthalpy change ({delta}H), entropy change ({delta}S) and Gibbs free-energy change ({delta}G) for the reactions were also calculated according to the thermodynamic equations. The main forces in the interactions of these drugs with BSA were evaluated. It was found that the interactions of MMC and FU with BSA were exothermic processes and those of MP and DXR with BSA were endothermic. In addition, the binding sites on BSA for the four drugs were probed by the changes of binding properties of these drugs with BSA in the presence of two important site markers such as ibuprofen and indomethacin. Based on the Foester theory of non-radiation energy transfer, the binding distances between the drugs and tryptophane were calculated and they were 3.00, 1.14, 2.85, and 2.79 nm for MMC, FU, MP and DXR, respectively.

  14. Relative Binding Free Energy Calculations in Drug Discovery: Recent Advances and Practical Considerations.

    Science.gov (United States)

    Cournia, Zoe; Allen, Bryce; Sherman, Woody

    2017-12-26

    Accurate in silico prediction of protein-ligand binding affinities has been a primary objective of structure-based drug design for decades due to the putative value it would bring to the drug discovery process. However, computational methods have historically failed to deliver value in real-world drug discovery applications due to a variety of scientific, technical, and practical challenges. Recently, a family of approaches commonly referred to as relative binding free energy (RBFE) calculations, which rely on physics-based molecular simulations and statistical mechanics, have shown promise in reliably generating accurate predictions in the context of drug discovery projects. This advance arises from accumulating developments in the underlying scientific methods (decades of research on force fields and sampling algorithms) coupled with vast increases in computational resources (graphics processing units and cloud infrastructures). Mounting evidence from retrospective validation studies, blind challenge predictions, and prospective applications suggests that RBFE simulations can now predict the affinity differences for congeneric ligands with sufficient accuracy and throughput to deliver considerable value in hit-to-lead and lead optimization efforts. Here, we present an overview of current RBFE implementations, highlighting recent advances and remaining challenges, along with examples that emphasize practical considerations for obtaining reliable RBFE results. We focus specifically on relative binding free energies because the calculations are less computationally intensive than absolute binding free energy (ABFE) calculations and map directly onto the hit-to-lead and lead optimization processes, where the prediction of relative binding energies between a reference molecule and new ideas (virtual molecules) can be used to prioritize molecules for synthesis. We describe the critical aspects of running RBFE calculations, from both theoretical and applied perspectives

  15. Identification of distant drug off-targets by direct superposition of binding pocket surfaces.

    Science.gov (United States)

    Schumann, Marcel; Armen, Roger S

    2013-01-01

    Correctly predicting off-targets for a given molecular structure, which would have the ability to bind a large range of ligands, is both particularly difficult and important if they share no significant sequence or fold similarity with the respective molecular target ("distant off-targets"). A novel approach for identification of off-targets by direct superposition of protein binding pocket surfaces is presented and applied to a set of well-studied and highly relevant drug targets, including representative kinases and nuclear hormone receptors. The entire Protein Data Bank is searched for similar binding pockets and convincing distant off-target candidates were identified that share no significant sequence or fold similarity with the respective target structure. These putative target off-target pairs are further supported by the existence of compounds that bind strongly to both with high topological similarity, and in some cases, literature examples of individual compounds that bind to both. Also, our results clearly show that it is possible for binding pockets to exhibit a striking surface similarity, while the respective off-target shares neither significant sequence nor significant fold similarity with the respective molecular target ("distant off-target").

  16. Prediction of Drug-Plasma Protein Binding Using Artificial Intelligence Based Algorithms.

    Science.gov (United States)

    Kumar, Rajnish; Sharma, Anju; Siddiqui, Mohammed Haris; Tiwari, Rajesh Kumar

    2018-01-01

    Plasma protein binding (PPB) has vital importance in the characterization of drug distribution in the systemic circulation. Unfavorable PPB can pose a negative effect on clinical development of promising drug candidates. The drug distribution properties should be considered at the initial phases of the drug design and development. Therefore, PPB prediction models are receiving an increased attention. In the current study, we present a systematic approach using Support vector machine, Artificial neural network, k- nearest neighbor, Probabilistic neural network, Partial least square and Linear discriminant analysis to relate various in vitro and in silico molecular descriptors to a diverse dataset of 736 drugs/drug-like compounds. The overall accuracy of Support vector machine with Radial basis function kernel came out to be comparatively better than the rest of the applied algorithms. The training set accuracy, validation set accuracy, precision, sensitivity, specificity and F1 score for the Suprort vector machine was found to be 89.73%, 89.97%, 92.56%, 87.26%, 91.97% and 0.898, respectively. This model can potentially be useful in screening of relevant drug candidates at the preliminary stages of drug design and development. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Interpretation of Ocular Melanin Drug Binding Assays. Alternatives to the Model of Multiple Classes of Independent Sites.

    Science.gov (United States)

    Manzanares, José A; Rimpelä, Anna-Kaisa; Urtti, Arto

    2016-04-04

    Melanin has a high binding affinity for a wide range of drugs. The determination of the melanin binding capacity and its binding affinity are important, e.g., in the determination of the ocular drug distribution, the prediction of drug effects in the eye, and the trans-scleral drug delivery. The binding parameters estimated from a given data set vary significantly when using different isotherms or different nonlinear fitting methods. In this work, the commonly used bi-Langmuir isotherm, which assumes two classes of independent sites, is confronted with the Sips isotherm. Direct, log-log, and Scatchard plots are used, and the interpretation of the binding curves in the latter is critically analyzed. In addition to the goodness of fit, the emphasis is placed on the physical meaning of the binding parameters. The bi-Langmuir model imposes a bimodal distribution of binding energies for the sites on the melanin granules, but the actual distribution is most likely continuous and unimodal, as assumed by the Sips isotherm. Hence, the latter describes more accurately the distribution of binding energies and also the experimental results of melanin binding to drugs and metal ions. Simulations are used to show that the existence of two classes of sites cannot be confirmed on the sole basis of the shape of the binding curve in the Scatchard plot, and that serious doubts may appear on the meaning of the binding parameters of the bi-Langmuir model. Experimental results of melanin binding to chloroquine and metoprolol are used to illustrate the importance of the choice of the binding isotherm and of the method used to evaluate the binding parameters.

  18. Structural basis of non-steroidal anti-inflammatory drug diclofenac binding to human serum albumin.

    Science.gov (United States)

    Zhang, Yao; Lee, Philbert; Liang, Shichu; Zhou, Zuping; Wu, Xiaoyang; Yang, Feng; Liang, Hong

    2015-11-01

    Human serum albumin (HSA) is the most abundant protein in plasma, which plays a central role in drug pharmacokinetics because most compounds bound to HSA in blood circulation. To understand binding characterization of non-steroidal anti-inflammatory drugs to HSA, we resolved the structure of diclofenac and HSA complex by X-ray crystallography. HSA-palmitic acid-diclofenac structure reveals two distinct binding sites for three diclofenac in HSA. One diclofenac is located at the IB subdomain, and its carboxylate group projects toward polar environment, forming hydrogen bond with one water molecule. The other two diclofenac molecules cobind in big hydrophobic cavity of the IIA subdomain without interactive association. Among them, one binds in main chamber of big hydrophobic cavity, and its carboxylate group forms hydrogen bonds with Lys199 and Arg218, as well as one water molecule, whereas another diclofenac binds in side chamber, its carboxylate group projects out cavity, forming hydrogen bond with Ser480. © 2015 John Wiley & Sons A/S.

  19. A magnetic bead-based ligand binding assay to facilitate human kynurenine 3-monooxygenase drug discovery.

    Science.gov (United States)

    Wilson, Kris; Mole, Damian J; Homer, Natalie Z M; Iredale, John P; Auer, Manfred; Webster, Scott P

    2015-02-01

    Human kynurenine 3-monooxygenase (KMO) is emerging as an important drug target enzyme in a number of inflammatory and neurodegenerative disease states. Recombinant protein production of KMO, and therefore discovery of KMO ligands, is challenging due to a large membrane targeting domain at the C-terminus of the enzyme that causes stability, solubility, and purification difficulties. The purpose of our investigation was to develop a suitable screening method for targeting human KMO and other similarly challenging drug targets. Here, we report the development of a magnetic bead-based binding assay using mass spectrometry detection for human KMO protein. The assay incorporates isolation of FLAG-tagged KMO enzyme on protein A magnetic beads. The protein-bound beads are incubated with potential binding compounds before specific cleavage of the protein-compound complexes from the beads. Mass spectrometry analysis is used to identify the compounds that demonstrate specific binding affinity for the target protein. The technique was validated using known inhibitors of KMO. This assay is a robust alternative to traditional ligand-binding assays for challenging protein targets, and it overcomes specific difficulties associated with isolating human KMO. © 2014 Society for Laboratory Automation and Screening.

  20. Carrageenans as a new source of drugs with metal binding properties.

    Science.gov (United States)

    Khotimchenko, Yuri S; Khozhaenko, Elena V; Khotimchenko, Maxim Y; Kolenchenko, Elena A; Kovalev, Valeri V

    2010-04-01

    Carrageenans are abundant and safe non-starch polysaccharides exerting their biological effects in living organisms. Apart from their known pro-inflammation properties and some pharmacological activity, carrageenans can also strongly bind and hold metal ions. This property can be used for creation of the new drugs for elimination of metals from the body or targeted delivery of these metal ions for healing purposes. Metal binding activity of different carrageenans in aqueous solutions containing Y(3+) or Pb(2+) ions was studied in a batch sorption system. The metal uptake by carrageenans is not affected by the change of the pH within the range from 2.0 to 6.0. The rates and binding capacities of carrageenans regarding metal ions were evaluated. The Langmuir, Freundlich and BET sorption models were applied to describe the isotherms and constants, and the sorption isothermal data could be explained well by the Langmuir equation. The results obtained through the study suggest that kappa-, iota-, and lambda-carrageenans are favorable sorbents. The largest amount of Y(3+) and Pb(2+) ions are bound by iota-carrageenan. Therefore, it can be concluded that this type of polysaccharide is the more appropriate substance for elaboration of the drugs with high selective metal binding properties.

  1. Carrageenans as a New Source of Drugs with Metal Binding Properties

    Directory of Open Access Journals (Sweden)

    Yuri S. Khotimchenko

    2010-04-01

    Full Text Available Carrageenans are abundant and safe non-starch polysaccharides exerting their biological effects in living organisms. Apart from their known pro-inflammation properties and some pharmacological activity, carrageenans can also strongly bind and hold metal ions. This property can be used for creation of the new drugs for elimination of metals from the body or targeted delivery of these metal ions for healing purposes. Metal binding activity of different carrageenans in aqueous solutions containing Y3+ or Pb2+ ions was studied in a batch sorption system. The metal uptake by carrageenans is not affected by the change of the pH within the range from 2.0 to 6.0. The rates and binding capacities of carrageenans regarding metal ions were evaluated. The Langmuir, Freundlich and BET sorption models were applied to describe the isotherms and constants, and the sorption isothermal data could be explained well by the Langmuir equation. The results obtained through the study suggest that κ-, ι-, and λ-carrageenans are favorable sorbents. The largest amount of Y3+ and Pb2+ ions are bound by i-carrageenan. Therefore, it can be concluded that this type of polysaccharide is the more appropriate substance for elaboration of the drugs with high selective metal binding properties.

  2. Laser grooving of surface cracks on hot work tool steel

    Directory of Open Access Journals (Sweden)

    D. Klobčar

    2011-10-01

    Full Text Available The paper presents the analysis of laser grooving of 1.2343 tool steel hardened to 46 HRC. The effect of laser power and grooving speed on groove shape (i.e. depth and width, the material removal rate and the purity of produced groove as a measure of groove quality was investigated and analyzed using response surface methodology. Optimal parameters of laser grooving were found, which enables pure grooves suitable for laser welding.

  3. Differential diagnosis of groove pancreatic carcinomas vs. groove pancreatitis: Usefulness of the portal venous phase

    International Nuclear Information System (INIS)

    Ishigami, Kousei; Tajima, Tsuyoshi; Nishie, Akihiro; Kakihara, Daisuke; Fujita, Nobuhiro; Asayama, Yoshiki; Ushijima, Yasuhiro; Irie, Hiroyuki; Nakamura, Masafumi; Takahata, Shunichi; Ito, Tetsuhide; Honda, Hiroshi

    2010-01-01

    Purpose: To clarify if the portal venous phase is helpful for the differential diagnosis of groove pancreatic carcinomas and groove pancreatitis. Materials and methods: MDCT and MRI of groove pancreatic carcinomas (n = 7) and groove pancreatitis (n = 15) were retrospectively reviewed by two radiologists independently. The signal intensity on T2-weighted images was subjectively assessed. The presence or absence of common bile duct (CBD) and main pancreatic duct (MPD) strictures, calcifications, and cystic lesions was evaluated. Additionally, the appearance of groove pancreatic carcinoma and that of groove pancreatitis in the portal venous phase on dynamic MDCT and MRI were compared. Results: There were no significant differences in the signal intensity on T2-weighted images and in the presence or absence of CBD and MPD strictures, calcifications, and cystic lesions between groove pancreatic carcinomas and groove pancreatitis. However, patchy focal enhancement in the portal venous phase was more commonly observed in groove pancreatitis than groove pancreatic carcinoma (Reviewers 1 and 2: 14/15 [93.3%] vs. 1/7 [14.3%], P < 0.0001). In addition, peripheral enhancement was only seen in groove pancreatic carcinomas (Reviewer 1: 4/7 [57.1%] vs. 0/15 [0%], P < 0.005, and Reviewer 2: 3/7 [42.9%] vs. 0/15 [0%], P < 0.05). Conclusion: The portal venous phase may be helpful for the differential diagnosis of groove pancreatic carcinomas and groove pancreatitis.

  4. Experimental and molecular docking studies on DNA binding interaction of adefovir dipivoxil: Advances toward treatment of hepatitis B virus infections

    Science.gov (United States)

    Shahabadi, Nahid; Falsafi, Monireh

    The toxic interaction of adefovir dipivoxil with calf thymus DNA (CT-DNA) was investigated in vitro under simulated physiological conditions by multi-spectroscopic techniques and molecular modeling study. The fluorescence spectroscopy and UV absorption spectroscopy indicated drug interacted with CT-DNA in a groove binding mode. The binding constant of UV-visible and the number of binding sites were 3.33 ± 0.2 × 104 L mol-1and 0.99, respectively. The fluorimetric studies showed that the reaction between the drug and CT-DNA is exothermic (ΔH = 34.4 kJ mol-1; ΔS = 184.32 J mol-1 K-1). Circular dichroism spectroscopy (CD) was employed to measure the conformational change of CT-DNA in the presence of adefovir dipivoxil, which verified the groove binding mode. Furthermore, the drug induces detectable changes in its viscosity. The molecular modeling results illustrated that adefovir strongly binds to groove of DNA by relative binding energy of docked structure -16.83 kJ mol-1. This combination of multiple spectroscopic techniques and molecular modeling methods can be widely used in the investigation on the toxic interaction of small molecular pollutants and drugs with bio macromolecules, which contributes to clarify the molecular mechanism of toxicity or side effect in vivo.

  5. Towards a Structural View of Drug Binding to hERG K+ Channels.

    Science.gov (United States)

    Vandenberg, Jamie I; Perozo, Eduardo; Allen, Toby W

    2017-10-01

    The human ether-a-go-go-related gene (hERG) K + channel is of great medical and pharmaceutical relevance. Inherited mutations in hERG result in congenital long-QT syndrome which is associated with a markedly increased risk of cardiac arrhythmia and sudden death. hERG K + channels are also remarkably susceptible to block by a wide range of drugs, which in turn can cause drug-induced long-QT syndrome and an increased risk of sudden death. The recent determination of the near-atomic resolution structure of the hERG K + channel, using single-particle cryo-electron microscopy (cryo-EM), provides tremendous insights into how these channels work. It also suggests a way forward in our quest to understand why these channels are so promiscuous with respect to drug binding. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Influence of musical groove on postural sway.

    Science.gov (United States)

    Ross, Jessica M; Warlaumont, Anne S; Abney, Drew H; Rigoli, Lillian M; Balasubramaniam, Ramesh

    2016-03-01

    Timescales of postural fluctuation reflect underlying neuromuscular processes in balance control that are influenced by sensory information and the performance of concurrent cognitive and motor tasks. An open question is how postural fluctuations entrain to complex environmental rhythms, such as in music, which also vary on multiple timescales. Musical groove describes the property of music that encourages auditory-motor synchronization and is used to study voluntary motor entrainment to rhythmic sounds. The influence of groove on balance control mechanisms remains unexplored. We recorded fluctuations in center of pressure (CoP) of standing participants (N = 40) listening to low and high groove music and during quiet stance. We found an effect of musical groove on radial sway variability, with the least amount of variability in the high groove condition. In addition, we observed that groove influenced postural sway entrainment at various temporal scales. For example, with increasing levels of groove, we observed more entrainment to shorter, local timescale rhythmic musical occurrences. In contrast, we observed more entrainment to longer, global timescale features of the music, such as periodicity, with decreasing levels of groove. Finally, musical experience influenced the amount of postural variability and entrainment at local and global timescales. We conclude that groove in music and musical experience can influence the neural mechanisms that govern balance control, and discuss implications of our findings in terms of multiscale sensorimotor coupling. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  7. Spectroscopic study of drug-binding characteristics of unmodified and pNPA-based acetylated human serum albumin: Does esterase activity affect microenvironment of drug binding sites on the protein?

    Energy Technology Data Exchange (ETDEWEB)

    Moradi, Nastaran [Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah (Iran, Islamic Republic of); Faculty of Pharmaceutical Sciences, Kermanshah University of Medical Sciences, Kermanshah (Iran, Islamic Republic of); Ashrafi-Kooshk, Mohammad Reza [Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah (Iran, Islamic Republic of); Ghobadi, Sirous [Department of Biology, Faculty of Sciences, Razi University, Kermanshah (Iran, Islamic Republic of); Shahlaei, Mohsen [Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah (Iran, Islamic Republic of); Faculty of Pharmaceutical Sciences, Kermanshah University of Medical Sciences, Kermanshah (Iran, Islamic Republic of); Khodarahmi, Reza, E-mail: rkhodarahmi@mbrc.ac.ir [Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah (Iran, Islamic Republic of); Faculty of Pharmaceutical Sciences, Kermanshah University of Medical Sciences, Kermanshah (Iran, Islamic Republic of)

    2015-04-15

    Human serum albumin (HSA) is the most prominent extracellular protein in blood plasma. There are several binding sites on the protein which provide accommodation for structurally-unrelated endogenous and exogenous ligands and a wide variety of drugs. “Esterase-like” activity (hydrolysis of p-nitrophenyl esters) by the protein has been also reported. In the current study, we set out to investigate the interaction of indomethacin and ibuprofen with the unmodified and modified HSA (pNPA-modified HSA) using various spectroscopic techniques. Fluorescence data showed that 1:1 binding of drug to HSA is associated with quenching of the protein intrinsic fluorescence. Decrease of protein surface hydrophobicity (PSH), alteration in drug binding affinity and change of the protein stability, after esterase-like activity and permanent acetylation of HSA, were also documented. Analysis of the quenching and thermodynamic parameters indicated that forces involved in drug–HSA interactions change upon the protein modification. - Highlights: • Binding propensity of indomethacin extremely decreased upon the protein acetylation. • There is no ibuprofen binding after protein acetylation. • Protein stability changes upon drug binding as well as protein acetylation. • Drug pharmacokinetics may be influenced under co-administration of HSA-modifier drugs.

  8. Spectroscopic study of drug-binding characteristics of unmodified and pNPA-based acetylated human serum albumin: Does esterase activity affect microenvironment of drug binding sites on the protein?

    International Nuclear Information System (INIS)

    Moradi, Nastaran; Ashrafi-Kooshk, Mohammad Reza; Ghobadi, Sirous; Shahlaei, Mohsen; Khodarahmi, Reza

    2015-01-01

    Human serum albumin (HSA) is the most prominent extracellular protein in blood plasma. There are several binding sites on the protein which provide accommodation for structurally-unrelated endogenous and exogenous ligands and a wide variety of drugs. “Esterase-like” activity (hydrolysis of p-nitrophenyl esters) by the protein has been also reported. In the current study, we set out to investigate the interaction of indomethacin and ibuprofen with the unmodified and modified HSA (pNPA-modified HSA) using various spectroscopic techniques. Fluorescence data showed that 1:1 binding of drug to HSA is associated with quenching of the protein intrinsic fluorescence. Decrease of protein surface hydrophobicity (PSH), alteration in drug binding affinity and change of the protein stability, after esterase-like activity and permanent acetylation of HSA, were also documented. Analysis of the quenching and thermodynamic parameters indicated that forces involved in drug–HSA interactions change upon the protein modification. - Highlights: • Binding propensity of indomethacin extremely decreased upon the protein acetylation. • There is no ibuprofen binding after protein acetylation. • Protein stability changes upon drug binding as well as protein acetylation. • Drug pharmacokinetics may be influenced under co-administration of HSA-modifier drugs

  9. A single acidic residue can guide binding site selection but does not govern QacR cationic-drug affinity.

    Directory of Open Access Journals (Sweden)

    Kate M Peters

    Full Text Available Structures of the multidrug-binding repressor protein QacR with monovalent and bivalent cationic drugs revealed that the carboxylate side-chains of E90 and E120 were proximal to the positively charged nitrogens of the ligands ethidium, malachite green and rhodamine 6G, and therefore may contribute to drug neutralization and binding affinity. Here, we report structural, biochemical and in vivo effects of substituting these glutamate residues. Unexpectedly, substitutions had little impact on ligand affinity or in vivo induction capabilities. Structures of QacR(E90Q and QacR(E120Q with ethidium or malachite green took similar global conformations that differed significantly from all previously described QacR-drug complexes but still prohibited binding to cognate DNA. Strikingly, the QacR(E90Q-rhodamine 6G complex revealed two mutually exclusive rhodamine 6G binding sites. Despite multiple structural changes, all drug binding was essentially isoenergetic. Thus, these data strongly suggest that rather than contributing significantly to ligand binding affinity, the role of acidic residues lining the QacR multidrug-binding pocket is primarily to attract and guide cationic drugs to the "best available" positions within the pocket that elicit QacR induction.

  10. Effects of dopaminergic drug treatments on in vivo radioligand binding to brain vesicular monoamine transporters

    Energy Technology Data Exchange (ETDEWEB)

    Kilbourn, Michael R; Frey, Kirk A; Vander Borght, Thierry; Sherman, Phillip S

    1996-05-01

    The effects of various dopaminergic drug treatments on the in vivo regional brain distribution of high-affinity radioligands ([{sup 11}C]dihydrotetrabenazine and [{sup 11}C]methoxytetrabenazine) for the rat brain vesicular monoamine transporter (VMAT2) were determined. Acute treatments with reserpine (2 mg/kg i.p.), tetrabenazine (10 mg/kg i.v.) or related benzoisoquinolines significantly reduced radiotracer binding in vivo. In contrast, radiotracer distributions remained unchanged after treatments with other dopaminergic drugs, whether given by single injection (haloperidol, 1 mg/kg i.p., pargyline 80 mg/kg), repeatedly (pargyline, 80 mg/kg s.c., 14 days), or by continuous infusion (deprenyl, 10 mg/kg/day, 5 days; L-DOPA methyl ester 100 mg/kg/day, 5 days). Repeated injections of tetrabenazine (5 mg/kg i.p., twice daily, 3 days) did not alter in vivo radioligand binding measured after allowing drug washout from the brain. These studies support the proposal that in vivo PET imaging of VMAT2 radioligands in patients with extrapyramidal movement disorders will not be affected by concurrent use of L-DOPA or deprenyl.

  11. Liposomal Tumor Targeting in Drug Delivery Utilizing MMP-2- and MMP-9-Binding Ligands

    Directory of Open Access Journals (Sweden)

    Oula Penate Medina

    2011-01-01

    Full Text Available Nanotechnology offers an alternative to conventional treatment options by enabling different drug delivery and controlled-release delivery strategies. Liposomes being especially biodegradable and in most cases essentially nontoxic offer a versatile platform for several different delivery approaches that can potentially enhance the delivery and targeting of therapies to tumors. Liposomes penetrate tumors spontaneously as a result of fenestrated blood vessels within tumors, leading to known enhanced permeability and subsequent drug retention effects. In addition, liposomes can be used to carry radioactive moieties, such as radiotracers, which can be bound at multiple locations within liposomes, making them attractive carriers for molecular imaging applications. Phage display is a technique that can deliver various high-affinity and selectivity peptides to different targets. In this study, gelatinase-binding peptides, found by phage display, were attached to liposomes by covalent peptide-PEG-PE anchor creating a targeted drug delivery vehicle. Gelatinases as extracellular targets for tumor targeting offer a viable alternative for tumor targeting. Our findings show that targeted drug delivery is more efficient than non-targeted drug delivery.

  12. Structures of BmrR-Drug Complexes Reveal a Rigid Multidrug Binding Pocket And Transcription Activation Through Tyrosine Expulsion

    Energy Technology Data Exchange (ETDEWEB)

    Newberry, K.J.; Huffman, J.L.; Miller, M.C.; Vazquez-Laslop, N.; Neyfakh, A.A.; Brennan, R.G.

    2009-05-22

    BmrR is a member of the MerR family and a multidrug binding transcription factor that up-regulates the expression of the bmr multidrug efflux transporter gene in response to myriad lipophilic cationic compounds. The structural mechanism by which BmrR binds these chemically and structurally different drugs and subsequently activates transcription is poorly understood. Here, we describe the crystal structures of BmrR bound to rhodamine 6G (R6G) or berberine (Ber) and cognate DNA. These structures reveal each drug stacks against multiple aromatic residues with their positive charges most proximal to the carboxylate group of Glu-253 and that, unlike other multidrug binding pockets, that of BmrR is rigid. Substitution of Glu-253 with either alanine (E253A) or glutamine (E253Q) results in unpredictable binding affinities for R6G, Ber, and tetraphenylphosphonium. Moreover, these drug binding studies reveal that the negative charge of Glu-253 is not important for high affinity binding to Ber and tetraphenylphosphonium but plays a more significant, but unpredictable, role in R6G binding. In vitro transcription data show that E253A and E253Q are constitutively active, and structures of the drug-free E253A-DNA and E253Q-DNA complexes support a transcription activation mechanism requiring the expulsion of Tyr-152 from the multidrug binding pocket. In sum, these data delineate the mechanism by which BmrR binds lipophilic, monovalent cationic compounds and suggest the importance of the redundant negative electrostatic nature of this rigid drug binding pocket that can be used to discriminate against molecules that are not substrates of the Bmr multidrug efflux pump.

  13. Thermal Bridge Effects in Window Grooves

    DEFF Research Database (Denmark)

    Rose, Jørgen

    1997-01-01

    In this report thermal bridge effects in window grooves are analyzed. The analysis is performed using different thicknesses of the window groove insulation, to evaluate what the optimal solution is.All analysis in the report is performed using both 2- and 3-dimensional numerical analysis....

  14. Mixed convection in a baffled grooved channel

    Indian Academy of Sciences (India)

    MS received 16 May 2014; revised 19 October 2014; accepted 06 November 2014. Abstract. In the present numerical work, flow structure and heat transfer charac- teristics are investigated in a baffled grooved channel, differentially heated from the sides. The baffle is placed vertically downward from the top wall of grooved ...

  15. Spiral groove seal. [for rotating shaft

    Science.gov (United States)

    Ludwig, L. P.; Strom, T. N. (Inventor)

    1974-01-01

    Mating flat surfaces inhibit leakage of a fluid around a stationary shaft. A spiral groove produces a pumping action toward the fluid when the shaft rotates. This prevents leakage while a generated hydraulic lifting force separates the mating surfaces to minimize wear. Provision is made for placing these spiral grooves in communication with the fluid to accelerate the generation of the hydraulic lifting force.

  16. Dielectric image line groove antennas for millimeterwaves

    Science.gov (United States)

    Solbach, K.; Wolff, I.

    Grooves in the ground plane of dielectric image lines are proposed as a new radiating structure. A figure is included showing the proposed groove structure as a discontinuity in a dielectric image line. A wave incident on the dielectric image line is partly reflected by the discontinuity, partly transmitted across the groove, and partly radiated into space above the line. In a travelling-wave antenna, a number of grooves are arranged below a dielectric guide, with spacings around one guide wavelength to produce a beam in the upper half space. A prescribed aperture distribution can be effected by tapering the series radiation resistance of the grooves. This can be done by adjusting the depths of the grooves with a constant width or by varying the widths of the grooves with a constant depth. Attention is also given to circular grooves. Here, the widths of the holes are chosen so that they can be considered as waveguides operating far below the cut-off frequency of the fundamental circular waveguide mode.

  17. Rapid Phospho-Turnover by Receptor Tyrosine Kinases Impacts Downstream Signaling and Drug Binding

    OpenAIRE

    Kleiman, Laura B.; Maiwald, Thomas; Conzelmann, Holger; Lauffenburger, Douglas A.; Sorger, Peter K.

    2011-01-01

    Epidermal growth factor receptors (ErbB1–4) are oncogenic receptor tyrosine kinases (RTKs) that regulate diverse cellular processes. In this study, we combine measurement and mathematical modeling to quantify phospho-turnover at ErbB receptors in human cells and to determine the consequences for signaling and drug binding. We find that phosphotyrosine residues on ErbB1 have half-lives of a few seconds and therefore turn over 100–1000 times in the course of a typical immediate-early response t...

  18. Microcirculation within Grooved Substrates regulates Cell Positioning and Cell Docking inside Microfluidic Channels

    Science.gov (United States)

    Manbachi, Amir; Shrivastava, Shamit; Cioffi, Margherita; Chung, Bong Geun; Moretti, Matteo; Demirci, Utkan; Yliperttula, Marjo; Khademhosseini, Ali

    2009-01-01

    Immobilization of cells inside microfluidic devices is a promising approach for enabling studies related to drug screening and cell biology. Despite extensive studies in using grooved substrates for immobilizing cells inside channels, a systematic study of the effects of various parameters that influence cell docking and retention within grooved substrates has not been performed. We demonstrate using computational simulations that the fluid dynamic environment within microgrooves significantly varies with groove width, generating micro-circulation areas in smaller microgrooves. Wall shear stress simulation predicted that shear stresses were in opposite direction in smaller grooves (25 and 50 μm wide) in comparison to those in wider grooves (75 and 100 μm wide). To validate the simulations, cells were seeded within microfluidic devices, where microgrooves of different widths were aligned perpendicularly to the direction of the flow. Experimental results showed that, as predicted, the inversion of the local direction of shear stress within the smaller grooves resulted in alignment of cells on two opposite sides of the grooves under the same flow conditions. Also, the amplitude of shear stress within microgrooved channels significantly influenced cell retainment in the channels. Therefore, our studies suggest that microscale shear stresses greatly influence cellular docking, immobilization, and retention in fluidic systems and should be considered for the design of cell-based microdevices. PMID:18432345

  19. The investigation of groove geometry effect on heat transfer for internally grooved tubes

    International Nuclear Information System (INIS)

    Bilen, Kadir; Cetin, Murat; Gul, Hasan; Balta, Tuba

    2009-01-01

    An experimental study of surface heat transfer and friction characteristics of a fully developed turbulent air flow in different grooved tubes is reported. Tests were performed for Reynolds number range 10,000-38,000 and for different geometric groove shapes (circular, trapezoidal and rectangular). The ratio of tube length-to-diameter is 33. Among the grooved tubes, heat transfer enhancement is obtained up to 63% for circular groove, 58% for trapezoidal groove and 47% for rectangular groove, in comparison with the smooth tube at the highest Reynolds number (Re = 38,000). Correlations of heat transfer and friction coefficient were obtained for different grooved tubes. In evaluation of thermal performance, it is seen that the grooved tubes are thermodynamically advantageous (Ns, a < 1) up to Re = 30,000 for circular and trapezoidal grooves and up to Re = 28,000 for rectangular grooves. It is observed that there is an optimum value of the entropy generation number at about Re = 17,000 for all investigated grooves

  20. Selective pharmacological modulation of renal peripheral-type benzodiazepine binding by treatment with diuretic drugs

    International Nuclear Information System (INIS)

    Lukeman, D.S.; Vaughn, D.A.; Fanestil, D.D.

    1988-01-01

    The authors have assessed the effects of in vivo administration of different classes of diuretic drugs on the expression of the peripheral-type benzodiazepine binding site (PBBS) in crude membranes derived from the cortex and outer medulla of rat kidney by saturation analysis with the PBBS-selective ligands [ 3 H]RO5-4864 and [ 3 H]PH 11195 in cortex and [ 3 H]RO5-4864 in outer medulla. Administration for 14-15 days of furosemide, a drug that blocks NaCl-KCl coupled transport in the thick ascending limb of the loop of Henle, produced a significant doubling in the PBBS density (B/sub max/) in outer medulla, a region of the kidney rich in thick ascending limbs, and produced a lesser but significant increase in PBBS density in the cortex. Conversely, administration for 14-15 days of the carbonic anhydrase inhibitor acetazolamide, which acts predominantly in the proximal tubule, and hydrochlorothiazide, which acts predominantly in the early distal tubule, elicited statistically significant increases in PBBS density in renal cortex but not in renal outer medulla. Furthermore, all drug treatments were without effect on the equilibrium dissociation constants (K/sub d/s) of [ 3 H]RO5-4864 and [ 3 H]PK 11195 binding to cortical and outer medullary membrane preparations. These findings demonstrate that the PBBS can be selectively up-regulated in different regions of the kidney by diuretic drugs with different modes/sites of action. 50 references, 1 table

  1. Alignment-independent comparison of binding sites based on DrugScore potential fields encoded by 3D Zernike descriptors.

    Science.gov (United States)

    Nisius, Britta; Gohlke, Holger

    2012-09-24

    Analyzing protein binding sites provides detailed insights into the biological processes proteins are involved in, e.g., into drug-target interactions, and so is of crucial importance in drug discovery. Herein, we present novel alignment-independent binding site descriptors based on DrugScore potential fields. The potential fields are transformed to a set of information-rich descriptors using a series expansion in 3D Zernike polynomials. The resulting Zernike descriptors show a promising performance in detecting similarities among proteins with low pairwise sequence identities that bind identical ligands, as well as within subfamilies of one target class. Furthermore, the Zernike descriptors are robust against structural variations among protein binding sites. Finally, the Zernike descriptors show a high data compression power, and computing similarities between binding sites based on these descriptors is highly efficient. Consequently, the Zernike descriptors are a useful tool for computational binding site analysis, e.g., to predict the function of novel proteins, off-targets for drug candidates, or novel targets for known drugs.

  2. Crystal structure of equine serum albumin in complex with cetirizine reveals a novel drug-binding site

    OpenAIRE

    Handing, Katarzyna B.; Shabalin, Ivan G.; Szlachta, Karol; Majorek, Karolina A.; Minor, Wladek

    2016-01-01

    Serum albumin (SA) is the main transporter of drugs in mammalian blood plasma. Here, we report the first crystal structure of equine serum albumin (ESA) in complex with antihistamine drug cetirizine at a resolution of 2.1 ?. Cetirizine is bound in two sites ? a novel drug binding site (CBS1) and the fatty acid binding site 6 (CBS2). Both sites differ from those that have been proposed in multiple reports based on equilibrium dialysis and fluorescence studies for mammalian albumins as cetirizi...

  3. Binding Mode and Induced Fit Predictions for Prospective Computational Drug Design.

    Science.gov (United States)

    Grebner, Christoph; Iegre, Jessica; Ulander, Johan; Edman, Karl; Hogner, Anders; Tyrchan, Christian

    2016-04-25

    Computer-aided drug design plays an important role in medicinal chemistry to obtain insights into molecular mechanisms and to prioritize design strategies. Although significant improvement has been made in structure based design, it still remains a key challenge to accurately model and predict induced fit mechanisms. Most of the current available techniques either do not provide sufficient protein conformational sampling or are too computationally demanding to fit an industrial setting. The current study presents a systematic and exhaustive investigation of predicting binding modes for a range of systems using PELE (Protein Energy Landscape Exploration), an efficient and fast protein-ligand sampling algorithm. The systems analyzed (cytochrome P, kinase, protease, and nuclear hormone receptor) exhibit different complexities of ligand induced fit mechanisms and protein dynamics. The results are compared with results from classical molecular dynamics simulations and (induced fit) docking. This study shows that ligand induced side chain rearrangements and smaller to medium backbone movements are captured well in PELE. Large secondary structure rearrangements, however, remain challenging for all employed techniques. Relevant binding modes (ligand heavy atom RMSD PELE method within a few hours of simulation, positioning PELE as a tool applicable for rapid drug design cycles.

  4. Rapid phospho-turnover by receptor tyrosine kinases impacts downstream signaling and drug binding.

    Science.gov (United States)

    Kleiman, Laura B; Maiwald, Thomas; Conzelmann, Holger; Lauffenburger, Douglas A; Sorger, Peter K

    2011-09-02

    Epidermal growth factor receptors (ErbB1-4) are oncogenic receptor tyrosine kinases (RTKs) that regulate diverse cellular processes. In this study, we combine measurement and mathematical modeling to quantify phospho-turnover at ErbB receptors in human cells and to determine the consequences for signaling and drug binding. We find that phosphotyrosine residues on ErbB1 have half-lives of a few seconds and therefore turn over 100-1000 times in the course of a typical immediate-early response to ligand. Rapid phospho-turnover is also observed for EGF-activated ErbB2 and ErbB3, unrelated RTKs, and multiple intracellular adaptor proteins and signaling kinases. Thus, the complexes formed on the cytoplasmic tail of active receptors and the downstream signaling kinases they control are highly dynamic and antagonized by potent phosphatases. We develop a kinetic scheme for binding of anti-ErbB1 drugs to receptors and show that rapid phospho-turnover significantly impacts their mechanisms of action. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. DNA-binding studies of valrubicin as a chemotherapy drug using spectroscopy and electrochemical techniques

    Directory of Open Access Journals (Sweden)

    Reza Hajian

    2017-06-01

    Full Text Available In this study, the molecular interactions between valrubicin, an anticancer drug, and fish sperm DNA have been studied in phosphate buffer solution (pH 7.4 using UV–Vis spectrophotometry and cyclic voltammetry techniques. Valrubicin intercalated into double stranded DNA under a weak displacement reaction with methylene blue (MB molecule in a competitive reaction. The binding constant (kb of valrubicin-DNA was determined as 1.75×103 L/mol by spectrophotometric titration. The value of non-electrostatic binding constant (kt0 was almost constant at different ionic strengths while the ratio of kt0/kb increased from 4.51% to 23.77%. These results indicate that valrubicin binds to ds-DNA via electrostatic and intercalation modes. Thermodynamic parameters including ΔH0, ΔS0 and ΔG0 for valrubicin-DNA interaction were determined as −25.21×103 kJ/mol, 1.55×102 kJ/mol K and −22.03 kJ/mol, respectively. Cyclic voltammetry study shows a pair of redox peaks for valrubicin at 0.45 V and 0.36 V (vs. Ag/AgCl. The peak currents decreased and peak positions shifted to positive direction in the presence of DNA, showing intercalation mechanism due to the variation in formal potential.

  6. In vitro membrane binding and protein binding (IAM MB/PB technology to estimate in vivo distribution: applications in early drug discovery

    Directory of Open Access Journals (Sweden)

    Klara Livia Valko

    2017-03-01

    Full Text Available The drug discovery process can be accelerated by chromatographic profiling of the analogs to model in vivo distribution and the major non-specific binding. A balanced potency and chromatographically determined membrane and protein binding (IAM MB/PB data enable selecting drug discovery compounds for further analysis that have the highest probability to show the desired in vivo distribution behavior for efficacy and reduced chance for toxicity. Although the basic principles of the technology have already appeared in numerous publications, the lack of standardized procedures limited its widespread applications especially in academia and small drug discovery biotech companies. In this paper, the standardized procedures are described that has been trademarked as Regis IAM MB/PB Technology®. Comparison between the Drug Efficiency Index (DEI=pIC50-logVdu+2 and generally used Ligand Lipophilicity Efficiency (LLE has been made, demonstrating the advantage of measured IAM and HSA binding over calculated log P. The power of the proposed chromatographic technology is demonstrated using the data of marketed drugs.

  7. Catalytic transitions in the human MDR1 P-glycoprotein drug binding sites.

    Science.gov (United States)

    Wise, John G

    2012-06-26

    Multidrug resistance proteins that belong to the ATP-binding cassette family like the human P-glycoprotein (ABCB1 or Pgp) are responsible for many failed cancer and antiviral chemotherapies because these membrane transporters remove the chemotherapeutics from the targeted cells. Understanding the details of the catalytic mechanism of Pgp is therefore critical to the development of inhibitors that might overcome these resistances. In this work, targeted molecular dynamics techniques were used to elucidate catalytically relevant structures of Pgp. Crystal structures of homologues in four different conformations were used as intermediate targets in the dynamics simulations. Transitions from conformations that were wide open to the cytoplasm to transition state conformations that were wide open to the extracellular space were studied. Twenty-six nonredundant transitional protein structures were identified from these targeted molecular dynamics simulations using evolutionary structure analyses. Coupled movement of nucleotide binding domains (NBDs) and transmembrane domains (TMDs) that form the drug binding cavities were observed. Pronounced twisting of the NBDs as they approached each other as well as the quantification of a dramatic opening of the TMDs to the extracellular space as the ATP hydrolysis transition state was reached were observed. Docking interactions of 21 known transport ligands or inhibitors were analyzed with each of the 26 transitional structures. Many of the docking results obtained here were validated by previously published biochemical determinations. As the ATP hydrolysis transition state was approached, drug docking in the extracellular half of the transmembrane domains seemed to be destabilized as transport ligand exit gates opened to the extracellular space.

  8. Drug binding and mobility relating to the thermal fluctuation in fluid lipid membranes

    Science.gov (United States)

    Okamura, Emiko; Yoshii, Noriyuki

    2008-12-01

    Drug binding and mobility in fluid lipid bilayer membranes are quantified in situ by using the multinuclear solution NMR combined with the pulsed-field-gradient technique. One-dimensional and pulsed-field-gradient F19 and H1 NMR signals of an anticancer drug, 5-fluorouracil (5FU) are analyzed at 283-313 K in the presence of large unilamellar vesicles (LUVs) of egg phosphatidylcholine (EPC) as model cell membranes. The simultaneous observation of the membrane-bound and free 5FU signals enables to quantify in what amount of 5FU is bound to the membrane and how fast 5FU is moving within the membrane in relation to the thermal fluctuation of the soft, fluid environment. It is shown that the mobility of membrane-bound 5FU is slowed down by almost two orders of magnitude and similar to the lipid movement in the membrane, the movement closely related to the intramembrane fluidity. The mobility of 5FU and EPC is, however, not similar at 313 K; the 5FU movement is enhanced in the membrane as a result of the loose binding of 5FU in the lipid matrices. The membrane-bound fraction of 5FU is ˜0.1 and almost unaltered over the temperature range examined. It is also independent of the 5FU concentration from 2 to 30 mM with respect to the 40-50 mM LUV. The free energy of the 5FU binding is estimated at -4 to -2 kJ/mol, the magnitude always close to the thermal fluctuation, 2.4-2.6 kJ/mol.

  9. Effect of bioceramic functional groups on drug binding and release kinetics

    Science.gov (United States)

    Trujillo, Christopher

    Bioceramics have been studied extensively as drug delivery systems (DDS). Those studies have aimed to tailor the drug binding and release kinetics to successfully treat infections and other diseases. This research suggests that the drug binding and release kinetics are predominantly driven by the functional groups available on the surface of a bioceramic. The goal of the present study is to explain the role of silicate and phosphate functional groups in drug binding to and release kinetics from bioceramics. alpha-cristobalite (Cris; SiO2) particles (90-150 microm) were prepared and doped with 0 microg (P-0), 39.1 microg (P-39.1), 78.2 microg (P-78.2), 165.5 microg (P-165.5) or 331 microg (P-331) of P 2O5 per gram Cris, using 85% orthophosphoric (H3PO 4) acid and thermal treatment. The material structure was analyzed using X-ray diffraction (XRD) with Rietveld Refinement and Fourier Transform Infrared (FTIR) spectroscopy with Gaussian fitting. XRD demonstrated an increase from sample P-0 (170.5373 A3) to P-331 (170.6466 A 3) in the unit cell volume as the P2O5 concentration increased in the material confirming phosphate silicate substitution in Cris. Moreover, FTIR showed the characteristic bands of phosphate functional groups of nu4 PO4/O-P-O bending, P-O-P stretching, P-O-P bending, P=O stretching, and P-O-H bending in doped Cris indicating phosphate incorporation in the silicate structure. Furthermore, FTIR showed that the nu4 PO4/O-P-O bending band around 557.6 cm-1 and P=O stretching band around 1343.9 cm-1 increased in area for samples P-39.1 to P-331 from 3.5 to 10.5 and from 10.1 to 22.4, respectively due to phosphate doping. In conjunction with the increase of the nu4 PO4/O-P-O bending band and P=O stretching band, a decrease in area of the O-Si-O bending bands around 488.1 and 629.8 cm-1 was noticed for samples P-39.1 to P-331 from 5 to 2 and from 11.8 to 5.4, respectively. Furthermore, Cris samples (200 mg, n=5 for each sample) were immersed separately in

  10. Effect of anticonvulsant drugs on (/sup 35/S)t-butylbicyclophosphorothionate binding in vitro and ex vivo

    Energy Technology Data Exchange (ETDEWEB)

    Pitkaenen, A.; Riekkinen, P.J.; Saano, V.; Tuomisto, L.

    1987-01-01

    Using several concentrations of eight anticonvulsant drugs in clinical use (carbamazepine, clonazepam, phenytoin, phenobarbital, ethosuximide, primidone, sodium valproate, and D,L-..gamma..-vinyl GABA), we studied their abilities in vitro to displace (/sup 35/S)t-butylbicyclophosphorothionate (/sup 35/S-TBPS) from its binding site in a homogenate of rat brain. Thereafter ethosuximide (150 mg/kg), phenobarbital (30 mg/kg), clonazepam (0.3 mg/kg), or phenytoin (100 mg/kg) was injected intraperitoneally into rats for 16-20 days; and the effect of drug administration on /sup 35/S-TBPS binding was studied in the cortex and hippocampus ex vivo. Phenobarbital (100 ..mu..M, P<0.001), ethosuximide (500 ..mu..M, P<0.001), and phenytoin (40 ..mu..M, P<0.001) decreased the specific /sup 35/S-TBPS binding in vitro by 10-16%. After drug administration of phenobarbital (concentration in plasma 168 ..mu..M), the number of binding sites decreased and the binding affinity (p<0.05) in the cortex increased. Other anticonvulsants did not modulate /sup 35/S-TBPS binding in vitro at the concentration analogous to therapeutic plasma levels or ex vivo at the dose used. These results suggest that the use of phenobarbital may modulate the TBPS binding site, but the role of the present findings in the anticonvulsant action of phenobarbital needs to be further studied.

  11. Time-dependent recovery of in vivo binding sites after drug dosing: A method for radiotracer evaluation

    International Nuclear Information System (INIS)

    Kilbourn, Michael R.

    1997-01-01

    The recovery of in vivo binding sites for (±)-α-[ 11 C]methoxytetrabenazine, a radioligand for the monoamine vesicular transporter (VMAT2), was determined in mouse brain at various times following a pharmacological dose of tetrabenazine. Concentrations of in vivo radioligand binding sites progressively increased and had reached control values by 8.5 h, and this recovery was consistent with the pharmacokinetics of the competing drug tetrabenazine and its active metabolite, dihydrotetrabenazine. This study demonstrates a simple experimental protocol of using a single dose of a reversible competing drug and time-dependent measurements of in vivo binding of a radioligand. This protocol is suitable for testing the sensitivity of an in vivo radiotracer for measurement of varying concentrations of in vivo binding sites

  12. Resistance Patterns Associated with HCV NS5A Inhibitors Provide Limited Insight into Drug Binding

    Directory of Open Access Journals (Sweden)

    Moheshwarnath Issur

    2014-11-01

    Full Text Available Direct-acting antivirals (DAAs have significantly improved the treatment of infection with the hepatitis C virus. A promising class of novel antiviral agents targets the HCV NS5A protein. The high potency and broad genotypic coverage are favorable properties. NS5A inhibitors are currently assessed in advanced clinical trials in combination with viral polymerase inhibitors and/or viral protease inhibitors. However, the clinical use of NS5A inhibitors is also associated with new challenges. HCV variants with decreased susceptibility to these drugs can emerge and compromise therapy. In this review, we discuss resistance patterns in NS5A with focus prevalence and implications for inhibitor binding.

  13. Mouse ATP-Binding Cassette (ABC) Transporters Conferring Multi-Drug Resistance

    Science.gov (United States)

    Shuaizhang, L I; Zhang, Wen; Yin, Xuejiao; Xing, Shilai; Xie, Qunhui; Cao, Zhengyu; Zhao, Bin

    2015-04-28

    The ABC (ATP-binding cassette) transporter is one of the largest and most ancient protein families with members functioning from protozoa to human. The resistance of cancer and tumor cells to anticancer drugs is due to the over-expression of some ABC transporters, which may finally lead to chemotherapy failure. The mouse ABC transporters are classified into seven subfamilies by phylogenetic analysis. The mouse ABC transporter gene, alias, chromosomal location and function have been determined. Within the ABC super-family, the MDR transporters (Abcb1, Abcc1, Abcg2) in mouse models have been proved to be valuable to investigate the biochemistry and physiological functions. This review concentrates on the multidrug resistance of mouse ABC transporters in cancer and tumor cells.

  14. Experimental Studies on Grooved Double Pipe Heat Exchanger with Different Groove Space

    Science.gov (United States)

    Sunu, P. W.; Arsawan, I. M.; Anakottapary, D. S.; Santosa, I. D. M. C.; Yasa, I. K. A.

    2018-01-01

    Experimental studies were performed on grooved double pipe heat exchanger (DPHE) with different groove space. The objective of this work is to determine optimal heat transfer parameter especially logarithmic mean temperature difference (LMTD). The document in this paper also provides the total heat observed by the cold fluid. The rectangular grooves were incised on outer surface of tube side with circumferential pattern and two different grooves space, namely 1 mm and 2 mm. The distance between grooves and the grooves high were kept constant, 8 mm and 0.3 mm respectively. The tube diameter is 20 mm and its made of aluminium. The shell is made of acrylic which has 28 mm in diameter. Water is used as the working fluid. Using counter flow scheme, the cold fluid flows in the annulus room of DPHE. The volume flowrate of hot fluid remains constant at 15 lpm. The volume flowrate of cold fluid were varied from 11 lpm to 15 lpm. Based on logarithmic mean temperature difference analysis, the LMTD of 1 mm grooves space was higher compared to that of 2 mm grooves space. The smaller grooves space has more advantage since the recirculating region are increased which essentially cause larger heat transfer enhancement.

  15. Binding of the neuroleptic drug, gabapentin, to bovine serum albumin: Insights from experimental and computational studies

    International Nuclear Information System (INIS)

    Jalali, Fahimeh; Dorraji, Parisa S.; Mahdiuni, Hamid

    2014-01-01

    The interaction between antiepileptic drug, gabapentin (GP), and bovin serum albumin (BSA) was studied by spectroscopic and computational methods. The native fluorescence of BSA was quenched by GP. Stern–Volmer quenching constant was calculated at different temperatures which suggested a static mechanism. The association constant (K a ) was calculated from fluorescence quenching studies, which increased with temperature rising. GP competed well with warfarine for hydrophobic subdomain IIA (Sudlow's site I) on the protein. Enthalpy and entropy changes during the interaction of GP with BSA were obtained using van't Hoff plot, which showed an entropy-driven process and involvement of hydrophobic forces (ΔH>0 and ΔS>0). Synchronous fluorescence measurements of BSA solution in the presence of GP showed a considerable blue shift when Δλ=15 nm, therefore, GP interacts with tyrosine-rich sites on BSA. Optimized docked model of BSA–GP mixture confirmed the experimental results. -- Highlights: • Interaction of gabapentin and bovine serum albumin (BSA) is investigated by spectroscopic techniques. • Gabapentin can quench the fluorescence of BSA through a static quenching procedure. • The binding of gabapentin to BSA is driven mainly by hydrophobic interactions. • Subdomain IIA (Sudlow's site I) of BSA is found to be the main binding site for gabapentin. • Molecular docking modeling confirmed the experimental results

  16. Allosteric Binding in the Serotonin Transporter - Pharmacology, Structure, Function and Potential Use as a Novel Drug Target

    DEFF Research Database (Denmark)

    Loland, Claus J.; Sanchez, Connie; Plenge, Per

    2017-01-01

    The serotonin transporter (SERT) is an important drug target and the majority of currently used antidepressants are potent inhibitors of SERT, binding primarily to the substrate binding site. However, even though the existence of an allosteric modulator site was realized more than 30 years ago......, the research into this mechanism is still in its early days. The current knowledge about the allosteric site with respect to pharmacology, structure and function, and pharmacological tool compounds, is reviewed and a perspective is given on its potential as a drug target....

  17. Revealing kinetics and state-dependent binding properties of IKur-targeting drugs that maximize atrial fibrillation selectivity

    Science.gov (United States)

    Ellinwood, Nicholas; Dobrev, Dobromir; Morotti, Stefano; Grandi, Eleonora

    2017-09-01

    The KV1.5 potassium channel, which underlies the ultra-rapid delayed-rectifier current (IKur) and is predominantly expressed in atria vs. ventricles, has emerged as a promising target to treat atrial fibrillation (AF). However, while numerous KV1.5-selective compounds have been screened, characterized, and tested in various animal models of AF, evidence of antiarrhythmic efficacy in humans is still lacking. Moreover, current guidelines for pre-clinical assessment of candidate drugs heavily rely on steady-state concentration-response curves or IC50 values, which can overlook adverse cardiotoxic effects. We sought to investigate the effects of kinetics and state-dependent binding of IKur-targeting drugs on atrial electrophysiology in silico and reveal the ideal properties of IKur blockers that maximize anti-AF efficacy and minimize pro-arrhythmic risk. To this aim, we developed a new Markov model of IKur that describes KV1.5 gating based on experimental voltage-clamp data in atrial myocytes from patient right-atrial samples in normal sinus rhythm. We extended the IKur formulation to account for state-specificity and kinetics of KV1.5-drug interactions and incorporated it into our human atrial cell model. We simulated 1- and 3-Hz pacing protocols in drug-free conditions and with a [drug] equal to the IC50 value. The effects of binding and unbinding kinetics were determined by examining permutations of the forward (kon) and reverse (koff) binding rates to the closed, open, and inactivated states of the KV1.5 channel. We identified a subset of ideal drugs exhibiting anti-AF electrophysiological parameter changes at fast pacing rates (effective refractory period prolongation), while having little effect on normal sinus rhythm (limited action potential prolongation). Our results highlight that accurately accounting for channel interactions with drugs, including kinetics and state-dependent binding, is critical for developing safer and more effective pharmacological anti

  18. Mg2+ in the major groove modulates B-DNA structure and dynamics.

    Directory of Open Access Journals (Sweden)

    Marc Guéroult

    Full Text Available This study investigates the effect of Mg(2+ bound to the DNA major groove on DNA structure and dynamics. The analysis of a comprehensive dataset of B-DNA crystallographic structures shows that divalent cations are preferentially located in the DNA major groove where they interact with successive bases of (A/GpG and the phosphate group of 5'-CpA or TpG. Based on this knowledge, molecular dynamics simulations were carried out on a DNA oligomer without or with Mg(2+ close to an ApG step. These simulations showed that the hydrated Mg(2+ forms a stable intra-strand cross-link between the two purines in solution. ApG generates an electrostatic potential in the major groove that is particularly attractive for cations; its intrinsic conformation is well-adapted to the formation of water-mediated hydrogen bonds with Mg(2+. The binding of Mg(2+ modulates the behavior of the 5'-neighboring step by increasing the BII (ε-ζ>0° population of its phosphate group. Additional electrostatic interactions between the 5'-phosphate group and Mg(2+ strengthen both the DNA-cation binding and the BII character of the 5'-step. Cation binding in the major groove may therefore locally influence the DNA conformational landscape, suggesting a possible avenue for better understanding how strong DNA distortions can be stabilized in protein-DNA complexes.

  19. The pleuromutilin drugs tiamulin and valnemulin bind to the RNA at the peptidyl transferase centre on the ribosome

    DEFF Research Database (Denmark)

    Poulsen, S M; Karlsson, M; Johansson, L B

    2001-01-01

    The pleuromutilin antibiotic derivatives, tiamulin and valnemulin, inhibit protein synthesis by binding to the 50S ribosomal subunit of bacteria. The action and binding site of tiamulin and valnemulin was further characterized on Escherichia coli ribosomes. It was revealed that these drugs...... centre and have been associated with binding of several antibiotics. Competitive footprinting shows that tiamulin and valnemulin can bind concurrently with the macrolide erythromycin but compete with the macrolide carbomycin, which is a peptidyl transferase inhibitor. We infer from these and previous...... results that tiamulin and valnemulin interact with the rRNA in the peptidyl transferase slot on the ribosomes in which they prevent the correct positioning of the CCA-ends of tRNAs for peptide transfer....

  20. Fatty acid and drug binding to a low-affinity component of human serum albumin, purified by affinity chromatography

    DEFF Research Database (Denmark)

    Vorum, H; Pedersen, A O; Honoré, B

    1992-01-01

    Binding equilibria for decanoate to a defatted, commercially available human serum albumin preparation were investigated by dialysis exchange rate determinations. The binding isotherm could not be fitted by the general binding equation. It was necessary to assume that the preparation was a mixture...... of two albumin components about 40% of the albumin having high affinity and about 60% having low affinity. By affinity chromatography we succeeded in purifying the low-affinity component from the mixture. The high-affinity component, however, could not be isolated. We further analyzed the fatty acid...... and drug binding abilities of the low-affinity component. The fatty acids decanoate, laurate, myristate and palmitate were bound with higher affinity to the mixture than to the low-affinity component. Diazepam was bound with nearly the same affinity to the low-affinity component as to the albumin mixture...

  1. Local-scale stratigraphy of grooved terrain on Ganymede

    Science.gov (United States)

    Murchie, Scott L.; Head, James W.; Helfenstein, Paul; Plescia, Jeffrey B.

    1987-01-01

    The surface of the Jovian satellite, Ganymede, is divided into two main units, dark terrain cut by arcuate and subradial furrows, and light terrain consisting largely of areas with pervasive U-shaped grooves. The grooved terrain may be subdivided on the basis of pervasive morphology of groove domains into four terrain types: (1) elongate bands of parallel grooves (groove lanes); (2) polygonal domains of parallel grooves (grooved polygons); (3) polygonal domains of two orthogonal groove sets (reticulate terrain); and (4) polygons having two to several complexly cross-cutting groove sets (complex grooved terrain). Reticulate terrain is frequently dark and not extensively resurfaced, and grades to a more hummocky terrain type. The other three grooved terrain types have almost universally been resurfaced by light material during their emplacement. The sequence of events during grooved terrain emplacement has been investigated. An attempt is made to integrate observed geologic and tectonic patterns to better constrain the relative ages and styles of emplacement of grooved terrain types. A revised model of grooved terrain emplacement is proposed and is tested using detailed geologic mapping and measurement of crater density.

  2. Structural and functional analysis of cyclin D1 reveals p27 and substrate inhibitor binding requirements.

    Science.gov (United States)

    Liu, Shu; Bolger, Joshua K; Kirkland, Lindsay O; Premnath, Padmavathy N; McInnes, Campbell

    2010-12-17

    An alternative strategy for inhibition of the cyclin dependent kinases (CDKs) in antitumor drug discovery is afforded through the substrate recruitment site on the cyclin positive regulatory subunit. Critical CDK substrates such as the Rb and E2F families must undergo cyclin groove binding before phosphorylation, and hence inhibitors of this interaction also block substrate specific kinase activity. This approach offers the potential to generate highly selective and cell cycle specific CDK inhibitors and to reduce the inhibition of transcription mediated through CDK7 and 9, commonly observed with ATP competitive compounds. While highly potent peptide and small molecule inhibitors of CDK2/cyclin A, E substrate recruitment have been reported, little information has been generated on the determinants of inhibitor binding to the cyclin groove of the CDK4/cyclin D1 complex. CDK4/cyclin D is a validated anticancer drug target and continues to be widely pursued in the development of new therapeutics based on cell cycle blockade. We have therefore investigated the structural basis for peptide binding to its cyclin groove and have examined the features contributing to potency and selectivity of inhibitors. Peptidic inhibitors of CDK4/cyclin D of pRb phosphorylation have been synthesized, and their complexes with CDK4/cyclin D1 crystal structures have been generated. Based on available structural information, comparisons of the cyclin grooves of cyclin A2 and D1 are presented and provide insights into the determinants for peptide binding and the basis for differential binding and inhibition. In addition, a complex structure has been generated in order to model the interactions of the CDKI, p27(KIP)¹, with cyclin D1. This information has been used to shed light onto the endogenous inhibition of CDK4 and also to identify unique aspects of cyclin D1 that can be exploited in the design of cyclin groove based CDK inhibitors. Peptidic and nonpeptidic compounds have been

  3. Effect of Methamphetamine on Spectral Binding, Ligand Docking and Metabolism of Anti-HIV Drugs with CYP3A4

    Science.gov (United States)

    Ande, Anusha; Wang, Lei; Vaidya, Naveen K.; Li, Weihua; Kumar, Santosh; Kumar, Anil

    2016-01-01

    Cytochrome P450 3A4 (CYP3A4) is the major drug metabolic enzyme, and is involved in the metabolism of antiretroviral drugs, especially protease inhibitors (PIs). This study was undertaken to examine the effect of methamphetamine on the binding and metabolism of PIs with CYP3A4. We showed that methamphetamine exhibits a type I spectral change upon binding to CYP3A4 with δAmax and KD of 0.016±0.001 and 204±18 μM, respectively. Methamphetamine-CYP3A4 docking showed that methamphetamine binds to the heme of CYP3A4 in two modes, both leading to N-demethylation. We then studied the effect of methamphetamine binding on PIs with CYP3A4. Our results showed that methamphetamine alters spectral binding of nelfinavir but not the other type I PIs (lopinavir, atazanavir, tipranavir). The change in spectral binding for nelfinavir was observed at both δAmax (0.004±0.0003 vs. 0.0068±0.0001) and KD (1.42±0.36 vs.2.93±0.08 μM) levels. We further tested effect of methamphetamine on binding of 2 type II PIs; ritonavir and indinavir. Our results showed that methamphetamine alters the ritonavir binding to CYP3A4 by decreasing both the δAmax (0.0038±0.0003 vs. 0.0055±0.0003) and KD (0.043±0.0001 vs. 0.065±0.001 nM), while indinavir showed only reduced KD in presence of methamphetamine (0.086±0.01 vs. 0.174±0.03 nM). Furthermore, LC-MS/MS studies in high CYP3A4 human liver microsomes showed a decrease in the formation of hydroxy ritonavir in the presence of methamphetamine. Finally, CYP3A4 docking with lopinavir and ritonavir in the absence and presence of methamphetamine showed that methamphetamine alters the docking of ritonavir, which is consistent with the results obtained from spectral binding and metabolism studies. Overall, our results demonstrated differential effects of methamphetamine on the binding and metabolism of PIs with CYP3A4. These findings have clinical implication in terms of drug dose adjustment of antiretroviral medication, especially with ritonavir

  4. Graphene Plasmons in Triangular Wedges and Grooves

    DEFF Research Database (Denmark)

    Gonçalves, P. A. D.; Dias, E. J. C.; Xiao, Sanshui

    2016-01-01

    and tunability of graphene plasmons guided along the apex of a graphene-covered dielectric wedge or groove. In particular, we present a quasi-analytic model to describe the plasmonic eigenmodes in such a system, including the complete determination of their spectrum and corresponding induced potential...... and electric-field distributions. We have found that the dispersion of wedge/groove graphene plasmons follows the same functional dependence as their flat-graphene plasmon counterparts, but now scaled by a (purely) geometric factor in which all the information about the system’s geometry is contained. We...

  5. Analysis of chiral non-steroidal anti-inflammatory drugs flurbiprofen, ketoprofen and etodolac binding with HSA

    Directory of Open Access Journals (Sweden)

    Chang-Chuan Guo

    2011-08-01

    Full Text Available The protein binding of non-steroidal anti-inflammatory drugs flurbiprofen, ketoprofen and etodolac with human serum albumin (HSA was investigated using indirect chiral high performance liquid chromatography (HPLC and ultrafiltration techniques. S-(–-1-(1-naphthyl-ethylamine (S-NEA was utilized as chiral derivatization reagent and pre-column derivatization RP-HPLC method was established for the separation and assay of the three pairs of enantiomer. The method had good linear relationship over the investigated concentration range without interference. The average extraction efficiency was higher than 85% in different systems, and the intra-day and inter-day precisions were less than 15%. In serum albumin, the protein binding of etodolac enantiomers showed significant stereoselectivity that the affinity of S-enantiomer was stronger than R-enantiomer, and the stereoselectivity ratio reached 6.06; Flurbiprofen had only weak stereoselectivity in HSA, and ketoprofen had no stereoselectivity at all. Scatchard curves showed that all the three chiral drugs had two types of binding sites in HSA. Keywords: Protein binding, Non-steroidal anti-inflammatory drugs, Enantiomer, Stereoselectivity, Human serum albumin

  6. Considerations on pharmacodynamics and pharmacokinetics: can everything be explained by the extent of drug binding to its receptor?

    Science.gov (United States)

    Castañeda-Hernández, G; Granados-Soto, V

    2000-03-01

    It is frequently assumed that pharmacological responses depend solely on the extent of drug binding to its receptor according to the occupational theory. It is therefore presumed that the intensity of the effect is determined by drug concentration at its receptor site, yielding a unique concentration-effect relationship. However, when dependence, abstinence, and tolerance phenomena occur, as well as for pharmacological responses in vivo that are modulated by homeostatic mechanisms, the rate of drug input shifts the concentration-effect relationship. Hence, such responses cannot be explained on the sole basis of the extent of drug binding to its receptor. Information on the cellular and molecular processes involved in the generation of abstinence, dependence, and tolerance will undoubtedly result in the development of pharmacodynamic models allowing a satisfactory explanation of drug effects modulated by these phenomena. Notwithstanding, integrative physiology concepts are required to develop pharmacokinetic-pharmacodynamic models allowing the description of drug effects in an intact organism. It is therefore important to emphasize that integrative physiology cannot be neglected in pharmacology teaching and research, but should be considered as an equally valuable tool as molecular biology and other biomedical disciplines for the understanding of pharmacological effects.

  7. Synthesis, characterization and target protein binding of drug-conjugated quantum dots in vitro and in living cells

    International Nuclear Information System (INIS)

    Choi, Youngseon; Kim, Minjung; Cho, Yoojin; Yun, Eunsuk; Song, Rita

    2013-01-01

    Elucidation of unknown target proteins of a drug is of great importance in understanding cell biology and drug discovery. There have been extensive studies to discover and identify target proteins in the cell. Visualization of targets using drug-conjugated probes has been an important approach to gathering mechanistic information of drug action at the cellular level. As quantum dot (QD) nanocrystals have attracted much attention as a fluorescent probe in the bioimaging area, we prepared drug-conjugated QD to explore the potential of target discovery. As a model drug, we selected a well-known anticancer drug, methotrexate (MTX), which has been known to target dihydrofolate reductase (DHFR) with high affinity binding (K d = 0.54 nM). MTX molecules were covalently attached to amino-PEG-polymer-coated QDs. Specific interactions of MTX-conjugated QDs with DHFR were identified using agarose gel electrophoresis and fluorescence microscopy. Cellular uptake of the MTX-conjugated QDs in living CHO cells was investigated with regard to their localization and distribution pattern. MTX–QD was found to be internalized into the cells via caveolae-medicated endocytosis without significant sequestration in endosomes. A colocalization experiment of the MTX–QD conjugate with antiDHFR-TAT-QD also confirmed that MTX–QD binds to the target DHFR. This study showed the potential of the drug-QD conjugate to identify or visualize drug–target interactions in the cell, which is currently of great importance in the area of drug discovery and chemical biology. (paper)

  8. Entrapment of alpha1-acid glycoprotein in high-performance affinity columns for drug-protein binding studies.

    Science.gov (United States)

    Bi, Cong; Jackson, Abby; Vargas-Badilla, John; Li, Rong; Rada, Giana; Anguizola, Jeanethe; Pfaunmiller, Erika; Hage, David S

    2016-05-15

    A slurry-based method was developed for the entrapment of alpha1-acid glycoprotein (AGP) for use in high-performance affinity chromatography to study drug interactions with this serum protein. Entrapment was achieved based on the physical containment of AGP in hydrazide-activated porous silica supports and by using mildly oxidized glycogen as a capping agent. The conditions needed for this process were examined and optimized. When this type of AGP column was used in binding studies, the association equilibrium constant (Ka) measured by frontal analysis at pH 7.4 and 37°C for carbamazepine with AGP was found to be 1.0 (±0.5)×10(5)M(-1), which agreed with a previously reported value of 1.0 (±0.1)×10(5)M(-1). Binding studies based on zonal elution were conducted for several other drugs with such columns, giving equilibrium constants that were consistent with literature values. An entrapped AGP column was also used in combination with a column containing entrapped HSA in a screening assay format to compare the binding of various drugs to AGP and HSA. These results also agreed with previous data that have been reported in literature for both of these proteins. The same entrapment method could be extended to other proteins and to the investigation of additional types of drug-protein interactions. Potential applications include the rapid quantitative analysis of biological interactions and the high-throughput screening of drug candidates for their binding to a given protein. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Spiral groove seal. [for hydraulic rotating shaft

    Science.gov (United States)

    Ludwig, L. P. (Inventor)

    1973-01-01

    Mating flat surfaces inhibit leakage of a fluid around a stationary shaft. A spiral groove pattern produces a pumping action toward the fluid when the shaft rotates which prevents leakage while a generated hydraulic lifting force separates the mating surfaces to minimize wear.

  10. Optimization of Grooved Micromixer for Microengineering Technologies

    DEFF Research Database (Denmark)

    Sabotin, I.; Tristo, G.; Bissacco, Giuliano

    2013-01-01

    Due to the absence of turbulent flow and the slow diffusion process, mixing of solutions at micro-scale is a difficult task. This paper describes the optimization route towards the efficient design of a bottom grooved micromixer. Based on thoroughly discussed mixing mechanisms, the optimization w...

  11. Appraisal of transverse nasal groove: a study.

    Science.gov (United States)

    Sathyanarayana, Belagola D; Basavaraj, Halevoor B; Nischal, Kuchangi C; Swaroop, Mukunda R; Umashankar, Puttagangu N; Agrawal, Dhruv P; Swamy, Suchetha S; Okram, Sarda

    2012-01-01

    Transverse nasal groove is a condition of cosmetic concern which awaits due recognition and has been widely described as a shallow groove that extends transversely over the dorsum of nose. However, we observed variations in the clinical presentations of this entity, hitherto undescribed in literature. We conducted a clinicoepidemiological study of transverse nasal lesions in patients attending our outpatient department. We conducted a prospective observational study. We screened all patients attending our out-patient department for presence of transverse nasal lesions, signs of any dermatosis and associated other skin conditions. One hundred patients were recruited in the study. Females (80%) predominated over males. Most patients were of 15-45 years age group (70%). Majority of the transverse nasal lesions were classical transverse nasal groove (39%) and others included transverse nasal line (28%), strip (28%), ridge (4%) and loop (1%). Seborrhoeic diathesis was the most common condition associated with transverse nasal lesion. Occurrence of transverse nasal line, strip, ridge and loop, in addition to classical transverse nasal groove implies that latter is actually a subset of transverse nasal lesions. Common association of this entity with seborrheic dermatitis, seborrhea and dandruff raises a possibility of whether transverse nasal lesion is a manifestation of seborrheic diathesis.

  12. Structures of Two Coronavirus Main Proteases: Implications for Substrate Binding and Antiviral Drug Design

    Energy Technology Data Exchange (ETDEWEB)

    Xue, Xiaoyu; Yu, Hongwei; Yang, Haitao; Xue, Fei; Wu, Zhixin; Shen, Wei; Li, Jun; Zhou, Zhe; Ding, Yi; Zhao, Qi; Zhang, Xuejun C.; Liao, Ming; Bartlam, Mark; Rao, Zihe (SCAU); (Tsinghua); (Chinese Aca. Sci.)

    2008-07-21

    Coronaviruses (CoVs) can infect humans and multiple species of animals, causing a wide spectrum of diseases. The coronavirus main protease (M{sup pro}), which plays a pivotal role in viral gene expression and replication through the proteolytic processing of replicase polyproteins, is an attractive target for anti-CoV drug design. In this study, the crystal structures of infectious bronchitis virus (IBV) MP{sup pro} and a severe acute respiratory syndrome CoV (SARS-CoV) M{sup pro} mutant (H41A), in complex with an N-terminal autocleavage substrate, were individually determined to elucidate the structural flexibility and substrate binding of M{sup pro}. A monomeric form of IBV M{sup pro} was identified for the first time in CoV M{sup pro} structures. A comparison of these two structures to other available M{sup pro} structures provides new insights for the design of substrate-based inhibitors targeting CoV M{sup pro}s. Furthermore, a Michael acceptor inhibitor (named N3) was cocrystallized with IBV M{sup pro} and was found to demonstrate in vitro inactivation of IBV M{sup pro} and potent antiviral activity against IBV in chicken embryos. This provides a feasible animal model for designing wide-spectrum inhibitors against CoV-associated diseases. The structure-based optimization of N3 has yielded two more efficacious lead compounds, N27 and H16, with potent inhibition against SARS-CoV M{sup pro}.

  13. In silico analysis of conformational changes induced by mutation of aromatic binding residues: consequences for drug binding in the hERG K+ channel.

    Directory of Open Access Journals (Sweden)

    Kirsten Knape

    Full Text Available Pharmacological inhibition of cardiac hERG K(+ channels is associated with increased risk of lethal arrhythmias. Many drugs reduce hERG current by directly binding to the channel, thereby blocking ion conduction. Mutation of two aromatic residues (F656 and Y652 substantially decreases the potency of numerous structurally diverse compounds. Nevertheless, some drugs are only weakly affected by mutation Y652A. In this study we utilize molecular dynamics simulations and docking studies to analyze the different effects of mutation Y652A on a selected number of hERG blockers. MD simulations reveal conformational changes in the binding site induced by mutation Y652A. Loss of π-π-stacking between the two aromatic residues induces a conformational change of the F656 side chain from a cavity facing to cavity lining orientation. Docking studies and MD simulations qualitatively reproduce the diverse experimentally observed modulatory effects of mutation Y652A and provide a new structural interpretation for the sensitivity differences.

  14. Intentional replantation: A viable alternative for management of palatogingival groove

    OpenAIRE

    Vijay Kumar; Ajay Logani; Naseem Shah

    2013-01-01

    Radicular groove is an anatomical malformation that often leads to combined endodontic-periodontic lesions. Treatment of complex groove presents a clinical challenge to the operator. A case of type III palatogingival groove is successfully treated with intentional replantation. With the understanding of the procedure and strict adherence to guidelines improves, practitioners can use intentional replantation as an easy and cost-effective alternative for the management of radicular groove. The ...

  15. Platelet alpha 2-adrenergic receptors in major depressive disorder. Binding of tritiated clonidine before and after tricyclic antidepressant drug treatment

    International Nuclear Information System (INIS)

    Garcia-Sevilla, J.A.; Zis, A.P.; Hollingsworth, P.J.; Greden, J.F.; Smith, C.B.

    1981-01-01

    The specific binding of tritiated (3H)-clonidine, an alpha 2-adrenergic receptor agonist, to platelet membranes was measured in normal subjects and in patients with major depressive disorder. The number of platelet alpha 2-adrenergic receptors from the depressed group was significantly higher than that found in platelets obtained from the control population. Treatment with tricyclic antidepressant drugs led to significant decreases in the number of platelet alpha 2-adrenergic receptors. These results support the hypothesis that the depressive syndrome is related to an alpha 2-adrenergic receptor supersensitivity and that the clinical effectiveness of tricyclic antidepressant drugs is associated with a decrease in the number of these receptors

  16. Effect of NAD on binding and liberation of 14C-GABA in administration of the convulsion producing drug

    International Nuclear Information System (INIS)

    Fomenko, A.I.; Stepanenko, S.P.; Parkhomets, P.K.; Donchenko, G.V.

    1993-01-01

    Administration of corazole into animals led to a decrease in content of NAD and gamma-aminobutyric acid (GABA) in brain. Under these conditions, binding of 14 C-GABA was increased and its liberation was inhibited in the synaptosomes of the brain cortex. Additional administration of incotinamide, accompanied by considerable increase in content of NAD and GABA, caused a decrease in accumulation of exogenous GABA in the synaptosomes and removed the effects produced by the convulsant agent. Kinetics of 14 C-GABA binding in the presence of NAD demonstrated that the more effective inhibition of the binding occurred in the animals treated with the convulsant drug. NAD appears to affect the GABA-ergic transmission at the postsynaptic level

  17. Evolution of camel CYP2E1 and its associated power of binding toxic industrial chemicals and drugs.

    Science.gov (United States)

    Kandeel, Mahmoud; Altaher, Abdullah; Kitade, Yukio; Abdelaziz, Magdi; Alnazawi, Mohamed; Elshazli, Kamal

    2016-10-01

    Camels are raised in harsh desert environment for hundreds of years ago. By modernization of live and the growing industrial revolution in camels rearing areas, camels are exposed to considerable amount of chemicals, industrial waste, environmental pollutions and drugs. Furthermore, camels have unique gene evolution of some genes to withstand living in harsh environments. In this work, the camel cytochrome P450 2E1 (CYP2E1) is compromised to detect its evolution rate and its power to bind with various chemicals, protoxins, procarcinogens, industrial toxins and drugs. In comparison with human CYP2E1, camel CYP2E1 more efficiently binds to small toxins as aniline, benzene, catechol, amides, butadiene, toluene and acrylamide. Larger compounds were more preferentially bound to the human CYP2E1 in comparison with camel CYP2E1. The binding of inhalant anesthetics was almost similar in both camel and human CYP2E1 coinciding with similar anesthetic effect as well as toxicity profiles. Furthermore, evolutionary analysis indicated the high evolution rate of camel CYP2E1 in comparison with human, farm and companion animals. The evolution rate of camel CYP2E1 was among the highest evolution rate in a subset of 57 different organisms. These results indicate rapid evolution and potent toxin binding power of camel CYP2E1. Copyright © 2016. Published by Elsevier Ltd.

  18. Direct binding of radioiodinated monoclonal antibody to tumor cells: significance of antibody purity and affinity for drug targeting or tumor imaging

    International Nuclear Information System (INIS)

    Kennel, S.J.; Foote, L.J.; Lankford, P.K.; Johnson, M.; Mitchell, T.; Braslawsky, G.R.

    1983-01-01

    For MoAb to be used efficiently for drug targeting and tumor imaging, the fraction of antibody binding to tumor cells must be maximized. The authors have studied the binding of 125 I MoAb in three different tumor systems. The fraction of antibody that could be bound to the cell surface was directly proportional to the antibody purity. The affinity constant also limits the fraction of antibody that can bind to cells at a given antigen concentration. Rearrangement of the standard expression for univalent equilibrium binding between two reactants shows that in antigen excess, the maximum fraction of antibody that can bind =Ka[Ag total]/1 + Ka[Ag total]. Binding data using four different MoAb with three cell systems confirm this relationship. Estimates for reasonable concentrations of tumor antigens in vivo indicate that antibodies with binding constants less than 10 8 M -1 are not likely to be useful for drug targeting or tumor imaging

  19. Binding of the Multimodal Antidepressant Drug Vortioxetine to the Human Serotonin Transporter

    DEFF Research Database (Denmark)

    Andersen, Jacob; Ladefoged, Lucy Kate; Wang, Danyang

    2015-01-01

    the orientation of vortioxetine within the central binding site and showed that only one of the proposed binding modes is functionally relevant. The findings provide important new insight about the molecular basis for high affinity recognition of vortioxetine in hSERT, which is essential for future structure...

  20. Intentional replantation: A viable alternative for management of palatogingival groove

    Directory of Open Access Journals (Sweden)

    Vijay Kumar

    2013-01-01

    Full Text Available Radicular groove is an anatomical malformation that often leads to combined endodontic-periodontic lesions. Treatment of complex groove presents a clinical challenge to the operator. A case of type III palatogingival groove is successfully treated with intentional replantation. With the understanding of the procedure and strict adherence to guidelines improves, practitioners can use intentional replantation as an easy and cost-effective alternative for the management of radicular groove. The paper presents a brief review of palatogingival groove and highlights an easy and predictable alternative for its management.

  1. A Combined Molecular Docking/Dynamics Approach to Probe the Binding Mode of Cancer Drugs with Cytochrome P450 3A4

    Directory of Open Access Journals (Sweden)

    Suresh Panneerselvam

    2015-08-01

    Full Text Available Cytarabine, daunorubicin, doxorubicin and vincristine are clinically used for combinatorial therapies of cancers in different combinations. However, the knowledge about the interaction of these drugs with the metabolizing enzyme cytochrome P450 is limited. Therefore, we utilized computational methods to predict and assess the drug-binding modes. In this study, we performed docking, MD simulations and free energy landscape analysis to understand the drug-enzyme interactions, protein domain motions and the most populated free energy minimum conformations of the docked protein-drug complexes, respectively. The outcome of docking and MD simulations predicted the productive, as well as the non-productive binding modes of the selected drugs. Based on these interaction studies, we observed that S119, R212 and R372 are the major drug-binding residues in CYP3A4. The molecular mechanics Poisson–Boltzmann surface area analysis revealed the dominance of hydrophobic forces in the CYP3A4-drug association. Further analyses predicted the residues that may contain favorable drug-specific interactions. The probable binding modes of the cancer drugs from this study may extend the knowledge of the protein-drug interaction and pave the way to design analogs with reduced toxicity. In addition, they also provide valuable insights into the metabolism of the cancer drugs.

  2. Structural and quantum mechanical computations to elucidate the altered binding mechanism of metal and drug with pyrazinamidase from Mycobacterium tuberculosis due to mutagenicity.

    Science.gov (United States)

    Rasool, Nouman; Iftikhar, Saima; Amir, Anam; Hussain, Waqar

    2018-03-01

    Pyrazinamide is known to be the most effective treatment against tuberculosis disease and is known to have bacteriostatic action. By targeting the bacterial spores, this drug reduces the chances for the progression of the infection in organisms. In recent years, increased instances of the drug resistance of bacterial strains are reported. Pyrazinamidase, activator for pyrazinamide, leads to resistance against the drug due to mutagenicity across the world. The present study aimed at the quantum mechanistic analysis of mutations in pyrazinamidase to gain insights into the mechanism of this enzyme. Quantum mechanical calculations were performed to analyse the effect of mutations at the metal coordination site using ORCA software program. Moreover, conformational changes in PZase binding cavity has also been analysed due to mutations of binding pocket residues using CASTp server. In order to elucidate the behaviour of the mutant pyrazinamidase, docking of PZA in the binding pocket of PZase was performed using AutoDock Vina. Analysis of results revealed that iron showed weak binding with the metal coordination site of the mutant proteins due to alteration in electron transfer mechanism. The binding cavity of the mutant PZase has undergone major conformational changes as the volume of pocket increased due to bulky R-chains of mutated amino acids. These conformational changes lead to weak binding of the drug at binding cavity of PZase and reduce the drug activation mechanism leading to increased drug resistance in the bacterial strains. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire

    DEFF Research Database (Denmark)

    Ostrov, David A; Grant, Barry J; Pompeu, Yuri A

    2012-01-01

    cells, thus causing the equivalent of an alloreactive T-cell response. Indeed, we identified specific self-peptides that are presented only in the presence of abacavir and that were recognized by T cells of hypersensitive patients. The assays that we have established can be applied to test additional...... unclear. Here we show that abacavir can bind within the F pocket of the peptide-binding groove of HLA-B*57:01, thereby altering its specificity. This provides an explanation for HLA-linked idiosyncratic adverse drug reactions, namely that drugs can alter the repertoire of self-peptides presented to T...

  4. Labiogingival groove: A rare developmental tooth anomaly

    Directory of Open Access Journals (Sweden)

    Shiva Chauhan

    2017-01-01

    Full Text Available Labiogingival groove is a congenital morphologic dental anomaly, in which an infolding of the inner enamel epithelium and Hertwig's epithelial root sheath create a groove extending varying depth into root. Epithelial attachment can be breached by gingival irritation secondary to plaque accumulation creating a periodontal defect that spreads to the pulp causing primary periodontal/secondary endodontic. A 12-year-old boy reported with the complaint of painful tooth with pus discharge from labial gingival surface in the maxillary right lateral incisor for 4 months. Intraoral examination revealed bluish red gingiva with loss of contour in relation to maxillary right lateral incisor and purulent discharge in relation to it. A provisional diagnosis of localized gingival abscess in relation to maxillary right incisor (primary periodontic and secondary endodontic involvement was given, and required treatment was carried out. On exposure of the involved tooth, a labiogingival groove was noticed which could have been a contributing factor for the progression of the condition.

  5. How does fatty acid influence anti-thyroid drugs binding and ...

    Indian Academy of Sciences (India)

    This study reports an AutoDock-based blind docking simulation investigation to characterize the binding interaction of ... In the present program we report a molecular dock- ..... Representative examples for clustering analysis of docked poses.

  6. From old alkylating agents to new minor groove binders.

    Science.gov (United States)

    Puyo, Stéphane; Montaudon, Danièle; Pourquier, Philippe

    2014-01-01

    Alkylating agents represent the oldest class of anticancer agents with the approval of mechloretamine by the FDA in 1949. Even though their clinical use is far beyond the use of new targeted therapies, they still occupy a major place in the treatment of specific malignancies, sometimes representing the unique option for the treatment of refractory tumors. Here, we are reviewing the major classes of alkylating agents, with a particular focus on the latest generations of compounds that specifically target the minor groove of the DNA. These naturally occurring derivatives have a unique mechanism of action that explains the recent regain of interest in developing new classes of alkylating agents that could be used in combination with other anticancer drugs to enhance tumor response in the clinic. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  7. Molecular spectroscopic and thermodynamic studies on the interaction of anti-platelet drug ticlopidine with calf thymus DNA

    Science.gov (United States)

    Afrin, Shumaila; Rahman, Yusra; Sarwar, Tarique; Husain, Mohammed Amir; Ali, Abad; Shamsuzzaman; Tabish, Mohammad

    2017-11-01

    Ticlopidine is an anti-platelet drug which belongs to the thienopyridine structural family and exerts its effect by functioning as an ADP receptor inhibitor. Ticlopidine inhibits the expression of TarO gene in S. aureus and may provide protection against MRSA. Groove binding agents are known to disrupt the transcription factor DNA complex and consequently inhibit gene expression. Understanding the mechanism of interaction of ticlopidine with DNA can prove useful in the development of a rational drug designing system. At present, there is no such study on the interaction of anti-platelet drugs with nucleic acids. A series of biophysical experiments were performed to ascertain the binding mode between ticlopidine and calf thymus DNA. UV-visible and fluorescence spectroscopic experiments confirmed the formation of a complex between ticlopidine and calf thymus DNA. Moreover, the values of binding constant were found to be in the range of 103 M- 1, which is indicative of groove binding between ticlopidine and calf thymus DNA. These results were further confirmed by studying the effect of denaturation on double stranded DNA, iodide quenching, viscometric studies, thermal melting profile as well as CD spectral analysis. The thermodynamic profile of the interaction was also determined using isothermal titration calorimetric studies. The reaction was found to be endothermic and the parameters obtained were found to be consistent with those of known groove binders. In silico molecular docking studies further corroborated well with the experimental results.

  8. Sequence-specific high mobility group box factors recognize 10-12-base pair minor groove motifs

    DEFF Research Database (Denmark)

    van Beest, M; Dooijes, D; van De Wetering, M

    2000-01-01

    Sequence-specific high mobility group (HMG) box factors bind and bend DNA via interactions in the minor groove. Three-dimensional NMR analyses have provided the structural basis for this interaction. The cognate HMG domain DNA motif is generally believed to span 6-8 bases. However, alignment...

  9. Accurate Estimation of the Standard Binding Free Energy of Netropsin with DNA

    Directory of Open Access Journals (Sweden)

    Hong Zhang

    2018-01-01

    Full Text Available DNA is the target of chemical compounds (drugs, pollutants, photosensitizers, etc., which bind through non-covalent interactions. Depending on their structure and their chemical properties, DNA binders can associate to the minor or to the major groove of double-stranded DNA. They can also intercalate between two adjacent base pairs, or even replace one or two base pairs within the DNA double helix. The subsequent biological effects are strongly dependent on the architecture of the binding motif. Discriminating between the different binding patterns is of paramount importance to predict and rationalize the effect of a given compound on DNA. The structural characterization of DNA complexes remains, however, cumbersome at the experimental level. In this contribution, we employed all-atom molecular dynamics simulations to determine the standard binding free energy of DNA with netropsin, a well-characterized antiviral and antimicrobial drug, which associates to the minor groove of double-stranded DNA. To overcome the sampling limitations of classical molecular dynamics simulations, which cannot capture the large change in configurational entropy that accompanies binding, we resort to a series of potentials of mean force calculations involving a set of geometrical restraints acting on collective variables.

  10. The pleuromutilin drugs tiamulin and valnemulin bind to the RNA at the peptidyl transferase centre on the ribosome.

    Science.gov (United States)

    Poulsen, S M; Karlsson, M; Johansson, L B; Vester, B

    2001-09-01

    The pleuromutilin antibiotic derivatives, tiamulin and valnemulin, inhibit protein synthesis by binding to the 50S ribosomal subunit of bacteria. The action and binding site of tiamulin and valnemulin was further characterized on Escherichia coli ribosomes. It was revealed that these drugs are strong inhibitors of peptidyl transferase and interact with domain V of 23S RNA, giving clear chemical footprints at nucleotides A2058-9, U2506 and U2584-5. Most of these nucleotides are highly conserved phylogenetically and functionally important, and all of them are at or near the peptidyl transferase centre and have been associated with binding of several antibiotics. Competitive footprinting shows that tiamulin and valnemulin can bind concurrently with the macrolide erythromycin but compete with the macrolide carbomycin, which is a peptidyl transferase inhibitor. We infer from these and previous results that tiamulin and valnemulin interact with the rRNA in the peptidyl transferase slot on the ribosomes in which they prevent the correct positioning of the CCA-ends of tRNAs for peptide transfer.

  11. Frontal dopamine D(2/3) receptor binding in drug-naive first-episode schizophrenic patients correlates with positive psychotic symptoms and gender

    DEFF Research Database (Denmark)

    Glenthoj, Birte Y; Mackeprang, Torben; Svarer, Claus

    2006-01-01

    BACKGROUND: The aim of the study was to examine extrastriatal dopamine D(2/3) receptor binding and psychopathology in schizophrenic patients, and to relate binding potential (BP) values to psychopathology. METHODS: Twenty-five drug-naive schizophrenic patients and 20 healthy controls were examined...

  12. The changes in drug binding activity of GABA receptor and animal neural-behavior after gamma irradiation

    International Nuclear Information System (INIS)

    Zheng Hui; Zhen Rong; Zhao Naikun; Xue Hong; Wang Zihui

    2004-01-01

    Objective: The purpose of this study was to investigate the effect of irradiation on gamma-aminobutyric-acid receptor (GABA-R) as well as behavioral changes after brain 60 Co γ-irradiation. Methods: The mice were irradiated with gamma rays (20 Gy; 10 Gy and 5 Gy) . The drug binding activity of GABA receptor in brain receptor was measured by fluorescence anisotropy (FA) and equilibrium dissociation constants. The behavioral changes were observed by the locomotor activity test, elevated plus-maze test and hole-board test at 1, 10, 24 and 48 hr after irradiation. Results: 1. The drug binding activity of the GABA receptor was decreased and the equilibrium dissociation constant (K d ) was significantly increased compared with the negative control group 2 hr after irradiation, and a spike value appeared at 24 hr. It showed that the irradiation might damage or decrease the binding activity and the bio-activity of GABA receptor. 2. The animal experiment confirmed that the irradiated animal model showed neural-behavioral changes of anxiety or depression. 3. The decreased binding activity of GABA receptor and changes in behavior of irradiated animal were dependent on radiation intensity. 4. The changes of behavior was similar to the blocked GABA receptor group. It suggests the relationship of radiation and GABA receptor. Conclusion: These results suggest that GABA receptor may be involved in radiation injury. The functional changes of GABA receptor may be an induction factor of behavioral disorder. The article also discussed the effect of anxiety and results obtained from the point of view of GABA receptor system involvement in the changes observed after irradiation. (authors)

  13. Displacement of specific serotonin and lysergic acid diethylamide binding by Ergalgin, a new antiserotonin drug

    International Nuclear Information System (INIS)

    Oelszner, W.

    1980-01-01

    [ 3 H]-serotonin and [ 3 H]-lysergic acid diethylamide (LSD) bind with a high affinity, Ksub(D) = 12 nM and 6 nM, respectively, to distinct receptors of rat caudate membranes in vitro. Displacement experiments with unlabeled serotonin and LSD support the hypothesis of serotonin receptors existing in an agonist and antagonist state. Methysergide and Ergalgin display quite similar potenties in displacing [ 3 H]-serontonin and [ 3 H]-LSD from their specific binding sites (Ksub(i) = 46.7 and 53.4 nM; 22.3 and 36.5 nM, respectively). Contrary to pharmacological findings these binding results are in favour of mixed agonist/antagonist properties of these compounds. (author)

  14. Hydroxychloroquine binding to cytoplasmic domain of Band 3 in human erythrocytes: Novel mechanistic insights into drug structure, efficacy and toxicity.

    Science.gov (United States)

    Nakagawa, Mizuki; Sugawara, Kotomi; Goto, Tatsufumi; Wakui, Hideki; Nunomura, Wataru

    2016-05-13

    Hydroxychloroquine (HCQ) is a widely used drug in the treatment of autoimmune diseases, such as arthritis and systemic lupus erythematosus. It has also been prescribed for the treatment of malaria owing to its lower toxicity compared to its closely related compound chloroquine (CQ). However, the mechanisms of action of HCQ in erythrocytes (which bind preferentially this drug) have not been documented and the reasons underlying the lower side effects of HCQ compared to CQ remain unclear. Here we show that, although the activity of erythrocyte lactate dehydrogenase (LDH), but not GAPDH, was inhibited by both HCQ and CQ in vitro, LDH activity in erythrocytes incubated with 20 mM HCQ was not significantly reduced within 5 h in contrast to CQ did. Using HCQ coupled Sepharose chromatography (HCQ-Sepharose), we identified Band 3, spectrin, ankyrin, protein 4.1R and protein 4.2 as HCQ binding proteins in human erythrocyte plasma membrane. Recombinant cytoplasmic N-terminal 43 kDa domain of Band 3 bound to HCQ-Sepharose and was eluted with 40 mM (but not 20 mM) HCQ. Band 3 transport activity was reduced by only 23% in the presence of 20 mM HCQ. Taken together, these data demonstrate that HCQ binds to the cytoplasmic N-terminal domain of Band 3 in human erythrocytes but does not inhibit dramatically its transport activity. We hypothesize that the trapping of HCQ on Band 3 contributes to the lower side effects of the drug on energy production in erythrocytes. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. An investigation of drug binding ability of a surface active ionic liquid: micellization, electrochemical, and spectroscopic studies.

    Science.gov (United States)

    Mahajan, Suruchi; Sharma, Rabia; Mahajan, Rakesh Kumar

    2012-12-18

    Keeping in view the use of surfactants in drug delivery, the interactions of surface active ionic liquids, such as 1-tetradecyl-3-methylimidazolium bromide (C(14)mimBr), with drugs, viz., dopamine hydrochloride (DH) and acetylcholine chloride (AC), have been studied, and the results are further compared with that of the structurally similar conventional cationic surfactant tetradecyltrimethylammonium bromide (TTAB). The micellization and interfacial behavior of C(14)mimBr and TTAB, in the presence of DH and AC, has been investigated from conductivity and surface tension measurements. Various micellar and adsorption characteristics for these drug-surfactant systems (DH/AC + C(14)mimBr/TTAB) have been investigated, indicating favorable interactions between them. The more detailed information regarding the nature of interactions between C(14)mimBr/TTAB and DH/AC is obtained from cyclic voltammetry (CV) and (1)H NMR measurements. CV measurements have been employed to evaluate the binding constant (K) and the Gibbs free energy change (ΔG) for these drug-surfactant complexes. These measurements indicate the existence of cation-π as well as π-π interactions between drugs and surfactants. A detailed analysis of chemical shifts of protons of drug molecules (DH and AC) in the presence of C(14)mimBr and TTAB has been done by (1)H NMR. The results obtained from (1)H NMR are in agreement with those of CV measurements. (1)H NMR studies along with the conductivity and surface tension measurements help in predicting the possible location of adsorption of these drug molecules in C(14)mimBr and TTAB micelles.

  16. Albumin binding of anti-inflammatory drugs. Utility of a site-oriented versus a stoichiometric analysis

    DEFF Research Database (Denmark)

    Honoré, B; Brodersen, R

    1984-01-01

    Binding equilibria of 12 nonsteroidal, anti-inflammatory substances, salicylic acid, diflunisal, phenylbutazone, azapropazone, fenbufen, biphenylacetic acid, naproxen, flurbiprofen, ibuprofin, diclofenac, indomethacin, and benoxaprofen, to defatted human serum albumin has been investigated at 37...... degrees, pH 7.4, in a sodium phosphate buffer, 66 mM, by means of equilibrium dialysis and, in case of salicylic acid, by dialysis rate determinations. Cobinding of each of these drugs with monoacetyl-4,4'-diaminodiphenyl sulfone, warfarin, and diazepam has been studied by measuring dialysis rates...

  17. Application of pressure ultrafiltration in determining the binding capacity of drugs to human albumin and to plasma proteins of intact and irradiated rat females

    International Nuclear Information System (INIS)

    Zima, M.

    1976-01-01

    The significance of the binding of drugs to plasma proteins has repeatedly been demonstrated and draws the interest of many pharmacologists. The described experiments served to study the binding of isoniazid (INH) to human albumin of various dilution and to whole plasma proteins of irradiated (on the Oth, 3rd and 6th day after exposure to 154.8 mC/kg=600 R) and non-irradiated rats using the technique of modified accelerated ultrafiltration through cellophane. The total characteristics of the binding and its changes were demonstrated by the equilibrium constant, the numbers of binding sites and the changes of free binding energy. The results show that the dilution of human albumin affects the strength of the INH binding on this albumin and further that the normally weak INH binding is diminished even more in irradiated rats. This cannot be explained by the change in the percentage composition of the rat plasma. (author)

  18. Post processing of protein-compound docking for fragment-based drug discovery (FBDD): in-silico structure-based drug screening and ligand-binding pose prediction.

    Science.gov (United States)

    Fukunishi, Yoshifumi

    2010-01-01

    For fragment-based drug development, both hit (active) compound prediction and docking-pose (protein-ligand complex structure) prediction of the hit compound are important, since chemical modification (fragment linking, fragment evolution) subsequent to the hit discovery must be performed based on the protein-ligand complex structure. However, the naïve protein-compound docking calculation shows poor accuracy in terms of docking-pose prediction. Thus, post-processing of the protein-compound docking is necessary. Recently, several methods for the post-processing of protein-compound docking have been proposed. In FBDD, the compounds are smaller than those for conventional drug screening. This makes it difficult to perform the protein-compound docking calculation. A method to avoid this problem has been reported. Protein-ligand binding free energy estimation is useful to reduce the procedures involved in the chemical modification of the hit fragment. Several prediction methods have been proposed for high-accuracy estimation of protein-ligand binding free energy. This paper summarizes the various computational methods proposed for docking-pose prediction and their usefulness in FBDD.

  19. G protein-coupled receptor transmembrane binding pockets and their applications in GPCR research and drug discovery: a survey.

    Science.gov (United States)

    Kratochwil, Nicole A; Gatti-McArthur, Silvia; Hoener, Marius C; Lindemann, Lothar; Christ, Andreas D; Green, Luke G; Guba, Wolfgang; Martin, Rainer E; Malherbe, Pari; Porter, Richard H P; Slack, Jay P; Winnig, Marcel; Dehmlow, Henrietta; Grether, Uwe; Hertel, Cornelia; Narquizian, Robert; Panousis, Constantinos G; Kolczewski, Sabine; Steward, Lucinda

    2011-01-01

    G protein-coupled receptors (GPCRs) share a common architecture consisting of seven transmembrane (TM) domains. Various lines of evidence suggest that this fold provides a generic binding pocket within the TM region for hosting agonists, antagonists, and allosteric modulators. Hence, an automated method was developed that allows a fast analysis and comparison of these generic ligand binding pockets across the entire GPCR family by providing the relevant information for all GPCRs in the same format. This methodology compiles amino acids lining the TM binding pocket including parts of the ECL2 loop in a so-called 1D ligand binding pocket vector and translates these 1D vectors in a second step into 3D receptor pharmacophore models. It aims to support various aspects of GPCR drug discovery in the pharmaceutical industry. Applications of pharmacophore similarity analysis of these 1D LPVs include definition of receptor subfamilies, prediction of species differences within subfamilies in regard to in vitro pharmacology and identification of nearest neighbors for GPCRs of interest to generate starting points for GPCR lead identification programs. These aspects of GPCR research are exemplified in the field of melanopsins, trace amine-associated receptors and somatostatin receptor subtype 5. In addition, it is demonstrated how 3D pharmacophore models of the LPVs can support the prediction of amino acids involved in ligand recognition, the understanding of mutational data in a 3D context and the elucidation of binding modes for GPCR ligands and their evaluation. Furthermore, guidance through 3D receptor pharmacophore modeling for the synthesis of subtype-specific GPCR ligands will be reported. Illustrative examples are taken from the GPCR family class C, metabotropic glutamate receptors 1 and 5 and sweet taste receptors, and from the GPCR class A, e.g. nicotinic acid and 5-hydroxytryptamine 5A receptor. © 2011 Bentham Science Publishers

  20. Molecular Containers Bind Drugs of Abuse in Vitro and Reverse the Hyperlocomotive Effect of Methamphetamine in Rats.

    Science.gov (United States)

    Ganapati, Shweta; Grabitz, Stephanie D; Murkli, Steven; Scheffenbichler, Flora; Rudolph, Maíra I; Zavalij, Peter Y; Eikermann, Matthias; Isaacs, Lyle

    2017-08-17

    We measured the affinity of five molecular container compounds (calabadions 1 and 2, CB[7], sulfocalix[4]arene, and HP-β-CD) toward seven drugs of abuse in homogenous aqueous solution at physiological pH by various methods ( 1 H NMR, UV/Vis, isothermal titration calorimetry [ITC]) and found binding constants (K a values) spanning from 10 8  m -1 . We also report X-ray crystal structures of CB[7]⋅methamphetamine and 1⋅methamphetamine. We found that 2, but not CB[7], was able to ameliorate the hyperlocomotive activity of rats treated with methamphetamine. The bioavailability of the calabadions and their convergent building block synthesis suggest potential for further structural optimization as reversal agents for intoxication with nonopioid drugs of abuse for which no treatments are currently available. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  1. Detecting drug-target binding in cells using fluorescence-activated cell sorting coupled with mass spectrometry analysis

    Science.gov (United States)

    Wilson, Kris; Webster, Scott P.; Iredale, John P.; Zheng, Xiaozhong; Homer, Natalie Z.; Pham, Nhan T.; Auer, Manfred; Mole, Damian J.

    2018-01-01

    The assessment of drug-target engagement for determining the efficacy of a compound inside cells remains challenging, particularly for difficult target proteins. Existing techniques are more suited to soluble protein targets. Difficult target proteins include those with challenging in vitro solubility, stability or purification properties that preclude target isolation. Here, we report a novel technique that measures intracellular compound-target complex formation, as well as cellular permeability, specificity and cytotoxicity-the toxicity-affinity-permeability-selectivity (TAPS) technique. The TAPS assay is exemplified here using human kynurenine 3-monooxygenase (KMO), a challenging intracellular membrane protein target of significant current interest. TAPS confirmed target binding of known KMO inhibitors inside cells. We conclude that the TAPS assay can be used to facilitate intracellular hit validation on most, if not all intracellular drug targets.

  2. [Microsurgical removal of olfactory groove meningiomas].

    Science.gov (United States)

    Liang, Ri-Sheng; Zhou, Liang-Fu; Mao, Ying; Zhang, Rong; Yang, Wei-Zhong

    2011-01-01

    To explore an effective method for further improving the surgical results of treatment of olfactory groove meningiomas. Sixty seven cases of olfactory groove meningiomas were treated by microneurosurgery, among which fifty seven were de novo cases, eight were recurrent tumors and the other two re-recurrent cases. Modified Derome approach was used in 12 cases, bilateral subfrontal approach in 28 cases, modified pterional approach in 21 cases and unilateral subfrontal approach in six cases. Tumors were resected microsurgically with radical removal of invaded dura, bone, and paranasal sinus mucosa. Reconstruction was performed in patients with skull base defect. Simpson grade I removal was accomplished in 59 cases, grade II in seven cases and grade IV in one case. Among 57 patients with de novo tumor, Simpson I resection was accomplished in 54 cases. Postoperative rhinorrhea and intracranial infection occurred in one case and was cured after temporal lumbar CSF drainage and antibiotic therapy. Two patients (2.9%) died within one month after operation, i.e.one aged patient of heart failure and the other of severe hypothalamus complication. Forty seven patients (72.3%) were followed up from one to ten years with an average of five years and four months. With the exception of two cases died, among the alive 45 patients, there were only three patients with tumor recurrence, which had undergone Simpson II or IV tumor resection. No recurrence was found in cases with Simpson I tumor removal. Previous blurred vision was not improved in three patients, hemiparalysis in two patients, and the other patients recovered well, resuming previous jobs or being able to take care themselves. Total tumor removal (Simpson I) should be the surgical goal for treatment of olfactory groove meningiomas, especially for de novo cases. An appropriate approach is fundamental in the effort to remove an OGM totally. Appropriate anterior skull base reconstruction with vascularized material is

  3. Laser Surface Hardening of Groove Edges

    Science.gov (United States)

    Hussain, A.; Hamdani, A. H.; Akhter, R.; Aslam, M.

    2013-06-01

    Surface hardening of groove-edges made of 3Cr13 Stainless Steel has been carried out using 500 W CO2 laser with a rectangular beam of 2.5×3 mm2. The processing speed was varied from 150-500 mm/min. It was seen that the hardened depth increases with increase in laser interaction time. A maximum hardened depth of around 1mm was achieved. The microhardness of the transformed zone was 2.5 times the hardness of base metal. The XRD's and microstructural analysis were also reported.

  4. Syncopation, body-movement and pleasure in groove music.

    OpenAIRE

    Witek, MA; Clarke, EF; Wallentin, M; Kringelbach, ML; Vuust, P

    2014-01-01

    Moving to music is an essential human pleasure particularly related to musical groove. Structurally, music associated with groove is often characterised by rhythmic complexity in the form of syncopation, frequently observed in musical styles such as funk, hip-hop and electronic dance music. Structural complexity has been related to positive affect in music more broadly, but the function of syncopation in eliciting pleasure and body-movement in groove is unknown. Here we report results from a ...

  5. Comparative studies on drug binding to the purified and pharmaceutical-grade human serum albumins: Bridging between basic research and clinical applications of albumin.

    Science.gov (United States)

    Ashrafi-Kooshk, Mohammad Reza; Ebrahimi, Farangis; Ranjbar, Samira; Ghobadi, Sirous; Moradi, Nastaran; Khodarahmi, Reza

    2015-09-01

    Human serum albumin (HSA), the most abundant protein in blood plasma, is a monomeric multidomain protein that possesses an extraordinary capacity for binding, so that serves as a circulating depot for endogenous and exogenous compounds. During the heat sterilization process, the structure of pharmaceutical-grade HSA may change and some of its activities may be lost. In this study, to provide deeper insight on this issue, we investigated drug-binding and some physicochemical properties of purified albumin (PA) and pharmaceutical-grade albumin (PGA) using two known drugs (indomethacin and ibuprofen). PGA displayed significantly lower drug binding capacity compared to PA. Analysis of the quenching and thermodynamic parameters indicated that intermolecular interactions between the drugs and the proteins are different from each other. Surface hydrophobicity as well as the stability of PGA decreased compared to PA, also surface hydrophobicity of PA and PGA increased upon drugs binding. Also, kinetic analysis of pseudo-esterase activities indicated that Km and Vmax parameters for PGA enzymatic activity are more and less than those of PA, respectively. This in vitro study demonstrates that the specific drug binding of PGA is significantly reduced. Such studies can act as connecting bridge between basic research discoveries and clinical applications. Copyright © 2015 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

  6. Investigation and identification of functional post-translational modification sites associated with drug binding and protein-protein interactions.

    Science.gov (United States)

    Su, Min-Gang; Weng, Julia Tzu-Ya; Hsu, Justin Bo-Kai; Huang, Kai-Yao; Chi, Yu-Hsiang; Lee, Tzong-Yi

    2017-12-21

    Protein post-translational modification (PTM) plays an essential role in various cellular processes that modulates the physical and chemical properties, folding, conformation, stability and activity of proteins, thereby modifying the functions of proteins. The improved throughput of mass spectrometry (MS) or MS/MS technology has not only brought about a surge in proteome-scale studies, but also contributed to a fruitful list of identified PTMs. However, with the increase in the number of identified PTMs, perhaps the more crucial question is what kind of biological mechanisms these PTMs are involved in. This is particularly important in light of the fact that most protein-based pharmaceuticals deliver their therapeutic effects through some form of PTM. Yet, our understanding is still limited with respect to the local effects and frequency of PTM sites near pharmaceutical binding sites and the interfaces of protein-protein interaction (PPI). Understanding PTM's function is critical to our ability to manipulate the biological mechanisms of protein. In this study, to understand the regulation of protein functions by PTMs, we mapped 25,835 PTM sites to proteins with available three-dimensional (3D) structural information in the Protein Data Bank (PDB), including 1785 modified PTM sites on the 3D structure. Based on the acquired structural PTM sites, we proposed to use five properties for the structural characterization of PTM substrate sites: the spatial composition of amino acids, residues and side-chain orientations surrounding the PTM substrate sites, as well as the secondary structure, division of acidity and alkaline residues, and solvent-accessible surface area. We further mapped the structural PTM sites to the structures of drug binding and PPI sites, identifying a total of 1917 PTM sites that may affect PPI and 3951 PTM sites associated with drug-target binding. An integrated analytical platform (CruxPTM), with a variety of methods and online molecular docking

  7. Dual-phase CT findings of groove pancreatitis

    Energy Technology Data Exchange (ETDEWEB)

    Zaheer, Atif, E-mail: azaheer1@jhmi.edu [The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD 21231 (United States); Pancreatitis Center, Division of Gastroenterology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21231 (United States); Haider, Maera, E-mail: mhaider3@jhmi.edu [The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD 21231 (United States); Kawamoto, Satomi, E-mail: skawamo1@jhmi.edu [The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD 21231 (United States); Hruban, Ralph H., E-mail: rhruban1@jhmi.edu [Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, MD 21231 (United States); Fishman, Elliot K., E-mail: efishma1@jhmi.edu [The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD 21231 (United States)

    2014-08-15

    Purpose: Groove pancreatitis is a rare focal form of chronic pancreatitis that occurs in the pancreaticoduodenal groove between the major and minor papillae, duodenum and pancreatic head. Radiologic appearance and clinical presentation can result in suspicion of malignancy rendering pancreaticoduodenectomy inevitable. This study reports dual phase CT findings in a series of 12 patients with pathology proven groove pancreatitis. Materials and methods: Retrospective review of preoperative CT findings in 12 patients with histologically proven groove pancreatitis after pancreaticoduodenectomy. Size, location, attenuation, presence of mass or cystic components in the pancreas, groove and duodenum, calcifications, duodenal stenosis and ductal changes were recorded. Clinical data, laboratory values, endoscopic ultrasonographic and histopathological findings were collected. Results: Soft tissue thickening in the groove was seen in all patients. Pancreatic head, groove and duodenum were all involved in 75% patients. A discrete lesion in the pancreatic head was seen in half of the patients, most of which appeared hypodense on both arterial and venous phases. Cystic changes in pancreatic head were seen in 75% patients. Duodenal involvement was seen in 92% patients including wall thickening and cyst formation. The main pancreatic duct was dilated in 7 patients, with an abrupt cut off in 3 and a smooth tapering stricture in 4. Five patients had evidence of chronic pancreatitis with parenchymal calcifications. Conclusion: Presence of mass or soft tissue thickening in the groove with cystic duodenal thickening is highly suggestive of groove pancreatitis. Recognizing common radiological features may help in diagnosis and reduce suspicion of malignancy.

  8. Wetting morphologies and their transitions in grooved substrates

    Energy Technology Data Exchange (ETDEWEB)

    Seemann, Ralf; Bommer, Stefan; Herrmann, Carsten; Michler, Dominik [Experimental Physics, Saarland University, D-66123 Saarbruecken (Germany); Brinkmann, Martin; Herminghaus, Stephan; Khare, Krishnacharya; Kostourou, Konstantina; Gurevich, Evgeny [Max Planck Institute for Dynamics and Self-Organization, D-37073 Goettingen (Germany); Law, Bruce M; McBride, Sean, E-mail: r.seemann@physik.uni-saarland.de [Department of Physics, Kansas State University, Manhattan, KS 66506 (United States)

    2011-05-11

    When exposed to a partially wetting liquid, many natural and artificial surfaces equipped with complex topographies display a rich variety of liquid interfacial morphologies. In the present article, we focus on a few simple paradigmatic surface topographies and elaborate on the statics and dynamics of the resulting wetting morphologies. It is demonstrated that the spectrum of wetting morphologies increases with increasing complexity of the groove structure. On elastically deformable substrates, additional structures in the liquid morphologies can be observed, which are caused by deformations of the groove geometry in the presence of capillary forces. The emergence of certain liquid morphologies in grooves can be actively controlled by changes in wettability and geometry. For electrically conducting solid substrates, the apparent contact angle can be varied by electrowetting. This allows, depending on groove geometry, a reversible or irreversible transport of liquid along surface grooves. In the case of irreversible liquid transport in triangular grooves, the dynamics of the emerging instability is sensitive to the apparent hydrodynamic slip at the substrate. On elastic substrates, the geometry can be varied in a straightforward manner by stretching or relaxing the sample. The imbibition velocity in deformable grooves is significantly reduced compared to solid grooves, which is a result of the microscopic deformation of the elastic groove material close to the three phase contact line.

  9. sigma opiates and certain antipsychotic drugs mutually inhibit (+)-[3H]SKF 10,047 and [3H]haloperidol binding in guinea pig brain membranes

    International Nuclear Information System (INIS)

    Tam, S.W.; Cook, L.

    1984-01-01

    The relationship between binding of antipsychotic drugs and sigma psychotomimetic opiates to binding sites for the sigma agonist (+)-[ 3 H]SKF 10,047 (N-allylnormetazocine) and to dopamine D 2 sites was investigated. In guinea pig brain membranes, (+)-[ 3 H]SKF 10,047 bound to single class of sites with a K/sub d/ of 4 x 10 -8 M and a B/sub max/ of 333 fmol/mg of protein. This binding was different from μ, kappa, or delta opiate receptor binding. It was inhibited by opiates that produce psychotomimetic activities but not by opiates that lack such activities. Some antipsychotic drugs inhibited (+)-[ 3 H]SKF 10,047 binding with high to moderate affinities in the following order of potency: haloperidol > perphenazine > fluphenazine > acetophenazine > trifluoperazine > molindone greater than or equal to pimozide greater than or equal to thioridazine greater than or equal to chlorpromazine greater than or equal to triflupromazine. However, there were other antipsychotic drugs such as spiperone and clozapine that showed low affinity for the (+)-[ 3 H]SKF 10,047 binding sites. Affinities of antipsychotic drugs for (+)-[ 3 H]SKF 10,047 binding sites did not correlate with those for [ 3 H]spiperone (dopamine D 2 ) sites. [ 3 H]-Haloperidol binding in whole brain membranes was also inhibited by the sigma opiates pentazocine, cyclazocine, and (+)-[ 3 H]SKF 10,047. In the striatum, about half of the saturable [ 3 H]haloperidol binding was to [ 3 H]spiperone (D 2 ) sites and the other half was to sites similar to (+)-[ 3 H]SKF 10,047 binding sites. 15 references, 4 figures, 1 table

  10. Repurposing metformin: an old drug with new tricks in its binding pockets

    Science.gov (United States)

    Pryor, Rosina; Cabreiro, Filipe

    2015-01-01

    Improvements in healthcare and nutrition have generated remarkable increases in life expectancy worldwide. This is one of the greatest achievements of the modern world yet it also presents a grave challenge: as more people survive into later life, more also experience the diseases of old age, including type 2 diabetes (T2D), cardiovascular disease (CVD) and cancer. Developing new ways to improve health in the elderly is therefore a top priority for biomedical research. Although our understanding of the molecular basis of these morbidities has advanced rapidly, effective novel treatments are still lacking. Alternative drug development strategies are now being explored, such as the repurposing of existing drugs used to treat other diseases. This can save a considerable amount of time and money since the pharmacokinetics, pharmacodynamics and safety profiles of these drugs are already established, effectively enabling preclinical studies to be bypassed. Metformin is one such drug currently being investigated for novel applications. The present review provides a thorough and detailed account of our current understanding of the molecular pharmacology and signalling mechanisms underlying biguanide–protein interactions. It also focuses on the key role of the microbiota in regulating age-associated morbidities and a potential role for metformin to modulate its function. Research in this area holds the key to solving many of the mysteries of our current understanding of drug action and concerted effects to provide sustained and long-life health. PMID:26475449

  11. The order of condensation in capillary grooves

    International Nuclear Information System (INIS)

    Rascón, Carlos; Parry, Andrew O; Nürnberg, Robert; Pozzato, Alessandro; Tormen, Massimo; Bruschi, Lorenzo; Mistura, Giampaolo

    2013-01-01

    We consider capillary condensation in a deep groove of width L. The transition occurs at a pressure p co (L) described, for large widths, by the Kelvin equation p sat − p co (L) = 2σcosθ/L, where θ is the contact angle at the side walls and σ is the surface tension. The order of the transition is determined by the contact angle of the capped end θ cap ; it is continuous if the liquid completely wets the cap, and first-order otherwise. When the transition is first-order, corner menisci at the bottom of the capillary lead to a pronounced metastability, determined by a complementary Kelvin equation Δp(L) = 2σsinθ cap /L. On approaching the wetting temperature of the capillary cap, the corner menisci merge and a single meniscus unbinds from the bottom of the groove. Finite-size scaling shifts, crossover behaviour and critical singularities are determined at mean-field level and beyond. Numerical and experimental results showing the continuous nature of condensation for θ cap = 0 and the influence of corner menisci on adsorption isotherms are presented. (fast track communication)

  12. The order of condensation in capillary grooves.

    Science.gov (United States)

    Rascón, Carlos; Parry, Andrew O; Nürnberg, Robert; Pozzato, Alessandro; Tormen, Massimo; Bruschi, Lorenzo; Mistura, Giampaolo

    2013-05-15

    We consider capillary condensation in a deep groove of width L. The transition occurs at a pressure p(co)(L) described, for large widths, by the Kelvin equation p(sat) - p(co)(L) = 2σ cosθ/L, where θ is the contact angle at the side walls and σ is the surface tension. The order of the transition is determined by the contact angle of the capped end θcap; it is continuous if the liquid completely wets the cap, and first-order otherwise. When the transition is first-order, corner menisci at the bottom of the capillary lead to a pronounced metastability, determined by a complementary Kelvin equation Δp(L) = 2σ sinθcap/L. On approaching the wetting temperature of the capillary cap, the corner menisci merge and a single meniscus unbinds from the bottom of the groove. Finite-size scaling shifts, crossover behaviour and critical singularities are determined at mean-field level and beyond. Numerical and experimental results showing the continuous nature of condensation for θcap = 0 and the influence of corner menisci on adsorption isotherms are presented.

  13. Drug-binding ability of human serum albumin at children with chronic virus hepatitis radiochemical definition method

    International Nuclear Information System (INIS)

    Kim, A.A.; Dadakhanov, J.A.; Djuraeva, G.T.; Shukurov, B.V.; Mavlyanov, I.R.

    2006-01-01

    chronic virus hepatitis B and C at children the hypoproteinaemia and disproteinemia are observed. Thus the contents of common protein and albumin fraction at chronic hepatitis B is reduced in comparison with control group 1,3 times on the average (P<0,05). It was marked disproteinemia due to increasing of gamma-globulin fraction of blood serum. At a chronic virus hepatitis B at children the ability of serum albumin to bind the tritium labeled drotaverine hydrochloride was reduced in comparison with control groip on the average in 1,3 times. At a chronic hepatitis C hypoproteinemia was expressed less than at a chronic virus hepatitis B, however paid to itself attention more expressed disproteinemia due to increasing of gamma-globulin fraction. Thus ability of serum albumin to bind the tritium labeled drotaverine hydrochloride dropped in comparison with control group on the average in 1,5 times (P<0,05). Thus, received results testify that at a chronic virus hepatitis B and C at children infringement of complexing properties of albumin of a blood is marked that testifies to downstroke of drug-binding function. The radiochemical method of definition of ability of serum albumin to bind the tritium labeled drotaverine hydrochloride is efficient and high informative. (author)

  14. DNA Binding Drugs Targeting the Regulatory DNA Binding Site of the ETS Domain Family Transcription Factor Associated With Human Breast Cancer

    National Research Council Canada - National Science Library

    Wang, Yong-Dong

    1999-01-01

    .... The key approach is to prevent the binding of two transcription factors, ESX and AP-2, to the consensus DNA binding sites contained within the Her2/neu promoter resulting in inhibition of transcription factor function...

  15. Regional blockade by neuroleptic drugs of in vivo /sup 3/H-spiperone binding in the rat brain. Relation to blockade of apomorphine induced hyperactivity and stereotypies

    Energy Technology Data Exchange (ETDEWEB)

    Koehler, C; Haglund, L; Oegren, S O; Aengeby, T [Astra Lackemedel AB, Soedertaelje (Sweden). Dept. of Pharmacology

    1981-01-01

    The regional prevention by neuroleptic drugs of specific in vivo /sup 3/H-spiperone binding was studied in the rat brain. L-sulpiride, thioridazine and clozapine were found to reduce the /sup 3/H-spiperone bindings selectively in the olfactory tubercle, septum, substantia nigra and frontal cortex but not the striatum at dose levels which preferentially block apomorphine (APO) induced hyperactivity. The maximal prevention of specific /sup 3/H-spiperone binding by l-sulpiride and clozapine reached 60-80% in the former structures while the displacement of striatal /sup 3/H-spiperone binding did not exceed 40%. In contrast to l-sulpiride, thioridazine and clozapine both chlorpromazine and haloperidol reduced the /sup 3/H-spiperone binding to the same extent in all regions studied. Chlorpromazine and haloperidol were potent in prevention of striatal /sup 3/H-spiperone binding in vivo which reached 60-80% in this structure.

  16. Regional blockade by neuroleptic drugs of in vivo 3H-spiperone binding in the rat brain. Relation to blockade of apomorphine induced hyperactivity and stereotypies

    International Nuclear Information System (INIS)

    Koehler, C.; Haglund, L.; Oegren, S.-O.; Aengeby, T.

    1981-01-01

    The regional prevention by neuroleptic drugs of specific in vivo 3 H-spiperone binding was studied in the rat brain. L-sulpiride, thioridazine and clozapine were found to reduce the 3 H-spiperone bindings selectively in the olfactory tubercle, septum, substantia nigra and frontal cortex but not the striatum at dose levels which preferentially block apomorphine (APO) induced hyperactivity. The maximal prevention of specific 3 H-spiperone binding by l-sulpiride and clozapine reached 60-80% in the former structures while the displacement of striatal 3 H-spiperone binding did not exceed 40%. In contrast to l-sulpiride, thioridazine and clozapine both chlorpromazine and haloperidol reduced the 3 H-spiperone binding to the same extent in all regions studied. Chlorpromazine and haloperidol were potent in prevention of striatal 3 H-spiperone binding in vivo which reached 60-80% in this structure. (Author)

  17. Numerical analysis of flow in a centrifugal compressor with circumferential grooves: influence of groove location and number on flow instability

    Science.gov (United States)

    Chen, X.; Qin, G.; Ai, Z.; Ji, Y.

    2017-08-01

    As an effective and economic method for flow range enhancement, circumferential groove casing treatment (CGCT) is widely used to increase the stall margin of compressors. Different from traditional grooved casing treatments, in which the grooves are always located over the rotor in both axial and radial compressors, one or several circumferential grooves are located along the shroud side of the diffuser passage in this paper. Numerical investigations were conducted to predict the performance of a low flow rate centrifugal compressor with CGCT in diffuser. Computational fluid dynamics (CFD) analysis is performed under stage environment in order to find the optimum location of the circumferential casing groove in consideration of stall margin enhancement and efficiency gain at design point, and the impact of groove number to the effect of this grooved casing treatment configuration in enhancing the stall margin of the compressor stage is studied. The results indicate that the centrifugal compressor with circumferential groove in vaned diffuser can obtain obvious improvement in the stall margin with sacrificing design efficiency a little. Efforts were made to study blade level flow mechanisms to determine how the CGCT impacts the compressor’s stall margin (SM) and performance. The flow structures in the passage, the tip gap, and the grooves as well as their mutual interactions were plotted and analysed.

  18. DNA modifications by platinum antitumor drugs and its recognition by DNA-binding proteins

    Czech Academy of Sciences Publication Activity Database

    Brabec, Viktor

    2004-01-01

    Roč. 271, Suppl. 1 (2004), s. 90 ISSN 0014-2956. [Meeting of the Federation of the European Biochemical Societies /29./. 26.06.2004-01.07.2004, Warsaw] R&D Projects: GA ČR GA305/02/1552 Keywords : platinum drugs * DNA-protein interaction * NF-kappaB Subject RIV: BO - Biophysics

  19. Low dose tubulin-binding drugs rescue peroxisome trafficking deficit in patient-derived stem cells in Hereditary Spastic Paraplegia

    Directory of Open Access Journals (Sweden)

    Yongjun Fan

    2014-05-01

    Full Text Available Hereditary Spastic Paraplegia (HSP is a genetically heterogeneous group of disorders, diagnosed by progressive gait disturbances with muscle weakness and spasticity, for which there are no treatments targeted at the underlying pathophysiology. Mutations in spastin are a common cause of HSP. Spastin is a microtubule-severing protein whose mutation in mouse causes defective axonal transport. In human patient-derived olfactory neurosphere-derived (ONS cells, spastin mutations lead to lower levels of acetylated α-tubulin, a marker of stabilised microtubules, and to slower speed of peroxisome trafficking. Here we screened multiple concentrations of four tubulin-binding drugs for their ability to rescue levels of acetylated α-tubulin in patient-derived ONS cells. Drug doses that restored acetylated α-tubulin to levels in control-derived ONS cells were then selected for their ability to rescue peroxisome trafficking deficits. Automated microscopic screening identified very low doses of the four drugs (0.5 nM taxol, 0.5 nM vinblastine, 2 nM epothilone D, 10 µM noscapine that rescued acetylated α-tubulin in patient-derived ONS cells. These same doses rescued peroxisome trafficking deficits, restoring peroxisome speeds to untreated control cell levels. These results demonstrate a novel approach for drug screening based on high throughput automated microscopy for acetylated α-tubulin followed by functional validation of microtubule-based peroxisome transport. From a clinical perspective, all the drugs tested are used clinically, but at much higher doses. Importantly, epothilone D and noscapine can enter the central nervous system, making them potential candidates for future clinical trials.

  20. Low dose tubulin-binding drugs rescue peroxisome trafficking deficit in patient-derived stem cells in Hereditary Spastic Paraplegia

    Science.gov (United States)

    Fan, Yongjun; Wali, Gautam; Sutharsan, Ratneswary; Bellette, Bernadette; Crane, Denis I.; Sue, Carolyn M.; Mackay-Sim, Alan

    2014-01-01

    ABSTRACT Hereditary Spastic Paraplegia (HSP) is a genetically heterogeneous group of disorders, diagnosed by progressive gait disturbances with muscle weakness and spasticity, for which there are no treatments targeted at the underlying pathophysiology. Mutations in spastin are a common cause of HSP. Spastin is a microtubule-severing protein whose mutation in mouse causes defective axonal transport. In human patient-derived olfactory neurosphere-derived (ONS) cells, spastin mutations lead to lower levels of acetylated α-tubulin, a marker of stabilised microtubules, and to slower speed of peroxisome trafficking. Here we screened multiple concentrations of four tubulin-binding drugs for their ability to rescue levels of acetylated α-tubulin in patient-derived ONS cells. Drug doses that restored acetylated α-tubulin to levels in control-derived ONS cells were then selected for their ability to rescue peroxisome trafficking deficits. Automated microscopic screening identified very low doses of the four drugs (0.5 nM taxol, 0.5 nM vinblastine, 2 nM epothilone D, 10 µM noscapine) that rescued acetylated α-tubulin in patient-derived ONS cells. These same doses rescued peroxisome trafficking deficits, restoring peroxisome speeds to untreated control cell levels. These results demonstrate a novel approach for drug screening based on high throughput automated microscopy for acetylated α-tubulin followed by functional validation of microtubule-based peroxisome transport. From a clinical perspective, all the drugs tested are used clinically, but at much higher doses. Importantly, epothilone D and noscapine can enter the central nervous system, making them potential candidates for future clinical trials. PMID:24857849

  1. The heparin-binding domain of HB-EGF as an efficient cell-penetrating peptide for drug delivery.

    Science.gov (United States)

    Luo, Zhao; Cao, Xue-Wei; Li, Chen; Wu, Miao-Dan; Yang, Xu-Zhong; Zhao, Jian; Wang, Fu-Jun

    2016-11-01

    Cell-penetrating peptides (CPPs) have been shown to be potential drug carriers for cancer therapy. The inherently low immunogenicity and cytotoxicity of human-derived CPPs make them more suitable for intracellular drug delivery compared to other delivery vehicles. In this work, the protein transduction ability of a novel CPP (termed HBP) derived from the heparin-binding domain of HB-EGF was evaluated. Our data shows, for the first time, that HBP possesses similar properties to typical CPPs and is a potent drug delivery vector for improving the antitumor activity of impermeable MAP30. The intrinsic bioactivities of recombinant MAP30-HBP were well preserved compared to those of free MAP30. Furthermore, HBP conjugated to the C-terminus of MAP30 promoted the cellular uptake of recombinant MAP30-HBP. Moreover, the fusion of HBP to MAP30 gave rise to significantly enhanced cytotoxic effects in all of the tumor cell lines tested. In HeLa cells, this cytotoxicity was mainly caused by the induction of cell apoptosis. Further investigation revealed that HBP enhanced MAP30-induced apoptosis through the activation of the mitochondrial- and death receptor-mediated signaling pathways. In addition, the MAP30-HBP fusion protein caused more HeLa cells to become arrested in S phase compared to MAP30 alone. These results highlight the MAP30-HBP fusion protein as a promising drug candidate for cancer therapy and demonstrate HBP, a novel CPP derived from human HB-EGF, as a new potential vector for antitumor drug delivery. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

  2. A strategy for increasing the brain uptake of a radioligand in animals: use of a drug that inhibits plasma protein binding

    Energy Technology Data Exchange (ETDEWEB)

    Haradahira, Terushi E-mail: terushi@nirs.go.jp; Zhang, Ming-Rong; Maeda, Jun; Okauchi, Takashi; Kawabe, Kouichi; Kida, Takayo; Suzuki, Kazutoshi; Suhara, Tetsuya

    2000-05-01

    A positron-emitter labeled radioligand for the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor, [{sup 11}C]L-703,717, was examined for its ability to penetrate the brain in animals by simultaneous use with drugs having high-affinity separate binding sites on human serum albumin. [{sup 11}C]L-703,717 has poor blood-brain barrier (BBB) permeability because it binds tightly to plasma proteins. Co-injection of warfarin (50-200 mg/kg), a drug that binds to albumin and resembles L-703,717 in structure, dose-dependently enhanced the penetration by [{sup 11}C]L-703,717 in mice, resulting in a five-fold increase in the brain radioactivity at 1 min after the injection. Drugs structurally unrelated to L-703,717, salicylate, phenol red, and L-tryptophan, were less effective or ineffective in increasing the uptake of [{sup 11}C]L-703,717. These results suggest that the simultaneous use of a drug that inhibits the binding of a radioligand to plasma proteins is a useful way to overcome the poor BBB permeability of the radioligand triggered by its tight binding to plasma proteins. In brain distribution studies in rodents, it was found that, after the increase in brain uptake with warfarin, much of the glycine site antagonist accumulates in the cerebellum but its pharmacological specificity did not match the glycine site of NMDA receptors.

  3. A strategy for increasing the brain uptake of a radioligand in animals: use of a drug that inhibits plasma protein binding

    International Nuclear Information System (INIS)

    Haradahira, Terushi; Zhang, Ming-Rong; Maeda, Jun; Okauchi, Takashi; Kawabe, Kouichi; Kida, Takayo; Suzuki, Kazutoshi; Suhara, Tetsuya

    2000-01-01

    A positron-emitter labeled radioligand for the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor, [ 11 C]L-703,717, was examined for its ability to penetrate the brain in animals by simultaneous use with drugs having high-affinity separate binding sites on human serum albumin. [ 11 C]L-703,717 has poor blood-brain barrier (BBB) permeability because it binds tightly to plasma proteins. Co-injection of warfarin (50-200 mg/kg), a drug that binds to albumin and resembles L-703,717 in structure, dose-dependently enhanced the penetration by [ 11 C]L-703,717 in mice, resulting in a five-fold increase in the brain radioactivity at 1 min after the injection. Drugs structurally unrelated to L-703,717, salicylate, phenol red, and L-tryptophan, were less effective or ineffective in increasing the uptake of [ 11 C]L-703,717. These results suggest that the simultaneous use of a drug that inhibits the binding of a radioligand to plasma proteins is a useful way to overcome the poor BBB permeability of the radioligand triggered by its tight binding to plasma proteins. In brain distribution studies in rodents, it was found that, after the increase in brain uptake with warfarin, much of the glycine site antagonist accumulates in the cerebellum but its pharmacological specificity did not match the glycine site of NMDA receptors

  4. Unexpected DNA affinity and sequence selectivity through core rigidity in guanidinium-based minor groove binders.

    Science.gov (United States)

    Nagle, Padraic S; McKeever, Caitriona; Rodriguez, Fernando; Nguyen, Binh; Wilson, W David; Rozas, Isabel

    2014-09-25

    In this paper we report the design and biophysical evaluation of novel rigid-core symmetric and asymmetric dicationic DNA binders containing 9H-fluorene and 9,10-dihydroanthracene cores as well as the synthesis of one of these fluorene derivatives. First, the affinity toward particular DNA sequences of these compounds and flexible core derivatives was evaluated by means of surface plasmon resonance and thermal denaturation experiments finding that the position of the cations significantly influence the binding strength. Then their affinity and mode of binding were further studied by performing circular dichroism and UV studies and the results obtained were rationalized by means of DFT calculations. We found that the fluorene derivatives prepared have the ability to bind to the minor groove of certain DNA sequences and intercalate to others, whereas the dihydroanthracene compounds bind via intercalation to all the DNA sequences studied here.

  5. In vitro DNA binding studies of lenalidomide using spectroscopic in combination with molecular docking techniques

    Science.gov (United States)

    Xu, Liang; Hu, Yan-Xi; Li, Yan-Cheng; Zhang, Li; Ai, Hai-Xin; Liu, Yu-Feng; Liu, Hong-Sheng

    2018-02-01

    In the present work, the binding interaction between lenalidomide (LEN) and calf thymus DNA (ct-DNA) was systematically studied by using fluorescence, ultraviolet-visible (UV-vis) absorption, circular dichroism (CD) spectroscopies under imitated physiological conditions (pH = 7.4) coupled with molecular docking. It was found that LEN was bound to ct-DNA with high binding affinity (Ka = 2.308 × 105 M-1 at 283 K) through groove binding as evidenced by a slight decrease in the absorption intensity in combination with CD spectra. Thermodynamic parameters (ΔG 0 and ΔS interaction. Furthermore, competitive binding experiments with ethidium bromide and 4‧, 6-dia-midino-2-phenylindoleas probes showed that LEN could preferentially bind in the minor groove of double-stranded DNA. The average lifetime of LEN was calculated to be 7.645 ns. The φ of LEN was measured as 0.09 and non-radiation energy transfer between LEN and DNA had occurred. The results of the molecular docking were consistent with the experimental results. This study explored the potential applicability of the spectroscopic properties of LEN and also investigated its interactions with relevant biological targets. In addition, it will provide some theoretical references for the deep research of simultaneous administration of LEN with other drugs.

  6. From the Bandstand to the Classroom: Thinking and Playing Grooves

    Science.gov (United States)

    Baxter, Marsha; Santantasio, Christopher

    2012-01-01

    In this article, narratives of a salsa concert and a lesson with a Native American flute performer provide openings for exploring grooves and their application in the music classroom. The term "groove" is examined, along with some non-Western ideas about time as represented in the music of the West African Kpelle people. A sixth-grade…

  7. Heat transfer and thermal stress analysis in grooved tubes

    Indian Academy of Sciences (India)

    Heat transfer and thermal stresses, induced by temperature differencesin the internally grooved tubes of heat transfer equipment, have been analysed numerically. The analysis has been conducted for four different kinds of internally grooved tubes and three different mean inlet water velocities. Constant temperature was ...

  8. Grooves on the occipital lobe of Indian brains.

    Science.gov (United States)

    Bisaria, K K

    1984-01-01

    The existence of a groove on the occipital lobe formed by the dural venous sinus or ridge has only rarely been described in the past. As observed in this study such grooves are either unilateral or bilateral and their incidence is very high in Indian brains. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:6490537

  9. Grooves on the occipital lobe of Indian brains.

    OpenAIRE

    Bisaria, K K

    1984-01-01

    The existence of a groove on the occipital lobe formed by the dural venous sinus or ridge has only rarely been described in the past. As observed in this study such grooves are either unilateral or bilateral and their incidence is very high in Indian brains.

  10. Observations of secondary oscillations in thermal grain boundary grooves

    International Nuclear Information System (INIS)

    Sachenko, P.P.; Schneibel, J.H.; Zhang, W.

    2004-01-01

    Thermal grain boundary grooving by surface diffusion is accompanied not only by main maxima on either side of a groove, but also by secondary maxima and minima. We measure these oscillations in tungsten and give reasons why the observed secondary maxima and minima are larger than predicted

  11. Computational Biology Tools for Identifying Specific Ligand Binding Residues for Novel Agrochemical and Drug Design.

    Science.gov (United States)

    Neshich, Izabella Agostinho Pena; Nishimura, Leticia; de Moraes, Fabio Rogerio; Salim, Jose Augusto; Villalta-Romero, Fabian; Borro, Luiz; Yano, Inacio Henrique; Mazoni, Ivan; Tasic, Ljubica; Jardine, Jose Gilberto; Neshich, Goran

    2015-01-01

    The term "agrochemicals" is used in its generic form to represent a spectrum of pesticides, such as insecticides, fungicides or bactericides. They contain active components designed for optimized pest management and control, therefore allowing for economically sound and labor efficient agricultural production. A "drug" on the other side is a term that is used for compounds designed for controlling human diseases. Although drugs are subjected to much more severe testing and regulation procedures before reaching the market, they might contain exactly the same active ingredient as certain agrochemicals, what is the case described in present work, showing how a small chemical compound might be used to control pathogenicity of Gram negative bacteria Xylella fastidiosa which devastates citrus plantations, as well as for control of, for example, meningitis in humans. It is also clear that so far the production of new agrochemicals is not benefiting as much from the in silico new chemical compound identification/discovery as pharmaceutical production. Rational drug design crucially depends on detailed knowledge of structural information about the receptor (target protein) and the ligand (drug/agrochemical). The interaction between the two molecules is the subject of analysis that aims to understand relationship between structure and function, mainly deciphering some fundamental elements of the nanoenvironment where the interaction occurs. In this work we will emphasize the role of understanding nanoenvironmental factors that guide recognition and interaction of target protein and its function modifier, an agrochemical or a drug. The repertoire of nanoenvironment descriptors is used for two selected and specific cases we have approached in order to offer a technological solution for some very important problems that needs special attention in agriculture: elimination of pathogenicity of a bacterium which is attacking citrus plants and formulation of a new fungicide. Finally

  12. Olfactory groove meningiomas: approaches and complications.

    Science.gov (United States)

    Aguiar, Paulo Henrique Pires de; Tahara, Adriana; Almeida, Antonio Nogueira; Simm, Renata; Silva, Arnaldo Neves da; Maldaun, Marcos Vinicius Calfatt; Panagopoulos, Alexandros Theodoros; Zicarelli, Carlos Alexandre; Silva, Pedro Gabriel

    2009-09-01

    Olfactory groove meningiomas (OGM) account for 4.5% of all intracranial meningiomas. We report 21 patients with OGMs. Tumors were operated on using three surgical approaches: bifrontal (7 patients), fronto-pterional (11 patients) and fronto-orbital (3 patients). Total tumor removal (Simpson Grade 1) was achieved in 13 patients and Simpson II in 8 patients. Perioperative mortality was 4.76%. The average size of the OGM was 4.3+/-1.1cm. The overall recurrence rate was 19%. We preferred to use the pterional approach, which provides quick access to the tumor with less brain exposure. It also allows complete drainage of cisternal cerebrospinal fluid, providing a good level of brain relaxation during surgery. However, for long, thin tumors, hemostasis can be difficult using this approach.

  13. Laboratory automation of high-quality and efficient ligand-binding assays for biotherapeutic drug development.

    Science.gov (United States)

    Wang, Jin; Patel, Vimal; Burns, Daniel; Laycock, John; Pandya, Kinnari; Tsoi, Jennifer; DeSilva, Binodh; Ma, Mark; Lee, Jean

    2013-07-01

    Regulated bioanalytical laboratories that run ligand-binding assays in support of biotherapeutics development face ever-increasing demand to support more projects with increased efficiency. Laboratory automation is a tool that has the potential to improve both quality and efficiency in a bioanalytical laboratory. The success of laboratory automation requires thoughtful evaluation of program needs and fit-for-purpose strategies, followed by pragmatic implementation plans and continuous user support. In this article, we present the development of fit-for-purpose automation of total walk-away and flexible modular modes. We shared the sustaining experience of vendor collaboration and team work to educate, promote and track the use of automation. The implementation of laboratory automation improves assay performance, data quality, process efficiency and method transfer to CRO in a regulated bioanalytical laboratory environment.

  14. Plasma interaction with emmissive surface with Debye-scale grooves

    Science.gov (United States)

    Schweigert, Irina; Burton, Thomas S.; Thompson, Gregory B.; Langendorf, Samuel; Walker, Mitchell L. R.; Keidar, Michael

    2018-04-01

    The sheath development over emissive grooved surface in dc discharge plasma controlled by an electron beam is studied in the experiment and in 2D kinetic simulations. Grooved hexagonal boron nitride surfaces with different aspect ratios, designed to mimic the erosion channels, were exposed to an argon plasma. The characteristic size of the grooves (1 mm and 5 mm) is about of the Debye length. The secondary electrons emission from the grooved surfaces is provided by the bombardment with energetic electrons originated from the heated powered cathode. The transition between a developed and a collapsed sheaths near emissive surface takes place with an increase of the beam electron energy. For grooved emissive surfaces, the sheath transition happens at essentially higher voltage compared to the planar one. This phenomenon is analyzed in the terms of the electron energy distribution function.

  15. Characteristics of Multiplexed Grooved Nozzles for High Flow Rate Electrospray

    International Nuclear Information System (INIS)

    Kim, Kyoung Tae; Kim, Woo Jin; Kim, Sang Soo

    2007-01-01

    The electrospray operated in the cone-jet mode can generate highly charged micro droplets in an almost uniform size at flow rates. Therefore, the multiplexing system which can retain the characteristics of the cone-jet mode is inevitable for the electrospray application. This experiment reports the multiplexed grooved nozzle system with the extractor. The effects of the grooves and the extractor on the performance of the electrospray were evaluated through experiments. Using the grooved nozzle, the stable cone-jet mode can be achieved at the each groove in the grooved mode. Furthermore, the number of nozzles per unit area is increased by the extractor. The multiplexing density is 12 jets per cm 2 at 30 mm distance from the nozzle tip to the ground plate. The multiplexing system for the high flow rate electrospray is realized with the extractor which can diminish the space charge effect without sacrificing characteristics of the cone-jet mode

  16. Elimination of Endogenous Toxin, Creatinine from Blood Plasma Depends on Albumin Conformation: Site Specific Uremic Toxicity & Impaired Drug Binding

    Science.gov (United States)

    Varshney, Ankita; Rehan, Mohd; Subbarao, Naidu; Rabbani, Gulam; Khan, Rizwan Hasan

    2011-01-01

    Uremic syndrome results from malfunctioning of various organ systems due to the retention of uremic toxins which, under normal conditions, would be excreted into the urine and/or metabolized by the kidneys. The aim of this study was to elucidate the mechanisms underlying the renal elimination of uremic toxin creatinine that accumulate in chronic renal failure. Quantitative investigation of the plausible correlations was performed by spectroscopy, calorimetry, molecular docking and accessibility of surface area. Alkalinization of normal plasma from pH 7.0 to 9.0 modifies the distribution of toxin in the body and therefore may affect both the accumulation and the rate of toxin elimination. The ligand loading of HSA with uremic toxin predicts several key side chain interactions of site I that presumably have the potential to impact the specificity and impaired drug binding. These findings provide useful information for elucidating the complicated mechanism of toxin disposition in renal disease state. PMID:21386972

  17. A binding site for non-steroidal anti-inflammatory drugs in FAAH

    Science.gov (United States)

    Bertolacci, Laura; Romeo, Elisa; Veronesi, Marina; Magotti, Paola; Albani, Clara; Dionisi, Mauro; Lambruschini, Chiara; Scarpelli, Rita; Cavalli, Andrea; Vivo, Marco De; Piomelli, Daniele; Garau, Gianpiero

    2013-01-01

    In addition to inhibiting the cyclooxygenasemediated biosynthesis of prostanoids, various widely used non-steroidal anti-inflammatory drugs (NSAIDs) enhance endocannabinoid signaling by blocking the anandamidedegrading membrane enzyme, fatty acid amide hydrolase (FAAH). The X-ray structure of FAAH in complex with the NSAID carprofen, along with studies of site-directed mutagenesis, enzyme activity assays, and nuclear magnetic resonance, now reveal the molecular details of this interaction, providing information that may guide the design of dual FAAH-cyclooxygenase inhibitors with superior analgesic efficacy. PMID:23240907

  18. Assessment of Drug Binding Potential of Pockets in the NS2B/NS3 Dengue Virus Protein

    Science.gov (United States)

    Amelia, F.; Iryani; Sari, P. Y.; Parikesit, A. A.; Bakri, R.; Toepak, E. P.; Tambunan, U. S. F.

    2018-04-01

    Every year an endemic dengue fever estimated to affect over 390 million cases in over 128 countries occurs. However, the antigen types which stimulate the human immune response are variable, as a result, neither effective vaccines nor antiviral treatments have been successfully developed for this disease. The NS2B/NS3 protease of the dengue virus (DENV) responsible for viral replication is a potential drug target. The ligand-enzyme binding site determination is a key role in the success of virtual screening of new inhibitors. The NS2B/NS3 protease of DENV (PDB ID: 2FOM) has two pockets consisting of 37 (Pocket 1) and 27 (Pocket 2) amino acid residues in each pocket. In this research, we characterized the amino acid residues for binding sites in NS3/NS2B based on the hydrophobicity, the percentage of charged residues, volume, depth, ΔGbinding, hydrogen bonding and bond length. The hydrophobic percentages of both pockets are high, 59 % (Pocket 1) and 41% (Pocket 2) and the percentage of charged residues in Pocket 1 and 2 are 22% and 48%, and the pocket volume is less than 700 Å3. An interaction analysis using molecular docking showed that interaction between the ligand complex and protein in Pocket 1 is more negative than Pocket 2. As a result, Pocket 1 is the better potential target for a ligand to inhibit the action of NS2B/NS3 DENV.

  19. Calculating Water Thermodynamics in the Binding Site of Proteins - Applications of WaterMap to Drug Discovery.

    Science.gov (United States)

    Cappel, Daniel; Sherman, Woody; Beuming, Thijs

    2017-01-01

    The ability to accurately characterize the solvation properties (water locations and thermodynamics) of biomolecules is of great importance to drug discovery. While crystallography, NMR, and other experimental techniques can assist in determining the structure of water networks in proteins and protein-ligand complexes, most water molecules are not fully resolved and accurately placed. Furthermore, understanding the energetic effects of solvation and desolvation on binding requires an analysis of the thermodynamic properties of solvent involved in the interaction between ligands and proteins. WaterMap is a molecular dynamics-based computational method that uses statistical mechanics to describe the thermodynamic properties (entropy, enthalpy, and free energy) of water molecules at the surface of proteins. This method can be used to assess the solvent contributions to ligand binding affinity and to guide lead optimization. In this review, we provide a comprehensive summary of published uses of WaterMap, including applications to lead optimization, virtual screening, selectivity analysis, ligand pose prediction, and druggability assessment. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  20. Drug binding affinities and potencies are best described by a log-normal distribution and use of geometric means

    International Nuclear Information System (INIS)

    Stanisic, D.; Hancock, A.A.; Kyncl, J.J.; Lin, C.T.; Bush, E.N.

    1986-01-01

    (-)-Norepinephrine (NE) is used as an internal standard in their in vitro adrenergic assays, and the concentration of NE which produces a half-maximal inhibition of specific radioligand binding (affinity; K/sub I/), or half-maximal contractile response (potency; ED 50 ) has been measured numerous times. The goodness-of-fit test for normality was performed on both normal (Gaussian) or log 10 -normal frequency histograms of these data using the SAS Univariate procedure. Specific binding of 3 H-prazosin to rat liver (α 1 -), 3 H rauwolscine to rat cortex (α 2 -) and 3 H-dihydroalprenolol to rat ventricle (β 1 -) or rat lung (β 2 -receptors) was inhibited by NE; the distributions of NE K/sub I/'s at all these sites were skewed to the right, with highly significant (p 50 's of NE in isolated rabbit aorta (α 1 ), phenoxybenzamine-treated dog saphenous vein (α 2 ) and guinea pig atrium (β 1 ). The vasorelaxant potency of atrial natriuretic hormone in histamine-contracted rabbit aorta also was better described by a log-normal distribution, indicating that log-normalcy is probably a general phenomenon of drug-receptor interactions. Because data of this type appear to be log-normally distributed, geometric means should be used in parametric statistical analyses

  1. Protein and Drug Interactions in the Minor Groove of DNA

    Czech Academy of Sciences Publication Activity Database

    Morávek, Z.; Neidle, S.; Schneider, Bohdan

    2002-01-01

    Roč. 30, č. 5 (2002), s. 1182-1191 ISSN 0305-1048 R&D Projects: GA MŠk LN00A032 Institutional research plan: CEZ:AV0Z4040901 Keywords : protein * DNA * interactions Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 7.051, year: 2002

  2. Heparin-binding peptide amphiphile supramolecular architectures as platforms for angiogenesis and drug delivery

    Science.gov (United States)

    Chow, Lesleyann W.

    A fascinating phenomenon in nature is the self-assembly of molecules into a functional, hierarchical structure. In the past decade, the Stupp Laboratory has developed several classes of self-assembling biomaterials, one of which is the synthetic peptide amphiphile (PA). Self-assembling PAs are attractive and versatile biomolecules that can be customized for specific applications in regenerative medicine. In particular, a heparin-binding peptide amphiphile (HBPA) containing a specific heparin-binding peptide sequence was used here to induce angiogenesis and serve as a delivery vehicle for growth factors and small hydrophobic molecules. Throughout this dissertation, the HBPA/heparin system is used in different architectures for a variety of regenerative medicine applications. In one aspect of this work, hybrid scaffolds made from HBPA/heparin gelled on a poly(L-lactic acid) (PLLA) fiber mesh were used to promote angiogenesis to facilitate pancreatic islet transplantation for the treatment of type 1 diabetes. Delivery of growth factors with HBPA/PLLA scafflolds increased vessel density in vivo and correlated with improved transplant outcomes in a streptozotocin-induced diabetic mouse model. Soluble HBPA nanofiber architectures were also useful for islet transplantation applications. These nanofibers were used at concentrations below gelation to deliver growth factors into the dense islet cell aggregate, promoting cell survival and angiogenesis in vitro. The nanostructures infiltrated the islets and promoted the retention of heparin and growth factors within the islet. Another interesting growth factor release system discussed here is the HBPA membrane structure. HBPA was found to self-assemble with hyaluronic acid, a large biopolymer found in the body, into macroscopic, hierarchically-ordered membranes. Heparin was incorporated into these membranes and affected the membrane's mechanical properties and growth factor release. Human mesenchymal stem cells were also shown

  3. 2D IR spectroscopy reveals the role of water in the binding of channel-blocking drugs to the influenza M2 channel

    International Nuclear Information System (INIS)

    Ghosh, Ayanjeet; Gai, Feng; Hochstrasser, Robin M.; Wang, Jun; DeGrado, William F.; Moroz, Yurii S.; Korendovych, Ivan V.; Zanni, Martin

    2014-01-01

    Water is an integral part of the homotetrameric M2 proton channel of the influenza A virus, which not only assists proton conduction but could also play an important role in stabilizing channel-blocking drugs. Herein, we employ two dimensional infrared (2D IR) spectroscopy and site-specific IR probes, i.e., the amide I bands arising from isotopically labeled Ala30 and Gly34 residues, to probe how binding of either rimantadine or 7,7-spiran amine affects the water dynamics inside the M2 channel. Our results show, at neutral pH where the channel is non-conducting, that drug binding leads to a significant increase in the mobility of the channel water. A similar trend is also observed at pH 5.0 although the difference becomes smaller. Taken together, these results indicate that the channel water facilitates drug binding by increasing its entropy. Furthermore, the 2D IR spectral signatures obtained for both probes under different conditions collectively support a binding mechanism whereby amantadine-like drugs dock in the channel with their ammonium moiety pointing toward the histidine residues and interacting with a nearby water cluster, as predicted by molecular dynamics simulations. We believe these findings have important implications for designing new anti-influenza drugs

  4. 2D IR spectroscopy reveals the role of water in the binding of channel-blocking drugs to the influenza M2 channel

    Energy Technology Data Exchange (ETDEWEB)

    Ghosh, Ayanjeet, E-mail: ayanjeet@sas.upenn.edu, E-mail: gai@sas.upenn.edu; Gai, Feng, E-mail: ayanjeet@sas.upenn.edu, E-mail: gai@sas.upenn.edu; Hochstrasser, Robin M. [Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104 (United States); Wang, Jun; DeGrado, William F. [Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California 94143 (United States); Moroz, Yurii S.; Korendovych, Ivan V. [Department of Chemistry, Syracuse University, Syracuse, New York 13244 (United States); Zanni, Martin [Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706 (United States)

    2014-06-21

    Water is an integral part of the homotetrameric M2 proton channel of the influenza A virus, which not only assists proton conduction but could also play an important role in stabilizing channel-blocking drugs. Herein, we employ two dimensional infrared (2D IR) spectroscopy and site-specific IR probes, i.e., the amide I bands arising from isotopically labeled Ala30 and Gly34 residues, to probe how binding of either rimantadine or 7,7-spiran amine affects the water dynamics inside the M2 channel. Our results show, at neutral pH where the channel is non-conducting, that drug binding leads to a significant increase in the mobility of the channel water. A similar trend is also observed at pH 5.0 although the difference becomes smaller. Taken together, these results indicate that the channel water facilitates drug binding by increasing its entropy. Furthermore, the 2D IR spectral signatures obtained for both probes under different conditions collectively support a binding mechanism whereby amantadine-like drugs dock in the channel with their ammonium moiety pointing toward the histidine residues and interacting with a nearby water cluster, as predicted by molecular dynamics simulations. We believe these findings have important implications for designing new anti-influenza drugs.

  5. Electrophoresis in ice surface grooves for probing protein affinity to a specific plane of ice crystal.

    Science.gov (United States)

    Inagawa, Arinori; Okada, Yusuke; Okada, Tetsuo

    2018-06-01

    Channel-like grooves are formed on the surface of frozen aqueous sucrose. They are filled with a freeze concentrated solution (FCS) and act as an efficient size-tunable separation field for micro and nanoparticles. The width of the channel can be easily varied by changing the temperature. Because the channel width decreases with decreasing temperature, particles become immobilized due to physical interference from the ice wall when the temperature reaches a threshold point specific to the particle size. Surface modification of particles can add a factor of chemical interaction between the particles and ice walls. In this study, anti-freeze proteins (AFPs) are anchored on 1µm-polystyrene (PS) particles, and their behavior in the surface grooves on the ice is studied. The threshold temperature is an effective criterion for evaluating chemical interactions between particles and ice walls. The AFP binding on 1µm PS particles lowers the threshold temperature by 2.5°C, indicating interactions between AFPs on the PS particles and the ice wall. Because the AFPs studied here show selectivity towards the prism plane, it is critical that the prism plane of the ice crystal is in contact with the FCS in the surface grooves. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Double-grooved nanofibre surfaces with enhanced anisotropic hydrophobicity.

    Science.gov (United States)

    Liang, Meimei; Chen, Xin; Xu, Yang; Zhu, Lei; Jin, Xiangyu; Huang, Chen

    2017-11-02

    This study reports a facile method for fabricating double-grooved fibrous surfaces. The primary grooves of the surface are formed by aligned fibres, while the secondary grooves are achieved by oriented nanogrooves on the fibre surface. Investigation into the formation mechanism reveals that the nanogrooves can be readily tailored through adjusting the solvent ratio and relative humidity. With this understanding, a variety of polymers have been successfully electrospun into fibres having the same nanogrooved feature. These fibres show high resemblance to natural hierarchical structures, and thereby endowing the corresponding double-grooved surface with enhanced anisotropic hydrophobicity. A water droplet at a parallel direction to the grooves exhibits a much higher contact angle and a lower roll-off angle than the droplet at a perpendicular direction. The application potential of such anisotropic hydrophobicity has been demonstrated via a fog collection experiment, in which the double-grooved surface can harvest the largest amount of water. Moreover, the fabrication method requires neither post-treatment nor sophisticated equipment, making us anticipate that the double-grooved surface would be competitive in areas where a highly ordered surface, a large surface area and an anisotropic hydrophobicity are preferred.

  7. Evaluations of in vitro metabolism, drug-drug interactions mediated by reversible and time-dependent inhibition of CYPs, and plasma protein binding of MMB4 DMS.

    Science.gov (United States)

    Hong, S Peter; Lusiak, Bozena D; Burback, Brian L; Johnson, Jerry D

    2013-01-01

    1,1'-Methylenebis[4-[(hydroxyimino)methyl]-pyridinium] (MMB4) dimethanesulfonate (DMS) is a bisquaternary pyridinium aldoxime that reactivates acetylcholinesterase inhibited by organophosphorus nerve agent. Drug metabolism and plasma protein binding for MMB4 DMS were examined using various techniques and a wide range of species. When (14)C-MMB4 DMS was incubated in liver microsomes, 4-pyridine aldoxime (4-PA) and an additional metabolite were detected in all species tested. Identity of the additional metabolite was postulated to be isonicotinic acid (INA) based on liquid chromatography with a tandem mass spectrometry analysis, which was confirmed by comparison with authentic INA. Formation of INA was dependent on species, with the highest level found in monkey liver microsomes. The MMB4 DMS exhibited reversible inhibition in a concentration-dependent manner toward cytochrome P450 1A2 (CYP1A2), CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in human liver microsomes showing the highest inhibition for CYP2D6. Human recombinant CYPs were used to evaluate inhibitory curves more adequately and determine detailed kinetic constants for reversible inhibition and potential time-dependent inhibition (TDI). The MMB4 DMS exhibited reversible inhibition toward human-recombinant CYP2D6 with an inhibition constant (K i) value of 66.6 µmol/L. Based on the k inact/K I values, MMB4 DMS was found to exhibit the most potent TDI toward CYP2D6. The MMB4 DMS at 5 different concentrations was incubated in plasma for 5 hours using an equilibrium dialysis device. For all species tested, there were no concentration-dependent changes in plasma protein binding, ranging from 10% to 17%. These results suggest that MMB4 was not extensively bound to plasma protein, and there were no overt species-related differences in the extent of MMB4 bound to plasma protein.

  8. Binding studies of guggulsterone-E to calf thymus DNA by multi-spectroscopic, calorimetric and molecular docking studies

    Science.gov (United States)

    Ikhlas, Shoeb; Ahmad, Masood

    2018-02-01

    Guggulsterone, a sterol found in plants is used as an ayurvedic medicine for many diseases such as obesity, internal tumors, ulcers etc. E and Z are two isoforms of guggulsterone, wherein guggulsterone-E (GUGE) has also been shown to have anticancer potential. Most of the anticancer drugs target nucleic acids. Therefore, we studied the mode of interaction between ctDNA and GUGE using UV-Vis, fluorescence and CD spectroscopy, isothermal calorimetry along with molecular docking studies. Hoechst 3325, ethidium bromide and rhodamine-B displacement experiments confirms that GUGE binds in the minor groove of DNA. ITC results further suggest these interactions to be feasible and spontaneous with hydrogen bond formation and van der waals interactions. Lastly, molecular docking also suggests GUGE to be a minor groove binder interacting through a single hydrogen bond formation between OH group of GUGE and nitrogen (N3) of adenosine (A6).

  9. Vacuum sealing with a spiral grooved gas dynamic seal

    International Nuclear Information System (INIS)

    Sawada, Tadashi

    1979-01-01

    Gas dynamic seals with rectangular spiral grooves are studied theoretically taking the effects of sidewalls of the grooves and the effects of gas compressibility into account, and slip boundary conditions are employed. The results are compared with the existing experimental data and the validity of the theory is confirmed over a wide pressure range except for the extremely low pressures. Suggestions are made regarding the choice of the geometrical dimensions, i.e., aspect ratio, helix angle, clearance parameter and groove width ratio. (author)

  10. Grooved Fuel Rings for Nuclear Thermal Rocket Engines

    Science.gov (United States)

    Emrich, William

    2009-01-01

    An alternative design concept for nuclear thermal rocket engines for interplanetary spacecraft calls for the use of grooved-ring fuel elements. Beyond spacecraft rocket engines, this concept also has potential for the design of terrestrial and spacecraft nuclear electric-power plants. The grooved ring fuel design attempts to retain the best features of the particle bed fuel element while eliminating most of its design deficiencies. In the grooved ring design, the hydrogen propellant enters the fuel element in a manner similar to that of the Particle Bed Reactor (PBR) fuel element.

  11. Investigation of the binding free energies of FDA approved drugs against subtype B and C-SA HIV PR: ONIOM approach.

    Science.gov (United States)

    Sanusi, Z K; Govender, T; Maguire, G E M; Maseko, S B; Lin, J; Kruger, H G; Honarparvar, B

    2017-09-01

    Human immune virus subtype C is the most widely spread HIV subtype in Sub-Sahara Africa and South Africa. A profound structural insight on finding potential lead compounds is therefore necessary for drug discovery. The focus of this study is to rationalize the nine Food and Drugs Administration (FDA) HIV antiviral drugs complexed to subtype B and C-SA PR using ONIOM approach. To achieve this, an integrated two-layered ONIOM model was used to optimize the geometrics of the FDA approved HIV-1 PR inhibitors for subtype B. In our hybrid ONIOM model, the HIV-1 PR inhibitors as well as the ASP 25/25' catalytic active residues were treated at high level quantum mechanics (QM) theory using B3LYP/6-31G(d), and the remaining HIV PR residues were considered using the AMBER force field. The experimental binding energies of the PR inhibitors were compared to the ONIOM calculated results. The theoretical binding free energies (?G bind ) for subtype B follow a similar trend to the experimental results, with one exemption. The computational model was less suitable for C-SA PR. Analysis of the results provided valuable information about the shortcomings of this approach. Future studies will focus on the improvement of the computational model by considering explicit water molecules in the active pocket. We believe that this approach has the potential to provide much improved binding energies for complex enzyme drug interactions. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Extending the scope of amantadine drug by incorporation of phenolic azo Schiff bases as potent selective inhibitors of carbonic anhydrase II, drug likeness and binding analysis.

    Science.gov (United States)

    Channar, Pervaiz Ali; Saeed, Aamer; Shahzad, Danish; Larik, Fayaz Ali; Hassan, Mubashir; Raza, Hussain; Abbas, Qamar; Seo, Sung-Yum

    2018-05-16

    A series of Amantadine based azo Schiff base dyes 6a-6e have been synthesized and characterized by 1 H NMR and 13 C NMR and evaluated for their in vitro carbonic anhydrase II inhibition activity and antioxidant activity. All of the synthesized showed excellent carbonic inhibition. Compound 6b was found to be the most potent derivative in the series, the IC 50 of 6b was found to be 0.0849 ± 0.00245μM (standard Acetazolamide IC 50 =0.9975±0.049μM). The binding interactions of the most active analogs were confirmed through molecular docking studies. Docking studies showed 6b is interacting by making two hydrogen bonds w at His93 and Ser1 residues respectively. All compounds showed a good drug score and followed Lipinski's rule. In summary, our studies have shown that these amantadine derived phenolic azo Schiff base derivatives are a new class of carbonic anhydrase II inhibitors. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  13. Investigation of β-lactam antibacterial drugs, β-lactamases, and penicillin-binding proteins with fluorescence polarization and anisotropy: a review

    Science.gov (United States)

    Shapiro, Adam B.

    2016-06-01

    This review covers the uses of fluorescence polarization and anisotropy for the investigation of bacterial penicillin binding proteins (PBPs), which are the targets of β-lactam antibacterial drugs (penicillins, cephalosporins, carbapenems, and monobactams), and of the β-lactamase enzymes that destroy these drugs and help to render bacterial pathogens resistant to them. Fluorescence polarization and anisotropy-based methods for quantitation of β-lactam drugs are also reviewed. A particular emphasis is on methods for quantitative measurement of the interactions of β-lactams and other inhibitors with PBPs and β-lactamases.

  14. Surgical Management of Olfactory Groove Meningiomas | El-Naggar ...

    African Journals Online (AJOL)

    Objective: To study the bifrontal approach to olfactory groove meningiomas ... in all patients was Grade I meningiomas (World Health Organization grading). ... Bifrontal approach offers excellent exposure, and when combined with modern ...

  15. Interproximal grooving in the Atapuerca-SH hominid dentitions.

    Science.gov (United States)

    Bermúdez de Castro, J M; Arsuaga, J L; Pérez, P J

    1997-03-01

    The dental sample recovered from the Sima de los Huesos (SH) Middle Pleistocene cave site of the Sierra de Atapuerca (Spain) includes 296 specimens. Interproximal wear grooves have been observed in 20 maxillary and mandibular posterior teeth belonging to at least five of the 32 individuals identified so far in the SH hypodigm. Interproximal grooving affected only the adults, and at an age between 25 and 40 years. The appearance, morphology, and location pattern of the SH wear grooves are similar to those reported in other fossil hominids and in more recent human populations. Two alternative proposals, the toothpicking and the fiber or sinew processing hypotheses, compete for explaining the formation of this anomalous wear. The characteristics observed in the wear grooves of the SH teeth are compatible only with the habitual probing of interdental spaces by means of hard and inflexible objects. Dietary grit may also have contributed to the abrasion of the root walls during the motion of the dental probes.

  16. Fractures of the proximal humerus involving the intertubercular groove

    International Nuclear Information System (INIS)

    Ahovuo, J.; Paavolainen, P.; Bjoerkenheim, J.M.; Helsinki Univ. Central Hospital

    1989-01-01

    The purpose of this study was to analyse the involvement of the gliding surface of the biceps tendon in fractures of the proximal humerus. Fifteen patients had a fracture of the proximal humerus verified with antero-posterior and axillary radiographs. Tangential radiographs of the intertubercular groove, obtained from the shoulder joint, showed involvement of the intertubercular groove in 13 patients (87%), which could not be shown with other projections. Groove radiographs revealed in 3 patients a dislocation of the fragments of the greater tuberosity large enough to require surgical treatment, but which had not been found using conventional techniques. Therefore, a groove radiograph should be used to precise fractures of the proximal humerus. (orig.)

  17. V-groove plasmonic waveguides fabricated by nanoimprint lithography

    DEFF Research Database (Denmark)

    Fernandez-Cuesta, I.; Nielsen, R.B.; Boltasseva, Alexandra

    2007-01-01

    Propagation of channel plasmon-polariton modes in the bottom of a metal V groove has been recently demonstrated. It provides a unique way of manipulating light at nanometer length scale. In this work, we present a method based on nanoimprint lithography that allows parallel fabrication of integra...... of integrated optical devices composed of metal V grooves. This method represents an improvement with respect to previous works, where the V grooves were fabricated by direct milling of the metal, in terms of robustness and throughput. © 2007 American Vacuum Society......Propagation of channel plasmon-polariton modes in the bottom of a metal V groove has been recently demonstrated. It provides a unique way of manipulating light at nanometer length scale. In this work, we present a method based on nanoimprint lithography that allows parallel fabrication...

  18. Homology modeling and docking analyses of M. leprae Mur ligases reveals the common binding residues for structure based drug designing to eradicate leprosy.

    Science.gov (United States)

    Shanmugam, Anusuya; Natarajan, Jeyakumar

    2012-06-01

    Multi drug resistance capacity for Mycobacterium leprae (MDR-Mle) demands the profound need for developing new anti-leprosy drugs. Since most of the drugs target a single enzyme, mutation in the active site renders the antibiotic ineffective. However, structural and mechanistic information on essential bacterial enzymes in a pathway could lead to the development of antibiotics that targets multiple enzymes. Peptidoglycan is an important component of the cell wall of M. leprae. The biosynthesis of bacterial peptidoglycan represents important targets for the development of new antibacterial drugs. Biosynthesis of peptidoglycan is a multi-step process that involves four key Mur ligase enzymes: MurC (EC:6.3.2.8), MurD (EC:6.3.2.9), MurE (EC:6.3.2.13) and MurF (EC:6.3.2.10). Hence in our work, we modeled the three-dimensional structure of the above Mur ligases using homology modeling method and analyzed its common binding features. The residues playing an important role in the catalytic activity of each of the Mur enzymes were predicted by docking these Mur ligases with their substrates and ATP. The conserved sequence motifs significant for ATP binding were predicted as the probable residues for structure based drug designing. Overall, the study was successful in listing significant and common binding residues of Mur enzymes in peptidoglycan pathway for multi targeted therapy.

  19. [Developmental radicular groove as a cause of endodontic failure].

    Science.gov (United States)

    Fabra Campos, H; Millet Part, J

    1989-01-01

    A clinical case of apical injury on an upper lateral incisor with endodontical and surgical failures in its treatment is presented. Extraction of the incisor and its study at the stereoscopic microscope showed the existence of a developmental groove running from the cingulum to the end of the root, establishing a communication between the crevice and the apical part of the tooth. Bacterial infection through the groove could provide an explanation for treatment failure.

  20. Evaluation of the binding of the radiolabeled antidepressant drug, {sup 18}F-fluoxetine in the rodent brain: an in vitro and in vivo study

    Energy Technology Data Exchange (ETDEWEB)

    Mukherjee, Jogeshwar E-mail: jogeshwar_mukherjee@ketthealth.com; Das, Malay K.; Yang Zhiying; Lew, Robert

    1998-10-01

    We have developed {sup 18}F-fluoxetine as a radiotracer analog of the antidepressant drug fluoxetine (Prozac). In vitro saturation experiments of {sup 18}F-fluoxetine were carried out on rat midbrain tissue and citalopram was used for measuring nonspecific binding. A saturation curve for the binding of {sup 18}F-fluoxetine was not obtained. Even when fluoxetine (10 {mu}M) was used for measurements of nonspecific binding, a saturation curve was difficult to obtain. Other compounds, such as deprenyl, clorgyline, amphetamine, and reserpine were also not able to reduce the binding of {sup 18}F-fluoxetine. Ex vivo autoradiographic experiments with {sup 18}F-fluoxetine did not reveal any specific uptake in various brain regions. In vivo administration of {sup 18}F-fluoxetine in rats showed similar uptake in all the brain regions with little regional selectivity. A subcellular analysis of rat brain tissue after intravenous (IV) administration of {sup 18}F-fluoxetine indicated significant amounts of binding in mitochondria and synaptosomes. In summary, in vitro experiments with {sup 18}F-fluoxetine indicate little specific binding. Binding to the serotonin transporter was not identifiable. High nonspecific binding of the tracer resulting from its subcellular nature in the brain masks the ability to detect binding to the serotonin uptake sites in vivo. These findings indicate that a large portion of the binding of {sup 18}F-fluoxetine in rat brains is subcellular and clears slowly out of the cells. Other sites, such as monoamine oxidase, may also play a significant role in the action of fluoxetine.

  1. Evaluation of the binding of the radiolabeled antidepressant drug, 18F-fluoxetine in the rodent brain: an in vitro and in vivo study

    International Nuclear Information System (INIS)

    Mukherjee, Jogeshwar; Das, Malay K.; Yang Zhiying; Lew, Robert

    1998-01-01

    We have developed 18 F-fluoxetine as a radiotracer analog of the antidepressant drug fluoxetine (Prozac). In vitro saturation experiments of 18 F-fluoxetine were carried out on rat midbrain tissue and citalopram was used for measuring nonspecific binding. A saturation curve for the binding of 18 F-fluoxetine was not obtained. Even when fluoxetine (10 μM) was used for measurements of nonspecific binding, a saturation curve was difficult to obtain. Other compounds, such as deprenyl, clorgyline, amphetamine, and reserpine were also not able to reduce the binding of 18 F-fluoxetine. Ex vivo autoradiographic experiments with 18 F-fluoxetine did not reveal any specific uptake in various brain regions. In vivo administration of 18 F-fluoxetine in rats showed similar uptake in all the brain regions with little regional selectivity. A subcellular analysis of rat brain tissue after intravenous (IV) administration of 18 F-fluoxetine indicated significant amounts of binding in mitochondria and synaptosomes. In summary, in vitro experiments with 18 F-fluoxetine indicate little specific binding. Binding to the serotonin transporter was not identifiable. High nonspecific binding of the tracer resulting from its subcellular nature in the brain masks the ability to detect binding to the serotonin uptake sites in vivo. These findings indicate that a large portion of the binding of 18 F-fluoxetine in rat brains is subcellular and clears slowly out of the cells. Other sites, such as monoamine oxidase, may also play a significant role in the action of fluoxetine

  2. ABC transporter Cdr1p harbors charged residues in the intracellular loop and nucleotide-binding domain critical for protein trafficking and drug resistance.

    Science.gov (United States)

    Shah, Abdul Haseeb; Banerjee, Atanu; Rawal, Manpreet Kaur; Saxena, Ajay Kumar; Mondal, Alok Kumar; Prasad, Rajendra

    2015-08-01

    The ABC transporter Cdr1 protein of Candida albicans, which plays a major role in antifungal resistance, has two transmembrane domains (TMDs) and two nucleotide-binding domains (NBDs). The 12 transmembrane helices of TMDs that are interconnected by extracellular and intracellular loops (ICLs) mainly harbor substrate recognition sites where drugs bind while cytoplasmic NBDs hydrolyze ATP which powers drug efflux. The coupling of ATP hydrolysis to drug transport requires proper communication between NBDs and TMDs typically accomplished by ICLs. This study examines the role of cytoplasmic ICLs of Cdr1p by rationally predicting the critical residues on the basis of their interatomic distances. Among nine pairs that fall within a proximity of trafficking. These results point to a new role for ICL/NBD interacting residues in PDR ABC transporters in protein folding and trafficking. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  3. A Physiologically Based Pharmacokinetic Model to Predict the Pharmacokinetics of Highly Protein-Bound Drugs and Impact of Errors in Plasma Protein Binding

    Science.gov (United States)

    Ye, Min; Nagar, Swati; Korzekwa, Ken

    2015-01-01

    Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data was often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding, and blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for terminal elimination half-life (t1/2, 100% of drugs), peak plasma concentration (Cmax, 100%), area under the plasma concentration-time curve (AUC0–t, 95.4%), clearance (CLh, 95.4%), mean retention time (MRT, 95.4%), and steady state volume (Vss, 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. PMID:26531057

  4. A physiologically based pharmacokinetic model to predict the pharmacokinetics of highly protein-bound drugs and the impact of errors in plasma protein binding.

    Science.gov (United States)

    Ye, Min; Nagar, Swati; Korzekwa, Ken

    2016-04-01

    Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data were often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding and the blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate the model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for the terminal elimination half-life (t1/2 , 100% of drugs), peak plasma concentration (Cmax , 100%), area under the plasma concentration-time curve (AUC0-t , 95.4%), clearance (CLh , 95.4%), mean residence time (MRT, 95.4%) and steady state volume (Vss , 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  5. Experimental and Numerical Investigation on Tribological Performance of Grooved Texture

    Directory of Open Access Journals (Sweden)

    CHEN Ping

    2016-06-01

    Full Text Available In order to study the influence of the angle and arrangement forms of micro-grooves on the tribological performance of the contact surface, the finite element analysis software was used to simulate the grooved textures with different angles and arrangements. The YLP-20 laser processing system was used to process grooved texture on stainless steel disk surfaces, and the Tribometer (UMT-2 was also used to conduct tribological test under the condition of rotation. The results show that the numerical simulation values are basically consistent with experimental results of grooved textures, and the tribological performance of the friction pairs with textures is also improved. The grooved textures with different angles and arrangement forms have different influence on tribological performance of friction pairs. When the friction velocity is less than 300r/min, the parallel texture with 0° has smaller friction coefficients. While the friction velocity is larger than 300r/min, the parallel texture with 90° has a better ability of reducing friction. Therefore, different grooved textures should be chosen according to operation conditions.

  6. Analysis of drug-protein binding using on-line immunoextraction and high-performance affinity microcolumns: Studies with normal and glycated human serum albumin.

    Science.gov (United States)

    Matsuda, Ryan; Jobe, Donald; Beyersdorf, Jared; Hage, David S

    2015-10-16

    A method combining on-line immunoextraction microcolumns with high-performance affinity chromatography (HPAC) was developed and tested for use in examining drug-protein interactions with normal or modified proteins. Normal human serum albumin (HSA) and glycated HSA were used as model proteins for this work. High-performance immunoextraction microcolumns with sizes of 1.0-2.0 cm × 2.1mm i.d. and containing anti-HSA polyclonal antibodies were developed and tested for their ability to bind normal HSA or glycated HSA. These microcolumns were able to extract up to 82-93% for either type of protein at 0.05-0.10 mL/min and had a binding capacity of 0.34-0.42 nmol HSA for a 1.0 cm × 2.1mm i.d. microcolumn. The immunoextraction microcolumns and their adsorbed proteins were tested for use in various approaches for drug binding studies. Frontal analysis was used with the adsorbed HSA/glycated HSA to measure the overall affinities of these proteins for the drugs warfarin and gliclazide, giving comparable values to those obtained previously using similar protein preparations that had been covalently immobilized within HPAC columns. Zonal elution competition studies with gliclazide were next performed to examine the specific interactions of this drug at Sudlow sites I and II of the adsorbed proteins. These results were also comparable to those noted in prior work with covalently immobilized samples of normal HSA or glycated HSA. These experiments indicated that drug-protein binding studies can be carried out by using on-line immunoextraction microcolumns with HPAC. The same method could be used in the future with clinical samples and other drugs or proteins of interest in pharmaceutical studies or biomedical research. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Computational Studies of a Mechanism for Binding and Drug Resistance in the Wild Type and Four Mutations of HIV-1 Protease with a GRL-0519 Inhibitor

    Directory of Open Access Journals (Sweden)

    Guodong Hu

    2016-05-01

    Full Text Available Drug resistance of mutations in HIV-1 protease (PR is the most severe challenge to the long-term efficacy of HIV-1 PR inhibitor in highly active antiretroviral therapy. To elucidate the molecular mechanism of drug resistance associated with mutations (D30N, I50V, I54M, and V82A and inhibitor (GRL-0519 complexes, we have performed five molecular dynamics (MD simulations and calculated the binding free energies using the molecular mechanics Poisson–Boltzmann surface area (MM-PBSA method. The ranking of calculated binding free energies is in accordance with the experimental data. The free energy spectra of each residue and inhibitor interaction for all complexes show a similar binding model. Analysis based on the MD trajectories and contribution of each residues show that groups R2 and R3 mainly contribute van der Waals energies, while groups R1 and R4 contribute electrostatic interaction by hydrogen bonds. The drug resistance of D30N can be attributed to the decline in binding affinity of residues 28 and 29. The size of Val50 is smaller than Ile50 causes the residue to move, especially in chain A. The stable hydrophobic core, including the side chain of Ile54 in the wild type (WT complex, became unstable in I54M because the side chain of Met54 is flexible with two alternative conformations. The binding affinity of Ala82 in V82A decreases relative to Val82 in WT. The present study could provide important guidance for the design of a potent new drug resisting the mutation inhibitors.

  8. Kinetics of [123I]iodide uptake and discharge by perchlorate in studies of inhibition of iodide binding by antithyroid drugs

    International Nuclear Information System (INIS)

    McCruden, D.C.; Connell, J.M.C.; Alexander, W.D.; Hilditch, T.E.

    1985-01-01

    Thyroidal binding of iodide was studied by kinetic analysis of [ 123 ]iodide uptake and its discharge by perchlorate in 80 hyperthyroid subjects receiving antithyroid drug therapy. Five dosage regimens ranging from 5 mg carbimazole twice daily to 15 mg methimazole twice daily were studied. Binding inhibition was estimated at 5-7 h after drug as an index of the mean effect of the 12 hourly regimen. In all cases, except one in the lowest dose group, binding was found to be markedly reduced with mean binding rates ranging from 0.002 to 0.020 min -1 (normal > 0.15 min -1 ). The net clearance of iodide in the lowest dose group was reduced to a mean value near the upper limit of the euthyroid range, whereas in the highest dose group it lay at the lower limit of the euthyroid range. These results were reflected in the serum thyroid hormone response. There was a reducing incidence of inadequate control of hyperthyroidism and an increasing incidence of hypothyroidism with increasing thiourylene dose. The exit rate constant of free iodide for the various doses showed values from 0.048 to 0.055 min -1 . Correpsonding mean values for the discharge rate constant after perchlorate were 0.087 to 0.105 min -1 . This suggests that perchlorate increases the rate of iodide release from the thyroid gland. Studies at a later interval after drug (12-14 h) showed no change in discharge rate constant. This leads to the conclusion that perchlorate may further inhibit iodide binding in subjects receiving antithyroid drug therapy. (author)

  9. SALL4, a stem cell factor, affects the side population by regulation of the ATP-binding cassette drug transport genes.

    Directory of Open Access Journals (Sweden)

    Ha-Won Jeong

    2011-04-01

    Full Text Available Our previous work shows that the stem cell factor SALL4 plays a central role in embryonic and leukemic stem cells. In this study, we report that SALL4 expression was higher in drug resistant primary acute myeloid leukemic patients than those from drug-responsive cases. In addition, while overexpression of SALL4 led to drug resistance in cell lines, cells with decreased SALL4 expression were more sensitive to drug treatments than the parental cells. This led to our investigation of the implication of SALL4 in drug resistance and its role in side population (SP cancer stem cells. SALL4 expression was higher in SP cells compared to non-SP cells by 2-4 fold in various malignant hematopoietic cell lines. Knocking down of SALL4 in isolated SP cells resulted in a reduction of SP cells, indicating that SALL4 is required for their self-renewal. The SP phenotype is known to be mediated by members of the ATP-binding cassette (ABC drug transport protein family, such as ABCG2 and ABCA3. Using chromatin-immunoprecipitation (ChIP, quantitative reverse transcription polymerase chain reaction (qRT-PCR and electrophoretic mobility shift assay(EMSA, we demonstrated that SALL4 was able to bind to the promoter region of ABCA3 and activate its expression while regulating the expression of ABCG2 indirectly. Furthermore, SALL4 expression was positively correlated to those of ABCG2 and ABCA3 in primary leukemic patient samples. Taken together, our results suggest a novel role for SALL4 in drug sensitivity, at least in part through the maintenance of SP cells, and therefore may be responsible for drug-resistance in leukemia. We are the first to demonstrate a direct link between stem cell factor SALL4, SP and drug resistance in leukemia.

  10. Novel nootropic drug sunifiram enhances hippocampal synaptic efficacy via glycine-binding site of N-methyl-D-aspartate receptor.

    Science.gov (United States)

    Moriguchi, Shigeki; Tanaka, Tomoya; Narahashi, Toshio; Fukunaga, Kohji

    2013-10-01

    Sunifiram is a novel pyrrolidone nootropic drug structurally related to piracetam, which was developed for neurodegenerative disorder like Alzheimer's disease. Sunifiram is known to enhance cognitive function in some behavioral experiments such as Morris water maze task. To address question whether sunifiram affects N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic function in the hippocampal CA1 region, we assessed the effects of sunifiram on NMDAR-dependent long-term potentiation (LTP) by electrophysiology and on phosphorylation of synaptic proteins by immunoblotting analysis. In mouse hippocampal slices, sunifiram at 10-100 nM significantly enhanced LTP in a bell-shaped dose-response relationship which peaked at 10 nM. The enhancement of LTP by sunifiram treatment was inhibited by 7-chloro-kynurenic acid (7-ClKN), an antagonist for glycine-binding site of NMDAR, but not by ifenprodil, an inhibitor for polyamine site of NMDAR. The enhancement of LTP by sunifilam was associated with an increase in phosphorylation of α-amino-3-hydroxy-5-methylisozazole-4-propionate receptor (AMPAR) through activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and an increase in phosphorylation of NMDAR through activation of protein kinase Cα (PKCα). Sunifiram treatments at 1-1000 nM increased the slope of field excitatory postsynaptic potentials (fEPSPs) in a dose-dependent manner. The enhancement was associated with an increase in phosphorylation of AMPAR receptor through activation of CaMKII. Interestingly, under the basal condition, sunifiram treatments increased PKCα (Ser-657) and Src family (Tyr-416) activities with the same bell-shaped dose-response curve as that of LTP peaking at 10 nM. The increase in phosphorylation of PKCα (Ser-657) and Src (Tyr-416) induced by sunifiram was inhibited by 7-ClKN treatment. The LTP enhancement by sunifiram was significantly inhibited by PP2, a Src family inhibitor. Finally, when pretreated with a high

  11. Origin of DNA-Induced Circular Dichroism in a Minor-Groove Binder.

    Science.gov (United States)

    Holmgaard List, Nanna; Knoops, Jérémie; Rubio-Magnieto, Jenifer; Idé, Julien; Beljonne, David; Norman, Patrick; Surin, Mathieu; Linares, Mathieu

    2017-10-25

    Induced circular dichroism (ICD) of DNA-binding ligands is well known to be strongly influenced by the specific mode of binding, but the relative importance of the possible mechanisms has remained undetermined. With a combination of molecular dynamics simulations, CD response calculations, and experiments on an AT-sequence, we show that the ICD of minor-groove-bound 4',6-diamidino-2-phenylindole (DAPI) originates from an intricate interplay between the chiral imprint of DNA, off-resonant excitonic coupling to nucleobases, charge-transfer, and resonant excitonic coupling between DAPIs. The significant contributions from charge-transfer and the chiral imprint to the ICD demonstrate the inadequacy of a standard Frenkel exciton theory of the DAPI-DNA interactions.

  12. Ion implantation planar in targets with semi-cylindrical grooves

    International Nuclear Information System (INIS)

    Filiz, Y.; Demokan, O.

    2002-01-01

    The experimental and numerical investigations suggest that the ion-matrix phase of the sheath evolution plays a crucial role in determining the ion flux to the target surfaces . It can easily be realized that conformal mapping of the target's surface by the sheath is questionable, or even inapplicable in the case of surfaces with fine irregularities or this continuities. The theoretical analysis of such cases is evidently quite complicated. On the other hand, most actual targets fall into this category, and hence, the understanding of the corresponding sheath behavior remains vital for accomplishing uniform implantation. The ion- matrix sheaths have been treated analytically by Conrad for planar, cylindrical and spherical targets successfully. Similar y, Sheridan and Zang et al. have investigated the ion matrix sheath in cylindrical bores, without and with axial electrodes, respectively. All these works assumed targets with infinite areas or length, Zeng et al. and Kwok et al. have started studying implantation into grooves, by carrying out simulations for the inner and outer races of bearings, which are modeled as semi- cylinders of infinite length. Finally, Demokan has presented the first analytic treatment of on matrix sheaths in two- dimensions, by considering targets with rectangular grooves of infinite length, representing a broad range of industrial items. In this work, ion-matrix sheath near infinite length are theoretically analysed. Understanding the sheath formation near such targets is essential for achieving successful ion implantation on the surfaces of a broad range of industrial products, including all types of bearings. The potential profiles both inside and outside the groove are derived and the consequent ion velocity higher plasma densities may improve the uniformity of implantation on the surfaces of such grooves. Furthermore, the sheath edge deformation due to the grooves, the variation of the angle of incidence on the surface of the groove

  13. Formation Mechanisms for Spur and Groove Features on Fringing Reefs

    Science.gov (United States)

    Bramante, J. F.; Ashton, A. D.; Perron, J. T.

    2016-12-01

    Spur and groove systems (SAGs) are ubiquitous morphological features found on fore-reef slopes globally. SAGs consist of parallel, roughly shore-normal ridges of actively growing coral and coralline algae (spurs) separated by offshore-sloping depressions typically carpeted by a veneer of sediment (grooves). Although anecdotal observations and recent statistical analyses have reported correlations between wave exposure and the distribution of SAGs on fore-reef slopes, the physical mechanisms driving SAG formation remain poorly understood. For example, there remains significant debate regarding the importance of coral growth versus bed erosion for SAG formation. Here we investigate a hypothesis that SAG formation is controlled by feedbacks between sediment production and diffusion and coral growth. Using linear stability analysis, we find that sediment production, coral growth, and the feedbacks between them are unable to produce stable periodic structures without a sediment sink. However, if incipient grooves act as conduits for sediment transport offshore, a positive feedback can develop as the groove bed erodes through wave-driven abrasion during offshore transport. Eventually a negative feedback slows groove deepening when the groove bed is armored by sediment, and the groove bed relaxes to a sediment-veneered equilibrium profile analogous to sediment-rich shorefaces. To test this hypothesis, we apply a numerical model that incorporates coral growth and sediment production, sediment diffusion, non-linear wave-driven abrasion, and sediment advection offshore. This model produces the periodic, linear features characteristic of SAG morphology. The relative magnitude of growth, production, diffusion, abrasion, and advection rates affect periodic spacing or wavelength of the modeled SAGs. Finally, we evaluate the ability of the model to replicate geographical variability in SAG characteristics using previously published datasets and reanalysis wave data.

  14. The AT-Hook motif as a versatile minor groove anchor for promoting DNA binding of transcription factor fragments? ?Electronic supplementary information (ESI) available: Peptide synthesis, full experimental procedures and analytical data of the peptides and products obtained. See DOI: 10.1039/c5sc01415h Click here for additional data file.

    OpenAIRE

    Rodr?guez, J?ssica; Mosquera, Jes?s; Couceiro, Jose R.; V?zquez, M. Eugenio; Mascare?as, Jos? L.

    2015-01-01

    We report the development of chimeric DNA binding peptides comprising a DNA binding fragment of natural transcription factors (the basic region of a bZIP protein or a monomeric zinc finger module) and an AT-Hook peptide motif. The resulting peptide conjugates display high DNA affinity and excellent sequence selectivity. Furthermore, the AT-Hook motif also favors the cell internalization of the conjugates.

  15. Spectroscopic study on flavonoid–drug interactions: Competitive binding for human serum albumin between three flavonoid compounds and ticagrelor, a new antiplatelet drug

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Bing-Mi, E-mail: liubingmi@163.com [Department of Pharmacy, Liaoning University, Shenyang 110036 (China); Zhang, Jun [Department of Pharmacy, Liaoning University, Shenyang 110036 (China); Bai, Chong-Liang [Centre for Molecular Science and Engineering, Northeastern University, Shenyang 110819 (China); Wang, Xin; Qiu, Xin-Zhi; Wang, Xiao-Li; Ji, Hui [Department of Pharmacy, Liaoning University, Shenyang 110036 (China); Liu, Bin, E-mail: liubinzehao@163.com [Department of Pharmacy, Liaoning University, Shenyang 110036 (China)

    2015-12-15

    The effects of three kinds of flavonoids, quercetin, rutin and baicalin, on the binding of ticagrelor to human serum albumin (HSA) were systematically investigated using fluorescence, UV–vis absorption and circular dichroism (CD) spectroscopic techniques. The results indicated that ticagrelor strongly quenched the HSA fluorescence by the style of static quenching and non-radiation energy transferring as a result of the HSA–ticagrelor complex formation, while the presence of flavonoids could not change the quenching mechanism. Ticagrelor could spontaneously bind in site I on HSA with high affinity, and this binding process was mainly driven by both hydrophobic forces and hydrogen bonding. The significantly decreased binding affinity and the unchanged binding mode and distance between ticagrelor and HSA indicated that that flavonoids could compete against ticagrelor in site I, and baicalin was the most effective competitor. The conformation investigation of HSA further confirmed the flavonoid/ticagrelor competitive binding mechanism. - Highlights: • Ticagrelor could spontaneously bind in subdomain IIA (site I) on HSA with high affinity. • The presence of flavonoids could not change the quenching mechanism. • The presence of flavonoids significantly decreased the binding affinity of ticagrelor with HSA. • Flavonoids could compete against ticagrelor in site I. • Baicalin was the most effective competitor among the three flavonoids.

  16. Spectroscopic study on flavonoid–drug interactions: Competitive binding for human serum albumin between three flavonoid compounds and ticagrelor, a new antiplatelet drug

    International Nuclear Information System (INIS)

    Liu, Bing-Mi; Zhang, Jun; Bai, Chong-Liang; Wang, Xin; Qiu, Xin-Zhi; Wang, Xiao-Li; Ji, Hui; Liu, Bin

    2015-01-01

    The effects of three kinds of flavonoids, quercetin, rutin and baicalin, on the binding of ticagrelor to human serum albumin (HSA) were systematically investigated using fluorescence, UV–vis absorption and circular dichroism (CD) spectroscopic techniques. The results indicated that ticagrelor strongly quenched the HSA fluorescence by the style of static quenching and non-radiation energy transferring as a result of the HSA–ticagrelor complex formation, while the presence of flavonoids could not change the quenching mechanism. Ticagrelor could spontaneously bind in site I on HSA with high affinity, and this binding process was mainly driven by both hydrophobic forces and hydrogen bonding. The significantly decreased binding affinity and the unchanged binding mode and distance between ticagrelor and HSA indicated that that flavonoids could compete against ticagrelor in site I, and baicalin was the most effective competitor. The conformation investigation of HSA further confirmed the flavonoid/ticagrelor competitive binding mechanism. - Highlights: • Ticagrelor could spontaneously bind in subdomain IIA (site I) on HSA with high affinity. • The presence of flavonoids could not change the quenching mechanism. • The presence of flavonoids significantly decreased the binding affinity of ticagrelor with HSA. • Flavonoids could compete against ticagrelor in site I. • Baicalin was the most effective competitor among the three flavonoids.

  17. Continuous blood fractionation using an array of slanted grooves

    Science.gov (United States)

    Bernate, Jorge A.; Chengxun, Liu; Lagae, Liesbet; Drazer, German

    2011-11-01

    Blood is a complex fluid having different specialized biological functions and containing a plethora of clinical information. The separation of different blood components is a crucial step in many research and clinical applications. In this work we take advantage of the flow characteristics in microfluidic devices in which the bottom surface is patterned with slanted rectangular grooves to continuously fractionate blood. We exploit the flow in the vicinity of the patterned surface when the dimensions of the grooves are much smaller than the dimensions of the main channel. In these devices, we observed that the grooves act as open channels guiding flow along them with the flow over them being in the direction of the main channel. We present experiments in which the different blood components are deflected laterally to a different extent by the flow along the grooves depending on their sedimentation velocity, which allows their continuous fractionation. In particular, the heavier red blood cells experience the largest deflection while the lighter white blood cells deflect the least, allowing their passive and minimally invasive isolation. In addition, this fluidic platform can also be used to separate magnetically labeled circulating cancer cells which can be retained in the flow along the grooves using a sufficiently strong magnetic force.

  18. Performance optimization of grooved slippers for aero hydraulic pumps

    Directory of Open Access Journals (Sweden)

    Juan Chen

    2016-06-01

    Full Text Available A computational fluid dynamics (CFD simulation method based on 3-D Navier–Stokes equation and Arbitrary Lagrangian–Eulerian (ALE method is presented to analyze the grooved slipper performance of piston pump. The moving domain of grooved slipper is transformed into a fixed reference domain by the ALE method, which makes it convenient to take the effects of rotate speed, body force, temperature, and oil viscosity into account. A geometric model to express the complex structure, which covers the orifice of piston and slipper, vented groove and the oil film, is constructed. Corresponding to different oil film thicknesses calculated in light of hydrostatic equilibrium theory and boundary conditions, a set of simulations is conducted in COMSOL to analyze the pump characteristics and effects of geometry (groove width and radius, orifice size on these characteristics. Furthermore, the mechanics and hydraulics analyses are employed to validate the CFD model, and there is an excellent agreement between simulation and analytical results. The simulation results show that the sealing land radius, orifice size and groove width all dramatically affect the slipper behavior, and an optimum tradeoff among these factors is conducive to optimizing the pump design.

  19. Documentation of roller-bearing effect on butterfly inspired grooves

    Science.gov (United States)

    Gautam, Sashank; Lang, Amy

    2017-11-01

    Butterfly wings are covered with scales in a roof shingle pattern which align together to form grooves. The increase or decrease of laminar friction drag depends on the flow orientation to the scales. Flow in the longitudinal direction to the grooves encounters increased surface area which increases the friction drag. However, in the transverse direction, for low Re laminar flow, a single vortex is formed inside each groove and is predicted to remain stable due to the very low Re of the flow in each cavity. These embedded vortices act as roller bearings to the flow above, such that the fluid from the outer boundary layer does not mix with fluid inside the cavities. This leads to a reduction of skin friction drag when compared to a smooth surface. When the cavity flow Re is increased beyond a critical point, the vortex becomes unstable and the low-momentum fluid in the grooves mixes with the outer boundary layer flow, increasing the drag. The objective of this experiment is to determine the critical Re where the embedded vortex transitions from a stable to an unstable state using DPIV. Subsequently, for steady vortex conditions, a comparison of skin friction drag between the grooved and flat plate can show that the butterfly scaled surface can result in sub-laminar friction drag. The National Science Foundation (Grant No. 1335848).

  20. Design of pellet surface grooves for fission gas plenum

    International Nuclear Information System (INIS)

    Carter, T.J.; Jones, L.R.; Macici, N.; Miller, G.C.

    1986-01-01

    In the Canada deuterium uranium pressurized heavy water reactor, short (50-cm) Zircaloy-4 clad bundles are fueled on-power. Although internal void volume within the fuel rods is adequate for the present once-through natural uranium cycle, the authors have investigated methods for increasing the internal gas storage volume needed in high-power, high-burnup, experimental ceramic fuels. This present work sought to prove the methodology for design of gas storage volume within the fuel pellets - specifically the use of grooves pressed or machined into the relatively cool pellet/cladding interface. Preanalysis and design of pellet groove shape and volume was accomplished using the TRUMP heat transfer code. Postirradiation examination (PIE) was used to check the initial design and heat transfer assumptions. Fission gas release was found to be higher for the grooved pellet rods than for the comparison rods with hollow or unmodified pellets. This had been expected from the initial TRUMP thermal analyses. The ELESIM fuel modeling code was used to check in-reactor performance, but some modifications were necessary to accommodate the loss of heat transfer surface to the grooves. It was concluded that for plenum design purposes, circumferential pellet grooves could be adequately modeled by the codes TRUMP and ELESIM

  1. Cyclophilin B mediates cyclosporin A incorporation in human blood T-lymphocytes through the specific binding of complexed drug to the cell surface.

    Science.gov (United States)

    Allain, F; Denys, A; Spik, G

    1996-07-15

    Cyclophilin B (CyPB) is a cyclosporin A (CsA)-binding protein located within intracellular vesicles and released in biological fluids. We recently reported the specific binding of this protein to T-cell surface receptor which is internalized even in the presence of CsA. These results suggest that CyPB might target the drug to lymphocytes and consequently modify its activity. To verify this hypothesis, we have first investigated the binding capacity and internalization of the CsA-CyPB complex in human peripheral blood T-lymphocytes and secondly compared the inhibitory effect of both free and CyPB-complexed CsA on the CD3-induced activation and proliferation of T-cells. Here, we present evidence that both the CsA-CyPB complex and free CyPB bind to the T-lymphocyte surface, with similar values of Kd and number of sites. At 37 degrees C, the complex is internalized but, in contrast to the protein, the drug is accumulated within the cell. Moreover, CyPB receptors are internalized together with the ligand and rapidly recycled to the cell surface. Finally, we demonstrate that CyPB-complexed CsA remains as efficient as uncomplexed CsA and that CyPB enhances the immunosuppressive activity of the drug. Taken together, our results support the hypothesis that surface CyPB receptors may be related to the selective and variable action of CsA, through specific binding and targeting of the CyPB-CsA complex to peripheral blood T-lymphocytes.

  2. New DNA-binding radioprotectors

    Science.gov (United States)

    Martin, Roger

    facilitated by the fact that, like the parent minor groove-binding drug Hoechst 33342, DNA-bound MP (and its analogues) are fluorescent, enabling quantitative assessment of delivery of topically applied drug to basal cells in the mouse oral mucosa. Comparison with the data from prior in vitro experiments described above, indicate that topical delivery is sufficient to confer radioprotection. Although the primary motivation for this project relates to Radiation Oncology, the new ra-dioprotectors obviously have more general potential.

  3. Spectroscopic profiling and computational study of the binding of tschimgine: A natural monoterpene derivative, with calf thymus DNA

    Science.gov (United States)

    Khajeh, Masoumeh Ashrafi; Dehghan, Gholamreza; Dastmalchi, Siavoush; Shaghaghi, Masoomeh; Iranshahi, Mehrdad

    2018-03-01

    DNA is a major target for a number of anticancer substances. Interaction studies between small molecules and DNA are essential for rational drug designing to influence main biological processes and also introducing new probes for the assay of DNA. Tschimgine (TMG) is a monoterpene derivative with anticancer properties. In the present study we tried to elucidate the interaction of TMG with calf thymus DNA (CT-DNA) using different spectroscopic methods. UV-visible absorption spectrophotometry, fluorescence and circular dichroism (CD) spectroscopies as well as molecular docking study revealed formation of complex between TMG and CT-DNA. Binding constant (Kb) between TMG and DNA was 2.27 × 104 M- 1, that is comparable to groove binding agents. The fluorescence spectroscopic data revealed that the quenching mechanism of fluorescence of TMG by CT-DNA is static quenching. Thermodynamic parameters (ΔH TMG with CT-DNA. Competitive binding assay with methylene blue (MB) and Hoechst 33258 using fluorescence spectroscopy displayed that TMG possibly binds to the minor groove of CT-DNA. These observations were further confirmed by CD spectral analysis, viscosity measurements and molecular docking.

  4. Research on performance of upstream pumping mechanical seal with different deep spiral groove

    International Nuclear Information System (INIS)

    Wang, Q; Chen, H L; Liu, T; Liu, Y H; Liu, Z B; Liu, D H

    2012-01-01

    As one new type of mechanical seal, Upstream Pumping Mechanical Seal has been widely used in fluid machinery. In this paper, structure of spiral groove is innovatively optimized to improve performance of Upstream Pumping Mechanical Seal with Spiral Groove: keeping the dam zone and the weir zone not changed, changing the bottom shape of spiral groove only, substituting different deep spiral groove for equal deep spiral groove. The simulation on Upstream Pumping Mechanical Seal with different deep spiral grooves is done using FVM method. According to calculation, the performances of opening force and pressure distribution on seals face are obtained. Five types of spiral grooves are analyzed, namely equal deep spiral groove, circumferential convergent ladder-like different deep spiral groove, circumferential divergent ladder-like different deep spiral groove, radial convergent ladder-like different deep spiral groove and radial divergent ladder-like different deep spiral groove. This paper works on twenty-five working conditions. The results indicate the performances of circumferential divergent 2-ladder different deep spiral groove are better than the others, with more opening force and better stabilization, while with the same leakage. The outcome provides theoretical support for application of Upstream Pumping Mechanical Seal with circumferential convergent ladder-like different deep spiral groove.

  5. Research on performance of upstream pumping mechanical seal with different deep spiral groove

    Science.gov (United States)

    Wang, Q.; Chen, H. L.; Liu, T.; Liu, Y. H.; Liu, Z. B.; Liu, D. H.

    2012-11-01

    As one new type of mechanical seal, Upstream Pumping Mechanical Seal has been widely used in fluid machinery. In this paper, structure of spiral groove is innovatively optimized to improve performance of Upstream Pumping Mechanical Seal with Spiral Groove: keeping the dam zone and the weir zone not changed, changing the bottom shape of spiral groove only, substituting different deep spiral groove for equal deep spiral groove. The simulation on Upstream Pumping Mechanical Seal with different deep spiral grooves is done using FVM method. According to calculation, the performances of opening force and pressure distribution on seals face are obtained. Five types of spiral grooves are analyzed, namely equal deep spiral groove, circumferential convergent ladder-like different deep spiral groove, circumferential divergent ladder-like different deep spiral groove, radial convergent ladder-like different deep spiral groove and radial divergent ladder-like different deep spiral groove. This paper works on twenty-five working conditions. The results indicate the performances of circumferential divergent 2-ladder different deep spiral groove are better than the others, with more opening force and better stabilization, while with the same leakage. The outcome provides theoretical support for application of Upstream Pumping Mechanical Seal with circumferential convergent ladder-like different deep spiral groove.

  6. Spectroscopic and nano-molecular modeling investigation on the binary and ternary bindings of colchicine and lomefloxacin to Human serum albumin with the viewpoint of multi-drug therapy

    International Nuclear Information System (INIS)

    Chamani, J.; Asoodeh, A.; Homayoni-Tabrizi, M.; Amiri Tehranizadeh, Z.; Baratian, A.; Saberi, M.R.; Gharanfoli, M.

    2010-01-01

    Combination of several drugs is often necessary especially during long-term therapy. The competitive binding drugs can cause a decrease in the amount of drug bound to protein and increase the biological active fraction of the drug. The aim of this study is to analyze the interactions of Lomefloxacin (LMF) and Colchicine (COL) with human serum albumin (HSA) and to evaluate the mechanism of simultaneous binding of LMF and COL to protein. Fluorescence analysis was used to estimate the effect of drugs on the protein fluorescence and to define the binding and quenching properties of drugs-HSA complexes. The binding sites for LMF and COL were identified in tertiary structure of HSA with the use of spectrofluorescence analysis. The analysis of fluorescence quenching of HSA in the binary and ternary systems show that LMF does not affect the complex formed between COL and HSA. On the contrary, COL decreases the interaction between LMF and HSA. The results of synchronous fluorescence, resonance light scattering and circular dichroism spectra of binary and ternary systems show that binding of LMF and COL to HSA can induce micro-environmental and conformational changes in HSA. The simultaneous presence of LMF and COL in binding to HSA should be taken into account in the multi-drug therapy, and necessity of using a monitoring therapy owning to the possible increase of the uncontrolled toxic effects. Molecular modeling of the possible binding sites of LMF and COL in binary and ternary systems to HSA confirms the spectroscopic results.

  7. A molecular dynamics investigation of CDK8/CycC and ligand binding: conformational flexibility and implication in drug discovery

    Science.gov (United States)

    Cholko, Timothy; Chen, Wei; Tang, Zhiye; Chang, Chia-en A.

    2018-05-01

    Abnormal activity of cyclin-dependent kinase 8 (CDK8) along with its partner protein cyclin C (CycC) is a common feature of many diseases including colorectal cancer. Using molecular dynamics (MD) simulations, this study determined the dynamics of the CDK8-CycC system and we obtained detailed breakdowns of binding energy contributions for four type-I and five type-II CDK8 inhibitors. We revealed system motions and conformational changes that will affect ligand binding, confirmed the essentialness of CycC for inclusion in future computational studies, and provide guidance in development of CDK8 binders. We employed unbiased all-atom MD simulations for 500 ns on twelve CDK8-CycC systems, including apoproteins and protein-ligand complexes, then performed principal component analysis (PCA) and measured the RMSF of key regions to identify protein dynamics. Binding pocket volume analysis identified conformational changes that accompany ligand binding. Next, H-bond analysis, residue-wise interaction calculations, and MM/PBSA were performed to characterize protein-ligand interactions and find the binding energy. We discovered that CycC is vital for maintaining a proper conformation of CDK8 to facilitate ligand binding and that the system exhibits motion that should be carefully considered in future computational work. Surprisingly, we found that motion of the activation loop did not affect ligand binding. Type-I and type-II ligand binding is driven by van der Waals interactions, but electrostatic energy and entropic penalties affect type-II binding as well. Binding of both ligand types affects protein flexibility. Based on this we provide suggestions for development of tighter-binding CDK8 inhibitors and offer insight that can aid future computational studies.

  8. Atypical olfactory groove meningioma associated with uterine fibromatosis; case report

    Directory of Open Access Journals (Sweden)

    Toma I. Papacocea

    2016-11-01

    Full Text Available The concomitant presence of the olfactory groove meningioma with uterine fibrosis is very rare. Our report presents the case of a giant olfactory groove meningioma revealed after a uterine fibroma resection in a 44 years-old female, due to a generalized seizure 10 days after operation. Cranial CT-scan identified the tumor as an olfactory groove meningioma. The tumor was operated with a macroscopically complete resection; the endothermal coagulation of the dura attachment was performed (Simpson II with a good postoperative evolution. Laboratory results showed the presence of receptors for steroid hormones both in meningioma and uterine tumor, and the histopathological examination revealed an atypical meningioma with 17% proliferation markers. Our findings suggest that even though meningiomas are benign tumors and a complete resection usually indicates a good prognosis, the association with uterine fibromatosis and the presence of high percentage of steroid receptors creates a higher risk to relapse, imposing therefore a good monitoring.

  9. Gap and channeled plasmons in tapered grooves: a review

    DEFF Research Database (Denmark)

    Smith, C. L. C.; Stenger, Nicolas; Kristensen, Anders

    2015-01-01

    Tapered metallic grooves have been shown to support plasmons - electromagnetically coupled oscillations of free electrons at metal-dielectric interfaces - across a variety of configurations and V-like profiles. Such plasmons may be divided into two categories: gap-surface plasmons (GSPs) that are......Tapered metallic grooves have been shown to support plasmons - electromagnetically coupled oscillations of free electrons at metal-dielectric interfaces - across a variety of configurations and V-like profiles. Such plasmons may be divided into two categories: gap-surface plasmons (GSPs...... platform to explore the fundamental science of plasmon excitations and their interactions. In this Review, we provide a research status update of plasmons in tapered grooves, starting with a presentation of the theory and important features of GSPs and CPPs, and follow with an overview of the broad range...

  10. Low serotonin1B receptor binding potential in the anterior cingulate cortex in drug-free patients with recurrent major depressive disorder.

    Science.gov (United States)

    Tiger, Mikael; Farde, Lars; Rück, Christian; Varrone, Andrea; Forsberg, Anton; Lindefors, Nils; Halldin, Christer; Lundberg, Johan

    2016-07-30

    The pathophysiology of major depressive disorder (MDD) is not fully understood and the diagnosis is largely based on history and clinical examination. So far, several lines of preclinical data and a single imaging study implicate a role for the serotonin1B (5-HT1B) receptor subtype. We sought to study 5-HT1B receptor binding in brain regions of reported relevance in patients with MDD. Subjects were examined at the Karolinska Institutet PET centre using positron emission tomography (PET) and the 5-HT1B receptor selective radioligand [(11)C]AZ10419369. Ten drug-free patients with recurrent MDD and ten control subjects matched for age and sex were examined. The main outcome measure was [(11)C]AZ10419369 binding in brain regions of reported relevance in the pathophysiology of MDD. The [(11)C]AZ10419369 binding potential was significantly lower in the MDD group compared with the healthy control group in the anterior cingulate cortex (20% between-group difference), the subgenual prefrontal cortex (17% between-group difference), and in the hippocampus (32% between-group difference). The low anterior cingulate [(11)C]AZ10419369 binding potential in patients with recurrent MDD positions 5-HT1B receptor binding in this region as a putative biomarker for MDD and corroborate a role of the anterior cingulate cortex and associated areas in the pathophysiology of recurrent MDD. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  11. A computational analysis of the binding mode of closantel as inhibitor of the Onchocerca volvulus chitinase: insights on macrofilaricidal drug design

    Science.gov (United States)

    Segura-Cabrera, Aldo; Bocanegra-García, Virgilio; Lizarazo-Ortega, Cristian; Guo, Xianwu; Correa-Basurto, José; Rodríguez-Pérez, Mario A.

    2011-12-01

    Onchocerciasis is a leading cause of blindness with at least 37 million people infected and more than 120 million people at risk of contracting the disease; most (99%) of this population, threatened by infection, live in Africa. The drug of choice for mass treatment is the microfilaricidal Mectizan® (ivermectin); it does not kill the adult stages of the parasite at the standard dose which is a single annual dose aimed at disease control. However, multiple treatments a year with ivermectin have effects on adult worms. The discovery of new therapeutic targets and drugs directed towards the killing of the adult parasites are thus urgently needed. The chitinase of filarial nematodes is a new drug target due to its essential function in the metabolism and molting of the parasite. Closantel is a potent and specific inhibitor of chitinase of Onchocerca volvulus (OvCHT1) and other filarial chitinases. However, the binding mode and specificity of closantel towards OvCHT1 remain unknown. In the absence of a crystallographic structure of OvCHT1, we developed a homology model of OvCHT1 using the currently available X-ray structures of human chitinases as templates. Energy minimization and molecular dynamics (MD) simulation of the model led to a high quality of 3D structure of OvCHIT1. A flexible docking study using closantel as the ligand on the binding site of OvCHIT1 and human chitinases was performed and demonstrated the differences in the closantel binding mode between OvCHIT1 and human chitinase. Furthermore, molecular dynamics simulations and free-energy calculation were employed to determine and compare the detailed binding mode of closantel with OvCHT1 and the structure of human chitinase. This comparative study allowed identification of structural features and properties responsible for differences in the computationally predicted closantel binding modes. The homology model and the closantel binding mode reported herein might help guide the rational development of

  12. Design, synthesis and DNA-binding study of some novel morpholine linked thiazolidinone derivatives.

    Science.gov (United States)

    War, Javeed Ahmad; Srivastava, Santosh Kumar; Srivastava, Savitri Devi

    2017-02-15

    The emergence of multiple drug resistance amongst bacterial strains resulted in many clinical drugs to be ineffective. Being vulnerable to bacterial infections any lack in the development of new antimicrobial drugs could pose a serious threat to public health. Here we report design and synthesis of a novel class of morpholine linked thiazolidinone hybrid molecules. The compounds were characterized by FT-IR, NMR and HRMS techniques. Susceptibility tests showed that most of the synthesized molecules were highly active against multiple bacterial strains. Compound 3f displayed MIC values which were better than the standard drug for most of the tested strains. DNA being a well defined target for many antimicrobial drugs was probed as possible target for these synthetic molecules. DNA-binding study of 3f with sm-DNA was probed through UV-vis absorption, fluorescence quenching, gel electrophoresis and molecular docking techniques. The studies revealed that compound 3f has strong affinity towards DNA and binds at the minor groove. The docking studies revealed that the compound 3f shows preferential binding towards A/T residues. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Design, synthesis and DNA-binding study of some novel morpholine linked thiazolidinone derivatives

    Science.gov (United States)

    War, Javeed Ahmad; Srivastava, Santosh Kumar; Srivastava, Savitri Devi

    2017-02-01

    The emergence of multiple drug resistance amongst bacterial strains resulted in many clinical drugs to be ineffective. Being vulnerable to bacterial infections any lack in the development of new antimicrobial drugs could pose a serious threat to public health. Here we report design and synthesis of a novel class of morpholine linked thiazolidinone hybrid molecules. The compounds were characterized by FT-IR, NMR and HRMS techniques. Susceptibility tests showed that most of the synthesized molecules were highly active against multiple bacterial strains. Compound 3f displayed MIC values which were better than the standard drug for most of the tested strains. DNA being a well defined target for many antimicrobial drugs was probed as possible target for these synthetic molecules. DNA-binding study of 3f with sm-DNA was probed through UV-vis absorption, fluorescence quenching, gel electrophoresis and molecular docking techniques. The studies revealed that compound 3f has strong affinity towards DNA and binds at the minor groove. The docking studies revealed that the compound 3f shows preferential binding towards A/T residues.

  14. Raphides with barbs and grooves in Xanthosoma sagittifolium (Araceae).

    Science.gov (United States)

    Sakai, W S; Hanson, M; Jones, R C

    1972-10-20

    Raphides in petioles of Xanthosoma sagittifolium are needlelike crystals about 50 micrometers long. The rectangular cross sections have maximum dimensions of approximately 850 by 250 nanometers. The raphides have two distinct end structures. One end is narrow, acute, and tapered to a point; the other is broad, acute, and abruptly pointed. Barbs, about 750 angstroms long with tips oriented away from the narrow end, occur along the length of the raphide on ridges on either side of two longitudinal grooves. These grooves, located opposite each other, give the raphide cross section an H-shape.

  15. Membrane-Dependent Effects of a Cytoplasmic Helix on the Structure and Drug Binding of the Influenza Virus M2 Protein

    Science.gov (United States)

    Cady, Sarah; Wang, Tuo; Hong, Mei

    2011-01-01

    The influenza A M2 protein forms a proton channel for virus infection and also mediates virus assembly and budding. The minimum protein length that encodes both functions contains the transmembrane (TM) domain (roughly residues 22 to 46) for the amantadine-sensitive proton-channel activity and an amphipathic cytoplasmic helix (roughly residues 45 to 62) for curvature induction and virus budding. However, structural studies involving the TM domain with or without the amphipathic helix differed on the drug-binding site. Here we use solid-state NMR spectroscopy to determine the amantadine binding site in the cytoplasmic-helix-containing M2(21–61). 13C-2H distance measurements of 13C-labeled protein and 2H-labeled amantadine showed that in DMPC bilayers, the first equivalent of drug bound S31 inside the M2(21–61) pore, similar to the behavior of M2TM in DMPC bilayers. The non-specific surface site of D44 observed in M2TM is disfavored in the longer peptide. Thus, the pharmacologically relevant drug-binding site in the fully functional M2(21–61) is S31 in the TM pore. Interestingly, when M2(21–61) was reconstituted into a virus-mimetic membrane containing 30% cholesterol, no chemical shift perturbation was observed for pore-lining residues, while M2TM in the same membrane exhibited drug-induced chemical shift changes. Reduction of the cholesterol level and the use of unsaturated phospholipids shifted the conformational equilibrium of M2TM fully to the bound state, but did not rescue drug binding to M2(21–61). These results suggest that the amphipathic helix, together with cholesterol, modulates the ability of the TM helices to bind amantadine. Thus, the M2 protein interacts with the lipid membrane and small-molecule inhibitors in a complex fashion, and a careful examination of the environmental dependence of the protein conformation is required to fully understand the structure-function relation of this protein. PMID:21661724

  16. Conformational Plasticity of the Influenza A M2 Transmembrane Helix in Lipid Bilayers Under Varying pH, Drug Binding and Membrane Thickness

    Science.gov (United States)

    Hu, Fanghao; Luo, Wenbin; Cady, Sarah D.; Hong, Mei

    2010-01-01

    Membrane proteins change their conformations to respond to environmental cues, thus conformational plasticity is important for function. The influenza A M2 protein forms an acid-activated proton channel important for the virus lifecycle. Here we have used solid-state NMR spectroscopy to examine the conformational plasticity of membrane-bound transmembrane domain of M2 (M2TM). 13C and 15N chemical shifts indicate coupled conformational changes of several pore-facing residues due to changes in bilayer thickness, drug binding and pH. The structural changes are attributed to the formation of a well-defined helical kink at G34 in the drug-bound state and in thick lipid bilayers, non-ideal backbone conformation of the secondary-gate residue V27 in the presence of drug, and non-ideal conformation of the proton-sensing residue H37 at high pH. The chemical shifts constrained the (ϕ, ψ) torsion angles for three basis states, the equilibrium among which explains the multiple resonances per site in the NMR spectra under different combinations of bilayer thickness, drug binding and pH conditions. Thus, conformational plasticity is important for the proton conduction and inhibition of M2TM. The study illustrates the utility of NMR chemical shifts for probing the structural plasticity and folding of membrane proteins. PMID:20883664

  17. Mucosal injury and γ-irradiation produce persistent gastric ulcers in the rabbit. Evaluation of antiulcer drug binding to experimental ulcer sites

    International Nuclear Information System (INIS)

    Yokel, R.A.; Dickey, K.M.

    1991-01-01

    A method producing persistent gastric ulcers in the rhesus monkey by combined mucosal injury and γ-irradiation was modified and evaluated in the rabbit. γ-Irradiation (800-1000 cGy) immediately after removal of 2-mm-diameter sections of antral mucosa resulted in ulcer craters 5-7 days later. Ulcer sites were characterized by loss of the mucosa, muscularis mucosa, and much of the submucosa. The exposed submucosa was coated with fibrin and necrotic debris infiltrated with heterophils, the rabbit equivalent of neutrophils. These ulcers strongly resemble human chronic gastric ulcers. Binding of Carafate (sucralfate; Marion Laboratories, Inc., Kansas City, MO) and Maalox (magnesia-alumina oral suspension; Wm. H. Rorer, Inc., Ft. Washington, PA) to ulcer and nearby nonulcer sites in the antrum was assessed 1 hour after drug dosing. Drug binding was determined by aluminum quantitation of stomach wall punch biopsies at necropsy. Both drugs significantly increased aluminum bound to the stomach wall compared with vehicle treatment. Significantly more antiulcer drug was bound to ulcer sites than to nearby nonulcer sites only after sucralfate administration. This model of persistent gastric ulcer should be useful to further study gastric ulcer pathogenesis and treatment

  18. Tailoring channeled plasmon polaritons in metallic V-grooves

    DEFF Research Database (Denmark)

    Smith, Cameron; Thilsted, Anil Haraksingh; Marie, Rodolphe

    2013-01-01

    of propagating plasmons to optimize the trade-off between lateral confinement and loss [2]. Accordingly, the traits of CPPs in metallic V-grooves suggest their widespread implementation, with applications ranging from ultracompact photonic circuitry [3] to lab-on-a-chip sensing. Current CPP research focuses...

  19. Flow characterization in periodic microchannels containing asymmetric grooves

    Energy Technology Data Exchange (ETDEWEB)

    Osorio-Nesme, A; Delgado, A, E-mail: anuhar.nesme@fau.de [Institute of Fluid Mechanics, Friedrich-Alexander Erlangen-Nuremberg University, Cauerstrasse 4, D-91058 Erlangen (Germany)

    2017-10-15

    Characterization of two-dimensional flows in microchannels with anisotropic periodic grooves is numerically carried out by using the lattice Boltzmann method. Periodically placed microstructures, consisting of novel nozzle-diffuser-like grooves are deliberately designed to introduce a flow-direction dependent resistance. Simulations were conducted for a low-to-moderate Reynolds number in the laminar-transition flow regime. Different channel geometries, defined by the half-angle ϕ of the periodic grooves are considered. The influence of the half-angle on both the flow field and the onset of oscillatory flow regime at different driving body forces is analyzed. At a low Reynolds number, the flow is observed stationary and fully reversible, regardless of the groove geometry. In this regime, higher Reynolds numbers were observed when the geometry acts as a diffuser (negative flow) than as a nozzle (positive flow) for a given driving body force. At sufficiently high Reynolds number the flow turns from a steady state to a time-dependent oscillatory regime through a Hopf bifurcation. Successive flow bifurcations lead the flow structure from a periodic regime to a quasi-chaotic regime with three-dimensional structures. The onset of unsteady flow occurs earlier for positive flows and geometries with small half-angles. For higher driving forces, there is a reduction in the volume flow rate due to the advected material in the transversal direction, causing consequently a decrease in the Reynolds number. (paper)

  20. Syncopation, body-movement and pleasure in groove music.

    Science.gov (United States)

    Witek, Maria A G; Clarke, Eric F; Wallentin, Mikkel; Kringelbach, Morten L; Vuust, Peter

    2014-01-01

    Moving to music is an essential human pleasure particularly related to musical groove. Structurally, music associated with groove is often characterised by rhythmic complexity in the form of syncopation, frequently observed in musical styles such as funk, hip-hop and electronic dance music. Structural complexity has been related to positive affect in music more broadly, but the function of syncopation in eliciting pleasure and body-movement in groove is unknown. Here we report results from a web-based survey which investigated the relationship between syncopation and ratings of wanting to move and experienced pleasure. Participants heard funk drum-breaks with varying degrees of syncopation and audio entropy, and rated the extent to which the drum-breaks made them want to move and how much pleasure they experienced. While entropy was found to be a poor predictor of wanting to move and pleasure, the results showed that medium degrees of syncopation elicited the most desire to move and the most pleasure, particularly for participants who enjoy dancing to music. Hence, there is an inverted U-shaped relationship between syncopation, body-movement and pleasure, and syncopation seems to be an important structural factor in embodied and affective responses to groove.

  1. Novel scaffold design with multi-grooved PLA fibers

    International Nuclear Information System (INIS)

    Chung, Sangwon; King, Martin W; Gamcsik, Mike P

    2011-01-01

    A novel prototype nonwoven textile structure containing polylactide (PLA) multigrooved fibers has been proposed as a possible scaffold material for superior cell attachment and proliferation. Grooved cross-sectional fibers with larger surface area were obtained by a bi-component spinning system and the complete removal of the sacrificial component was confirmed by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and x-ray photon spectroscopy (XPS) analysis. These PLA nonwoven scaffolds containing the grooved fibers exhibited enhanced wettability, greater flexibility and tensile properties, and a larger surface area compared to a traditional PLA nonwoven fabric containing round fibers. To evaluate cellular attachment on the two types of PLA nonwoven scaffolds, NIH 3T3 fibroblasts were cultured for up to 12 days. It was evident that the initial cellular attachment was superior on the scaffold with grooved fibers, which was confirmed by MTT viability assay (p < 0.01) and SEM analysis. In the future, by modulating the size of the grooves on the fibers, such a scaffold material with a large surface area could serve as an alternative matrix for culturing different types of cells.

  2. Wet Weather Crater Repair Technologies for Grooved and Smooth Pavements

    Science.gov (United States)

    2018-04-30

    Dean Geotechnical and Structures Laboratory U.S. Army Engineer Research and Development Center 3909 Halls Ferry Road Vicksburg, MS 39180-6199...ORGANIZATION REPORT NUMBER U.S. Army Engineer Research and Development Center Geotechnical and Structures Laboratory 3909 Halls Ferry Road ...SUBJECT TERMS Crater Concrete Rain and rainfall ADR Grooved pavement Smooth pavement Runoff Runways (Aeronautics) – Maintenance and repair

  3. Syncopation, body-movement and pleasure in groove music.

    Directory of Open Access Journals (Sweden)

    Maria A G Witek

    Full Text Available Moving to music is an essential human pleasure particularly related to musical groove. Structurally, music associated with groove is often characterised by rhythmic complexity in the form of syncopation, frequently observed in musical styles such as funk, hip-hop and electronic dance music. Structural complexity has been related to positive affect in music more broadly, but the function of syncopation in eliciting pleasure and body-movement in groove is unknown. Here we report results from a web-based survey which investigated the relationship between syncopation and ratings of wanting to move and experienced pleasure. Participants heard funk drum-breaks with varying degrees of syncopation and audio entropy, and rated the extent to which the drum-breaks made them want to move and how much pleasure they experienced. While entropy was found to be a poor predictor of wanting to move and pleasure, the results showed that medium degrees of syncopation elicited the most desire to move and the most pleasure, particularly for participants who enjoy dancing to music. Hence, there is an inverted U-shaped relationship between syncopation, body-movement and pleasure, and syncopation seems to be an important structural factor in embodied and affective responses to groove.

  4. [Binding of the antileukemia drug Escherichia coli L-asparaginase to the plasma membrane of normal human mononuclear cells].

    Science.gov (United States)

    Mercado-Vianco, L; Arenas-Díaz, G

    1999-06-01

    To demonstrate that the enzyme L-asparaginase from Escherichia coli (EcA) binds to the plasma membranes of normal human lymphocytes and monocytes. Lymphocytes and monocytes were isolated from heparinized blood samples which came from healthy volunteer donors. The cells were incubated with EcA to detect a possible binding of the enzyme to the mononuclear cells by indirect immunofluorescence using confocal microscopy. Meanwhile, ultracentrifugation was used to obtain the erythrocyte ghost microsomal fraction (P100) which was then analyzed by Western blotting to determine if EcA binds the lipid bilayer unspecifically. For the immunoassays, monospecific polyclonal antibodies were obtained from ascitic tumors developed in mice immunized with commercial L-asparaginase. EcA bins the lymphocyte and monocyte plasma membranes. In monocytes, there occurs a capping phenomenon, that is, the accumulation of fluorescent marker in one region. The image analyzer highlights it clearly at a depth of 3.8 microns. This binding would be unspecific, that is, there is no mediation of a specific receptor that binds EcA. This arises from the ability of the enzyme to bind to the membranes of erythrocyte ghost, as evidenced by the ability of the molecule to associate with a hydrophobic medium. The antibodies against EcA obtained from ascitic tumours developed in mice do not show cross reactivity with Na+/K+ ATPase, aspartate aminotransferase, nor with extracts of blood cells, which would make it a specific tool for the detection of EcA in whole cells and in homogenates electrotransfered to nitrocellulose membranes. L-asparaginase from E. coli behaves as a lipoprotein due to its ability to insert itself into hydrophobic environments, in which it resembles an isozyme present in T. pyriformis. The binding of this enzyme to lymphocytes and monocytes, demonstrated in this work, would permit the modification of the antileukemic treatment injecting doses of EcA bound to patient's own isolated immune

  5. Investigation of the complex structure, comparative DNA-binding and DNA cleavage of two water-soluble mono-nuclear lanthanum(III) complexes and cytotoxic activity of chitosan-coated magnetic nanoparticles as drug delivery for the complexes

    Science.gov (United States)

    Asadi, Zahra; Nasrollahi, Neda; Karbalaei-Heidari, Hamidreza; Eigner, Vaclav; Dusek, Michal; Mobaraki, Nabiallah; Pournejati, Roya

    2017-05-01

    Two water-soluble mono-nuclear macrocyclic lanthanum(III) complexes of 2,6-diformyl-4-methylphenol with 1,3-diamino-2-propanol (C1) or 1,3-propylenediamine (C2) were synthesized and characterized by UV-Vis, FT-IR, 13C and 1H NMR spectroscopy and elemental analysis. C1 complex was structurally characterized by single-crystal X-ray diffraction, which revealed that the complex was mononuclear and ten-coordinated. The coordination sites around lanthanum(III) were occupied with a five-dentate ligand, two bidentate nitrates, and one water molecule. The interaction of complexes with DNA was studied in buffered aqueous solution at pH 7.4. UV-Vis absorption spectroscopy, emission spectroscopy, circular dichroism (CD) and viscometric measurements provided clear evidence of the intercalation mechanism of binding. The obtained intrinsic binding constants (Kb) 9.3 × 103 and 1.2 × 103 M- 1 for C1 and C2, respectively confirmed that C1 is better intercalator than C2. The DNA docking studies suggested that the complexes bind with DNA in a groove binding mode with the binding affinity of C1 > C2. Moreover, agarose gel electrophoresis study of the DNA-complex for both compounds revealed that the C1 intercalation cause ethidium bromide replacement in a competitive manner which confirms the suggested mechanism of binding. Finally, the anticancer experiments for the treated cancerous cell lines with both synthesized compounds show that these hydrophilic molecules need a suitable carrier to pass through the hydrophobic nature of cell membrane efficiently.

  6. Imidazopyridine/Pyrrole and hydroxybenzimidazole/pyrrole pairs for DNA minor groove recognition.

    Science.gov (United States)

    Renneberg, Dorte; Dervan, Peter B

    2003-05-14

    The DNA binding properties of fused heterocycles imidazo[4,5-b]pyridine (Ip) and hydroxybenzimidazole (Hz) paired with pyrrole (Py) in eight-ring hairpin polyamides are reported. The recognition profile of Ip/Py and Hz/Py pairs were compared to the five-membered ring pairs Im/Py and Hp/Py on a DNA restriction fragment at four 6-base pair recognition sites which vary at a single position 5'-TGTNTA-3', where N = G, C, T, A. The Ip/Py pair distinguishes G.C from C.G, T.A, and A.T, and the Hz/Py pair distinguishes T.A from A.T, G.C, and C.G, affording a new set of heterocycle pairs to target the four Watson-Crick base pairs in the minor groove of DNA.

  7. Development and Validation of an Enzyme-Linked Immunosorbent Assay for the Detection of Binding Anti-Drug Antibodies against Interferon Beta

    DEFF Research Database (Denmark)

    Ingenhoven, Kathleen; Kramer, Daniel; Jensen, Poul Erik Hyldgaard

    2017-01-01

    to be 26 ng/mL using commercially available polyclonal rabbit antihuman IFN-β in human sera as the positive control. CONCLUSION: An ultrasensitive ELISA for IFN-β-binding ADA testing has been validated. This will form the basis to assess anti-biopharmaceutical immunization toward IFN-β with regards to its......OBJECTIVE: To develop and validate a method for the detection of binding anti-drug antibodies (ADAs) against interferon beta (IFN-β) in human serum as part of a European initiative (ABIRISK) aimed at the prediction and analysis of clinical relevance of anti-biopharmaceutical immunization...... to minimize the risk. METHOD: A two-tiered bridging enzyme-linked immunosorbent assay (ELISA) format was selected and validated according to current recommendations. Screening assay: ADA in serum samples form complexes with immobilized IFN-β and biotinylated IFN-β, which are then detected using HRP labeled...

  8. The complex radicular groove: interdisciplinary management with mineral trioxide aggregate and bone substitute.

    Science.gov (United States)

    Narmatha, V J; Thakur, Sophia; Shetty, Sheetal; Bali, Praveen Kumar

    2014-11-01

    This article is a case report of the successful interdisciplinary management of a maxillary lateral incisor with a deep palatogingival groove. The tooth presented with severe periodontal destruction owing to the deep extension of the groove up to the root apex. The groove was meticulously diagnosed and treated by endodontic and subsequent periodontal surgery leading to complete resolution of the pathological process.

  9. Three-dimensional models of Mycobacterium tuberculosis proteins Rv1555, Rv1554 and their docking analyses with sildenafil, tadalafil, vardenafil drugs, suggest interference with quinol binding likely to affect protein's function.

    Science.gov (United States)

    Dash, Pallabini; Bala Divya, M; Guruprasad, Lalitha; Guruprasad, Kunchur

    2018-04-18

    Earlier based on bioinformatics analyses, we had predicted the Mycobacterium tuberculosis (M.tb) proteins; Rv1555 and Rv1554, among the potential new tuberculosis drug targets. According to the 'TB-drugome' the Rv1555 protein is 'druggable' with sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra) drugs. In the present work, we intended to understand via computer modeling studies, how the above drugs are likely to inhibit the M.tb protein's function. The three-dimensional computer models for M.tb proteins; Rv1555 and Rv1554 constructed on the template of equivalent membrane anchor subunits of the homologous E.coli quinol fumarate reductase respiratory protein complex, followed by drug docking analyses, suggested that the binding of above drugs interferes with quinol binding sites. Also, we experimentally observed the in-vitro growth inhibition of E.coli bacteria containing the homologous M.tb protein sequences with sildenafil and tadalafil drugs. The predicted binding sites of the drugs is likely to affect the above M.tb proteins function as quinol binding is known to be essential for electron transfer function during anaerobic respiration in the homologous E.coli protein complex. Therefore, sildenafil and related drugs currently used in the treatment of male erectile dysfunction targeting the human phosphodiesterase 5 enzyme may be evaluated for their plausible role as repurposed drugs to treat human tuberculosis.

  10. Influence of Divalent Counterions on the Dynamics in DNA as Probed by Using a Minor-Groove Binder.

    Science.gov (United States)

    Paul, Sneha; Ahmed, Tasnim; Samanta, Anunay

    2017-08-05

    DNA dynamics, to which water, counterions, and DNA motions contribute, is a topic of considerable interest because it is closely related to the efficiency of biological functions performed by it. Simulation studies and experiments suggest that the counterion dynamics in DNA probed by a minor-groove binder are similar for various monovalent counterions. To date, the influence on DNA dynamics of higher-valence counterions, which are also present around DNA and are known to bind more strongly to it than monovalent ions, has not been studied. Herein we investigated DNA dynamics in the presence of Mg 2+ and Ca 2+ , chosen for their relative abundance in cells, by using minor-groove binder 4',6-diamidino-2-phenylindole (DAPI) as a fluorescence probe. The dynamics, as measured from the time-resolved fluorescence Stokes shifts of DAPI bound to calf thymus DNA on a subpicosecond-to-nanosecond timescale, were found to be very similar in the presence of both the divalent ions and Na + ions. The observation is explained by considering the screening of the electric field of the divalent ion by its hydration shell, preferential binding of the ions to the phosphate groups, and displacement of ions from the minor groove by DAPI due to the stronger binding interaction of the latter. Furthermore, the similarity of our results in the presence of Na + to those reported for smaller oligonucleotides suggests that the chain length of DNA does not influence the DNA dynamics. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Phenylacetic acids and the structurally related non-steroidal anti-inflammatory drug diclofenac bind to specific gamma-hydroxybutyric acid sites in rat brain

    DEFF Research Database (Denmark)

    Wellendorph, Petrine; Høg, Signe; Skonberg, Christian

    2009-01-01

    with a twofold higher affinity than GHB. Measuring the affinities of structurally related NSAIDs for the [(3)H]NCS-382 site identified diclofenac, a clinically relevant NSAID (Voltaren, Diclon) of the phenylacetic acid (PAA) type, as a GHB ligand (K(i) value of 5.1 microM). Other non-NSAID PAAs also exhibited...... affinities similar to GHB. Our data raise the interesting possibility that the widely used over-the-counter drug compound, diclofenac, might affect GHB binding at relevant clinical dosages. Furthermore, the identification of PAAs as GHB ligands supplies new information about the structural preferences...

  12. HCV IRES domain IIb affects the configuration of coding RNA in the 40S subunit's decoding groove.

    Science.gov (United States)

    Filbin, Megan E; Kieft, Jeffrey S

    2011-07-01

    Hepatitis C virus (HCV) uses a structured internal ribosome entry site (IRES) RNA to recruit the translation machinery to the viral RNA and begin protein synthesis without the ribosomal scanning process required for canonical translation initiation. Different IRES structural domains are used in this process, which begins with direct binding of the 40S ribosomal subunit to the IRES RNA and involves specific manipulation of the translational machinery. We have found that upon initial 40S subunit binding, the stem-loop domain of the IRES that contains the start codon unwinds and adopts a stable configuration within the subunit's decoding groove. This configuration depends on the sequence and structure of a different stem-loop domain (domain IIb) located far from the start codon in sequence, but spatially proximal in the IRES•40S complex. Mutation of domain IIb results in misconfiguration of the HCV RNA in the decoding groove that includes changes in the placement of the AUG start codon, and a substantial decrease in the ability of the IRES to initiate translation. Our results show that two distal regions of the IRES are structurally communicating at the initial step of 40S subunit binding and suggest that this is an important step in driving protein synthesis.

  13. Photobehavior and docking simulations of drug within macromolecules: binding of an antioxidative isoquinolindione to a serine protease and albumin proteins.

    Science.gov (United States)

    Dhar, Sayaree; Rana, Dipak Kumar; Pal, Arunava; Bhattacharya, Subhash Chandra

    2013-12-05

    The principal intent of the present contribution is to decipher the binding domain and structural changes of trypsin (TPS), a proteolytic globular enzyme and two serum proteins, namely, bovine serum albumin (BSA), human serum albumin (HSA) association with a newly synthesized bioactive isoquinolindione derivative (ANAP) by employing steady state, time resolved fluorescence and circular dichroism (CD) techniques. Intramolecular charge transfer emission (ICT) of ANAP is found to be responsible for the commendable sensitivity of the probe as an extrinsic fluorescent marker to the protein environments. A sharp distinctive feature of determined micropolarities in proteinous media clearly demarcates the differential extent of hydrophobicity around the encapsulated ANAP. A proficient efficiency tunable fluorescence (Förster type) resonance energy transfer (FRET) from the excited tryptophan to ANAP reveals that ANAP binds in the close vicinity of the tryptophan residue in protein. Molecular modeling simulation has been exploited for evaluating the probable interaction site of ANAP in proteinous assembly which shows subdomain IIA are earmarked to possess affinity for ANAP in serum albumins whereas S1 binding pocket in TPS has been found potential binding region for ANAP. Copyright © 2013 Elsevier B.V. All rights reserved.

  14. Definition of the G protein-coupled receptor transmembrane bundle binding pocket and calculation of receptor similarities for drug design

    DEFF Research Database (Denmark)

    Gloriam, David Erik Immanuel; Foord, Steven M; Blaney, Frank E

    2009-01-01

    currently available crystal structures. This was used to characterize pharmacological relationships of Family A/Rhodopsin family GPCRs, minimizing evolutionary influence from parts of the receptor that do not generally affect ligand binding. The resultant dendogram tended to group receptors according...

  15. Genetically encoded photocrosslinkers locate the high-affinity binding site of antidepressant drugs in the human serotonin transporter

    DEFF Research Database (Denmark)

    Rannversson, Hafsteinn; Andersen, Jacob; Hall, Lena Sørensen

    2016-01-01

    with p-azido-L-phenylalanine (azF) at selected positions in hSERT to map the binding site of imipramine, a prototypical tricyclic antidepressant, and vortioxetine, a novel multimodal antidepressant. We find that the two antidepressants crosslink with azF incorporated at different positions within...

  16. Evaluation of the binding interaction between bovine serum albumin and dimethyl fumarate, an anti-inflammatory drug by multispectroscopic methods

    Science.gov (United States)

    Jattinagoudar, Laxmi; Meti, Manjunath; Nandibewoor, Sharanappa; Chimatadar, Shivamurti

    2016-03-01

    The information of the quenching reaction of bovine serum albumin with dimethyl fumarate is obtained by multi-spectroscopic methods. The number of binding sites, n and binding constants, KA were determined at different temperatures. The effect of increasing temperature on Stern-Volmer quenching constants (KD) indicates that a dynamic quenching mechanism is involved in the interaction. The analysis of thermodynamic quantities namely, ∆H° and ∆S° suggested hydrophobic forces playing a major role in the interaction between dimethyl fumarate and bovine serum albumin. The binding site of dimethyl fumarate on bovine serum albumin was determined by displacement studies, using the site probes viz., warfarin, ibuprofen and digitoxin. The determination of magnitude of the distance of approach for molecular interactions between dimethyl fumarate and bovine serum albumin is calculated according to the theory of Förster energy transfer. The CD, 3D fluorescence spectra, synchronous fluorescence measurements and FT-IR spectral results were indicative of the change in secondary structure of the protein. The influence of some of the metal ions on the binding interaction was also studied.

  17. Numerical investigation of the effects of geometric parameters on transverse motion with slanted-groove micro-mixers

    Energy Technology Data Exchange (ETDEWEB)

    Baik, Seung Joo; Cho, Jae Yong; Choi, Se Bin; Lee, Joon Sang [School of Mechanical Engineering, Yonsei University, Seoul (Korea, Republic of)

    2016-08-15

    We investigated hydrodynamic phenomena inside several passive microfluidic mixers using a Lattice Boltzmann method (LBM) based on particle mesoscopic kinetic equations. Mixing processes were simulated in a Slanted grooved micro-mixer (SGM), a Staggered herringbone grooved micro-mixer (SHM), and a Bi-layered staggered herringbone grooved micro-mixer (BSHM). Then, the effects of six geometric mixer parameters (i.e., groove height to channel height ratio, groove width to groove pitch length ratio, groove pitch to groove height ratio, groove intersection angle, herringbone groove asymmetric ratio and bi-layered groove asymmetric ratio) on mixing were investigated using computed cross-flow velocity and helicity density distributions in the flow cross-section. We demonstrated that helicity density provides sufficient information to analyze micro helical motion within a micro-mixer, allowing for micro-mixer design optimization.

  18. Grooved windows for scintillation crystals and light pipes of high refractive index

    International Nuclear Information System (INIS)

    Swinehart, C.F.

    1975-01-01

    Scintillation crystals are disclosed which have improved resolution and pulse height. An improved crystal has shallow grooves or spot depressions cut in the window, usually an end surface. Typical grooves are about 1.5 mm wide and about .1 mm deep. The grooves may be either horizontal, generally parallel grooves in spaced apart relationship, or concentric rings in radially spaced apart relationship. A light pipe of high refractive index, such as a crystal of pure sodium iodide, may also be improved with shallow grooves or spot depressions cut in an end surface

  19. Phenytoin-Bovine Serum Albumin interactions - modeling plasma protein - drug binding: A multi-spectroscopy and in silico-based correlation

    Science.gov (United States)

    Suresh, P. K.; Divya, Naik; Nidhi, Shah; Rajasekaran, R.

    2018-03-01

    The study focused on the analysis of the nature and site of binding of Phenytoin (PHT) -(a model hydrophobic drug) with Bovine Serum Albumin (BSA) (a model protein used as a surrogate for HSA). Interactions with defined amounts of Phenytoin and BSA demonstrated a blue shift (hypsochromic -change in the microenvironment of the tryptophan residue with decrease in the polar environment and more of hydrophobicity) with respect to the albumin protein and a red shift (bathochromic -hydrophobicity and polarity related changes) in the case of the model hydrophobic drug. This shift, albeit lower in magnitude, has been substantiated by a fairly convincing, Phenytoin-mediated quenching of the endogenous fluorophore in BSA. Spectral shifts studied at varying pH, temperatures and incubation periods (at varying concentrations of PHT with a defined/constant BSA concentration) showed no significant differences (data not shown). FTIR analysis provided evidence of the interaction of PHT with BSA with a stretching vibration of 1737.86 cm- 1, apart from the vibrations characteristically associated with the amine and carboxyl groups respectively. Our in vitro findings were extended to molecular docking of BSA with PHT (with the different ionized forms of the drug) and the subsequent LIGPLOT-based analysis. In general, a preponderance of hydrophobic interactions was observed. These hydrophobic interactions corroborate the tryptophan-based spectral shifts and the fluorescence quenching data. These results substantiates our hitherto unreported in vitro/in silico experimental flow and provides a basis for screening other hydrophobic drugs in its class.

  20. Unified design of sinusoidal-groove fused-silica grating.

    Science.gov (United States)

    Feng, Jijun; Zhou, Changhe; Cao, Hongchao; Lu, Peng

    2010-10-20

    A general design rule of deep-etched subwavelength sinusoidal-groove fused-silica grating as a highly efficient polarization-independent or polarization-selective device is studied based on the simplified modal method, which shows that the device structure depends little on the incident wavelength, but mainly on the ratio of groove depth to incident wavelength and the ratio of wavelength to grating period. These two ratios could be used as the design guidelines for wavelength-independent structure from deep ultraviolet to far infrared. The optimized grating profile with a different function as a polarizing beam splitter, a polarization-independent two-port beam splitter, or a polarization-independent grating with high efficiency of -1st order is obtained at a wavelength of 1064 nm, and verified by using the rigorous coupled-wave analysis. The performance of the sinusoidal grating is better than a conventional rectangular one, which could be useful for practical applications.

  1. Dance, Music, Meter and Groove: A Forgotten Partnership

    Directory of Open Access Journals (Sweden)

    W Tecumseh eFitch

    2016-03-01

    Full Text Available I argue that core aspects of musical rhythm, especially groove and syncopation, can only be fully understood in the context of their origins in the participatory social experience of dance. Musical meter is first considered in the context of bodily movement. I then offer an interpretation of the pervasive but somewhat puzzling phenomenon of syncopation in terms of acoustic emphasis on certain offbeat components of the accompanying dance style. The reasons for the historical tendency of many musical styles to divorce themselves from their dance-based roots are also briefly considered. To the extent that musical rhythms only make sense in the context of bodily movement, researchers interested in ecologically valid approaches to music cognition should make a more concerted effort to extend their analyses to dance, particularly if we hope to understand the cognitive constraints underlying rhythmic aspects of music like meter and groove.

  2. Dance, Music, Meter and Groove: A Forgotten Partnership.

    Science.gov (United States)

    Fitch, W Tecumseh

    2016-01-01

    I argue that core aspects of musical rhythm, especially "groove" and syncopation, can only be fully understood in the context of their origins in the participatory social experience of dance. Musical meter is first considered in the context of bodily movement. I then offer an interpretation of the pervasive but somewhat puzzling phenomenon of syncopation in terms of acoustic emphasis on certain offbeat components of the accompanying dance style. The reasons for the historical tendency of many musical styles to divorce themselves from their dance-based roots are also briefly considered. To the extent that musical rhythms only make sense in the context of bodily movement, researchers interested in ecologically valid approaches to music cognition should make a more concerted effort to extend their analyses to dance, particularly if we hope to understand the cognitive constraints underlying rhythmic aspects of music like meter and groove.

  3. Hydrodynamic simulations of microjetting from shock-loaded grooves

    Science.gov (United States)

    Roland, C.; de Rességuier, T.; Sollier, A.; Lescoute, E.; Soulard, L.; Loison, D.

    2017-01-01

    The interaction of a shock wave with a free surface which has geometrical defects, such as cavities or grooves, may lead to the ejection of micrometric debris at velocities of km/s. This process can be involved in many applications, like pyrotechnics or industrial safety. Recent laser shock experiments reported elsewhere in this conference have provided some insight into jet formation as well as jet tip velocities for various groove angles and shock pressures. Here, we present hydrodynamic simulations of these experiments, in both 2D and 3D geometries, using both finite element method and smoothed particle hydrodynamics. Numerical results are compared to several theoretical predictions including the Richtmyer-Meshkov instabilities. The role of the elastic-plastic behavior on jet formation is illustrated. Finally, the possibility to simulate the late stage of jet expansion and fragmentation is explored, to evaluate the mass distribution of the ejecta and their ballistic properties, still essentially unknown in the experiments.

  4. Numerical analysis of lateral illumination lightpipes using elliptical grooves

    Science.gov (United States)

    Sánchez-Guerrero, Guillermo E.; Viera-González, Perla M.; Martínez-Guerra, Edgar; Ceballos-Herrera, Daniel E.

    2017-09-01

    Lightpipes are used for illumination in applications such as back-lighting or solar cell concentrators due to the high irradiance uniformity, but its optimal design requires several parameters. This work presents a procedure to design a square lightpipe to control the light-extraction on its lateral face using commercial LEDs placed symmetrically in the lightpipe frontal face. We propose the use of grooves using total internal reflection placed successively in the same face of extraction to control the area of emission. The LED area of emission is small compared with the illuminated area, and, as expected, the lateral face total power is attenuated. These grooves reduce the optical elements in the system and can control areas of illumination. A mathematical and numerical analysis are presented to determine the dependencies on the light-extraction.

  5. Two-dimensional 1H and 31P NMR spectra of a decamer oligodeoxyribonucleotide duplex and a quinoxaline ([MeCys3, MeCys7]TANDEM) drug duplex complex

    International Nuclear Information System (INIS)

    Powers, R.; Olsen, R.K.; Gorenstein, D.G.

    1989-01-01

    Assignment of the 1H and 31P NMR spectra of a decamer oligodeoxyribonucleotide duplex, d(CCCGATCGGG), and its quinoxaline ([MeCys3, MeCys7]TANDEM) drug duplex complex has been made by two-dimensional 1H-1H and heteronuclear 31P-1H correlated spectroscopy. The 31P chemical shifts of this 10 base pair oligonucleotide follow the general observation that the more internal the phosphate is located within the oligonucleotide sequence, the more upfield the 31P resonance occurs. While the 31P chemical shifts show sequence-specific variations, they also do not generally follow the Calladine rules previously demonstrated. 31P NMR also provides a convenient monitor of the phosphate ester backbone conformational changes upon binding of the drug to the duplex. Although the quinoxaline drug, [MeCys3, MeCys7]TANDEM, is generally expected to bind to duplex DNA by bis-intercalation, only small 31P chemical shift changes are observed upon binding the drug to duplex d(CCCGATCGGG). Additionally, only small perturbations in the 1H NMR and UV spectra are observed upon binding the drug to the decamer, although association of the drug stabilizes the duplex form relative to the other states. These results are consistent with a non-intercalative mode of association of the drug. Modeling and molecular mechanics energy minimization demonstrate that a novel structure in which the two quinoxaline rings of the drug binds in the minor groove of the duplex is possible

  6. Condensation and Evaporation Transitions in Deep Capillary Grooves

    OpenAIRE

    Malijevský, A. (Alexandr); Parry, A.O.

    2014-01-01

    We study the order of capillary condensation and evaporation transitions of a simple fluid adsorbed in a deep capillary groove using a fundamental measure density functional theory (DFT). The walls of the capillary interact with the fluid particles via long-ranged, dispersion, forces while the fluid-fluid interaction is modelled as a truncated Lennard-Jones-like potential. We find that below the wetting temperature $T_w$ condensation is first-order and evaporation is continuous with the metas...

  7. Modification of radiation effects on E. coli B/r and a radiosensitive mutant Bsub(s-1) by membrane-binding drugs

    International Nuclear Information System (INIS)

    Yonei, S.

    1979-01-01

    In this study, the effects of chlorpromazine, procaine and quinidine on the X-radiation effects on Escherichia coli B/r and its radiosensitive mutant Bsub(s-1) (which is genetically unable to repair radiation damage to DNA) were examined. At chlorpromazine concentrations > = 25 mM, there was loss of colony-forming ability in both strains. Chlorpromazine (0.1 mM) markedly sensitized E. coli B/r under hypoxic conditions of irradiation but not under oxic conditions. There was no significant radiosensitization by chlorpromazine (0.1-1.0mM) in E. coli Bsub(s-1) under either oxic or hypoxic conditions. Similar results were obtained when procaine and quinidine were used as 'membrane-binding radiosensitizers'. Thus these results suggested that radiosensitization by such drugs in E. coli B/r was the result of inhibition of post-irradiation DNA repair in cells. It was concluded that the inhibition of DNA repair could be a secondary consequence of cell membrane alterations or damage caused by the membrane-binding of these drugs. (UK)

  8. NpPDR1, a Pleiotropic Drug Resistance-Type ATP-Binding Cassette Transporter from Nicotiana plumbaginifolia, Plays a Major Role in Plant Pathogen Defense1

    Science.gov (United States)

    Stukkens, Yvan; Bultreys, Alain; Grec, Sébastien; Trombik, Tomasz; Vanham, Delphine; Boutry, Marc

    2005-01-01

    Nicotiana plumbaginifolia NpPDR1, a plasma membrane pleiotropic drug resistance-type ATP-binding cassette transporter formerly named NpABC1, has been suggested to transport the diterpene sclareol, an antifungal compound. However, direct evidence for a role of pleiotropic drug resistance transporters in the plant defense is still lacking. In situ immunolocalization and histochemical analysis using the gusA reporter gene showed that NpPDR1 was constitutively expressed in the whole root, in the leaf glandular trichomes, and in the flower petals. However, NpPDR1 expression was induced in the whole leaf following infection with the fungus Botrytis cinerea, and the bacteria Pseudomonas syringae pv tabaci, Pseudomonas fluorescens, and Pseudomonas marginalis pv marginalis, which do not induce a hypersensitive response in N. plumbaginifolia, whereas a weaker response was observed using P. syringae pv syringae, which does induce a hypersensitive response. Induced NpPDR1 expression was more associated with the jasmonic acid than the salicylic acid signaling pathway. These data suggest that NpPDR1 is involved in both constitutive and jasmonic acid-dependent induced defense. Transgenic plants in which NpPDR1 expression was prevented by RNA interference showed increased sensitivity to sclareol and reduced resistance to B. cinerea. These data show that NpPDR1 is involved in pathogen resistance and thus demonstrate a new role for the ATP-binding cassette transporter family. PMID:16126865

  9. NpPDR1, a pleiotropic drug resistance-type ATP-binding cassette transporter from Nicotiana plumbaginifolia, plays a major role in plant pathogen defense.

    Science.gov (United States)

    Stukkens, Yvan; Bultreys, Alain; Grec, Sébastien; Trombik, Tomasz; Vanham, Delphine; Boutry, Marc

    2005-09-01

    Nicotiana plumbaginifolia NpPDR1, a plasma membrane pleiotropic drug resistance-type ATP-binding cassette transporter formerly named NpABC1, has been suggested to transport the diterpene sclareol, an antifungal compound. However, direct evidence for a role of pleiotropic drug resistance transporters in the plant defense is still lacking. In situ immunolocalization and histochemical analysis using the gusA reporter gene showed that NpPDR1 was constitutively expressed in the whole root, in the leaf glandular trichomes, and in the flower petals. However, NpPDR1 expression was induced in the whole leaf following infection with the fungus Botrytis cinerea, and the bacteria Pseudomonas syringae pv tabaci, Pseudomonas fluorescens, and Pseudomonas marginalis pv marginalis, which do not induce a hypersensitive response in N. plumbaginifolia, whereas a weaker response was observed using P. syringae pv syringae, which does induce a hypersensitive response. Induced NpPDR1 expression was more associated with the jasmonic acid than the salicylic acid signaling pathway. These data suggest that NpPDR1 is involved in both constitutive and jasmonic acid-dependent induced defense. Transgenic plants in which NpPDR1 expression was prevented by RNA interference showed increased sensitivity to sclareol and reduced resistance to B. cinerea. These data show that NpPDR1 is involved in pathogen resistance and thus demonstrate a new role for the ATP-binding cassette transporter family.

  10. Development and Validation of an Enzyme-Linked Immunosorbent Assay for the Detection of Binding Anti-Drug Antibodies against Interferon Beta

    Directory of Open Access Journals (Sweden)

    Kathleen Ingenhoven

    2017-07-01

    Full Text Available ObjectiveTo develop and validate a method for the detection of binding anti-drug antibodies (ADAs against interferon beta (IFN-β in human serum as part of a European initiative (ABIRISK aimed at the prediction and analysis of clinical relevance of anti-biopharmaceutical immunization to minimize the risk.MethodA two-tiered bridging enzyme-linked immunosorbent assay (ELISA format was selected and validated according to current recommendations. Screening assay: ADA in serum samples form complexes with immobilized IFN-β and biotinylated IFN-β, which are then detected using HRP labeled Streptavidin and TMB substrate. Confirmation assay: Screen “putative positive” samples are tested in the presence of excess drug (preincubation of sera with 0.3 µg/mL of soluble IFN-β and percentage of inhibition is calculated.ResultsThe assay is precise, and the sensitivity of the assay was confirmed to be 26 ng/mL using commercially available polyclonal rabbit antihuman IFN-β in human sera as the positive control.ConclusionAn ultrasensitive ELISA for IFN-β-binding ADA testing has been validated. This will form the basis to assess anti-biopharmaceutical immunization toward IFN-β with regards to its clinical relevance and may allow for the development of predictive tools, key aims within the ABIRISK consortium.

  11. General transfer matrix formalism to calculate DNA-protein-drug binding in gene regulation: application to OR operator of phage lambda.

    Science.gov (United States)

    Teif, Vladimir B

    2007-01-01

    The transfer matrix methodology is proposed as a systematic tool for the statistical-mechanical description of DNA-protein-drug binding involved in gene regulation. We show that a genetic system of several cis-regulatory modules is calculable using this method, considering explicitly the site-overlapping, competitive, cooperative binding of regulatory proteins, their multilayer assembly and DNA looping. In the methodological section, the matrix models are solved for the basic types of short- and long-range interactions between DNA-bound proteins, drugs and nucleosomes. We apply the matrix method to gene regulation at the O(R) operator of phage lambda. The transfer matrix formalism allowed the description of the lambda-switch at a single-nucleotide resolution, taking into account the effects of a range of inter-protein distances. Our calculations confirm previously established roles of the contact CI-Cro-RNAP interactions. Concerning long-range interactions, we show that while the DNA loop between the O(R) and O(L) operators is important at the lysogenic CI concentrations, the interference between the adjacent promoters P(R) and P(RM) becomes more important at small CI concentrations. A large change in the expression pattern may arise in this regime due to anticooperative interactions between DNA-bound RNA polymerases. The applicability of the matrix method to more complex systems is discussed.

  12. Pyrrolobenzodiazepines (PBDs do not bind to DNA G-quadruplexes.

    Directory of Open Access Journals (Sweden)

    Khondaker M Rahman

    Full Text Available The pyrrolo[2,1-c][1,4] benzodiazepines (PBDs are a family of sequence-selective, minor-groove binding DNA-interactive agents that covalently attach to guanine residues. A recent publication in this journal (Raju et al, PloS One, 2012, 7, 4, e35920 reported that two PBD molecules were observed to bind with high affinity to the telomeric quadruplex of Tetrahymena glaucoma based on Electrospray Ionisation Mass Spectrometry (ESI-MS, Circular Dichroism, UV-Visible and Fluorescence spectroscopy data. This was a surprising result given the close 3-dimensional shape match between the structure of all PBD molecules and the minor groove of duplex DNA, and the completely different 3-dimensional structure of quadruplex DNA. Therefore, we evaluated the interaction of eight PBD molecules of diverse structure with a range of parallel, antiparallel and mixed DNA quadruplexes using DNA Thermal Denaturation, Circular Dichroism and Molecular Dynamics Simulations. Those PBD molecules without large C8-substitutents had an insignificant affinity for the eight quadruplex types, although those with large π-system-containing C8-substituents (as with the compounds evaluated by Raju and co-workers were found to interact to some extent. Our molecular dynamics simulations support the likelihood that molecules of this type, including those examined by Raju and co-workers, interact with quadruplex DNA through their C8-substituents rather than the PBD moiety itself. It is important for the literature to be clear on this matter, as the mechanism of action of these agents will be under close scrutiny in the near future due to the growing number of PBD-based agents entering the clinic as both single-agents and as components of antibody-drug conjugates (ADCs.

  13. Neratinib Reverses ATP-Binding Cassette B1-Mediated Chemotherapeutic Drug Resistance In Vitro, In Vivo, and Ex Vivo

    OpenAIRE

    Zhao, Xiao-qin; Xie, Jing-dun; Chen, Xing-gui; Sim, Hong May; Zhang, Xu; Liang, Yong-ju; Singh, Satyakam; Talele, Tanaji T.; Sun, Yueli; Ambudkar, Suresh V.; Chen, Zhe-Sheng; Fu, Li-wu

    2012-01-01

    Neratinib, an irreversible inhibitor of epidermal growth factor receptor and human epidermal receptor 2, is in phase III clinical trials for patients with human epidermal receptor 2-positive, locally advanced or metastatic breast cancer. The objective of this study was to explore the ability of neratinib to reverse tumor multidrug resistance attributable to overexpression of ATP-binding cassette (ABC) transporters. Our results showed that neratinib remarkably enhanced the sensitivity of ABCB1...

  14. Groove Pancreatitis – A Mimic of Pancreatic and Periampullary Tumors

    Directory of Open Access Journals (Sweden)

    Sivakami R Pradheepkumar

    2017-10-01

    Full Text Available Groove Pancreatitis (GP is a rare form of focal chronic pancreatitis involving the pancreatico-duodenal groove (PDG. GP was first described by Becker in 1973. Though, GP has been described so many years ago, it is still unfamiliar among most physicians because of lack of sufficient case studies and clinical similarity of GP to conventional pancreatitis. Imaging based differentiation of GP from other lesions, like pancreatic and periampullary adenocarcinoma is also not possible in all the cases, unless there are typical findings favoring GP. Since, the line of treatment and outcome is totally different in these two conditions, appreciation of the fine differences between these two entities is very significant. Groove pancreatitis is symptomatically treated with medicines and only for patients with continuous and severe symptoms which are not amenable to medical treatment surgical management is considered. Radiological differentiation of GP from pancreatic and periampullary malignancies will help to avoid unnecessary surgery in the initial stages. We report two cases of GP, one of pure and other of segmental form where we found typical imaging features which pointed to the diagnosis of GP with a small discussion about the Computed tomography (CT and Magnetic Resonance Imaging (MRI appearance of this entity as well as its differential diagnosis.

  15. Separate and simultaneous binding effects of aspirin and amlodipine to human serum albumin based on fluorescence spectroscopic and molecular modeling characterizations: A mechanistic insight for determining usage drugs doses

    International Nuclear Information System (INIS)

    Abdollahpour, Nooshin; Asoodeh, Ahmad; Saberi, Mohammad Reza; Chamani, JamshidKhan

    2011-01-01

    The binding of aspirin (ASA) and amlodipine (AML) to human serum albumin (HSA) in aqueous solution was investigated by multiple techniques such as fluorescence quenching, resonance light scattering (RLS), three-dimensional fluorescence spectroscopy, FT-IR and zeta-potential measurements in an aqueous solution at pH=7.4. For the protein-ligand association reaction, fluorescence measurements can give important clues as to the binding of ligands to proteins, e.g., the binding mechanism, binding mode, binding constants, binding sites, etc. Fluorescence spectroscopy showed that ASA and AML could quench the HSA fluorescence spectra, and this quenching effect became more significant when both ASA and AML coexisted. The results pointed at the interaction between HSA and both drugs as ternary systems decreasing the binding constant and binding stability of the HSA-drug complex as a binary system. Therefore, by reducing the amount of drugs transported to their targets, the free drug concentration of the target would be reduced, lowering the efficacy of the drugs. It was demonstrated that there exists antagonistic behavior between the two drugs when it comes to binding of HSA. Furthermore, the fluorescence results also showed that the quenching mechanism of HSA-drug complexes as binary and ternary systems is a static procedure. The number of binding sites of HSA-ASA, (HSA-AML)ASA, HSA-AML and (HSA-ASA) AML were 1.31, 0.92, 1 and 0.93, respectively. Due to the existence of the antagonistic action between ASA and AML, the binding distance r was reduced. The results of synchronous fluorescence and three-dimensional fluorescence spectra showed that the antagonistic action between ASA and AML would alter the micro-environment around Trp and Tyr residues. Moreover, the simultaneous presence of ASA and AML during binding to HSA should be taken into account in multidrug therapy, as it induces the necessity of a monitoring therapy owing to the possible increase of uncontrolled toxic

  16. Separate and simultaneous binding effects of aspirin and amlodipine to human serum albumin based on fluorescence spectroscopic and molecular modeling characterizations: A mechanistic insight for determining usage drugs doses

    Energy Technology Data Exchange (ETDEWEB)

    Abdollahpour, Nooshin [Department of Biology, Faculty of Sciences, Mashhad Branch, Islamic Azad University, Mashhad (Iran, Islamic Republic of); Asoodeh, Ahmad [Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, Mashhad (Iran, Islamic Republic of); Saberi, Mohammad Reza [Department of Medical Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad (Iran, Islamic Republic of); Chamani, JamshidKhan, E-mail: chamani@ibb.ut.ac.ir [Department of Biology, Faculty of Sciences, Mashhad Branch, Islamic Azad University, Mashhad (Iran, Islamic Republic of)

    2011-09-15

    The binding of aspirin (ASA) and amlodipine (AML) to human serum albumin (HSA) in aqueous solution was investigated by multiple techniques such as fluorescence quenching, resonance light scattering (RLS), three-dimensional fluorescence spectroscopy, FT-IR and zeta-potential measurements in an aqueous solution at pH=7.4. For the protein-ligand association reaction, fluorescence measurements can give important clues as to the binding of ligands to proteins, e.g., the binding mechanism, binding mode, binding constants, binding sites, etc. Fluorescence spectroscopy showed that ASA and AML could quench the HSA fluorescence spectra, and this quenching effect became more significant when both ASA and AML coexisted. The results pointed at the interaction between HSA and both drugs as ternary systems decreasing the binding constant and binding stability of the HSA-drug complex as a binary system. Therefore, by reducing the amount of drugs transported to their targets, the free drug concentration of the target would be reduced, lowering the efficacy of the drugs. It was demonstrated that there exists antagonistic behavior between the two drugs when it comes to binding of HSA. Furthermore, the fluorescence results also showed that the quenching mechanism of HSA-drug complexes as binary and ternary systems is a static procedure. The number of binding sites of HSA-ASA, (HSA-AML)ASA, HSA-AML and (HSA-ASA) AML were 1.31, 0.92, 1 and 0.93, respectively. Due to the existence of the antagonistic action between ASA and AML, the binding distance r was reduced. The results of synchronous fluorescence and three-dimensional fluorescence spectra showed that the antagonistic action between ASA and AML would alter the micro-environment around Trp and Tyr residues. Moreover, the simultaneous presence of ASA and AML during binding to HSA should be taken into account in multidrug therapy, as it induces the necessity of a monitoring therapy owing to the possible increase of uncontrolled toxic

  17. The C-terminal helix of ribosomal P stalk recognizes a hydrophobic groove of elongation factor 2 in a novel fashion.

    Science.gov (United States)

    Tanzawa, Takehito; Kato, Koji; Girodat, Dylan; Ose, Toyoyuki; Kumakura, Yuki; Wieden, Hans-Joachim; Uchiumi, Toshio; Tanaka, Isao; Yao, Min

    2018-04-06

    Archaea and eukaryotes have ribosomal P stalks composed of anchor protein P0 and aP1 homodimers (archaea) or P1•P2 heterodimers (eukaryotes). These P stalks recruit translational GTPases to the GTPase-associated center in ribosomes to provide energy during translation. The C-terminus of the P stalk is known to selectively recognize GTPases. Here we investigated the interaction between the P stalk and elongation factor 2 by determining the structures of Pyrococcus horikoshii EF-2 (PhoEF-2) in the Apo-form, GDP-form, GMPPCP-form (GTP-form), and GMPPCP-form bound with 11 C-terminal residues of P1 (P1C11). Helical structured P1C11 binds to a hydrophobic groove between domain G and subdomain G' of PhoEF-2, where is completely different from that of aEF-1α in terms of both position and sequence, implying that such interaction characteristic may be requested by how GTPases perform their functions on the ribosome. Combining PhoEF-2 P1-binding assays with a structural comparison of current PhoEF-2 structures and molecular dynamics model of a P1C11-bound GDP form, the conformational changes of the P1C11-binding groove in each form suggest that in response to the translation process, the groove has three states: closed, open, and release for recruiting and releasing GTPases.

  18. The naphthoquinones, vitamin K3 and its structural analogue plumbagin, are substrates of the multidrug resistance linked ATP binding cassette drug transporter ABCG2.

    Science.gov (United States)

    Shukla, Suneet; Wu, Chung-Pu; Nandigama, Krishnamachary; Ambudkar, Suresh V

    2007-12-01

    Vitamin K3 (menadione; 2-methyl-1,4-naphthoquinone) is a structural precursor of vitamins K1 and K2, which are essential for blood clotting. The naturally occurring structural analogue of this vitamin, plumbagin (5-hydroxy-menadione), is known to modulate cellular proliferation, apoptosis, carcinogenesis, and radioresistance. We here report that both vitamin K3 and plumbagin are substrates of the multidrug resistance-linked ATP binding cassette drug transporter, ABCG2. Vitamin K3 and plumbagin specifically inhibited the ABCG2-mediated efflux of mitoxantrone but did not have any effect on the ABCB1-mediated efflux of rhodamine 123. This inhibition of ABCG2 function was due to their interaction at the substrate-binding site(s). Vitamin K3 and plumbagin inhibited the binding of [(125)I]iodoarylazidoprazosin, a substrate of ABCG2, to this transporter in a concentration-dependent manner with IC(50) values of 7.3 and 22.6 micromol/L, respectively, but had no effect on the binding of the photoaffinity analogue to ABCB1. Both compounds stimulated ABCG2-mediated ATP hydrolysis and also inhibited the mitoxantrone-stimulated ATPase activity of the ABCG2 transporter, but did not have any significant effect on the ATPase activity of ABCB1. In a cytotoxicity assay, ABCG2-expressing HEK cells were 2.8- and 2.3-fold resistant to plumbagin and vitamin K3, respectively, compared with the control cells, suggesting that they are substrates of this transporter. Collectively, these data show for the first time that vitamin K3 is a substrate of the ABCG2 transporter. Thus, ABCG2 may have a role in the regulation of vitamin K3 levels in the body. In addition, vitamin K3 and its structural derivative, plumbagin, could potentially be used to modulate ABCG2 function.

  19. A Study on Solubilization of Poorly Soluble Drugs by Cyclodextrins and Micelles: Complexation and Binding Characteristics of Sulfamethoxazole and Trimethoprim

    Directory of Open Access Journals (Sweden)

    Sinem Göktürk

    2012-01-01

    > α-CD. With taking into consideration of solubilization capacity of SDS micelles, it has been found that the solubility enhancement of TMP is much higher than that of SMX in the presence of SDS micelles. The binding constants of SMX and TMP obtained from the Benesi-Hildebrand equation are also confirmed by the estimated surface properties of SDS, employing the surface tension measurements. In order to elucidate the solubilization characteristics the surface tension measurements were also performed for nonionic surfactant Triton X-100. Polarity of the microenvironment and probable location of SMX and TMP were also discussed in the presence of various organic solvents.

  20. Synthesis of schiff bases of pyridine-4-carbaldehyde and their antioxidant and DNA binding studies

    International Nuclear Information System (INIS)

    Shamim, S.; Murtaza, S.; Nazar, M.F.

    2016-01-01

    A series of Schiff bases of pyridine-4-carbaldehyde with 3-aminobenzoic acid, 2-aminobenzoic acid, 4-aminobenzoic acid, 1,3-phenylenediamine, 1,2-phenylenediamine, 2-aminothiophenol, 4-aminoantipyrene, 2-aminophenol and naphthalene-1-amine was synthesized and compounds were characterized by FTIR, NMR and mass spectrometry. The synthesized compounds were evaluated for their antioxidant and DNA binding interaction studies. DPPH scavenging method was used to evaluate the antioxidant activities of synthesized Schiff bases at six gradually increasing concentrations of 0.5-5mg/ml. 2-((pyridin-4-ylmethylidene)amino)phenol came out to be the most efficient antioxidant at a concentration of 4mg/ml with 74% inhibition of free radicals generated by DPPH. The DNA binding interaction of the synthesized Schiff bases was determined using UV-Vis absorption titration method. Both the hypochromic and hyperchromic effects were observed along the series. The values for the binding constant (K) and free energy change (G) were calculated and most of the Schiff bases have high positive K values which indicate the efficient binding of Schiff bases with DNA. Molecular docking studies as carried out using PatchDock molecular algorithm software also indicated the high values for geometrical shape complementarity score suggesting the stabilities of Schiff bases/DNA complex. Docking studies also suggested the minor groove binding of the Schiff bases with DNA. Drug-likeness of the synthesized compounds was also tested in silico and the results are accordingly discussed. (author)

  1. Commentary on "spectral characterization of the binding and conformational changes of serum albumins upon interaction with an anticancer drug, anastrozole".

    Science.gov (United States)

    Korkmaz, Filiz

    2015-03-05

    The manuscript by R. Punith and J. Seetharamappa (http://dx.doi.org/10.1016/j.saa.201202.038) presents the interaction between serum albumin from human (HAS) and from bovine (BSA) with a drug called Anastrozole (AZ). The drug is on the market for treating patients with breast cancer after surgery and for metastasis in women. The study utilizes various spectroscopic techniques such as; fluorescence, synchronous fluorescence, 3D fluorescence measurements, FTIR, CD and UV. Although there are some relatively minor comments on the paper, the main point that needs to be reviewed by the authors is the result of FTIR measurements. Based on the data provided in the text (there is no figure), the protein sample is not in its native state, which makes the data inconvenient to be used in drawing conclusions. Authors are kindly requested to take another look at the FTIR experiments. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Neratinib reverses ATP-binding cassette B1-mediated chemotherapeutic drug resistance in vitro, in vivo, and ex vivo.

    Science.gov (United States)

    Zhao, Xiao-qin; Xie, Jing-dun; Chen, Xing-gui; Sim, Hong May; Zhang, Xu; Liang, Yong-ju; Singh, Satyakam; Talele, Tanaji T; Sun, Yueli; Ambudkar, Suresh V; Chen, Zhe-Sheng; Fu, Li-wu

    2012-07-01

    Neratinib, an irreversible inhibitor of epidermal growth factor receptor and human epidermal receptor 2, is in phase III clinical trials for patients with human epidermal receptor 2-positive, locally advanced or metastatic breast cancer. The objective of this study was to explore the ability of neratinib to reverse tumor multidrug resistance attributable to overexpression of ATP-binding cassette (ABC) transporters. Our results showed that neratinib remarkably enhanced the sensitivity of ABCB1-overexpressing cells to ABCB1 substrates. It is noteworthy that neratinib augmented the effect of chemotherapeutic agents in inhibiting the growth of ABCB1-overexpressing primary leukemia blasts and KBv200 cell xenografts in nude mice. Furthermore, neratinib increased doxorubicin accumulation in ABCB1-overexpressing cell lines and Rhodamine 123 accumulation in ABCB1-overexpressing cell lines and primary leukemia blasts. Neratinib stimulated the ATPase activity of ABCB1 at low concentrations but inhibited it at high concentrations. Likewise, neratinib inhibited the photolabeling of ABCB1 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner (IC(50) = 0.24 μM). Neither the expression of ABCB1 at the mRNA and protein levels nor the phosphorylation of Akt was affected by neratinib at reversal concentrations. Docking simulation results were consistent with the binding conformation of neratinib within the large cavity of the transmembrane region of ABCB1, which provides computational support for the cross-reactivity of tyrosine kinase inhibitors with human ABCB1. In conclusion, neratinib can reverse ABCB1-mediated multidrug resistance in vitro, ex vivo, and in vivo by inhibiting its transport function.

  3. Correcting groove error in gratings ruled on a 500-mm ruling engine using interferometric control.

    Science.gov (United States)

    Mi, Xiaotao; Yu, Haili; Yu, Hongzhu; Zhang, Shanwen; Li, Xiaotian; Yao, Xuefeng; Qi, Xiangdong; Bayinhedhig; Wan, Qiuhua

    2017-07-20

    Groove error is one of the most important factors affecting grating quality and spectral performance. To reduce groove error, we propose a new ruling-tool carriage system based on aerostatic guideways. We design a new blank carriage system with double piezoelectric actuators. We also propose a completely closed-loop servo-control system with a new optical measurement system that can control the position of the diamond relative to the blank. To evaluate our proposed methods, we produced several gratings, including an echelle grating with 79  grooves/mm, a grating with 768  grooves/mm, and a high-density grating with 6000  grooves/mm. The results show that our methods effectively reduce groove error in ruled gratings.

  4. Coronary sinus and atrioventricular groove avulsion after motor vehicle crash

    Directory of Open Access Journals (Sweden)

    Bradley M Dennis

    2014-01-01

    Full Text Available Simultaneous cardiac and pericardial rupture from blunt chest trauma is a highly lethal combination with rarely reported survival. We report of a case of young patient with a right atrioventricular groove injury, pericardial rupture and a unique description of a coronary sinus avulsion following blunt chest trauma. Rapid recognition of this injury is crucial to patient survival, but traditional diagnostic adjuncts such as ultrasound, echocardiography and computed tomography are often unhelpful. Successful repair of these injuries requires high suspicion of injury, early cardiac surgery involvement of and possible even placement of the patient on cardiopulmonary bypass.

  5. Constitutional Syndrome, Ascites and Duodenal Thickening Presenting as Groove Pancreatitis

    Directory of Open Access Journals (Sweden)

    Jose Maria Frutos Perez

    2017-12-01

    Full Text Available Groove pancreatitis (GP is a very infrequent subtype of chronic pancreatitis affecting the pancreatic-duodenal junction. It usually manifests in middle-aged men with a history of chronic alcoholism, though it has also been described in women and in individuals who do not consume alcohol[1]. Even though the underlying etiology is unclear, chronic alcohol consumption is known to increase the viscosity of the pancreatic juice and exacerbate the inflammatory process[2]. We present a case of GP that posed diagnostic difficulties because it manifested as ascites and duodenal thickening, with pancreatic imaging findings initially normal.

  6. Narrow groove gas metal-arc welding of aluminum

    International Nuclear Information System (INIS)

    Armstrong, R.E.

    1975-01-01

    The Gas Metal-Arc (GMA) welding process is explained and the equipment used described with an analysis of power supply function and the action of the arc, followed by discussion of general applications and problems. GMA braze welding of beryllium is then described, as is the development of a special high purity filler wire and a narrow deep groove joint design for improved weld strength in beryllium. This joint design and the special wire are applied in making high strength welds in high strength aluminum for special applications. High speed motion pictures of the welding operation are shown to illustrate the talk. (auth)

  7. LIBP-Pred: web server for lipid binding proteins using structural network parameters; PDB mining of human cancer biomarkers and drug targets in parasites and bacteria.

    Science.gov (United States)

    González-Díaz, Humberto; Munteanu, Cristian R; Postelnicu, Lucian; Prado-Prado, Francisco; Gestal, Marcos; Pazos, Alejandro

    2012-03-01

    Lipid-Binding Proteins (LIBPs) or Fatty Acid-Binding Proteins (FABPs) play an important role in many diseases such as different types of cancer, kidney injury, atherosclerosis, diabetes, intestinal ischemia and parasitic infections. Thus, the computational methods that can predict LIBPs based on 3D structure parameters became a goal of major importance for drug-target discovery, vaccine design and biomarker selection. In addition, the Protein Data Bank (PDB) contains 3000+ protein 3D structures with unknown function. This list, as well as new experimental outcomes in proteomics research, is a very interesting source to discover relevant proteins, including LIBPs. However, to the best of our knowledge, there are no general models to predict new LIBPs based on 3D structures. We developed new Quantitative Structure-Activity Relationship (QSAR) models based on 3D electrostatic parameters of 1801 different proteins, including 801 LIBPs. We calculated these electrostatic parameters with the MARCH-INSIDE software and they correspond to the entire protein or to specific protein regions named core, inner, middle, and surface. We used these parameters as inputs to develop a simple Linear Discriminant Analysis (LDA) classifier to discriminate 3D structure of LIBPs from other proteins. We implemented this predictor in the web server named LIBP-Pred, freely available at , along with other important web servers of the Bio-AIMS portal. The users can carry out an automatic retrieval of protein structures from PDB or upload their custom protein structural models from their disk created with LOMETS server. We demonstrated the PDB mining option performing a predictive study of 2000+ proteins with unknown function. Interesting results regarding the discovery of new Cancer Biomarkers in humans or drug targets in parasites have been discussed here in this sense.

  8. Evaluating the Immunogenicity of Protein Drugs by Applying In Vitro MHC Binding Data and the Immune Epitope Database and Analysis Resource

    Directory of Open Access Journals (Sweden)

    Sinu Paul

    2013-01-01

    Full Text Available The immune system has evolved to become highly specialized in recognizing and responding to pathogens and foreign molecules. Specifically, the function of HLA class II is to ensure that a sufficient sample of peptides derived from foreign molecules is presented to T cells. This leads to an important concern in human drug development as the possible immunogenicity of biopharmaceuticals, especially those intended for chronic administration, can lead to reduced efficacy and an undesired safety profile for biological therapeutics. As part of this review, we will highlight the molecular basis of antigen presentation as a key step in the induction of T cell responses, emphasizing the events associated with peptide binding to polymorphic and polygenic HLA class II molecules. We will further review methodologies that predict HLA class II binding peptides and candidate epitopes. We will focus on tools provided by the Immune Epitope Database and Analysis Resource, discussing the basic features of different prediction methods, the objective evaluation of prediction quality, and general guidelines for practical use of these tools. Finally the use, advantages, and limitations of the methodology will be demonstrated in a review of two previous studies investigating the immunogenicity of erythropoietin and timothy grass pollen.

  9. Free energy calculations offer insights into the influence of receptor flexibility on ligand-receptor binding affinities.

    Science.gov (United States)

    Dolenc, Jožica; Riniker, Sereina; Gaspari, Roberto; Daura, Xavier; van Gunsteren, Wilfred F

    2011-08-01

    Docking algorithms for computer-aided drug discovery and design often ignore or restrain the flexibility of the receptor, which may lead to a loss of accuracy of the relative free enthalpies of binding. In order to evaluate the contribution of receptor flexibility to relative binding free enthalpies, two host-guest systems have been examined: inclusion complexes of α-cyclodextrin (αCD) with 1-chlorobenzene (ClBn), 1-bromobenzene (BrBn) and toluene (MeBn), and complexes of DNA with the minor-groove binding ligands netropsin (Net) and distamycin (Dist). Molecular dynamics simulations and free energy calculations reveal that restraining of the flexibility of the receptor can have a significant influence on the estimated relative ligand-receptor binding affinities as well as on the predicted structures of the biomolecular complexes. The influence is particularly pronounced in the case of flexible receptors such as DNA, where a 50% contribution of DNA flexibility towards the relative ligand-DNA binding affinities is observed. The differences in the free enthalpy of binding do not arise only from the changes in ligand-DNA interactions but also from changes in ligand-solvent interactions as well as from the loss of DNA configurational entropy upon restraining.

  10. Combined endodontic-periodontic treatment of a palatal groove: a case report.

    Science.gov (United States)

    Schwartz, Scott A; Koch, Michael A; Deas, David E; Powell, Charles A

    2006-06-01

    The palatal groove is a developmental anomaly that predisposes the tooth involved to a severe periodontal defect. When further complicated by pulp necrosis, these grooves often present a diagnostic and treatment planning challenge that requires an interdisciplinary treatment approach. This case report describes the successful collaborative management of a maxillary lateral incisor with an extensive palatal groove using a combination of nonsurgical endodontic therapy, odontoplasty, and periodontal regenerative techniques.

  11. Global alteration of the drug-binding pocket of human P-glycoprotein (ABCB1) by substitution of fifteen conserved residues reveals a negative correlation between substrate size and transport efficiency.

    Science.gov (United States)

    Vahedi, Shahrooz; Chufan, Eduardo E; Ambudkar, Suresh V

    2017-11-01

    P-glycoprotein (P-gp), an ATP-dependent efflux pump, is linked to the development of multidrug resistance in cancer cells. However, the drug-binding sites and translocation pathways of this transporter are not yet well-characterized. We recently demonstrated the important role of tyrosine residues in regulating P-gp ATP hydrolysis via hydrogen bond formations with high affinity modulators. Since tyrosine is both a hydrogen bond donor and acceptor, and non-covalent interactions are key in drug transport, in this study we investigated the global effect of enrichment of tyrosine residues in the drug-binding pocket on the drug binding and transport function of P-gp. By employing computational analysis, 15 conserved residues in the drug-binding pocket of human P-gp that interact with substrates were identified and then substituted with tyrosine, including 11 phenylalanine (F72, F303, F314, F336, F732, F759, F770, F938, F942, F983, F994), two leucine (L339, L975), one isoleucine (I306), and one methionine (M949). Characterization of the tyrosine-rich P-gp mutant in HeLa cells demonstrated that this major alteration in the drug-binding pocket by introducing fifteen additional tyrosine residues is well tolerated and has no measurable effect on total or cell surface expression of this mutant. Although the tyrosine-enriched mutant P-gp could transport small to moderate size (transport large (>1000 Daltons) substrates such as NBD-cyclosporine A, Bodipy-paclitaxel and Bodipy-vinblastine was significantly decreased. This was further supported by the physico-chemical characterization of seventeen tested substrates, which revealed a negative correlation between drug transport and molecular size for the tyrosine-enriched P-gp mutant. Published by Elsevier Inc.

  12. Management of endodontic-periodontic lesion of a maxillary lateral incisor with palatoradicular groove

    Directory of Open Access Journals (Sweden)

    Jayshree Ramakrishna Vishwas

    2014-01-01

    Full Text Available Presence of palatal radicular grooves are considered to be an important contributing factor to the development of localized periodontitis, as it favored the accumulation and proliferation of bacterial plaque deep into the periodontium. Pulp involvement could result due to the introduction of bacterial toxins through channels that existed between the root canal system and the groove. Early diagnosis, elimination of inflammation and correction of anatomic complications are the key to a favorable outcome for managing palatoradicular groove. Present report describes successful management with an interdisciplinary approach of maxillary lateral incisor with combined endodontic periodontic lesion associated with palatoradicular groove.

  13. Enhanced heat transfer performances of molten salt receiver with spirally grooved pipe

    International Nuclear Information System (INIS)

    Lu, Jianfeng; Ding, Jing; Yu, Tao; Shen, Xiangyang

    2015-01-01

    The enhanced heat transfer performances of solar receiver with spirally grooved pipe were theoretically investigated. The physical model of heat absorption process was proposed using the general heat transfer correlation of molten salt in smooth and spirally grooved pipe. According to the calculation results, the convective heat transfer inside the receiver can remarkably enhance the heat absorption process, and the absorption efficiency increased with the flow velocity and groove height, while the wall temperature dropped. As the groove height increased, the heat losses of convection and radiation dropped with the decrease of wall temperature, and the average absorption efficiency of the heat receiver can be increased. Compared with the heat receiver with smooth pipe, the heat absorption efficiency of heat receiver with spirally grooved pipe e/d = 0.0475 can rise for 0.7%, and the maximum bulk fluid temperature can be increased for 31.1 °C. As a conclusion, spirally grooved pipe can be a very effective way for heat absorption enhancement of solar receiver, and it can also increase the operating temperature of molten salt. - Highlights: • Spirally grooved tube is a very effective way for solar receiver enhancement. • Heat absorption model of receiver is proposed with general heat transfer correlation. • Spirally groove tube increases absorption efficiency and reduces wall temperature. • Operating temperature of molten salt remarkably increases with groove height. • Heat absorption performance is promoted for first and second thermodynamics laws

  14. Endocytosis of ABCG2 drug transporter caused by binding of 5D3 antibody: trafficking mechanisms and intracellular fate.

    Science.gov (United States)

    Studzian, Maciej; Bartosz, Grzegorz; Pulaski, Lukasz

    2015-08-01

    ABCG2, a metabolite and xenobiotic transporter located at the plasma membrane (predominantly in barrier tissues and progenitor cells), undergoes a direct progressive endocytosis process from plasma membrane to intracellular compartments upon binding of 5D3 monoclonal antibody. This antibody is specific to an external epitope on the protein molecule and locks it in a discrete conformation within its activity cycle, presumably providing a structural trigger for the observed internalization phenomenon. Using routine and novel assays, we show that ABCG2 is endocytosed by a mixed mechanism: partially via a rapid, clathrin-dependent pathway and partially in a cholesterol-dependent, caveolin-independent manner. While the internalization process is entirely dynamin-dependent and converges initially at the early endosome, subsequent intracellular fate of ABCG2 is again twofold: endocytosis leads to only partial lysosomal degradation, while a significant fraction of the protein is retained in a post-endosomal compartment with the possibility of at least partial recycling back to the cell surface. This externally triggered, conformation-related trafficking pathway may serve as a general regulatory paradigm for membrane transporters, and its discovery was made possible thanks to consistent application of quantitative methods. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Space qualification of high capacity grooved heat pipes

    Energy Technology Data Exchange (ETDEWEB)

    Dubois, M; Mullender, B; Druart, J [SABCA, Societe Anomyme Belgel de Construction Aeronautique (Belgium); Supper, W; Beddows, A [ESTEC-The (Netherlands)

    1997-12-31

    Based on the thermal requirements of the future telecommunication satellites, the development of a High Capacity Grooved Heat Pipe (HPG), was contracted by ESA to SABCA leading to an aluminium extruded heat pipe (outer diameter of 25 mm) based on a multi re-entrant grooves design. After an intensive acceptance test campaign whose results showed a good confidence in the design and the fulfillment of the required specifications of heat transport and on tilt capability (experimental maximum heat transport capability of 1500 Watt metres for a vapour temperature of 20 deg C), similar heat pipes have been developed with various outer diameters (11 mm, 15 mm and 20 mm) and with various shapes (circular outer shapes, integrated saddles). Several of these heat pipes were tested during two parabolic flight campaigns, by varying the heat loads during the micro-gravity periods. This HGP heat pipe family is now being submitted to a space qualification program according to ESA standards (ESA PSS-49), both in straight and bent configuration. Within this qualification, the heat pipes are submitted to an extended test campaign including environmental (random/sinus vibration, constant acceleration) and thermal tests (thermal performance, thermal cycle, thermal soak, ageing). (authors) 9 refs.

  16. Syncopation affects free body-movement in musical groove

    DEFF Research Database (Denmark)

    Witek, Maria A. G.; Popescu, Tudor; Clarke, Eric F

    2016-01-01

    One of the most immediate and overt ways in which people respond to music is by moving their bodies to the beat. However, the extent to which the rhythmic complexity of groove-specifically its syncopation-contributes to how people spontaneously move to music is largely unexplored. Here, we measur...... on the body-part. We demonstrate that while people do not move or synchronise much to rhythms with high syncopation when dancing spontaneously to music, the relationship between rhythmic complexity and synchronisation is less linear than in simple finger-tapping studies.......One of the most immediate and overt ways in which people respond to music is by moving their bodies to the beat. However, the extent to which the rhythmic complexity of groove-specifically its syncopation-contributes to how people spontaneously move to music is largely unexplored. Here, we measured...... free movements in hand and torso while participants listened to drum-breaks with various degrees of syncopation. We found that drum-breaks with medium degrees of syncopation were associated with the same amount of acceleration and synchronisation as low degrees of syncopation. Participants who enjoyed...

  17. Capillary contact angle in a completely wet groove.

    Science.gov (United States)

    Parry, A O; Malijevský, A; Rascón, C

    2014-10-03

    We consider the phase equilibria of a fluid confined in a deep capillary groove of width L with identical side walls and a bottom made of a different material. All walls are completely wet by the liquid. Using density functional theory and interfacial models, we show that the meniscus separating liquid and gas phases at two phase capillary coexistence meets the bottom capped end of the groove at a capillary contact angle θ(cap)(L) which depends on the difference between the Hamaker constants. If the bottom wall has a weaker wall-fluid attraction than the side walls, then θ(cap) > 0 even though all the isolated walls are themselves completely wet. This alters the capillary condensation transition which is now first order; this would be continuous in a capped capillary made wholly of either type of material. We show that the capillary contact angle θ(cap)(L) vanishes in two limits, corresponding to different capillary wetting transitions. These occur as the width (i) becomes macroscopically large, and (ii) is reduced to a microscopic value determined by the difference in Hamaker constants. This second wetting transition is characterized by large scale fluctuations and essential critical singularities arising from marginal interfacial interactions.

  18. Flight trajectory of a rotating golf ball with grooves

    Science.gov (United States)

    Baek, Moonheum; Kim, Jooha; Choi, Haecheon

    2014-11-01

    Dimples are known to reduce drag on a sphere by the amount of 50% as compared to a smooth surface. Despite the advantage of reducing drag, dimples deteriorate the putting accuracy owing to their sharp edges. To minimize this putting error but maintain the same flight distance, we have devised a grooved golf ball (called G ball hereafter) for several years. In this study, we modify the shape and pattern of grooves, and investigate the flow characteristics of the G ball by performing wind-tunnel experiments at the Reynolds numbers of 0 . 5 ×105 - 2 . 5 ×105 and the spin ratios (ratio of surface velocity to the free-stream velocity) of 0 - 0.6 that include the real golf-ball velocity and rotational speed. We measure the drag and lift forces on the rotating G ball and compare them with those of a smooth ball and two well-known dimpled balls. The lift-to-drag ratio of the G ball is much higher than that of a smooth ball and is in between those of the two dimpled balls. The trajectories of flying golf balls are computed. The flight distance of G ball is almost the same as that of one dimpled ball but slightly shorter than that of the other dimpled ball. The fluid-dynamic aspects of these differences will be discussed at the talk. Supported by 2011-0028032, 2014M3C1B1033980.

  19. Space qualification of high capacity grooved heat pipes

    Energy Technology Data Exchange (ETDEWEB)

    Dubois, M.; Mullender, B.; Druart, J. [SABCA, Societe Anomyme Belgel de Construction Aeronautique (Belgium); Supper, W.; Beddows, A. [ESTEC-The (Netherlands)

    1996-12-31

    Based on the thermal requirements of the future telecommunication satellites, the development of a High Capacity Grooved Heat Pipe (HPG), was contracted by ESA to SABCA leading to an aluminium extruded heat pipe (outer diameter of 25 mm) based on a multi re-entrant grooves design. After an intensive acceptance test campaign whose results showed a good confidence in the design and the fulfillment of the required specifications of heat transport and on tilt capability (experimental maximum heat transport capability of 1500 Watt metres for a vapour temperature of 20 deg C), similar heat pipes have been developed with various outer diameters (11 mm, 15 mm and 20 mm) and with various shapes (circular outer shapes, integrated saddles). Several of these heat pipes were tested during two parabolic flight campaigns, by varying the heat loads during the micro-gravity periods. This HGP heat pipe family is now being submitted to a space qualification program according to ESA standards (ESA PSS-49), both in straight and bent configuration. Within this qualification, the heat pipes are submitted to an extended test campaign including environmental (random/sinus vibration, constant acceleration) and thermal tests (thermal performance, thermal cycle, thermal soak, ageing). (authors) 9 refs.

  20. Reassessing the Function of Grooves in Mycenaean Tombs

    Directory of Open Access Journals (Sweden)

    Constantina Katsari

    2001-11-01

    Full Text Available Normal 0 0 2 false false false MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman"; mso-ansi-language:#0400; mso-fareast-language:#0400; mso-bidi-language:#0400;} Among the Chamber and Tholos Tombs that were built in Greece during the Late Helladic period are some that show a particular feature: a pair of grooves that are carved on the floor of the 'stomion '(a short corridor that leads inside the tomb, leading from the 'dromos '(a long road that leads towards the tomb itself into the chamber. Archaeologists have suggested a number of explanations regarding their function; however, none of these seems entirely plausible. In this article, we offer a different kind of hypothesis mostly based on architectural evidence. We will suggest that, rather than being related to ritual practices, the grooves were mainly used to facilitate the construction of the graves.

  1. Drug resistance is conferred on the model yeast Saccharomyces cerevisiae by expression of full-length melanoma-associated human ATP-binding cassette transporter ABCB5.

    Science.gov (United States)

    Keniya, Mikhail V; Holmes, Ann R; Niimi, Masakazu; Lamping, Erwin; Gillet, Jean-Pierre; Gottesman, Michael M; Cannon, Richard D

    2014-10-06

    ABCB5, an ATP-binding cassette (ABC) transporter, is highly expressed in melanoma cells, and may contribute to the extreme resistance of melanomas to chemotherapy by efflux of anti-cancer drugs. Our goal was to determine whether we could functionally express human ABCB5 in the model yeast Saccharomyces cerevisiae, in order to demonstrate an efflux function for ABCB5 in the absence of background pump activity from other human transporters. Heterologous expression would also facilitate drug discovery for this important target. DNAs encoding ABCB5 sequences were cloned into the chromosomal PDR5 locus of a S. cerevisiae strain in which seven endogenous ABC transporters have been deleted. Protein expression in the yeast cells was monitored by immunodetection using both a specific anti-ABCB5 antibody and a cross-reactive anti-ABCB1 antibody. ABCB5 function in recombinant yeast cells was measured by determining whether the cells possessed increased resistance to known pump substrates, compared to the host yeast strain, in assays of yeast growth. Three ABCB5 constructs were made in yeast. One was derived from the ABCB5-β mRNA, which is highly expressed in human tissues but is a truncation of a canonical full-size ABC transporter. Two constructs contained full-length ABCB5 sequences: either a native sequence from cDNA or a synthetic sequence codon-harmonized for S. cerevisiae. Expression of all three constructs in yeast was confirmed by immunodetection. Expression of the codon-harmonized full-length ABCB5 DNA conferred increased resistance, relative to the host yeast strain, to the putative substrates rhodamine 123, daunorubicin, tetramethylrhodamine, FK506, or clorgyline. We conclude that full-length ABCB5 can be functionally expressed in S. cerevisiae and confers drug resistance.

  2. Diverse modes of binding in structures of Leishmania majorN-myristoyltransferase with selective inhibitors

    Directory of Open Access Journals (Sweden)

    James A. Brannigan

    2014-07-01

    Full Text Available The leishmaniases are a spectrum of global diseases of poverty associated with immune dysfunction and are the cause of high morbidity. Despite the long history of these diseases, no effective vaccine is available and the currently used drugs are variously compromised by moderate efficacy, complex side effects and the emergence of resistance. It is therefore widely accepted that new therapies are needed. N-Myristoyltransferase (NMT has been validated pre-clinically as a target for the treatment of fungal and parasitic infections. In a previously reported high-throughput screening program, a number of hit compounds with activity against NMT from Leishmania donovani have been identified. Here, high-resolution crystal structures of representative compounds from four hit series in ternary complexes with myristoyl-CoA and NMT from the closely related L. major are reported. The structures reveal that the inhibitors associate with the peptide-binding groove at a site adjacent to the bound myristoyl-CoA and the catalytic α-carboxylate of Leu421. Each inhibitor makes extensive apolar contacts as well as a small number of polar contacts with the protein. Remarkably, the compounds exploit different features of the peptide-binding groove and collectively occupy a substantial volume of this pocket, suggesting that there is potential for the design of chimaeric inhibitors with significantly enhanced binding. Despite the high conservation of the active sites of the parasite and human NMTs, the inhibitors act selectively over the host enzyme. The role of conformational flexibility in the side chain of Tyr217 in conferring selectivity is discussed.

  3. Multivariate Metal-Organic Frameworks for Dialing-in the Binding and Programming the Release of Drug Molecules.

    Science.gov (United States)

    Dong, Zhiyue; Sun, Yangzesheng; Chu, Jun; Zhang, Xianzheng; Deng, Hexiang

    2017-10-11

    We report the control of guest release profiles by dialing-in desirable interactions between guest molecules and pores in metal-organic frameworks (MOFs). The interactions can be derived by the rate constants that were quantitatively correlated with the type of functional group and its proportion in the porous structure; thus the release of guest molecules can be predicted and programmed. Specifically, three probe molecules (ibuprofen, rhodamine B, and doxorubicin) were studied in a series of robust and mesoporous MOFs with multiple functional groups [MIL-101(Fe)-(NH 2 ) x , MIL-101(Fe)-(C 4 H 4 ) x , and MIL-101(Fe)-(C 4 H 4 ) x (NH 2 ) 1-x ]. The release rate can be adjusted by 32-fold [rhodamine from MIL-101(Fe)-(NH 2 ) x ], and the time of release peak can be shifted by up to 12 days over a 40-day release period [doxorubicin from MIL-101(Fe)-(C 4 H 4 ) x (NH 2 ) 1-x ], which was not obtained in the physical mixture of the single component MOF counterparts nor in other porous materials. The corelease of two pro-drug molecules (ibuprofen and doxorubicin) was also achieved.

  4. Site-specific binding of a water molecule to the sulfa drugs sulfamethoxazole and sulfisoxazole: a laser-desorption isomer-specific UV and IR study.

    Science.gov (United States)

    Uhlemann, Thomas; Seidel, Sebastian; Müller, Christian W

    2018-03-07

    To determine the preferred water molecule binding sites of the polybasic sulfa drugs sulfamethoxazole (SMX) and sulfisoxazole (SIX), we have studied their monomers and monohydrated complexes through laser-desorption conformer-specific UV and IR spectroscopy. Both the SMX and SIX monomer adopt a single conformer in the molecular beam. On the basis of their conformer-specific IR spectra in the NH stretch region, these conformers were assigned to the SMX and SIX global minimum structures, both exhibiting a staggered sulfonamide group and an intramolecular C-HO[double bond, length as m-dash]S hydrogen bond. The SMX-H 2 O and SIX-H 2 O complexes each adopt a single isomer in the molecular beam. Their isomeric structures were determined based on their isomer-specific IR spectra in the NH/OH stretch region. Quantum Theory of Atoms in Molecules analysis of the calculated electron densities revealed that in the SMX-H 2 O complex the water molecule donates an O-HN hydrogen bond to the heterocycle nitrogen atom and accepts an N-HO hydrogen bond from the sulfonamide NH group. In the SIX-H 2 O complex, however, the water molecule does not bind to the heterocycle but instead donates an O-HO[double bond, length as m-dash]S hydrogen bond to the sulfonamide group and accepts an N-HO hydrogen bond from the sulfonamide NH group. Both water complexes are additionally stabilized by a C ph -HOH 2 hydrogen bond. Interacting Quantum Atoms analysis suggests that all intermolecular hydrogen bonds are dominated by the short-range exchange-correlation contribution.

  5. Treatment of combined endodontic: periodontic lesion by sealing of palato-radicular groove using biodentine

    OpenAIRE

    Naik, Mayuri; de Ataide, Ida de Noronha; Fernandes, Marina; Lambor, Rajan

    2014-01-01

    Introduction: Palatoradicular groove is a developmental anomaly which is predominantly found in maxillary lateral incisors. It provides a susceptible alcove for the progression of localised periodontal inflammation which can further cause pulpal involvement. This case report describes the successful treatment of a large periodontic - endodontic lesion usingnon surgical endodontic therapy and biodentine for the sealing of the palatoradicular groove.

  6. Treatment of combined endodontic: periodontic lesion by sealing of palato-radicular groove using biodentine.

    Science.gov (United States)

    Naik, Mayuri; de Ataide, Ida de Noronha; Fernandes, Marina; Lambor, Rajan

    2014-11-01

    Palatoradicular groove is a developmental anomaly which is predominantly found in maxillary lateral incisors. It provides a susceptible alcove for the progression of localised periodontal inflammation which can further cause pulpal involvement. This case report describes the successful treatment of a large periodontic - endodontic lesion usingnon surgical endodontic therapy and biodentine for the sealing of the palatoradicular groove.

  7. Grooved floor system for cattle housing: ammonia emission reduction and good slip resistance

    NARCIS (Netherlands)

    Swierstra, D.; Braam, C.R.; Smits, M.C.J.

    2001-01-01

    To improve the slip resistance of solid floors in dairy cow houses and to achieve the ammonia emission reduction prescribed by the Dutch government, precast concrete floors with grooves and a dung scraper were investigated. The grooves parallel to the alley had 160 mm center-to-center spacing and

  8. Side-coupled cavity model for surface plasmon-polariton transmission across a groove

    International Nuclear Information System (INIS)

    Liu, J.S.Q.

    2010-01-01

    We demonstrate that the transmission properties of surface plasmon-polaritons (SPPs) across a rectangular groove in a metallic film can be described by an analytical model that treats the groove as a side-coupled cavity to propagating SPPs on the metal surface. The coupling efficiency to the groove is quantified by treating it as a truncated metal-dielectric-metal (MDM) waveguide. Finite-difference frequency-domain (FDFD) simulations and mode orthogonality relations are employed to derive the basic scattering coefficients that describe the interaction between the relevant modes in the system. The modeled SPP transmission and reflection intensities show excellent agreement with full-field simulations over a wide range of groove dimensions, validating this intuitive model. The model predicts the sharp transmission minima that occur whenever an incident SPP resonantly couples to the groove. We also for the first time show the importance of evanescent, reactive MDM SPP modes to the transmission behavior. SPPs that couple to this mode are resonantly enhanced upon reflection from the bottom of the groove, leading to high field intensities and sharp transmission minima across the groove. The resonant behavior exhibited by the grooves has a number of important device applications, including SPP mirrors, filters, and modulators.

  9. Solving the N-Queens Problem with GROOVE - Towards a Compendium of Best Practices

    NARCIS (Netherlands)

    Zambon, Eduardo; Rensink, Arend; Hermann, F.; Sauer, S.

    We present a detailed solution to the N-queens puzzle using GROOVE, a graph transformation tool especially designed for state space exploration and analysis. While GROOVE has been freely available for more than a decade and has attracted a reasonable number of users, it is safe to say that only a

  10. Hybrid plasmonic waveguide in a metal V-groove

    Directory of Open Access Journals (Sweden)

    Zhao-xian Chen

    2014-01-01

    Full Text Available We propose and investigate a type of hybrid plasmonic waveguide in a metal V-groove. A high-permittivity nanowire was placed in the metal channel covered with a dielectric film of lower permittivity. Deeper sub-wavelength confinement and much longer propagation distance were achieved in comparison with conventional channel plasmonic waveguides. The overall performance was improved as compared with the conventional hybrid plasmonic structure based on a flat metal surface. Finite element analysis showed that both the mode propagation and field profile can be adjusted by changing the nanowire radius and film thickness. Some benefits, such as a reduced scattering loss caused by the surface roughness, are also expected owing to the unique mode profile. The proposed approach has potential for application in high-level photonic integration.

  11. Influence of edge conditions on material ejection from periodic grooves in laser shock-loaded tin

    Energy Technology Data Exchange (ETDEWEB)

    Rességuier, T. de; Roland, C. [Institut PPRIME, UPR 3346, CNRS, ENSMA, Université de Poitiers, 1 ave. Clément Ader, 86961 Futuroscope Cedex (France); Prudhomme, G.; Lescoute, E.; Mercier, P. [CEA, DAM, DIF, 91297 Arpajon (France); Loison, D. [Institut de Physique de Rennes, CNRS, Université de Rennes 1, 35042 Rennes (France)

    2016-05-14

    In a material subjected to high dynamic compression, the breakout of a shock wave at a rough free surface can lead to the ejection of high velocity debris. Anticipating the ballistic properties of such debris is a key safety issue in many applications involving shock loading, including pyrotechnics and inertial confinement fusion experiments. In this paper, we use laser driven shocks to investigate particle ejection from calibrated grooves of micrometric dimensions and approximately sinusoidal profile in tin samples, with various boundary conditions at the groove edges, including single groove and periodic patterns. Fast transverse shadowgraphy provides ejection velocities after shock breakout. They are found to depend not only on the groove depth and wavelength, as predicted theoretically and already observed in the past, but also, unexpectedly, on the edge conditions, with a jet tip velocity significantly lower in the case of a single groove than behind a periodic pattern.

  12. Dispersion characteristics of planar grating with arbitrary grooves for terahertz Smith-Purcell radiation

    International Nuclear Information System (INIS)

    Cao, Miaomiao; Li, Ke; Liu, Wenxin; Wang, Yong

    2015-01-01

    In this paper, a novel method of getting the dispersion relations in planar grating with arbitrary grooves for terahertz Smith-Purcell radiation is investigated analytically. The continuous profile of the groove is approximately replaced by a series of rectangular steps. By making use of field matches method and the continuity of transverse admittance, the universal dispersion equation for grating with arbitrarily shaped grooves is derived. By solving the dispersion equation in presence of electron beam, the growth rate is obtained directly and the dependence on beam parameters is analyzed. Comparisons of the dispersion characteristics among some special groove shapes have been made by numerical calculation. The results show that the rectangular-step approximation method provides a novel approach to obtain the universal dispersion relation for grating with arbitrary grooves for Smith-Purcell radiation

  13. Treatment of a Developmental Groove and Supernumerary Root Using Guided Tissue Regeneration Technique

    Directory of Open Access Journals (Sweden)

    Zahra Alizadeh Tabari

    2016-01-01

    Full Text Available Introduction. The radicular groove is a developmental groove which is usually found on the palatal or lateral aspects of the maxillary incisor teeth. The present case is a maxillary lateral incisor with a small second root and a deep radicular groove. The developmental groove caused a combined periodontal-endodontic lesion. Methods. Case was managed using a combined treatment procedure involving nonsurgical root canal therapy and surgical periodontal treatment. After completion of root canal treatment, guided tissue regeneration (GTR was carried out using decalcified freeze dried bone allograft (DFDBA and a bioabsorbable collagenous membrane. Tooth also was splinted for two months. Results. After 12 months the tooth was asymptomatic. The periapical radiolucency disappeared and probing depth did not exceed 3 mm. Conclusion. Combined treatment procedure involving nonsurgical root canal therapy and surgical periodontal regenerative treatment can be a predictable technique in treating combined endodontic-periodontal lesions caused by radicular groove.

  14. Individual differences in beat perception affect gait responses to low- and high-groove music.

    Directory of Open Access Journals (Sweden)

    Li-Ann eLeow

    2014-10-01

    Full Text Available Slowed gait in Parkinson’s disease (PD patients can be improved when patients synchronize footsteps to isochronous metronome cues, but limited retention of such improvements suggest that permanent cueing regimes are needed for long-term improvements. If so, music might make permanent cueing regimes more pleasant, improving adherence; however, music cueing requires patients to synchronize movements to the beat, which might be difficult for PD patients who tend to show weak beat perception. One solution may be to use high groove music, which has high beat salience that may facilitate synchronization, and affective properties which may improve motivation to move. As a first step in understanding how beat perception affects gait in complex neurological disorders, we examined how beat perception ability affected gait in neurotypical adults. Synchronization performance and gait parameters were assessed as healthy young adults with strong or weak beat perception synchronized to low groove music, high groove music, and metronome cues. High groove music was predicted to elicit better synchronization than low groove music, due to its higher beat salience. Two musical tempi, or rates, were used: (1 preferred tempo: beat rate matched to preferred step rate and (2 faster tempo: beat rate adjusted to 22.5% faster than preferred step rate. For both strong and weak beat-perceivers, synchronization performance was best with metronome cues, followed by high groove music, and worst with low groove music. In addition, high groove music elicited longer and faster steps than low groove music, both at preferred tempo and at faster tempo. Low groove music was particularly detrimental to gait in weak beat-perceivers, who showed slower and shorter steps compared to uncued walking. The findings show that individual differences in beat perception affect gait when synchronizing footsteps to music, and have implications for using music in gait rehabilitation.

  15. Individual Differences in Beat Perception Affect Gait Responses to Low- and High-Groove Music

    Science.gov (United States)

    Leow, Li-Ann; Parrott, Taylor; Grahn, Jessica A.

    2014-01-01

    Slowed gait in patients with Parkinson’s disease (PD) can be improved when patients synchronize footsteps to isochronous metronome cues, but limited retention of such improvements suggest that permanent cueing regimes are needed for long-term improvements. If so, music might make permanent cueing regimes more pleasant, improving adherence; however, music cueing requires patients to synchronize movements to the “beat,” which might be difficult for patients with PD who tend to show weak beat perception. One solution may be to use high-groove music, which has high beat salience that may facilitate synchronization, and affective properties, which may improve motivation to move. As a first step to understanding how beat perception affects gait in complex neurological disorders, we examined how beat perception ability affected gait in neurotypical adults. Synchronization performance and gait parameters were assessed as healthy young adults with strong or weak beat perception synchronized to low-groove music, high-groove music, and metronome cues. High-groove music was predicted to elicit better synchronization than low-groove music, due to its higher beat salience. Two musical tempi, or rates, were used: (1) preferred tempo: beat rate matched to preferred step rate and (2) faster tempo: beat rate adjusted to 22.5% faster than preferred step rate. For both strong and weak beat-perceivers, synchronization performance was best with metronome cues, followed by high-groove music, and worst with low-groove music. In addition, high-groove music elicited longer and faster steps than low-groove music, both at preferred tempo and at faster tempo. Low-groove music was particularly detrimental to gait in weak beat-perceivers, who showed slower and shorter steps compared to uncued walking. The findings show that individual differences in beat perception affect gait when synchronizing footsteps to music, and have implications for using music in gait rehabilitation. PMID:25374521

  16. Effects of groove shape of notch on the flow characteristics of spool valve

    International Nuclear Information System (INIS)

    Ye, Yi; Yin, Chen-Bo; Li, Xing-Dong; Zhou, Wei-jin; Yuan, Feng-feng

    2014-01-01

    Highlights: • Flow characteristics of notches are studied using CFD simulation and experiment. • Test data is fitted by least square method to analyze discharge coefficient. • The stable value of discharge coefficient is deduced. • Effects of groove shape on steady flow force and throttling stiffness are performed. • The groove shape has significant effects on the flow characteristics. - Abstract: The grooves of notches of hydraulic spool valves are usually designed into various shapes for their desired flow characteristics. The aim of this paper is to clarify the effects of the groove shape on the flow characteristics through computational fluid dynamics (CFD) and experimental investigations. The RNG k–ε turbulence model is used to simulate the pressure distributions of the flow fields inside three notches with their corresponding typical structural grooves in order to analyze the changes of restricted locations along with the openings and, furthermore, to calculate the flow areas of the notches. The accuracy of the employed model is demonstrated by comparing the computational results with the experimental data. Additionally, the flow rate vs. pressure drop data obtained from the experiment is fitted by least square method. On this basis, the discharge coefficient as a function of groove geometry, flow condition, fitting coefficients and its stable value is deduced, proving to be quite consistent with the experimental result. Thanks to the jet flow angles estimated by CFD simulation, the steady flow forces are calculated, which show good agreement with the experimental results except for some small differences. Finally, the throttling stiffness of the three notches is investigated, with that of divergent U-shape groove falls between spheroid-shape groove and triangle-shape groove. Similar results are found for steady flow force. The results indicate that the groove shape has significant effects on the flow characteristics (flow area, discharge

  17. Champagne Groove Lipectomy: A Safe Technique to Contour the Upper Abdomen in Abdominoplasty.

    Science.gov (United States)

    Brooks, Ron; Nguyen, Jonathan; Chowdhry, Saeed; Tutela, John Paul; Kelishadi, Sean; Yonick, David; Choo, Joshua; Wilhelmi, Bradon J

    2017-01-01

    Objective: Combined liposuction and abdominoplasty, or lipoabdominoplasty, is particularly helpful in sculpting a more aesthetically pleasing abdominal contour, particularly in the supraumbilical midline groove. This groove, coined the "champagne groove" by one of our patients, is a frequently sought-after attribute by patients. However, liposuction adds time and cost to an already costly abdominoplasty. We sought to create this groove without the addition of liposuction, utilizing what we call a champagne groove lipectomy. This study reports on our champagne groove lipectomy technique and compares our complication rates with those reported in the literature for standard abdominoplasty techniques. Methods: This is a retrospective review of a single surgeon's experience at our institution over a 6-year period (2007-2012). A total of 74 patients undergoing consecutive abdominoplasty were studied, all female nonsmokers. Two groups were recognized: 64 of 74 patients underwent abdominoplasty, partial belt lipectomy, and champagne groove lipectomy, while 10 of 74 patients underwent fleur-de-lis abdominoplasty without champagne groove lipectomy. Results: Overall, 10 of 74 patients (13.5%) suffered some type of complication, which compares favorably with reported rates in the literature. The majority of complications were related to delayed wound healing or superficial wound dehiscence. Among those patients who underwent champagne groove lipectomy, complications occurred in 6 of 64 patients (9.3%), versus 4 of 10 (40%) patients undergoing fleur-de-lis abdominoplasty. Conclusions: Champagne groove lipectomy is a cost-effective alternative to lipoabdominoplasty for achieving an aesthetically pleasing upper midline abdominal contour, with complication rates comparing favorably with those reported in the literature.

  18. High quality broadband spatial reflections of slow Rayleigh surface acoustic waves modulated by a graded grooved surface

    KAUST Repository

    Xu, Yanlong; Peng, Pai

    2015-01-01

    . The graded grooved surface is structured by drilling one dimensional array of graded grooves with increased depths on a flat surface. We investigate SAW dispersion relations, wave field distribution at several typical SAW wavelengths, and time evolution of a

  19. Conjugation of Benzylvanillin and Benzimidazole Structure Improves DNA Binding with Enhanced Antileukemic Properties

    Science.gov (United States)

    Al-Mudarris, Ban A.; Chen, Shih-Hsun; Liang, Po-Huang; Osman, Hasnah; Jamal Din, Shah Kamal Khan; Abdul Majid, Amin M. S.

    2013-01-01

    Benzyl-o-vanillin and benzimidazole nucleus serve as important pharmacophore in drug discovery. The benzyl vanillin (2-(benzyloxy)-3-methoxybenzaldehyde) compound shows anti-proliferative activity in HL60 leukemia cancer cells and can effect cell cycle progression at G2/M phase. Its apoptosis activity was due to disruption of mitochondrial functioning. In this study, we have studied a series of compounds consisting of benzyl vanillin and benzimidazole structures. We hypothesize that by fusing these two structures we can produce compounds that have better anticancer activity with improved specificity particularly towards the leukemia cell line. Here we explored the anticancer activity of three compounds namely 2-(2-benzyloxy-3-methoxyphenyl)-1H-benzimidazole, 2MP, N-1-(2-benzyloxy-3-methoxybenzyl)-2-(2-benzyloxy-3-methoxyphenyl)-1H-benzimidazole, 2XP, and (R) and (S)-1-(2-benzyloxy-3-methoxyphenyl)-2, 2, 2-trichloroethyl benzenesulfonate, 3BS and compared their activity to 2-benzyloxy-3-methoxybenzaldehyde, (Bn1), the parent compound. 2XP and 3BS induces cell death of U937 leukemic cell line through DNA fragmentation that lead to the intrinsic caspase 9 activation. DNA binding study primarily by the equilibrium binding titration assay followed by the Viscosity study reveal the DNA binding through groove region with intrinsic binding constant 7.39 µM/bp and 6.86 µM/bp for 3BS and 2XP respectively. 2XP and 3BS showed strong DNA binding activity by the UV titration method with the computational drug modeling showed that both 2XP and 3BS failed to form any electrostatic linkages except via hydrophobic interaction through the minor groove region of the nucleic acid. The benzylvanillin alone (Bn1) has weak anticancer activity even after it was combined with the benzimidazole (2MP), but after addition of another benzylvanillin structure (2XP), stronger activity was observed. Also, the combination of benzylvanillin with benzenesulfonate (3BS) significantly improved the

  20. Determination of Tongue and Groove parameters for multileaf collimators; Determinaco de parametros de Tongue and Groove de colimadores de multilaminas

    Energy Technology Data Exchange (ETDEWEB)

    Castro, Aluisio; Almeida, Carlos E. de, E-mail: alu_neto@hotmail.com [Universidade Estadual do Rio de Janeiro (UERJ), RJ (Brazil). Laboratorio de Ciencias Radiologicas; Nguyen, Bihn [Prowess Inc., Concord, CA (United States)

    2012-08-15

    The Tongue and Groove effect (TandG) is characterized by an additional attenuation between adjacent and opposing leaves on multileaf collimators (MLCs) in adjacent or complementary fields. This is a typical situation in of intensity-modulated radiotherapy treatments. The aim of this study was to measure the width and transmission of TandG effect for two commercial MLCs: Varian Millennium 120 (6 MV and 16 MV beams) and BrainLab m3 (only for 6 MV). The methodology used was based on the creation of MLC shapes that emphasizes TandG effect, the irradiation of these fields on radiochromic film and the sensitometric evaluation of the films in order to determine the TandG width and transmission. The results for TandG width for studied MLCs were 2.5, 1.8 and 2 mm, respectively, whit transmission TandG values of 87, 90 and 85%. (author)

  1. Laser melting of groove defect repair on high thermal conductivity steel (HTCS-150)

    Science.gov (United States)

    Norhafzan, B.; Aqida, S. N.; Fazliana, F.; Reza, M. S.; Ismail, I.; Khairil, C. M.

    2018-02-01

    This paper presents laser melting repair of groove defect on HTCS-150 surface using Nd:YAG laser system. Laser melting process was conducted using JK300HPS Nd:YAG twin lamp laser source with 1064 nm wavelength and pulsed mode. The parameters are pulse repetition frequency (PRF) that is set from 70 to 100 Hz, average power ( P A) of 50-70 W, and laser spot size of 0.7 mm. HTCS-150 samples were prepared with groove dimension of 0.3 mm width and depths of 0.5 mm using EDM wire cut. Groove defect repaired using laser melting process on groove surface area with various parameters' process. The melted surface within the groove was characterized for subsurface hardness profile, roughness, phase identification, chemical composition, and metallographic study. The roughness analysis indicates high PRF at large spot size caused high surface roughness and low surface hardness. Grain refinement of repaired layer was analyzed within the groove as a result of rapid heating and cooling. The hardness properties of modified HTCS inside the groove and the bulk surface increased two times from as received HTCS due to grain refinement which is in agreement with Hall-Petch equation. These findings are significant to parameter design of die repair for optimum surface integrity and potential for repairing crack depth and width of less than 0.5 and 0.3 mm, respectively.

  2. Effect of groove on socket welds under the condition of vibration fatigue

    International Nuclear Information System (INIS)

    Xiu, Junjie; Jing, Hongyang; Han, Yongdian; Zhao, Lei; Xu, Lianyong

    2013-01-01

    Root failures of socket welds in small bore piping caused by vibration mainly occur at nuclear power plants (NPPs). It was observed that at higher stress level failures tended to originate at the toe while for the case of lower stress failures tended to occur at the root. The groove can increase the penetration depth (PD) of root, which is beneficial to the fatigue life. The effect of groove was also investigated by finite element method (FEM). The simulation results show that groove can decline the stress distribution, stress triaxiality and maximum principal plastic strain in the weld root, and the 5 mm groove suffering σ max (the highest stress of root failure) is almost same as no groove subjecting to σ f (fatigue limit). The test results show that the socket weld with groove can increase the natural frequency and damping of specimen, which make the system more difficult to vibrate. Moreover, the groove can also improve the fatigue property of specimen which do not exist the root failure even under high cycle fatigue (HCF)

  3. The MLC tongue-and-groove effect on IMRT dose distributions

    Energy Technology Data Exchange (ETDEWEB)

    Deng Jun [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305 (United States). E-mail: jun@reyes.stanford.edu; Pawlicki, Todd; Chen Yan; Li Jinsheng; Jiang, Steve B.; Ma, C.-M. [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305 (United States)

    2001-04-01

    We have investigated the tongue-and-groove effect on the IMRT dose distributions for a Varian MLC. We have compared the dose distributions calculated using the intensity maps with and without the tongue-and-groove effect. Our results showed that, for one intensity-modulated treatment field, the maximum tongue-and-groove effect could be up to 10% of the maximum dose in the dose distributions. For an IMRT treatment with multiple gantry angles ({>=} 5), the difference between the dose distributions with and without the tongue-and-groove effect was hardly visible, less than 1.6% for the two typical clinical cases studied. After considering the patient setup errors, the dose distributions were smoothed with reduced and insignificant differences between plans with and without the tongue-and-groove effect. Therefore, for a multiple-field IMRT plan ({>=} 5), the tongue-and-groove effect on the IMRT dose distributions will be generally clinically insignificant due to the smearing effect of individual fields. The tongue-and-groove effect on an IMRT plan with small number of fields (<5) will vary depending on the number of fields in a plan (coplanar or non-coplanar), the MLC leaf sequences and the patient setup uncertainty, and may be significant (>5% of maximum dose) in some cases, especially when the patient setup uncertainty is small ({<=} 2 mm). (author)

  4. The effect of expert performance microtiming on listeners’ experience of groove in swing or funk music

    Directory of Open Access Journals (Sweden)

    Olivier Senn

    2016-10-01

    Full Text Available This study tested the influence of expert performance microtiming on listeners' groove experience. Two professional rhythm section (bass/drums performances in swing and funk style were recorded, and the performances' original microtemporal deviations from a regular metronomic grid were scaled to several magnitude levels. Music expert (n=79 and non-expert (n=81 listeners rated the groove qualities of stimuli using a newly developed questionnaire that measures three dimensions of the groove experience (Entrainment, Enjoyment, and the absence of Irritation. Findings show that music expert listeners were more sensitive to microtiming manipulations than non-experts. Across both expertise groups and for both styles, groove ratings were high for microtiming magnitudes equal or smaller than those originally performed and decreased for exaggerated microtiming magnitudes. In particular, both the fully quantized music and the music with the originally performed microtiming pattern were rated equally high on groove. This means that neither the claims of PD theory (that microtiming deviations are necessary for groove nor the opposing exactitude hypothesis (that microtiming deviations are detrimental to groove were supported by the data.

  5. A stereological approach for measuring the groove angles of intergranular corrosion

    International Nuclear Information System (INIS)

    Gwinner, B.; Borgard, J.-M.; Dumonteil, E.; Zoia, A.

    2017-01-01

    Highlights: • The ICG morphology has been characterized in 3D by X-ray μ-tomography. • The measurement of the angles of the IGC groove on 2D cross sections induces a bias. • A methodology is proposed to estimate the true value of the IGC groove angles in 3D. - Abstract: Non-sensitized austenitic stainless steels can be prone to intergranular corrosion when they are in contact with an oxidizing medium like nitric acid. Intergranular corrosion is characterized by the formation of grooves along the grain boundaries. The angle of these grooves is a key parameter, which directly informs of the intergranular corrosion kinetics. Most of the time, the angles of the grooves are experimentally measured on 2-dimensional cross sections of the corroded samples. This study discusses the relationship between the groove angle measured on 2-dimensional sections and the true groove angle in 3-dimensional space. This approach could also be easily extended to the study of crack angle in the domains of corrosion-fatigue, stress corrosion cracking or mechanical fracture.

  6. DNA binding studies of tartrazine food additive.

    Science.gov (United States)

    Kashanian, Soheila; Zeidali, Sahar Heidary

    2011-07-01

    The interaction of native calf thymus DNA with tartrazine in 10 mM Tris-HCl aqueous solution at neutral pH 7.4 was investigated. Tartrazine is a nitrous derivative and may cause allergic reactions, with a potential of toxicological risk. Also, tartrazine induces oxidative stress and DNA damage. Its DNA binding properties were studied by UV-vis and circular dichroism spectra, competitive binding with Hoechst 33258, and viscosity measurements. Tartrazine molecules bind to DNA via groove mode as illustrated by hyperchromism in the UV absorption band of tartrazine, decrease in Hoechst-DNA solution fluorescence, unchanged viscosity of DNA, and conformational changes such as conversion from B-like to C-like in the circular dichroism spectra of DNA. The binding constants (K(b)) of DNA with tartrazine were calculated at different temperatures. Enthalpy and entropy changes were calculated to be +37 and +213 kJ mol(-1), respectively, according to the Van't Hoff equation, which indicated that the reaction is predominantly entropically driven. Also, tartrazine does not cleave plasmid DNA. Tartrazine interacts with calf thymus DNA via a groove interaction mode with an intrinsic binding constant of 3.75 × 10(4) M(-1).

  7. Investigation of enhanced condensation heat transfer outside vertical titanium circularly-grooved tube

    International Nuclear Information System (INIS)

    Zhaorigetu; Huang Weitang; Lv Xiangbo; Liu Feng

    2005-01-01

    The investigation of enhanced condensation heat transfer had been conducted on the outside vertical Titanium circularly-grooved tube. The experimental result indicates that the Titanium circularly-grooved tube is fairly efficient in enhancing the heat transfer. Within the experimental scope, the total heat transfer coefficient of the optimum circularly-grooved tube is 1.12 to 1.36 times of that of the Titanium smooth tube. Through regression analysis on the experimental data, the experimental correlations for the inside heat transfer coefficient, the condensation heat transfer coefficient on film condensation and the friction coefficient were achieved. (authors)

  8. Unusual stress fracture in an adolescent baseball pitcher affecting the trochlear groove of the olecranon

    International Nuclear Information System (INIS)

    Blake, Joseph J.; Block, John J.; Kan, J.H.; Hannah, Gene A.

    2008-01-01

    Stress fractures of the proximal ulna are known to occur in throwing athletes. Most cases extend to involve the olecranon, and cases limited to the trochlear groove are rare. In this report we present a 17-year-old elite baseball pitcher with a stress fracture of the trochlear groove of the proximal ulna. Diagnosis was made by demonstration of characteristic signal changes on MRI of the elbow. The fracture occurred at the cortical notch, also known as the pseudodefect of the trochlear groove. This case suggests that the cortical notch serves as an area of weakness predisposing pitchers to development of a stress fracture. (orig.)

  9. Mathematical modeling of photovoltaic thermal PV/T system with v-groove collector

    Science.gov (United States)

    Zohri, M.; Fudholi, A.; Ruslan, M. H.; Sopian, K.

    2017-07-01

    The use of v-groove in solar collector has a higher thermal efficiency in references. Dropping the working heat of photovoltaic panel was able to raise the electrical efficiency performance. Electrical and thermal efficiency were produced by photovoltaic thermal (PV/T) system concurrently. Mathematical modeling based on steady-state thermal analysis of PV/T system with v-groove was conducted. With matrix inversion method, the energy balance equations are explained by means of the investigative method. The comparison results show that in the PV/T system with the V-groove collector is higher temperature, thermal and electrical efficiency than other collectors.

  10. Following the canyon to reach and remove olfactory groove meningiomas.

    Science.gov (United States)

    Stefini, Roberto; Zenga, Francesco; Giacomo, Esposito; Bolzoni, Andrea; Tartara, Fulvio; Spena, Giannantonio; Ambrosi, Claudia; Fontanella, Marco M

    2017-04-01

    Olfactory groove meningiomas (OGMs) represent approximately 10% of all intracranial meningiomas. They arise in the olfactory fossa, a variable depression delimited by the lateral lamella and perpendicular plate. The cribriform plate with the lateral lamella and ethmoidal and orbital roof could be viewed as a 'canyon' with the frontal sinus as the main entrance. Between January 2000 and December 2013, 32 consecutive patients underwent removal of OGMs through this 'canyon' at the Department of Neurosurgery of Brescia and Turin. Complete removal was achieved in all patients with this trans-frontal sinus subcranial approach (Simpson grade I; mean lesion volume, 46.6 cm3). Five patients (15.6%) experienced nasal CSF leakage, treated with external lumbar drain positioning for 4 days and resolved in all cases but one, which was re-operated. Two patients (6.2%) during the CSF leakage experienced meningitis at day 7 after surgery, both successfully treated by intravenous antibiotic therapy. After one month, one patient developed hydrocephalus, treated with a ventricular peritoneal shunt. In one patient, traction on the OGM caused bleeding of the callosomarginal artery, which was coagulated with superior frontal gyrus ischemia without neurological consequences. Glasgow Outcome Scale Score at 6 months was V in 29 patients, IV in one patient, and I in two patients. Advantages with this approach may include easy and early control of blood supply from its insertion in the skull base, minimal frontal lobe retraction, preservation of the frontal veins draining to the sagittal sinus, and a satisfactory aesthetic outcome.

  11. Traction suture modification to tongue-in-groove caudal septoplasty.

    Science.gov (United States)

    Indeyeva, Y A; Lee, T S; Gordin, E; Chan, D; Ducic, Y

    2018-02-01

    Caudal septal deviation leads to unfavorable esthetic as well as functional effects on the nasal airway. A modification to the tongue-in-groove (TIG) technique to correct these caudal septal deformities is described. With placement of a temporary suspension suture to the caudal septum, manual traction is applied, assuring that the caudal septum remains in the midline position while it is being secured with multiple through-and-through, trans-columellar and trans-septal sutures. From 2003 to 2016, 148 patients underwent endonasal septoplasty using this modified technique, with excellent functional and cosmetic outcomes and a revision rate of 1.4%. This modified TIG technique replaces the periosteal suture that secures the caudal septum to the midline nasal crest in the original TIG technique. This simplifies the procedure and minimizes the risk of securing the caudal septum off-midline when used in endonasal septoplasty. Copyright © 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

  12. Condensation and evaporation transitions in deep capillary grooves

    International Nuclear Information System (INIS)

    Malijevský, Alexandr; Parry, Andrew O

    2014-01-01

    We study the order of capillary condensation and evaporation transitions of a simple fluid adsorbed in a deep capillary groove using a fundamental measure density functional theory (DFT). The walls of the capillary interact with the fluid particles via long-ranged, dispersion, forces while the fluid-fluid interaction is modelled as a truncated Lennard–Jones-like potential. We find that below the wetting temperature T w condensation is first-order and evaporation is continuous with the metastability of the condensation being well described by the complementary Kelvin equation. In contrast above T w both phase transitions are continuous and their critical singularities are determined. In addition we show that for the evaporation transition above T w there is an elegant mapping, or covariance, with the complete wetting transition occurring at a planar wall. Our numerical DFT studies are complemented by analytical slab model calculations which explain how the asymmetry between condensation and evaporation arises out of the combination of long-ranged forces and substrate geometry. (paper)

  13. Condensation and evaporation transitions in deep capillary grooves.

    Science.gov (United States)

    Malijevský, Alexandr; Parry, Andrew O

    2014-09-03

    We study the order of capillary condensation and evaporation transitions of a simple fluid adsorbed in a deep capillary groove using a fundamental measure density functional theory (DFT). The walls of the capillary interact with the fluid particles via long-ranged, dispersion, forces while the fluid-fluid interaction is modelled as a truncated Lennard-Jones-like potential. We find that below the wetting temperature Tw condensation is first-order and evaporation is continuous with the metastability of the condensation being well described by the complementary Kelvin equation. In contrast above Tw both phase transitions are continuous and their critical singularities are determined. In addition we show that for the evaporation transition above Tw there is an elegant mapping, or covariance, with the complete wetting transition occurring at a planar wall. Our numerical DFT studies are complemented by analytical slab model calculations which explain how the asymmetry between condensation and evaporation arises out of the combination of long-ranged forces and substrate geometry.

  14. Characterisation of a grooved heat pipe with an anodised surface

    Science.gov (United States)

    Solomon, A. Brusly; Ram Kumar, A. M.; Ramachandran, K.; Pillai, B. C.; Senthil Kumar, C.; Sharifpur, Mohsen; Meyer, Josua P.

    2017-03-01

    A grooved heat pipe (GHP) is an important device for managing heat in space applications such as satellites and space stations, as it works efficiently in the absence of gravity. Apart from the above application, axial GHPs are used in many applications, such as electronic cooling units for temperature control and permafrost cooling. Improving the performance of GHPs is essential for better cooling and thermal management. In the present study, the effect of anodization on the heat transfer characteristics of a GHP is studied with R600a as a working fluid. In addition, the effects of fill ratio, inclination angle and heat inputs on the heat transfer performance of a GHP are studied. Furthermore, the effect of heat flux on dimensional numbers, such as the Webber, Bond, Kutateladze and condensation numbers, are studied. The inclination angle, heat input and fill ratio of GHPs are varied in the range of 0°-90°, 25-250 W and 10-70 % respectively. It is found that the above parameters have a significant effect on the performance of a GHP. Due to the anodisation, the maximum enhancement in heat transfer coefficient at the evaporator is 39 % for a 90° inclination at a heat flux of 11 kW/m2. The reported performance enhancement of a GHP may be due to the large numbers of nucleation sites created by the anodisation process and enhancement in the capillary force due to the coating.

  15. Palatal radicular groove: Clinical implications of early diagnosis and surgical sealing

    Directory of Open Access Journals (Sweden)

    P Corrêa-Faria

    2011-01-01

    Full Text Available Palatal radicular groove is a discreet alteration in tooth morphology, characterized by an invagination that begins near the cingulum of the tooth and moves in an apical direction. Clinically, palatal radicular groove may be associated with periodontal and/or endodontic problems. This paper describes a clinical case of a young patient with palatal radicular groove with no signs of periodontal disease or endodontic impairment. An early diagnosis was made and treatment consisted of surgical sealing of the defect. After a 2-year period, reexaminations demonstrated adequate hygiene, maintenance of tooth vitality and periodontal health. The early diagnosis and sealing of the groove observed surgically made the root surface smooth, avoiding subgingival bacterial plaque buildup, and preventing possible periodontal and/or pulp impairment stemming from the defect.

  16. Tunable THz notch filter with a single groove inside parallel-plate waveguides.

    Science.gov (United States)

    Lee, Eui Su; Jeon, Tae-In

    2012-12-31

    A single groove in a parallel-plate waveguide (PPWG) has been applied to a tunable terahertz (THz) notch filter with a transverse-electromagnetic (TEM) mode. When the air gap between the metal plates of the PPWG is controlled from 60 to 240 μm using a motor controlled translation stage or a piezo-actuator, the resonant frequency of the notch filter is changed from 1.75 up to 0.62 THz, respectively. Therefore, the measured tunable sensitivity of the notch filter increases to 6.28 GHz/μm. The measured resonant frequencies were found to be in good agreement with the calculation using an effective groove depth. Using a finite-difference time-domain (FDTD) simulation, we also demonstrate that the sensitivity of a THz microfluidic sensor can be increased via a small air gap, a narrow groove width, and a deep groove depth.

  17. Grooving of grain boundaries in multicrystalline silicon: Effect on solar cell performance

    International Nuclear Information System (INIS)

    Dimassi, W.; Bouaicha, M.; Nouri, H.; Boujmil, M.F.; Ben Nasrallah, S.; Bessais, B.

    2006-01-01

    In this work, we investigate the effect of grooving of grain boundaries (GB) in multicrystalline silicon using chemical etching in HF/HNO 3 solutions. The grain boundaries were grooved in order to reduce the area of these highly recombining regions. Using optimized conditions, grooved GBs enable deep phosphorus diffusion and deep metallic contacts. As a result, the internal quantum efficiency (IQE), and the I-V characteristics under the dark and AM1.5 illumination were improved. It was also observed a reduction of the GB recombination velocity, which was deduced from light-beam-induced-current (LBIC) measurements. Such grooving in multicrystalline silicon enables passivation of GB-related defects. These results are discussed and compared to solar cells based on untreated multicrystalline silicon wafers

  18. Groove Pancreatitis with Biliary and Duodenal Stricture: An Unusual Cause of Obstructive Jaundice

    Directory of Open Access Journals (Sweden)

    Marta Gravito-Soares

    2016-05-01

    Discussion: Groove pancreatitis is a benign cause of obstructive jaundice, whose main differential diagnosis is duodenal or pancreatic neoplasia. When this condition causes duodenal or biliary stricture, surgical treatment can be necessary.

  19. Effectiveness of noise barriers installed adjacent to transverse grooved concrete pavement : executive summary report.

    Science.gov (United States)

    2009-10-16

    In recent years the Ohio Department of Transportation (ODOT) has reconstructed a number of roadways where asphalt pavements were replaced with concrete pavements which were finished with a random transverse grooved surface texture (ODOT specification...

  20. Standardized performance tests of collectors of solar thermal energy: Prototype moderately concentrating grooved collectors

    Science.gov (United States)

    1976-01-01

    Prototypes of moderately concentrating grooved collectors were tested with a solar simulator for varying inlet temperature, flux level, and incident angle. Collector performance is correlated in terms of inlet temperature and flux level.

  1. 'Tongue-and-groove' effect in intensity modulated radiotherapy with static multileaf collimator fields

    International Nuclear Information System (INIS)

    Que, W; Kung, J; Dai, J

    2004-01-01

    The 'tongue-and-groove problem' in step-and-shoot delivery of intensity modulated radiotherapy is investigated. A 'tongue-and-groove' index (TGI) is introduced to quantify the 'tongue-and-groove' effect in step-and-shoot delivery. Four different types of leaf sequencing methods are compared. The sliding window method and the reducing level method use the same number of field segments to deliver the same intensity map, but the TGI is much less for the reducing level method. The leaf synchronization method of Van Santvoort and Heijmen fails in step-and-shoot delivery, but a new method inspired by the method of Van Santvoort and Heijmen is shown to eliminate 'tongue-and-groove' underdosage completely

  2. U-shaped micro-groove fiber based on femtosecond laser processing for humidity sensing

    Science.gov (United States)

    Fu, Gui; Ma, Li-li; Su, Fu-fang; Shi, Meng

    2018-05-01

    A novel optical fiber sensor with a U-shaped micro-groove structure ablated by femtosecond laser on single-mode fiber for measuring air relative humidity (RH) is reported in this paper. In order to improve the accuracy of sensor, a graphene oxide (GO)/polyvinyl alcohol (PVA) composite film is coated on the surface of micro-groove structure. In the U-shaped micro-groove structure, the remaining core and micro-cavity in the micro-groove make up two major optical propagation paths, forming a Mach-Zehnder interferometer (MZI). The sensor has a good linear response within the RH range of 30%—85%, and the maximum sensitivity can reach 0.638 1 nm/%RH. The effect of temperature on the overall performance of the humidity sensor is also investigated. As a new type of all-fiber device, the sensor shows excellent sensitivity and stability.

  3. Determinig the Shape Coefficient A of Groove on the Pen for the Shaft

    Science.gov (United States)

    Křístek, Ivo; Havlík, Jiří; Mosler, Václav; Daniš, Igor

    2017-12-01

    This article focuses on creating a diagram for determining the shape coefficient α for a tongue groove on the shaft. Experimental determination of curve diagrams by comparing diagrams and monograms used using FEM calculations.

  4. Large eddy simulation of the subcritical flow over a V grooved circular cylinder

    International Nuclear Information System (INIS)

    Alonzo-García, A.; Gutiérrez-Torres, C. del C.; Jiménez-Bernal, J.A.

    2015-01-01

    Highlights: • We compared numerically the turbulent flow over a smooth circular cylinder and a V grooved cylinder in the subcritical regime. • Turbulence intensities in both streamwise and normal direction suffered attenuations. • The swirls structures on grooves peaks seemed to have a cyclic behavior. • The evolution of the flow inside grooves showed that swirls structures located in peaks suffered elongations in the normal direction. • The secondary vortex structures formed in the grooved cylinder near wake were smaller in comparison of the smooth cylinder flow. - Abstract: In this paper, a comparative numerical study of the subcritical flow over a smooth cylinder and a cylinder with V grooves (Re = 140,000) is presented. The implemented technique was the Large Eddy Simulation (LES), which according to Kolmogorov's theory, resolves directly the most energetic largest eddies and models the smallest and considered universal high frequency ones. The Navier-Stokes (N-S) equations were solved using the commercial software ANSYS FLUENT V.12.1, which applied the finite volume method (FVM) to discretize these equations in their unsteady and incompressible forms. The grid densities were 2.6 million cells and 13.5 million cells for the smooth and V grooved cylinder, respectively. Both meshes were composed of structured hexahedral cells and close to the wall of the cylinders, additional refinements were employed in order to obtain y +<5 values. All cases were simulated during at least 15 vortex shedding cycles with the aim of obtaining significant statistical data. Results: showed that for both cases (smooth and V grooved cylinder flow), the numerical code was capable of reproducing the most important physical quantities of the subcritical regime. Velocity distribution and turbulence intensity in the flow direction suffered a slight attenuation along the wake, as a consequence of grooves perturbation, which also caused an increase in the pressure coefficient

  5. Schwann cell interactions with polymer films are affected by groove geometry and film hydrophilicity

    International Nuclear Information System (INIS)

    Mobasseri, S A; Downes, S; Terenghi, G

    2014-01-01

    We have developed a biodegradable polymer scaffold made of a polycaprolactone/polylactic acid (PCL/PLA) film. Surface properties such as topography and chemistry have a vital influence on cell–material interactions. Surface modifications of PCL/PLA films were performed using topographical cues and UV–ozone treatment to improve Schwann cell organisation and behaviour. Schwann cell attachment, alignment and proliferation were evaluated on the grooved UV–ozone treated and non-treated films. Solvent casting of the polymer solution on patterned silicon substrates resulted in films with different groove shapes: V (V), sloped (SL) and square (SQ) shapes. Pitted films, with no grooves, were prepared as a negative control. The UV–ozone treatment was performed to increase hydrophilicity. The process specifications for UV–ozone treatment were evaluated and 5 min radiation time and 6 cm distance to the UV source were suggested as the optimal practise. When cultured on grooved films, Schwann cells elongated on the V and SL shape grooves without crossing over, and grew in the direction of the grooves. However, there was less elongation with more crossing over on the SQ shape grooves. The maximum cell length (511 μm) was observed on the treated V-grooved films. The cells cultured on pitted UV–ozone treated surfaces showed random arrangements with no increase in length. We have demonstrated that the synergic effects of physical cues combined with UV–ozone treatment have the potential to enhance Schwann cell morphology and alignment. (paper)

  6. Management of endodontic-periodontic lesion of a maxillary lateral incisor with palatoradicular groove

    OpenAIRE

    Jayshree Ramakrishna Vishwas; Shoeb Yakub Shaikh; Varsha H. Tambe; Fareedi Mukram Ali; Mohammed Mustafa

    2014-01-01

    Presence of palatal radicular grooves are considered to be an important contributing factor to the development of localized periodontitis, as it favored the accumulation and proliferation of bacterial plaque deep into the periodontium. Pulp involvement could result due to the introduction of bacterial toxins through channels that existed between the root canal system and the groove. Early diagnosis, elimination of inflammation and correction of anatomic complications are the key to a favorabl...

  7. Optimal Tempo for Groove: Its Relation to Directions of Body Movement and Japanese nori.

    Science.gov (United States)

    Etani, Takahide; Marui, Atsushi; Kawase, Satoshi; Keller, Peter E

    2018-01-01

    The tendency for groove-based music to induce body movements has been linked to multiple acoustical factors. However, it is unclear how or whether tempo affects groove, although tempo significantly affects other aspects of music perception. To address this issue, the present study investigated effects of tempo, specific rhythmic organizations of patterns, and syncopation on groove and the induction of the sensation of wanting to move. We focused on the directions of body movement in particular by taking into account nori , which is an indigenous Japanese musical term used not only synonymously with groove, but also as a spatial metaphor indicating vertical or horizontal movement directions. Thus, the present study explored how groove was felt and defined, as well as how musical factors induced the sensation of wanting to move in cross-cultural context. A listening experiment was conducted using drum breaks as stimuli. Stimuli consisted of various rhythm patterns at six tempi from 60 to 200 BPM. The main findings are that: (1) an optimal tempo for groove existed for drum breaks at around 100-120 BPM, (2) an optimal tempo existed for the sensation of wanting to move the body in specific directions (i.e., back-and-forth and side-to-side), (3) groove and nori shared a similar concept of wanting to move but differed on several points (i.e., association with sense of pulse and fast tempo). Overall, the present study suggests that there is an optimal tempo for body movement related to groove. This finding has implications for the use of music or rhythmic stimuli to induce smooth motion in rehabilitation, therapy, or dance.

  8. Effect of heat treatment on the grooving corrosion resistance of ERW pipes

    International Nuclear Information System (INIS)

    Lee, Jong Kwon; Lee, Jae Young; Lim, Soo Hyun; Park, Ji Hwan; Seo, Bo Min; Kim, Seon Hwa

    2002-01-01

    The v-sharp grooving corrosion of ERW(electrical resistance welding) steel pipes limited their wide application in the industry in spite of their high productivity and efficiency. The grooving corrosion is caused mainly by the different microstructures between the matrix and weld that is formed during the rapid heating and cooling cycle in welding. By this localized corrosion reaction of pipes, it evolves economic problems such as the early damage of industrial facilities and pipe lines of apartment, and water pollution. Even though the diminishing of sulfur content is most effective to decrease the susceptibility of grooving corrosion, it requires costly process. In this study, improvement of grooving corrosion resistance was pursuited by post weld heat treatment in the temperature range between 650 .deg. C and 950 .deg. C. Also, the effect of heat input in the welding was investigated. By employing chromnoamperometry and potentiodynamic experiment, the corrosion rate and grooving corrosion index(α) were obtained. It was found that heat treatment could improve the grooving corrosion resistance. Among them, the heat treated at 900 .deg. C and 950 .deg. C had excellent grooving corrosion resistance. The index of heat treated specimen at 900 .deg. C and 950 .deg. C were 1.0, 1.2, respectively, which are almost immune to the grooving corrosion. Potential difference after the heat treatment, between base and weld metal was decreased considerably. While the as-received one measured 61∼71 mV, that of the 900 .deg. C heat treated steel pipe measured only 10mV. The results were explained and discussed

  9. Optimal Tempo for Groove: Its Relation to Directions of Body Movement and Japanese nori

    Directory of Open Access Journals (Sweden)

    Takahide Etani

    2018-04-01

    Full Text Available The tendency for groove-based music to induce body movements has been linked to multiple acoustical factors. However, it is unclear how or whether tempo affects groove, although tempo significantly affects other aspects of music perception. To address this issue, the present study investigated effects of tempo, specific rhythmic organizations of patterns, and syncopation on groove and the induction of the sensation of wanting to move. We focused on the directions of body movement in particular by taking into account nori, which is an indigenous Japanese musical term used not only synonymously with groove, but also as a spatial metaphor indicating vertical or horizontal movement directions. Thus, the present study explored how groove was felt and defined, as well as how musical factors induced the sensation of wanting to move in cross-cultural context. A listening experiment was conducted using drum breaks as stimuli. Stimuli consisted of various rhythm patterns at six tempi from 60 to 200 BPM. The main findings are that: (1 an optimal tempo for groove existed for drum breaks at around 100–120 BPM, (2 an optimal tempo existed for the sensation of wanting to move the body in specific directions (i.e., back-and-forth and side-to-side, (3 groove and nori shared a similar concept of wanting to move but differed on several points (i.e., association with sense of pulse and fast tempo. Overall, the present study suggests that there is an optimal tempo for body movement related to groove. This finding has implications for the use of music or rhythmic stimuli to induce smooth motion in rehabilitation, therapy, or dance.

  10. Grooved surface topography alters matrix-metalloproteinase production by human fibroblasts

    International Nuclear Information System (INIS)

    Brydone, Alistair S; Dominic Meek, R M; Dalby, Matthew J; Berry, Catherine C; McNamara, Laura E

    2011-01-01

    Extracellular matrix (ECM) remodelling is an essential physiological process in which matrix-metalloproteinases (MMPs) have a key role. Manipulating the manner in which cells produce MMPs and ECMs may enable the creation of a desired tissue type, i.e. effect repair, or the prevention of tissue invasion (e.g. metastasis). The aim of this project was to determine if culturing fibroblasts on grooved topography altered collagen deposition or MMP production. Human fibroblasts were seeded on planar or grooved polycaprolactone substrates (grooves were 12.5 μm wide with varying depths of 240 nm, 540 nm or 2300 nm). Cell behaviour and collagen production were studied using fluorescence microscopy and the spent culture medium was assessed using gel zymography to detect MMPs. Total collagen deposition was high on the 240 nm deep grooves, but decreased as the groove depth increased, i.e. as cell contact guidance decreased. There was an increase in gelatinase on the 2300 nm deep grooved topography and there was a difference in the temporal expression of MMP-3 observed on the planar surface compared to the 540 nm and 2300 nm topographies. These results show that topography can alter collagen and MMP production. A fuller understanding of these processes may permit the design of surfaces tailored to tissue regeneration e.g. tendon repair.

  11. Cold test of deep groove plarizer for 170 GHz ECCD system

    International Nuclear Information System (INIS)

    Saigusa, M.; Ookouti, K.; Sazawa, S.; Yuasa, S.; Takei, N.; Takahashi, K.; Sakamoto, K.; Imai, T.

    2001-01-01

    The single deep groove mirror was proposed as a new concept polarizer instead of the conventional two mirror polarizers for producing ordinary (or extraordinary) wave with high mode purity at an arbitrary injection angle in electron cyclotron current drive (ECCD) experiments. The estimated mode purity of O and X waves on the plasma surface is expected to be higher than about 93% for reasonable ECCD experimental conditions. The three types of deep groove mirrors, which are the rectangular groove mirror and the non-rectangular one, are manufactured and tested at the frequency range from 140 GHz to 170 GHz and the power level of 30 mW. The groove parameters are the period of 0.9-1 mm, the ridge width of 0.45-0.5 mm, and the groove depth of 1.98 mm, which is deeper than a wavelength at 170 GHz. The measured results of deep groove polarizers agree with the theoretical predictions, qualitatively. Those prove the feasibility of a single mirror polarizer for ECCD system

  12. V-groove SnO2 nanowire sensors: fabrication and Pt-nanoparticle decoration

    International Nuclear Information System (INIS)

    Sun, Gun-Joo; Choi, Sun-Woo; Jung, Sung-Hyun; Katoch, Akash; Kim, Sang Sub

    2013-01-01

    Networked SnO 2 nanowire sensors were achieved using the selective growth of SnO 2 nanowires and their tangling ability, particularly on on-chip V-groove structures, in an effort to overcome the disadvantages imposed on the conventional trench-structured SnO 2 nanowire sensors. The sensing performance of the V-groove-structured SnO 2 nanowire sensors was highly dependent on the geometrical dimension of the groove, being superior to those of their conventional trench-structured counterparts. Pt nanoparticles were decorated on the surface of the networked SnO 2 nanowires via γ-ray radiolysis to enhance the sensing performances of the V-groove sensors whose V-groove widths had been optimized. The V-groove-structured Pt-nanoparticle-decorated SnO 2 nanowire sensors exhibited outstanding and reliable sensing capabilities towards toluene and nitrogen dioxide gases, indicating their potential for use as a platform for chemical gas sensors. (paper)

  13. Grooved surface topography alters matrix-metalloproteinase production by human fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Brydone, Alistair S; Dominic Meek, R M [Department of Orthopaedics, Southern General Hospital, 1345 Govan Road, Glasgow G51 4TF (United Kingdom); Dalby, Matthew J; Berry, Catherine C; McNamara, Laura E, E-mail: alibrydone@gmail.com [Centre for Cell Engineering, Joseph Black Building, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ (United Kingdom)

    2011-06-15

    Extracellular matrix (ECM) remodelling is an essential physiological process in which matrix-metalloproteinases (MMPs) have a key role. Manipulating the manner in which cells produce MMPs and ECMs may enable the creation of a desired tissue type, i.e. effect repair, or the prevention of tissue invasion (e.g. metastasis). The aim of this project was to determine if culturing fibroblasts on grooved topography altered collagen deposition or MMP production. Human fibroblasts were seeded on planar or grooved polycaprolactone substrates (grooves were 12.5 {mu}m wide with varying depths of 240 nm, 540 nm or 2300 nm). Cell behaviour and collagen production were studied using fluorescence microscopy and the spent culture medium was assessed using gel zymography to detect MMPs. Total collagen deposition was high on the 240 nm deep grooves, but decreased as the groove depth increased, i.e. as cell contact guidance decreased. There was an increase in gelatinase on the 2300 nm deep grooved topography and there was a difference in the temporal expression of MMP-3 observed on the planar surface compared to the 540 nm and 2300 nm topographies. These results show that topography can alter collagen and MMP production. A fuller understanding of these processes may permit the design of surfaces tailored to tissue regeneration e.g. tendon repair.

  14. Modified Kelvin Equations for Capillary Condensation in Narrow and Wide Grooves

    Science.gov (United States)

    Malijevský, Alexandr; Parry, Andrew O.

    2018-03-01

    We consider the location and order of capillary condensation transitions occurring in deep grooves of width L and depth D . For walls that are completely wet by liquid (contact angle θ =0 ) the transition is continuous and its location is not sensitive to the depth of the groove. However, for walls that are partially wet by liquid, where the transition is first order, we show that the pressure at which it occurs is determined by a modified Kelvin equation characterized by an edge contact angle θE describing the shape of the meniscus formed at the top of the groove. The dependence of θE on the groove depth D relies, in turn, on whether corner menisci are formed at the bottom of the groove in the low density gaslike phase. While for macroscopically wide grooves these are always present when θ condensation transition is different depending on whether the contact angle is greater or less than a universal value θ*≈31 °. Our arguments are supported by detailed microscopic density functional theory calculations that show that the modified Kelvin equation remains highly accurate even when L and D are of the order of tens of molecular diameters.

  15. Measurement of sheath thickness by lining out grooves in the Hall-type stationary plasma thrusters

    International Nuclear Information System (INIS)

    Yu Daren; Wu Zhiwen; Ning Zhongxi; Wang Xiaogang

    2007-01-01

    Using grooves created along the axial direction of the discharge channel, a method for measuring sheath thickness in Hall-type stationary plasma thrusters has been developed. By distorting the wall surface using these grooves, it is possible to numerically study the effect of the wall surface on the sheath and near wall conductivity. Monte Carlo method is applied to calculate the electron temperature variation with different groove depths. The electron dynamic process in the plasma is described by a test particle method with the electron randomly entering the sheath from the discharge channel and being reflected back. Numerical results show that the reflected electron temperature is hardly affected by the wall surface if the groove depth is much less than the sheath thickness. On the other hand, the reflected electron temperature increases if the groove depth is much greater than the sheath thickness. The reflected electron temperature has a sharp jump when the depth of groove is on the order of the sheath thickness. The simulation is repeated with different sheath thicknesses and the results are the same. Therefore, a diagnosis mean of the sheath thickness can be developed based on the method. Also the simulation results are in accord with the experimental data. Besides, the measurement method may be applicable to other plasma device with similar orthogonal steady state electrical and magnetic fields

  16. Cycle time improvement for plastic injection moulding process by sub groove modification in conformal cooling channel

    Science.gov (United States)

    Kamarudin, K.; Wahab, M. S.; Batcha, M. F. M.; Shayfull, Z.; Raus, A. A.; Ahmed, Aqeel

    2017-09-01

    Mould designers have been struggling for the improvement of the cooling system performance, despite the fact that the cooling system complexity is physically limited by the fabrication capability of the conventional tooling methods. However, the growth of Solid Free Form Technology (SFF) allow the mould designer to develop more than just a regular conformal cooling channel. Numerous researchers demonstrate that conformal cooling channel was tremendously given significant result in the improvement of productivity and quality in the plastic injection moulding process. This paper presents the research work that applies the passive enhancement method in square shape cooling channel to enhance the efficiency of cooling performance by adding the sub groove to the cooling channel itself. Previous design that uses square shape cooling channel was improved by adding various numbers of sub groove to meet the best sub groove design that able reduced the cooling time. The effect of sub groove design on cooling time was investigated by Autodesk Modlflow Insight software. The simulation results showed that the various sub groove designs give different values to ejection time. The Design 7 showed the lowest value of ejection time with 24.3% increment. The addition of sub groove significantly increased a coolant velocity and a rate of heat transfer from molten plastic to coolant.

  17. Preservation of olfaction in surgery of olfactory groove meningiomas.

    Science.gov (United States)

    Jang, Woo-Youl; Jung, Shin; Jung, Tae-Young; Moon, Kyung-Sub; Kim, In-Young

    2013-08-01

    Olfaction is commonly considered as secondary among the sensory functions, perhaps reflecting a lack of interest in sparing olfaction after surgery for the olfactory groove meningiomas (OGM). However, considering the repercussions of olfaction for the quality of life, the assessment of post-operative olfaction should be necessary. We retrospectively reviewed the olfactory outcome in patients with OGM and investigated the factors associated with sparing the post-operative olfaction. Between 1993 and 2012, 40 patients with OGM underwent surgical resection and estimated the olfactory function using the Korean version of "Sniffin'Sticks" test (KVSS). Variable factors, such as tumor size, degree of preoperative edema, tumor consistency, preoperative olfactory function, surgical approaches, patient's age, and gender were analyzed with attention to the post-operative olfactory function. Anatomical and functional preservation of olfactory structures were achieved in 26 patients (65%) and 22 patients (55%), respectively. Among the variable factors, size of tumor was significant related to the preservation of post-operative olfaction. (78.6% in size4 cm, p=0.035). Sparing the olfaction was significantly better in patients without preoperative olfactory dysfunction (84.6%) compared with ones with preoperative olfactory dysfunction (40.7%, p=0.016). The frontolateral approach achieved much more excellent post-operative olfactory function (71.4%) than the bifrontal approach (36.8%, p=0.032). If the tumor was smaller than 4 cm and the patients did not present olfactory dysfunction preoperatively, the possibility of sparing the post-operative olfaction was high. Among the variable surgical approaches, frontolateral route may be preferable sparing the post-operative olfaction. Copyright © 2012 Elsevier B.V. All rights reserved.

  18. Clinical, radiological, surgical, and pathological determinants of olfactory groove schwannoma

    Directory of Open Access Journals (Sweden)

    Andi Sadayandi Ramesh

    2014-01-01

    Full Text Available Background: Olfactory groove schwannomas (OGS are rare anterior cranial fossa base tumors with only 41 cases reported in literature. Olfactory ensheathing cell schwannoma (OECS has similar clinico-radiological features as OGS, but a different cell of origin. In recent years, there is growing interest in OECS as more cases are being reported. Aims: The objective was to study the clinico-radiological features of OGS and define the histological differentiation from OECS. Materials and Methods: We retrospectively analyzed clinical, radiological, surgical and histopathological picture of all cases of OGS managed in our institute. Immuno histochemical studies were performed in these tumors for differentiating from OECS. A comprehensive review of articles published until date describing the operative treatment was done. Results: All three cases had presented with seizures, two had anosmia and papilledema. Gross-total resection was achieved in all our patients. One patient expired in the postoperative period due to septicemia. Positive expression to newer immuno histochemical biomarker CD57 (Leu7, with negative staining to smooth muscle α-actin (SMA was helpful in confirming the diagnosis of OGS and differentiating it from OECS in all our cases. Conclusions: OECS, though rare has to be differentiated from OGS using immuno histochemistry. Gross-total resection of OGS with preservation of olfactory function is often possible and curative. Although these tumors are commonly treated with microsurgical skull base approaches, an endoscopic endonasal approach can be considered in some cases, with repair using mucoperiosteal pedicled flap to prevent cerebrospinal fluid leak.

  19. Specific Binding of Adamantane Drugs and Direction of their Polar Amines in the Pore of the Influenza M2 Transmembrane Domain in Lipid Bilayers and Dodecylphosphocholine Micelles Determined by NMR Spectroscopy

    Science.gov (United States)

    Cady, Sarah D.; Wang, Jun; Wu, Yibing; DeGrado, William F.; Hong, Mei

    2011-01-01

    The transmembrane domain of the influenza M2 protein (M2TM) forms a tetrameric proton channel important for the virus lifecycle. The proton-channel activity is inhibited by amine-containing adamantyl drugs amantadine and rimantadine, which have been shown to bind specifically to the pore of M2TM near Ser31. However, whether the polar amine points to the N- or C-terminus of the channel has not yet been determined. Elucidating the polar group direction will shed light on the mechanism by which drug binding inhibits this proton channel and will facilitate rational design of new inhibitors. In this study, we determine the polar amine direction using M2TM reconstituted in lipid bilayers as well as DPC micelles. 13C-2H rotational-echo double-resonance NMR experiments of 13C-labeled M2TM and methyl-deuterated rimantadine in lipid bilayers showed that the polar amine pointed to the C-terminus of the channel, with the methyl group close to Gly34. Solution NMR experiments of M2TM in dodecylphosphocholine (DPC) micelles indicate that drug binding causes significant chemical shift perturbations of the protein that are very similar to those seen for M2TM and M2(18–60) bound to lipid bilayers. Specific 2H-labeling of the drugs permitted the assignment of drug-protein cross peaks, which indicate that amantadine and rimantadine bind to the pore in the same fashion as for bilayer-bound M2TM. These results strongly suggest that adamantyl inhibition of M2TM is achieved not only by direct physical occlusion of the pore but also by perturbing the equilibrium constant of the proton-sensing residue His37. The reproduction of the pharmacologically relevant specific pore-binding site in DPC micelles, which was not observed with a different detergent, DHPC, underscores the significant influence of the detergent environment on the functional structure of membrane proteins. PMID:21381693

  20. The impact of postoperative supraclavicular radiotherapy on tracheoesophageal groove lymph node metastasis in esophageal carcinoma

    International Nuclear Information System (INIS)

    Qian Pudong; Lu Jinchen; Mei Zeru; Zhu Jun

    2005-01-01

    Objective: To evaluate the prognostic factors of tracheoesophageal groove lymph node (TEGLN) metastasis in postoperative esophageal carcinoma. Methods: From January 1996 to December 1997, 101 postoperative cervical and thoracic esophageal carcinoma patients proved absence from tracheoesophageal groove lymph node (TEGIAN) metastasis before and after operation by physical examination and computer tomography examination were entered into this study. The patients were divided into three groups according to the treatment of supraclavicular region: no prophylactic radiotherapy (group A-, 30 patients); prophylactic radiotherapy with local dose < 45 Gy (Group B-, 71 patients); and prophylactic radiotherapy with local dose ≥45 Gy (Group C-, 19 patients). Radiotherapy was delivered by cobalt- 60 or 6 MV X-ray with the prescribed dose normalized to the point of tracheoesophageal groove, i. e, 5 cm in depth. The tracheoesophageal groove lymph node metastasis after treatment was observed. Results: The incidence of tracheoesophageal groove lymph node metastasis was 20% (6/30), 9.6% (5/71) and 0% (0/19) in groups A, B and C. Univariate analysis showed that there was significant difference of TEGLN metastasis between groups A and C only (P=0.039), but higher dose to supraclavicular region tended to lower the incidence of TEGLN metastasis. Multivariate analysis showed that only prophylactic radiotherapy to the supraclavicular region was independent prognostic factor for TEGLN metastasis (P=0.037). Gender, primary tumor site and pathological stage had no significant impact on TEGLN metastasis. Conclusions: Postoperative prophylactic supraclavicular region irradiation can lower the incidence of tracheoesophageal groove lymph node metastasis in esophageal carcinoma. Radiotherapy dose should not be less than 45 Gy and should be routinely normalized to a point 5 cm deep in the tracheoesophageal groove. (authors)

  1. Identifying Conformational-Selection and Induced-Fit Aspects in the Binding-Induced Folding of PMI from Markov State Modeling of Atomistic Simulations.

    Science.gov (United States)

    Paul, Fabian; Noé, Frank; Weikl, Thomas R

    2018-03-27

    Unstructured proteins and peptides typically fold during binding to ligand proteins. A challenging problem is to identify the mechanism and kinetics of these binding-induced folding processes in experiments and atomistic simulations. In this Article, we present a detailed picture for the folding of the inhibitor peptide PMI into a helix during binding to the oncoprotein fragment 25-109 Mdm2 obtained from atomistic, explicit-water simulations and Markov state modeling. We find that binding-induced folding of PMI is highly parallel and can occur along a multitude of pathways. Some pathways are induced-fit-like with binding occurring prior to PMI helix formation, while other pathways are conformational-selection-like with binding after helix formation. On the majority of pathways, however, binding is intricately coupled to folding, without clear temporal ordering. A central feature of these pathways is PMI motion on the Mdm2 surface, along the binding groove of Mdm2 or over the rim of this groove. The native binding groove of Mdm2 thus appears as an asymmetric funnel for PMI binding. Overall, binding-induced folding of PMI does not fit into the classical picture of induced fit or conformational selection that implies a clear temporal ordering of binding and folding events. We argue that this holds in general for binding-induced folding processes because binding and folding events in these processes likely occur on similar time scales and do exhibit the time-scale separation required for temporal ordering.

  2. Loop-to-helix transition in the structure of multidrug regulator AcrR at the entrance of the drug-binding cavity

    Energy Technology Data Exchange (ETDEWEB)

    Manjasetty, Babu A.; Halavaty, Andrei S.; Luan, Chi-Hao; Osipiuk, Jerzy; Mulligan, Rory; Kwon, Keehwan; Anderson, Wayne F.; Joachimiak, Andrzej

    2016-04-01

    Multidrug transcription regulator AcrR from Salmonella enterica subsp. enterica serovar Typhimurium str. LT2 belongs to the tetracycline repressor family, one of the largest groups of bacterial transcription factors. The crystal structure of dimeric AcrR was determined and refined to 1.56 Å resolution. The tertiary and quaternary structures of AcrR are similar to those of its homologs. The multidrug binding site was identified based on structural alignment with homologous proteins and has a di(hydroxyethyl)ether molecule bound. Residues from helices a4 and a7 shape the entry into this binding site. The structure of AcrR reveals that the extended helical conformation of helix a4 is stabilized by the hydrogen bond between Glu67 (helix a4) and Gln130 (helix a7). Based on the structural comparison with the closest homolog structure, the Escherichia coli AcrR, we propose that this hydrogen bond is responsible for control of the loop-to-helix transition within helix a4. This local conformational switch of helix a4 may be a key step in accessing the multidrug binding site and securing ligands at the binding site. Solution smallmolecule binding studies suggest that AcrR binds ligands with their core chemical structure resembling the tetracyclic ring of cholesterol.

  3. Loop-to-helix transition in the structure of multidrug regulator AcrR at the entrance of the drug-binding cavity.

    Science.gov (United States)

    Manjasetty, Babu A; Halavaty, Andrei S; Luan, Chi-Hao; Osipiuk, Jerzy; Mulligan, Rory; Kwon, Keehwan; Anderson, Wayne F; Joachimiak, Andrzej

    2016-04-01

    Multidrug transcription regulator AcrR from Salmonella enterica subsp. enterica serovar Typhimurium str. LT2 belongs to the tetracycline repressor family, one of the largest groups of bacterial transcription factors. The crystal structure of dimeric AcrR was determined and refined to 1.56Å resolution. The tertiary and quaternary structures of AcrR are similar to those of its homologs. The multidrug binding site was identified based on structural alignment with homologous proteins and has a di(hydroxyethyl)ether molecule bound. Residues from helices α4 and α7 shape the entry into this binding site. The structure of AcrR reveals that the extended helical conformation of helix α4 is stabilized by the hydrogen bond between Glu67 (helix α4) and Gln130 (helix α7). Based on the structural comparison with the closest homolog structure, the Escherichia coli AcrR, we propose that this hydrogen bond is responsible for control of the loop-to-helix transition within helix α4. This local conformational switch of helix α4 may be a key step in accessing the multidrug binding site and securing ligands at the binding site. Solution small-molecule binding studies suggest that AcrR binds ligands with their core chemical structure resembling the tetracyclic ring of cholesterol. Copyright © 2016. Published by Elsevier Inc.

  4. The increased binding affinity of curcumin with human serum albumin in the presence of rutin and baicalin: A potential for drug delivery system

    Science.gov (United States)

    Liu, Bing-Mi; Zhang, Jun; Hao, Ai-Jun; Xu, Liang; Wang, Dan; Ji, Hui; Sun, Shi-Jie; Chen, Bo-Qi; Liu, Bin

    2016-02-01

    The impacts of rutin and baicalin on the interaction of curcumin (CU) with human serum albumin (HSA) were investigated by fluorescence and circular dichroism (CD) spectroscopies under imitated physiological conditions. The results showed that the fluorescence quenching of HSA by CU was a simultaneous static and dynamic quenching process, irrespective of the presence or absence of flavonoids. The binding constants between CU and HSA in the absence and presence of rutin and baicalin were 2.268 × 105 M- 1, 3.062 × 105 M- 1, and 3.271 × 105 M- 1, indicating that the binding affinity was increased in the case of two flavonoids. Furthermore, the binding distance determined according to Förster's theory was decreased in the presence of flavonoids. Combined with the fact that flavonoids and CU have the same binding site (site I), it can be concluded that they may simultaneously bind in different regions in site I, and formed a ternary complex of flavonoid-HSA-CU. Meanwhile, the results of fluorescence quenching, CD and three-dimensional fluorescence spectra revealed that flavonoids further strengthened the microenvironmental and conformational changes of HSA induced by CU binding. Therefore, it is possible to develop a novel complex involving CU, flavonoid and HSA for CU delivery. The work may provide some valuable information in terms of improving the poor bioavailabiliy of CU.

  5. Host-guest chemistry of dendrimer-drug complexes. 4. An in-depth look into the binding/encapsulation of guanosine monophosphate by dendrimers.

    Science.gov (United States)

    Hu, Jingjing; Fang, Min; Cheng, Yiyun; Zhang, Jiahai; Wu, Qinglin; Xu, Tongwen

    2010-06-03

    In the present study, we investigated the host-guest chemistry of dendrimer/guanosine monophosphate (GMP) and present an in-depth look into the binding/encapsulation of GMP by dendrimers using NMR studies. (1)H NMR spectra showed a significant downfield shift of methylene protons in the outmost layer of the G5 dendrimer, indicating the formation of ion pairs between cationic amine groups of dendrimer and anionic phosphate groups of GMP. Chemical shift titration results showed that the binding constant between G5 dendrimer and GMP is 17,400 M(-1) and each G5 dendrimer has 107 binding sites. The binding of GMP to dendrimers prevents its aggregation in aqueous solutions and thereby enhances its stability. Nuclear Overhauser effect measurements indicated that a GMP binding and encapsulation balance occurs on the surface and in the interior of dendrimer. The binding/encapsulation transitions can be easily tailored by altering the surface and interior charge densities of the dendrimer. All these findings provide a new insight into the host-guest chemistry of dendrimer/guest complexes and may play important roles in the study of dendrimer/DNA aggregates by a "bottom-up" strategy.

  6. What musicians do to induce the sensation of groove in simple and complex melodies, and how listeners perceive it

    Directory of Open Access Journals (Sweden)

    Guy eMadison

    2014-08-01

    Full Text Available Groove is the experience of wanting to move when hearing music, such as snapping fingers or tapping feet. This is a central aspect of much music, in particular of music intended for dancing. While previous research has found considerable consistency in ratings of groove across individuals, it remains unclear how groove is induced, that is, what are the physical properties of the acoustic signal that differ between more and less groove-inducing versions. Here, we examined this issue with a performance experiment, in which 4 musicians performed 6 simple and 6 complex melodies in two conditions with the intention of minimizing and maximizing groove. Analyses of rhythmical and temporal properties from the performances demonstrated some general effects. For example, more groove was associated with more notes on faster metrical levels and syncopation, and less groove was associated with deadpan timing and destruction of the regular pulse. We did not observe that deviations from the metrical grid (i.e. micro-timing were a predictor of groove. A listener experiment confirmed that the musicians’ manipulations had the intended effects on the experience of groove. A Brunswikian lens model was applied, which estimates the performer-perceiver communication across the two experiments. It showed that the communication achievement for simple melodies was 0.62, and that the matching of performers’ and listeners’ use of 9 rhythmical cues was 0.83. For complex melodies with an already high level of groove, the corresponding values were 0.39 and 0.34, showing that it was much more difficult to take out groove from musical structures designed to induce groove.

  7. Cellulose binding domain proteins

    Science.gov (United States)

    Shoseyov, Oded; Shpiegl, Itai; Goldstein, Marc; Doi, Roy

    1998-01-01

    A cellulose binding domain (CBD) having a high affinity for crystalline cellulose and chitin is disclosed, along with methods for the molecular cloning and recombinant production thereof. Fusion products comprising the CBD and a second protein are likewise described. A wide range of applications are contemplated for both the CBD and the fusion products, including drug delivery, affinity separations, and diagnostic techniques.

  8. Transverse grooved artefacts from southwestern Asia and northern Eurasia: Common traits and the reconstruction of function

    Directory of Open Access Journals (Sweden)

    Irina Usacheva

    2016-10-01

    Full Text Available Transverse grooved artefacts (TGA appeared as a new cultural element in Mesolithic-Proto-Neolithic sites in southwestern Asia. We know of similar artefacts from northern Africa. Hundreds of TGA have also been found in northern Eurasia. Some common traits were found in specimens from far apart territories, such as the non-abrasive heat-resistant nature of the raw materials, specificity of fragmentation without any signs of physical impact, the standard size of the grooves, association with a specific type of landscape, the similar economic level of the societies with which the items are associated, and use-wear marks in the grooves. Based on these regularities we can speak of a single main function for these artefacts which support the earlier reconstruction of R.L. and R.S. Solecki, suggesting that grooved stones were used for straightening cane and reed shafts under heating. Other evidence and traces that have been identified on the surface of TGA outside the groove could be associated with a variety of additional functions.

  9. Development of an equine groove model to induce metacarpophalangeal osteoarthritis: a pilot study on 6 horses.

    Science.gov (United States)

    Maninchedda, Ugo; Lepage, Olivier M; Gangl, Monika; Hilairet, Sandrine; Remandet, Bernard; Meot, Francoise; Penarier, Geraldine; Segard, Emilie; Cortez, Pierre; Jorgensen, Christian; Steinberg, Régis

    2015-01-01

    The aim of this work was to develop an equine metacarpophalangeal joint model that induces osteoarthritis that is not primarily mediated by instability or inflammation. The study involved six Standardbred horses. Standardized cartilage surface damage or "grooves" were created arthroscopically on the distal dorsal aspect of the lateral and medial metacarpal condyles of a randomly chosen limb. The contralateral limb was sham operated. After 2 weeks of stall rest, horses were trotted 30 minutes every other day for 8 weeks, then evaluated for lameness and radiographed. Synovial fluid was analyzed for cytology and biomarkers. At 10 weeks post-surgery, horses were euthanized for macroscopic and histologic joint evaluation. Arthroscopic grooving allowed precise and identical damage to the cartilage of all animals. Under the controlled exercise regime, this osteoarthritis groove model displayed significant radiographic, macroscopic, and microscopic degenerative and reactive changes. Histology demonstrated consistent surgically induced grooves limited to non-calcified cartilage and accompanied by secondary adjacent cartilage lesions, chondrocyte necrosis, chondrocyte clusters, cartilage matrix softening, fissuring, mild subchondral bone inflammation, edema, and osteoblastic margination. Synovial fluid biochemistry and cytology demonstrated significantly elevated total protein without an increase in prostaglandin E2, neutrophils, or chondrocytes. This equine metacarpophalangeal groove model demonstrated that standardized non-calcified cartilage damage accompanied by exercise triggered altered osteochondral morphology and cartilage degeneration with minimal or inefficient repair and little inflammatory response. This model, if validated, would allow for assessment of disease processes and the effects of therapy.

  10. Development of an equine groove model to induce metacarpophalangeal osteoarthritis: a pilot study on 6 horses.

    Directory of Open Access Journals (Sweden)

    Ugo Maninchedda

    Full Text Available The aim of this work was to develop an equine metacarpophalangeal joint model that induces osteoarthritis that is not primarily mediated by instability or inflammation. The study involved six Standardbred horses. Standardized cartilage surface damage or "grooves" were created arthroscopically on the distal dorsal aspect of the lateral and medial metacarpal condyles of a randomly chosen limb. The contralateral limb was sham operated. After 2 weeks of stall rest, horses were trotted 30 minutes every other day for 8 weeks, then evaluated for lameness and radiographed. Synovial fluid was analyzed for cytology and biomarkers. At 10 weeks post-surgery, horses were euthanized for macroscopic and histologic joint evaluation. Arthroscopic grooving allowed precise and identical damage to the cartilage of all animals. Under the controlled exercise regime, this osteoarthritis groove model displayed significant radiographic, macroscopic, and microscopic degenerative and reactive changes. Histology demonstrated consistent surgically induced grooves limited to non-calcified cartilage and accompanied by secondary adjacent cartilage lesions, chondrocyte necrosis, chondrocyte clusters, cartilage matrix softening, fissuring, mild subchondral bone inflammation, edema, and osteoblastic margination. Synovial fluid biochemistry and cytology demonstrated significantly elevated total protein without an increase in prostaglandin E2, neutrophils, or chondrocytes. This equine metacarpophalangeal groove model demonstrated that standardized non-calcified cartilage damage accompanied by exercise triggered altered osteochondral morphology and cartilage degeneration with minimal or inefficient repair and little inflammatory response. This model, if validated, would allow for assessment of disease processes and the effects of therapy.

  11. A test for the minimum scale of grooving on the Amatrice and Norcia earthquakes

    Science.gov (United States)

    Okamoto, K.; Brodsky, E. E.; Billi, A.

    2017-12-01

    As stress builds up along a fault, elastic strain energy builds until it cannot be accommodated by small-scale ductile deformation and then the fault brittlely fails. This brittle failure is associated with the grooving process that causes slickensides along fault planes. Therefore the scale at which slickensides disappear could be geological evidence of earthquake nucleation. Past studies found the minimum scale of grooving, however the studied fault surfaces were not exposed by recent earthquakes. These measurements could have been a product of chemical or mechanical weathering. On August 24th and October 30th of 2016, MW 6.0 and 6.5 earthquakes shook central Italy. The earthquakes caused decimeter to meter scale fault scarps along the Mt. Vettoretto Fault. Here, we analyze samples of a scarp using white light interferometry in order to determine if the minimum scale of grooving is present. Results suggest that grooving begins around 100 μm for these samples, which is consistent with previous findings of faults without any direct evidence of earthquakes. The measurement is also consistent with typical values of the frictional weakening distance Dc, which also is associated with a transition between ductile and brittle behavior. The measurements show that the minimum scale of grooving is a useful measure of the behavior of faults.

  12. Thermal performance comparison of oscillating heat pipes with and without helical micro-grooves

    Science.gov (United States)

    Qu, Jian; Li, Xiaojun; Xu, Qian; Wang, Qian

    2017-11-01

    This paper presents an experimental investigation to compare the thermal performance of three closed loop oscillating heat pipes (OHPs) with and without internal helical microgrooves at vertical and horizontal orientations. All of these OHPs were made from copper tubes and have three turns with lengths of 70, 230 and 110 mm at the evaporator, adiabatic and condenser sections, respectively. Deionized water was used as the working fluid at a volumetric filling ratio of 50%. The internal diameters (IDs) of two smooth-tube OHPs are 4.0 and 4.8 mm, respectively, and the internal diameter of micro-grooved OHP without groove structures is about 4.5 mm. Experimental results demonstrated that the addition of groove structures make the OHP remarkably outperform smooth-tube OHPs in both effective thermal conductivity and thermal resistance. The thermal resistance of vertically-oriented micro-grooved OHP could be lowered to 0.057 °C/W associated with an effective thermal conductivity of 6.1 × 104 W/ (m·K) at the input heat flux of 3.8 × 104 W/m2. Compared to smooth-tube OHPs, preliminary mechanism analysis reveals that local heat transfer coefficients both at the heating and cooling sections of micro-grooved OHP could be significantly improved. Moreover, enhanced liquid backflow to the evaporator due to microgroove-induced capillarity is also responsible for the OHP performance enhancement.

  13. Study of mastoid canals and grooves in north karnataka human skulls.

    Science.gov (United States)

    Hadimani, Gavishiddappa Andanappa; Bagoji, Ishwar Basavantappa

    2013-08-01

    This study was undertaken to observe the frequency of mastoid canals and grooves in north Karnataka dry human skulls. 100 dry human skulls of unknown age and sex from the department of Anatomy were selected and observed for the present study. The mastoid regions of dry skulls were observed for the presence of mastoid canals and grooves, if any. A metallic wire was passed through the canal for its confirmation and then the length was measured. The Mastoid canals were present in 53% of the total 100 skulls observed either bilaterally or unilaterally. Mastoid grooves were present in 18% of the total skulls (100) observed. Double mastoid canal was found in 01% of total skull studied and both Mastoid canals & Mastoid grooves together were present in 02% of the total skulls (100) observed. The knowledge of mastoid canals and grooves is very important for otolaryngologists and neurosurgeons. Because they contain an arterial branch of occipital artery with its accompanying vein which is liable to injury resulting into severe bleeding.

  14. Research on fatigue behavior and residual stress of large-scale cruciform welding joint with groove

    International Nuclear Information System (INIS)

    Zhao, Xiaohui; Liu, Yu; Liu, Yong; Gao, Yuan

    2014-01-01

    Highlights: • The fatigue behavior of the large-scale cruciform welding joint with groove was studied. • The longitudinal residual stress of the large-scale cruciform welding joint was tested by contour method. • The fatigue fracture mechanism of the large-scale cruciform welding joint with groove was analyzed. - Abstract: Fatigue fracture behavior of the 30 mm thick Q460C-Z steel cruciform welded joint with groove was investigated. The fatigue test results indicated that fatigue strength of 30 mm thick Q460C-Z steel cruciform welded joint with groove can reach fatigue level of 80 MPa (FAT80). Fatigue crack source of the failure specimen initiated from weld toe. Meanwhile, the microcrack was also found in the fusion zones of the fatigue failure specimen, which was caused by weld quality and weld metal integrity resulting from the multi-pass welds. Two-dimensional map of the longitudinal residual stress of 30 mm thick Q460C-Z steel cruciform welded joint with groove was obtained by using the contour method. The stress nephogram of Two-dimensional map indicated that longitudinal residual stress in the welding center is the largest

  15. Structure and dynamics of a [1:1] drug-DNA complex: Analysis of 2D NMR data using molecular mechanics and molecular dynamics calculations

    International Nuclear Information System (INIS)

    Sarma, R.H.; Sarma, M.H.; Umemoto, K.

    1990-01-01

    1D/2D NMR studies are reported for a [1:1] complex of d(GA 4 T 4 C) 2 and Dst2 (an analogue of distamycin A). Full- Matrix NOESY Simulations, Molecular Mechanics and Molecular Dynamics Calculations are performed to analyze the NMR data. Results show that drug-DNA complex formation is driven by static features like H-bonding and steric interactions in the minor-groove of DNA. As a consequence of drug binding, a non-linear oscillatory mode is activated. In this mode the molecule samples equilibrium structural states of difference degrees of bending. It is noted that these structures belong to three distinctly different energy wells that satisfy the same NMR data. 14 refs., 4 figs., 2 tabs

  16. Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency

    Directory of Open Access Journals (Sweden)

    Mónica Fernández-Cancio

    2018-04-01

    Full Text Available The CYP17A1 gene regulates sex steroid biosynthesis in humans through 17α-hydroxylase/17,20 lyase activities and is a target of anti-prostate cancer drug abiraterone. In a 46, XY patient with female external genitalia, together with a loss of function mutation S441P, we identified a novel missense mutation V366M at the catalytic center of CYP17A1 which preferentially impaired 17,20 lyase activity. Kinetic experiments with bacterially expressed proteins revealed that V366M mutant enzyme can bind and metabolize pregnenolone to 17OH-pregnenolone, but 17OH-pregnenolone binding and conversion to dehydroepiandrosterone (DHEA was impaired, explaining the patient’s steroid profile. Abiraterone could not bind and inhibit the 17α-hydroxylase activity of the CYP17A1-V366M mutant. Molecular dynamics (MD simulations showed that V366M creates a “one-way valve” and suggests a mechanism for dual activities of human CYP17A1 where, after the conversion of pregnenolone to 17OH-pregnenolone, the product exits the active site and re-enters for conversion to dehydroepiandrosterone. The V366M mutant also explained the effectiveness of the anti-prostate cancer drug abiraterone as a potent inhibitor of CYP17A1 by binding tightly at the active site in the WT enzyme. The V366M is the first human mutation to be described at the active site of CYP17A1 that causes isolated 17,20 lyase deficiency. Knowledge about the specificity of CYP17A1 activities is of importance for the development of treatments for polycystic ovary syndrome and inhibitors for prostate cancer therapy.

  17. Ancient schwannoma at the olfactory groove mimicking meningioma: A case report

    Energy Technology Data Exchange (ETDEWEB)

    Heo, Young Jin; Jeong, Hae Woong [Dept. of Radiology, Busan Paik Hospital, Inje University College of Medicine, Busan (Korea, Republic of)

    2015-12-15

    Schwannomas are benign slow-growing nerve sheath tumors, which can develop in any peripheral or central nerve that contains Schwann cells. Schwannomas located near the olfactory groove are extremely rare and radiological diagnosis can be difficult. Moreover, ancient schwannoma is an uncommon variant, and radiologic findings are rarely reported. Herein, we reported a surgically confirmed case of ancient schwannoma at the olfactory groove in a 44-year-old woman presenting with headache and visual disturbance. Brain magnetic resonance imaging (MRI) showed a solid and cystic extra-axial mass located in the subfrontal area mimicking an olfactory groove meningioma. Histopathologic diagnosis of ancient schwannoma was confirmed by immunohistochemical staining for S100, CD56, vimentin, and other markers. Furthermore, we described the clinical manifestations, MRI characteristics, and histopathologic findings of the case, and presented a review of related literature.

  18. Polarizing beam splitter of deep-etched triangular-groove fused-silica gratings.

    Science.gov (United States)

    Zheng, Jiangjun; Zhou, Changhe; Feng, Jijun; Wang, Bo

    2008-07-15

    We investigated the use of a deep-etched fused-silica grating with triangular-shaped grooves as a highly efficient polarizing beam splitter (PBS). A triangular-groove PBS grating is designed at a wavelength of 1550 nm to be used in optical communication. When it is illuminated in Littrow mounting, the transmitted TE- and TM-polarized waves are mainly diffracted in the minus-first and zeroth orders, respectively. The design condition is based on the average differences of the grating mode indices, which is verified by using rigorous coupled-wave analysis. The designed PBS grating is highly efficient over the C+L band range for both TE and TM polarizations (>97.68%). It is shown that such a triangular-groove PBS grating can exhibit a higher diffraction efficiency, a larger extinction ratio, and less reflection loss than the binary-phase fused-silica PBS grating.

  19. Estimation of the binding modes with important human cytochrome P450 enzymes, drug interaction potential, pharmacokinetics, and hepatotoxicity of ginger components using molecular docking, computational, and pharmacokinetic modeling studies.

    Science.gov (United States)

    Qiu, Jia-Xuan; Zhou, Zhi-Wei; He, Zhi-Xu; Zhang, Xueji; Zhou, Shu-Feng; Zhu, Shengrong

    2015-01-01

    Ginger is one of the most commonly used herbal medicines for the treatment of numerous ailments and improvement of body functions. It may be used in combination with prescribed drugs. The coadministration of ginger with therapeutic drugs raises a concern of potential deleterious drug interactions via the modulation of the expression and/or activity of drug-metabolizing enzymes and drug transporters, resulting in unfavorable therapeutic outcomes. This study aimed to determine the molecular interactions between 12 main active ginger components (6-gingerol, 8-gingerol, 10-gingerol, 6-shogaol, 8-shogaol, 10-shogaol, ar-curcumene, β-bisabolene, β-sesquiphelandrene, 6-gingerdione, (-)-zingiberene, and methyl-6-isogingerol) and human cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6, and 3A4 and to predict the absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the 12 ginger components using computational approaches and comprehensive literature search. Docking studies showed that ginger components interacted with a panel of amino acids in the active sites of CYP1A2, 2C9, 2C19, 2D6, and 3A4 mainly through hydrogen bond formation, to a lesser extent, via π-π stacking. The pharmacokinetic simulation studies showed that the [I]/[Ki ] value for CYP2C9, 2C19, and 3A4 ranged from 0.0002 to 19.6 and the R value ranged from 1.0002 to 20.6 and that ginger might exhibit a high risk of drug interaction via inhibition of the activity of human CYP2C9 and CYP3A4, but a low risk of drug interaction toward CYP2C19-mediated drug metabolism. Furthermore, it has been evaluated that the 12 ginger components possessed a favorable ADMET profiles with regard to the solubility, absorption, permeability across the blood-brain barrier, interactions with CYP2D6, hepatotoxicity, and plasma protein binding. The validation results showed that there was no remarkable effect of ginger on the metabolism of warfarin in humans, whereas concurrent use of ginger and nifedipine exhibited a

  20. Comparative evaluation of three heat transfer enhancement strategies in a grooved channel

    Energy Technology Data Exchange (ETDEWEB)

    Herman, C.; Kang, E. [Dept. of Mechanical Engineering, Johns Hopkins Univ., Baltimore, MD (United States)

    2001-09-01

    Results of a comparative evaluation of three heat transfer enhancement strategies for forced convection cooling of a parallel plate channel populated with heated blocks, representing electronic components mounted on printed circuit boards, are reported. Heat transfer in the reference geometry, the asymmetrically heated parallel plate channel, is compared with that for the basic grooved channel, and the same geometry enhanced by cylinders and vanes placed above the downstream edge of each heated block. In addition to conventional heat transfer and pressure drop measurements, holographic interferometry combined with high-speed cinematography was used to visualize the unsteady temperature fields in the self-sustained oscillatory flow. The locations of increased heat transfer within one channel periodicity depend on the enhancement technique applied, and were identified by analyzing the unsteady temperature distributions visualized by holographic interferometry. This approach allowed gaining insight into the mechanisms responsible for heat transfer enhancement. Experiments were conducted at moderate flow velocities in the laminar, transitional and turbulent flow regimes. Reynolds numbers were varied in the range Re = 200-6500, corresponding to flow velocities from 0.076 to 2.36 m/s. Flow oscillations were first observed between Re = 1050 and 1320 for the basic grooved channel, and around Re = 350 and 450 for the grooved channels equipped with cylinders and vanes, respectively. At Reynolds numbers above the onset of oscillations and in the transitional flow regime, heat transfer rates in the investigated grooved channels exceeded the performance of the reference geometry, the asymmetrically heated parallel plate channel. Heat transfer in the grooved channels enhanced with cylinders and vanes showed an increase by a factor of 1.2-1.8 and 1.5-3.5, respectively, when compared to data obtained for the basic grooved channel; however, the accompanying pressure drop penalties

  1. The drug-binding activity of the multidrug-responding transcriptional regulator BmrR resides in its C-terminal domain.

    OpenAIRE

    Markham, P N; Ahmed, M; Neyfakh, A A

    1996-01-01

    Rhodamine and tetraphenylphosphonium, the substrates of the Bacillus subtilis multidrug efflux transporter Bmr, induce the expression of Bmr through direct interaction with its transcriptional activator BmrR. Here we show that the C-terminal domain of BmrR, expressed individually, binds both these compounds and therefore can be used as a model for molecular analysis of the phenomenon of multidrug recognition.

  2. Disk in a groove with friction: An analysis of static equilibrium and indeterminacy

    Science.gov (United States)

    Donolato, Cesare

    2018-05-01

    This note studies the statics of a rigid disk placed in a V-shaped groove with frictional walls and subjected to gravity and a torque. The two-dimensional equilibrium problem is formulated in terms of the angles that contact forces form with the normal to the walls. This approach leads to a single trigonometric equation in two variables whose domain is determined by Coulomb's law of friction. The properties of solutions (existence, uniqueness, or indeterminacy) as functions of groove angle, friction coefficient and applied torque are derived by a simple geometric representation. The results modify some of the conclusions by other authors on the same problem.

  3. Genetic Algorithm-Based Optimization for Surface Roughness in Cylindrically Grinding Process Using Helically Grooved Wheels

    Science.gov (United States)

    Çaydaş, Ulaş; Çelik, Mahmut

    The present work is focused on the optimization of process parameters in cylindrical surface grinding of AISI 1050 steel with grooved wheels. Response surface methodology (RSM) and genetic algorithm (GA) techniques were merged to optimize the input variable parameters of grinding. The revolution speed of workpiece, depth of cut and number of grooves on the wheel were changed to explore their experimental effects on the surface roughness of machined bars. The mathematical models were established between the input parameters and response by using RSM. Then, the developed RSM model was used as objective functions on GA to optimize the process parameters.

  4. Efficient Excitation of Channel Plasmons in Tailored, UV-Lithography-Defined V-Grooves

    DEFF Research Database (Denmark)

    Smith, Cameron L. C.; Thilsted, Anil Haraksingh; Garcia-Ortiz, Cesar E.

    2014-01-01

    We demonstrate the highly efficient (>50%) conversion of freely propagating light to channel plasmon-polaritons (CPPs) in gold V-groove waveguides using compact 1.6 μm long waveguide-termination coupling mirrors. Our straightforward fabrication process, involving UV-lithography and crystallographic...... silicon etching, forms the coupling mirrors innately and ensures exceptional-quality, wafer-scale device production. We tailor the V-shaped profiles by thermal silicon oxidation in order to shift initially wedge-located modes downward into the V-grooves, resulting in well-confined CPPs suitable...

  5. Numerical Calculation for Whirling Motion of a Centrifugal Blood Pump with Conical Spiral Groove Bearings

    Science.gov (United States)

    Shigemaru, Daichi; Tsukamoto, Hiroshi

    2010-06-01

    Whirling motion of a pump impeller was calculated for the centrifugal blood pump with Conical Spiral Groove Bearings to get a criterion for the instability of impeller whirling motion. The motion of the centrifugal blood pump impeller was calculated based on a spring damping model, and unsteady flow in the pump was computed using the commercial CFD package ANSYS CFX. Also the whirling motion of rotating impeller was measured using two displacement sensors fixed to the blood pump casing. The numerical calculations were done for the blood pump impeller with conical spiral groove bearings, and impeller whirling motion was evaluated.

  6. Liquid phase solvent bonding of plastic microfluidic devices assisted by retention grooves.

    Science.gov (United States)

    Wan, Alwin M D; Sadri, Amir; Young, Edmond W K

    2015-01-01

    We report a novel method for achieving consistent liquid phase solvent bonding of plastic microfluidic devices via the use of retention grooves at the bonding interface. The grooves are patterned during the regular microfabrication process, and can be placed at the periphery of a device, or surrounding microfluidic features with open ports, where they effectively mitigate solvent evaporation, and thus substantially reduce poor bond coverage. This method is broadly applicable to a variety of plastics and solvents, and produces devices with high bond quality (i.e., coverage, strength, and microfeature fidelity) that are suitable for studies in physics, chemistry, and cell biology at the microscale.

  7. Bifurcation analysis of an aerodynamic journal bearing system considering the effect of stationary herringbone grooves

    International Nuclear Information System (INIS)

    Wang, C.-C.

    2007-01-01

    This paper investigates the bifurcation and nonlinear behavior of an aerodynamic journal bearing system taking into account the effect of stationary herringbone grooves. A finite difference method based on the successive over relation approach is employed to solve the Reynolds' equation. The analysis reveals a complex dynamical behavior comprising periodic and quasi-periodic responses of the rotor center. The dynamic behavior of the bearing system varies with changes in the bearing number and rotor mass. The results of this study provide a better understanding of the nonlinear dynamics of aerodynamic grooved journal bearing systems

  8. High Excitation Efficiency of Channel Plasmon Polaritons in Tailored, UV-Lithography-Defined V-Grooves

    DEFF Research Database (Denmark)

    Smith, Cameron; Thilsted, Anil Haraksingh; Garcia-Ortiz, Cesar E.

    2014-01-01

    We demonstrate >50% conversion of light to V-groove channel plasmon-polaritons (CPPs) via compact waveguide-termination mirrors. Devices are fabricated using UV-lithography and crystallographic silicon etching. The V-shape is tailored by thermal oxidation to support confined CPPs.......We demonstrate >50% conversion of light to V-groove channel plasmon-polaritons (CPPs) via compact waveguide-termination mirrors. Devices are fabricated using UV-lithography and crystallographic silicon etching. The V-shape is tailored by thermal oxidation to support confined CPPs....

  9. Synthesis and DNA-binding study of imidazole linked thiazolidinone derivatives.

    Science.gov (United States)

    War, Javeed Ahmad; Srivastava, Santosh Kumar; Srivastava, Savitri Devi

    2017-02-01

    A novel series of imidazole-linked thiazolidinone hybrid molecules were designed and synthesized through a feasible synthetic protocol. The molecules were characterized with Fourier transform infrared (FT-IR), 1 H nuclear magnetic resonance (NMR), 13 C NMR and high-resolution mass spectrometry (HRMS) techniques. In vitro susceptibility tests against Gram-positive (S. aureus and B. subtilis) and Gram-negative bacteria (E. coli and P. aeruginosa) gave highly promising results. The most active molecule (3e) gave a minimal inhibitory concentration (MIC) value of 3.125 μg/mL which is on par with the reference drug streptomycin. Structure-activity relationships revealed activity enhancement by nitro and chloro groups when they occupied meta position of the arylidene ring in 2-((3-(imidazol-1-yl)propyl)amino)-5-benzylidenethiazolidin-4-ones. DNA-binding study of the most potent molecule 3e with salmon milt DNA (sm-DNA) under simulated physiological pH was probed with UV-visible absorption, fluorescence quenching, gel electrophoresis and molecular docking techniques. These studies established that compound 3e has a strong affinity towards DNA and binds at DNA minor groove with a binding constant (K b ) 0.18 × 10 2  L mol -1 . Molecular docking simulations predicted strong affinity of 3e towards DNA with a binding affinity (ΔG) -8.5 kcal/mol. Van der Waals forces, hydrogen bonding and hydrophobic interactions were predicted as the main forces of interaction. The molecule 3e exhibited specific affinity towards adenine-thiamine base pairs. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  10. HPMA copolymer conjugates with reduced anti-CD20 antibody for cell-specific drug targeting. I. Synthesis and in vitro evaluation of binding efficacy and cytostatic activity

    Czech Academy of Sciences Publication Activity Database

    Etrych, Tomáš; Strohalm, Jiří; Kovář, Lubomír; Kabešová, Martina; Říhová, Blanka; Ulbrich, Karel

    2009-01-01

    Roč. 140, č. 1 (2009), s. 18-26 ISSN 0168-3659 R&D Projects: GA MŠk 1M0505; GA AV ČR IAAX00500803 Institutional research plan: CEZ:AV0Z40500505; CEZ:AV0Z50200510 Keywords : HPMA copolymers * drug delivery systems * doxorubicin * monoclonal anti-CD20 antibody * drug targeting Subject RIV: CD - Macromolecular Chemistry Impact factor: 5.949, year: 2009

  11. Drug development and manufacturing

    Science.gov (United States)

    Warner, Benjamin P.; McCleskey, T. Mark; Burrell, Anthony K.

    2015-10-13

    X-ray fluorescence (XRF) spectrometry has been used for detecting binding events and measuring binding selectivities between chemicals and receptors. XRF may also be used for estimating the therapeutic index of a chemical, for estimating the binding selectivity of a chemical versus chemical analogs, for measuring post-translational modifications of proteins, and for drug manufacturing.

  12. Observations on the effects of grooved surfaces on the interfacial torque in highly loaded rolling and sliding tests

    DEFF Research Database (Denmark)

    Janakiraman, Shravan; Klit, Peder; Jensen, Niels Steenfeldt

    2014-01-01

    Some efforts have been undertaken to study the effects of grooved surfaces on the interfacial film thickness and torque between two contacting non-conformal surfaces under heavy loads. Transverse grooves of micrometer scale depth were engraved on polished, flat ring surfaces using established ind...

  13. Modeling and simulation of stamp deflections in nanoimprint lithography: Exploiting backside grooves to enhance residual layer thickness uniformity

    DEFF Research Database (Denmark)

    Taylor, Hayden; Smistrup, Kristian; Boning, Duane

    2011-01-01

    We describe a model for the compliance of a nanoimprint stamp etched with a grid of backside grooves. We integrate the model with a fast simulation technique that we have previously demonstrated, to show how etched grooves help reduce the systematic residual layer thickness (RLT) variations...

  14. DNA minor groove electrostatic potential: influence of sequence-specific transitions of the torsion angle gamma and deoxyribose conformations.

    Science.gov (United States)

    Zhitnikova, M Y; Shestopalova, A V

    2017-11-01

    The structural adjustments of the sugar-phosphate DNA backbone (switching of the γ angle (O5'-C5'-C4'-C3') from canonical to alternative conformations and/or C2'-endo → C3'-endo transition of deoxyribose) lead to the sequence-specific changes in accessible surface area of both polar and non-polar atoms of the grooves and the polar/hydrophobic profile of the latter ones. The distribution of the minor groove electrostatic potential is likely to be changing as a result of such conformational rearrangements in sugar-phosphate DNA backbone. Our analysis of the crystal structures of the short free DNA fragments and calculation of their electrostatic potentials allowed us to determine: (1) the number of classical and alternative γ angle conformations in the free B-DNA; (2) changes in the minor groove electrostatic potential, depending on the conformation of the sugar-phosphate DNA backbone; (3) the effect of the DNA sequence on the minor groove electrostatic potential. We have demonstrated that the structural adjustments of the DNA double helix (the conformations of the sugar-phosphate backbone and the minor groove dimensions) induce changes in the distribution of the minor groove electrostatic potential and are sequence-specific. Therefore, these features of the minor groove sizes and distribution of minor groove electrostatic potential can be used as a signal for recognition of the target DNA sequence by protein in the implementation of the indirect readout mechanism.

  15. High throughput testing of the SV40 Large T antigen binding to cellular p53 identifies putative drugs for the treatment of SV40-related cancers

    International Nuclear Information System (INIS)

    Carbone, Michele; Rudzinski, Jennifer; Bocchetta, Maurizio

    2003-01-01

    SV40 has been linked to some human malignancies, and the evidence that this virus plays a causative role in mesothelioma and brain tumors is mounting. The major SV40 oncoprotein is the Large tumor antigen (Tag). A key Tag transforming activity is connected to its capability to bind and inactivate cellular p53. In this study we developed an effective, high throughput, ELISA-based method to study Tag-p53 interaction in vitro. This assay allowed us to screen a chemical library and to identify a chemical inhibitor of the Tag binding to p53. We propose that our in vitro assay is a useful method to identify molecules that may be used as therapeutic agents for the treatment of SV40-related human cancers

  16. Large-scale integration of small molecule-induced genome-wide transcriptional responses, Kinome-wide binding affinities and cell-growth inhibition profiles reveal global trends characterizing systems-level drug action

    Directory of Open Access Journals (Sweden)

    Dusica eVidovic

    2014-09-01

    Full Text Available The Library of Integrated Network-based Cellular Signatures (LINCS project is a large-scale coordinated effort to build a comprehensive systems biology reference resource. The goals of the program include the generation of a very large multidimensional data matrix and informatics and computational tools to integrate, analyze, and make the data readily accessible. LINCS data include genome-wide transcriptional signatures, biochemical protein binding profiles, cellular phenotypic response profiles and various other datasets for a wide range of cell model systems and molecular and genetic perturbations. Here we present a partial survey of this data facilitated by data standards and in particular a robust compound standardization workflow; we integrated several types of LINCS signatures and analyzed the results with a focus on mechanism of action and chemical compounds. We illustrate how kinase targets can be related to disease models and relevant drugs. We identified some fundamental trends that appear to link Kinome binding profiles and transcriptional signatures to chemical information and biochemical binding profiles to transcriptional responses independent of chemical similarity. To fill gaps in the datasets we developed and applied predictive models. The results can be interpreted at the systems level as demonstrated based on a large number of signaling pathways. We can identify clear global relationships, suggesting robustness of cellular responses to chemical perturbation. Overall, the results suggest that chemical similarity is a useful measure at the systems level, which would support phenotypic drug optimization efforts. With this study we demonstrate the potential of such integrated analysis approaches and suggest prioritizing further experiments to fill the gaps in the current data.

  17. Saying Hello World with GROOVE - A Solution to the TTC 2011 Instructive Case

    Directory of Open Access Journals (Sweden)

    Amir Hossein Ghamarian

    2011-11-01

    Full Text Available This report presents a solution to the Hello World case study of TTC 2011 using GROOVE. We provide and explain the grammar that we used to solve the case study. Every requested question of the case study was solved by a single rule application.

  18. Saying Hello World with GROOVE - A Solution to the TTC 2011 Instructive Case

    NARCIS (Netherlands)

    Ghamarian, A.H.; de Mol, M.J.; Rensink, Arend; Zambon, Eduardo; van Gorp, Pieter; Mazanek, Steffen; Rose, Louis

    2011-01-01

    This report presents a solution to the Hello World case study using GROOVE. We provide and explain the grammar that we used to solve the case study. Every requested question of the case study was solved by a single rule application.

  19. Measurement repeatability of tibial tuberosity-trochlear groove offset distance in red fox (Vulpes vulpes) cadavers

    NARCIS (Netherlands)

    Miles, J.E.; Jensen, B.R.; Kirpensteijn, J.; Svalastoga, E.L.; Eriksen, T.

    2013-01-01

    Abstract OBJECTIVE: To describe CT image reconstruction criteria for measurement of the tibial tuberosity-trochlear groove (TT-TG) offset distance, evaluate intra- and inter-reconstruction repeatability, and identify key sources of error in the measurement technique, as determined in vulpine hind

  20. Erosion of a grooved surface caused by impact of particle-laden flow

    Science.gov (United States)

    Jung, Sohyun; Yang, Eunjin; Kim, Ho-Young

    2016-11-01

    Solid erosion can be a life-limiting process for mechanical elements in erosive environments, thus it is of practical importance in many industries such as construction, mining, and coal conversion. Erosion caused by particle-laden flow occurs through diverse mechanisms, such as cutting, plastic deformation, brittle fracture, fatigue and melting, depending on particle velocity, total particle mass and impingement angle. Among a variety of attempts to lessen erosion, here we investigate the effectiveness of millimeter-sized grooves on the surface. By experimentally measuring the erosion rates of smooth and triangular-grooved surfaces under various impingement angles, we find that erosion can be significantly reduced within a finite range of impingement angles. We show that such erosion resistance is attributed to the swirls of air within grooves and the differences in erosive strength of normal and slanted impact. In particular, erosion is mitigated when we increase the effective area under normal impact causing plastic deformation and fracture while decreasing the area under slanted impact that cuts the surface to a large degree. Our quantitative model for the erosion rate of grooved surfaces considering the foregoing effects agrees with the measurement results.

  1. Optimal leaf sequencing with elimination of tongue-and-groove underdosage

    International Nuclear Information System (INIS)

    Kamath, Srijit; Sahni, Sartaj; Palta, Jatinder; Ranka, Sanjay; Li, Jonathan

    2004-01-01

    The individual leaves of a multileaf collimator (MLC) have a tongue-and-groove or stepped-edge design to minimize leakage radiation between adjacent leaves. This design element has a drawback in that it creates areas of underdosages in intensity-modulated photon beams unless a leaf trajectory is specifically designed such that for any two adjacent leaf pairs, the direct exposure under the tongue-and-groove is equal to the lower of the direct exposures of the leaf pairs. In this work, we present a systematic study of the optimization of a leaf sequencing algorithm for segmental multileaf collimator beam delivery that completely eliminates areas of underdosages due to tongue-and-groove or stepped-edge design of the MLC. Simultaneous elimination of tongue-and-groove effect and leaf interdigitation is also studied. This is an extension of our previous work (Kamath et al 2003a Phys. Med. Biol. 48 307) in which we described a leaf sequencing algorithm that is optimal for monitor unit (MU) efficiency under most common leaf movement constraints that include minimum leaf separation. Compared to our previously published algorithm (without constraints), the new algorithms increase the number of sub-fields by approximately 21% and 25%, respectively, but are optimal in MU efficiency for unidirectional schedules. (note)

  2. Torque scaling in small-gap Taylor-Couette flow with smooth or grooved wall

    Science.gov (United States)

    Zhu, Bihai; Ji, Zengqi; Lou, Zhengkun; Qian, Pengcheng

    2018-03-01

    The torque in the Taylor-Couette flow for radius ratios η ≥0.97 , with smooth or grooved wall static outer cylinders, is studied experimentally, with the Reynolds number of the inner cylinder reaching up to Rei=2 ×105 , corresponding to the Taylor number up to Ta =5 ×1010 . The grooves are perpendicular to the mean flow, and similar to the structure of a submersible motor stator. It is found that the dimensionless torque G , at a given Rei and η , is significantly greater for grooved cases than smooth cases. We compare our experimental torques for the smooth cases to the fit proposed by Wendt [F. Wendt, Ing.-Arch. 4, 577 (1993), 10.1007/BF02084936] and the fit proposed by Bilgen and Boulos [E. Bilgen and R. Boulos, J Fluids Eng. 95, 122 (1973), 10.1115/1.3446944], which shows both fits are outside their range for small gaps. Furthermore, an additional dimensionless torque (angular velocity flux) N uω in the smooth cases exhibits an effective scaling of N uω˜T a0.39 in the ultimate regime, which occurs at a lower Taylor number, Ta ≈3.5 ×107 , than the well-explored η =0.714 case (at Ta ≈3 ×108 ). The same effective scaling exponent, 0.39, is also evident in the grooved cases, but for η =0.97 and 0.985, there is a peak before this exponent appears.

  3. Effect of longitudinal grooves of the scallop surface on aerodynamic performance

    International Nuclear Information System (INIS)

    Kim, Tae Hun; Choi, Hae Cheon

    2008-01-01

    Some of the scallops like Amesium balloti have an excellent level-swimming ability, i.e. they can swim about 20m by single level swimming with a maximum swimming velocity of about 1.6m/s in the sea. On the other hand, some species like Patinopecten yessoensis have longitudinal grooves on the upper and lower surfaces and others do not. Therefore, in the present study, we measure the lift and drag forces on a real scallop model (Patinopecten yessoensis) in a wind tunnel. Experiments are performed at the Reynolds number of 75,000 based on the maximum chord length, which is within the swimming condition of real scallop (Re=30,000∼300,000). To see the effect of longitudinal grooves, we measure the aerodynamic forces on a scallop model by removing the grooves. With the grooves, the lift force increases at low angles of attack (α<10 .deg.). The drag force increases slightly at all the attack angles considered. The lift-to-drag ratio is increased by about 10% at α<10 .deg.

  4. Nanoscale Plasmonic V-Groove Waveguides for the Interrogation of Single Fluorescent Bacterial Cells

    DEFF Research Database (Denmark)

    Lotan, Oren; Bar-David, Jonathan; Smith, Cameron

    2017-01-01

    We experimentally demonstrate the interrogation of an individual Escherichia coli cell using a nanoscale plasmonic V-groove waveguide. Several different configurations were studied. The first involved the excitation of the cell in a liquid environment because it flows on top of the waveguide...

  5. Formation of grooves during the breakdown of a coal block by a water jet

    Energy Technology Data Exchange (ETDEWEB)

    Shavlovskii, S.S.

    1979-02-01

    A description is given of a method of coal excavation which provides for the initial formation of a grooved slit along the width of the opening equal in height to the diameter of the sinkhole. The formation of a groove in the coal block and the excavation of coal by water jets using the grooved crater method are illustrated in diagrams. Data are given on changes in the performance of the hydraulic jet in coal excavation in relation to the distance between the nozzle and the face and at given pressures in front of the nozzle. Functional relationships were mathematically constructed for the performance of the water jet in dimensionless coordinates. Data are also given on the comparative performance of a water jet when coal is excavated by the grooved funnel method and by hydraulic fracturing. The analytical computations indicate that the hydraulic fracturing of a coal block by water jets is economical with respect to the consumption of electric power and the unit rate of coal extraction, in addition to being a safe method. 4 references, 4 figures, 2 tables.

  6. Excitation of fluorescent nanoparticles by channel plasmon polaritons propagating in V-grooves

    DEFF Research Database (Denmark)

    Cuesta, Irene Fernandez; Nielsen, Rasmus Bundgaard; Boltasseva, Alexandra

    2009-01-01

    Recently, it has been proven that light can be squeezed into metallic channels with subwavelength lateral dimensions. Here, we present the study of the propagation of channel plasmon polaritons confined in gold V-grooves, filled with fluorescent particles. In this way, channel plasmon polaritons......-diameter beads, we show the possibility of individual excitation, what may have applications to develop very sensitive biosensors....

  7. Optimal leaf sequencing with elimination of tongue-and-groove underdosage

    Energy Technology Data Exchange (ETDEWEB)

    Kamath, Srijit [Department of Computer and Information Science and Engineering, University of Florida, Gainesville, FL (United States); Sahni, Sartaj [Department of Computer and Information Science and Engineering, University of Florida, Gainesville, FL (United States); Palta, Jatinder [Department of Radiation Oncology, University of Florida, Gainesville, FL (United States); Ranka, Sanjay [Department of Computer and Information Science and Engineering, University of Florida, Gainesville, FL (United States); Li, Jonathan [Department of Radiation Oncology, University of Florida, Gainesville, FL (United States)

    2004-02-07

    The individual leaves of a multileaf collimator (MLC) have a tongue-and-groove or stepped-edge design to minimize leakage radiation between adjacent leaves. This design element has a drawback in that it creates areas of underdosages in intensity-modulated photon beams unless a leaf trajectory is specifically designed such that for any two adjacent leaf pairs, the direct exposure under the tongue-and-groove is equal to the lower of the direct exposures of the leaf pairs. In this work, we present a systematic study of the optimization of a leaf sequencing algorithm for segmental multileaf collimator beam delivery that completely eliminates areas of underdosages due to tongue-and-groove or stepped-edge design of the MLC. Simultaneous elimination of tongue-and-groove effect and leaf interdigitation is also studied. This is an extension of our previous work (Kamath et al 2003a Phys. Med. Biol. 48 307) in which we described a leaf sequencing algorithm that is optimal for monitor unit (MU) efficiency under most common leaf movement constraints that include minimum leaf separation. Compared to our previously published algorithm (without constraints), the new algorithms increase the number of sub-fields by approximately 21% and 25%, respectively, but are optimal in MU efficiency for unidirectional schedules. (note)

  8. Ledges and grooves at γ/γ′ interfaces of single crystal superalloys

    Czech Academy of Sciences Publication Activity Database

    Parsa, A. B.; Wollgramm, P.; Buck, H.; Kostka, A.; Somsen, C.; Dlouhý, Antonín; Eggeler, G.

    2015-01-01

    Roč. 90, MAY (2015), s. 105-117 ISSN 1359-6454 R&D Projects: GA ČR(CZ) GA14-22834S Institutional support: RVO:68081723 Keywords : Ni-base single crystal superalloys * γ/γ′ interfaces * Interface dislocations * Rafting * Grooves Subject RIV: JG - Metallurgy Impact factor: 5.058, year: 2015

  9. Does Loading Influence the Severity of Cartilage Degeneration in the Canine Groove-Model of OA?

    NARCIS (Netherlands)

    Vos, Petra; Intema, Femke; van El, Benno; DeGroot, Jeroen; Bijlsma, J. W. J.; Lafeber, Floris; Mastbergen, Simon

    2009-01-01

    Many animal models are used to study osteoarthritis (OA). In these models the role of joint loading in the development of CA is not fully understood. We studied the effect of loading on the development of CIA in the canine Groove-model. In ten female beagle dogs OA was induced in one knee according

  10. Research on Grooved Concrete Pavement Based on the Durability of Its Anti-Skid Performance

    Directory of Open Access Journals (Sweden)

    Mulian Zheng

    2018-05-01

    Full Text Available The objectives of the present study are to investigate the anti-skid performance of concrete pavement and to attempt to enhance its durability by two different methods: using a longitudinally-transversely grooved (LT form, and using a self-developed composite curing agent containing paraffin and Na2SiO3 as the main ingredients. The friction coefficient (μ was measured by self-developed equipment to evaluate the anti-skid performance of samples with three different groove forms (LT, longitudinally grooved (L, and transversely grooved (T. Abrasion tests were then carried out to evaluate the durability of the anti-skid performance. The results indicated that anti-skid performance of LT samples was approximately 46.2% greater than that of T samples, but its durability was not as significant as that of T samples. However, the resistance to abrasion could be improved by using the aforementioned curing agent. Comparisons were carried out between samples sprayed the curing agent and control samples without any curing agent under standard conditions. It was found that the application of the curing agent increased the anti-skid durability of concrete by 35.4%~47.8%, proving it to be a useful and promising technique.

  11. Biomimetic "Cactus Spine" with Hierarchical Groove Structure for Efficient Fog Collection.

    Science.gov (United States)

    Bai, Fan; Wu, Juntao; Gong, Guangming; Guo, Lin

    2015-07-01

    A biomimetic "cactus spine" with hierarchical groove structure is designed and fabricated using simple electrospinning. This novel artificial cactus spine possesses excellent fog collection and water transportation ability. A model cactus equipped with artificial spines also shows a great water storage capacity. The results can be helpful in the development of water collectors and may make a contribution to the world water crisis.

  12. Study of Mastoid Canals and Grooves in North Karnataka Human Skulls

    OpenAIRE

    Hadimani, Gavishiddappa Andanappa; Bagoji, Ishwar Basavantappa

    2013-01-01

    Introduction: This study was undertaken to observe the frequency of mastoid canals and grooves in north Karnataka dry human skulls. 100 dry human skulls of unknown age and sex from the department of Anatomy were selected and observed for the present study.

  13. A surface embossing technique to create micro-grooves on an aluminum fin stock for drainage enhancement

    International Nuclear Information System (INIS)

    Liu Liping; Jacobi, Anthony M; Chvedov, Dmitri

    2009-01-01

    Recent advances using a surface embossing technique allow us to inexpensively impart micro-scale surface features on heat exchanger construction material, which we exploit to reduce condensate retention. The retention of condensate is important to the performance of heat exchangers in a broad range of air-cooling and dehumidification applications. We report a study of wetting behavior and drainage performance on a series of embossed surfaces with different micro-groove dimensions. Static contact angles, critical sliding angles, droplet aspect ratios, etc, are reported with detailed surface topographical information. Our results show that unless the spacing between grooves is very large (>100 µm), the parallel-grooved surface feature normally increases the apparent contact angle of a droplet on the surface. The micro-groove structure causes anisotropic wetting behavior of the droplets, and apparent contact angles measured by viewing along with the micro-grooves (θ p erpendicular) were found to be larger than those measured from the other direction (θ || ) (by viewing perpendicular to the grooves). A consistent reduction of a critical sliding angle was observed on surfaces after embossing (the micro-grooves are aligned to be parallel with gravity). This may be due to contact line discontinuities and contact-line pinning induced by a groove structure of the surface. Water droplets exhibit an elongated shape along the micro-grooves, which is in contrast to the nearly circular base contour observed on an isotropic surface. Smaller groove spacing, larger depth and steeper sidewalls are observed to be favorable for drainage enhancement and recommended as design guidelines in the future

  14. Rational optimization of drug-target residence time: Insights from inhibitor binding to the S. aureus FabI enzyme-product complex

    Science.gov (United States)

    Chang, Andrew; Schiebel, Johannes; Yu, Weixuan; Bommineni, Gopal R.; Pan, Pan; Baxter, Michael V.; Khanna, Avinash; Sotriffer, Christoph A.; Kisker, Caroline; Tonge, Peter J.

    2013-01-01

    Drug-target kinetics has recently emerged as an especially important facet of the drug discovery process. In particular, prolonged drug-target residence times may confer enhanced efficacy and selectivity in the open in vivo system. However, the lack of accurate kinetic and structural data for series of congeneric compounds hinders the rational design of inhibitors with decreased off-rates. Therefore, we chose the Staphylococcus aureus enoyl-ACP reductase (saFabI) - an important target for the development of new anti-staphylococcal drugs - as a model system to rationalize and optimize the drug-target residence time on a structural basis. Using our new, efficient and widely applicable mechanistically informed kinetic approach, we obtained a full characterization of saFabI inhibition by a series of 20 diphenyl ethers complemented by a collection of 9 saFabI-inhibitor crystal structures. We identified a strong correlation between the affinities of the investigated saFabI diphenyl ether inhibitors and their corresponding residence times, which can be rationalized on a structural basis. Due to its favorable interactions with the enzyme, the residence time of our most potent compound exceeds 10 hours. In addition, we found that affinity and residence time in this system can be significantly enhanced by modifications predictable by a careful consideration of catalysis. Our study provides a blueprint for investigating and prolonging drug-target kinetics and may aid in the rational design of long-residence-time inhibitors targeting the essential saFabI enzyme. PMID:23697754

  15. TR-PIV measurement of the wake behind a grooved cylinder at low Reynolds number

    Science.gov (United States)

    Liu, Ying Zheng; Shi, Liu Liu; Yu, Jun

    2011-04-01

    A comparative study of the wakes behind cylinders with grooved and smooth surfaces was performed with a view to understand the wake characteristics associated with the adult Saguaro cacti. A low-speed recirculation water channel was established for the experiment; the Reynolds number, based on the free-stream velocity and cylinder diameter (D), was kept at ReD=1500. State-of-the-art time-resolved particle image velocimetry (TR-PIV) was employed to measure a total of 20 480 realizations of the wake field at a frame rate of 250 Hz, enabling a comprehensive view of the time- and phase-averaged wake pattern. In comparison to the wake behind the smooth cylinder, the length of the recirculation zone behind the grooved cylinder was extended by nearly 18.2%, yet the longitudinal velocity fluctuation intensity was considerably weakened. A global view of the peaked spectrum of the longitudinal velocity component revealed that the intermediate region for the grooved cylinder, which approximately corresponds to the transition region where the shear layer vortices interact, merge and shed before the formation of the Karman-like vortex street, was much wider than that for the smooth one. The unsteady events near St=0.3-0.4 were detected in the intermediate region behind the grooved cylinder, but no such events were found in the smooth cylinder system. Although the formation of the Karman-like vortex street was delayed by about 0.6D downstream for the grooved cylinder, no prominent difference in the vortex street region was found in the far wake for both cylinders. The Proper Orthogonal Decomposition (POD) method was used extensively to decompose the vector and swirling strength fields, which gave a close-up view of the vortices in the near wake. The first two POD modes of the swirling strength clarified the spatio-temporal characteristics of the shear layer vortices behind the grooved cylinder. The small-scale vortices superimposed on the shear layers behind the grooved cylinder

  16. Human T-cell leukemia virus type 1 Tax requires direct access to DNA for recruitment of CREB binding protein to the viral promoter.

    Science.gov (United States)

    Lenzmeier, B A; Giebler, H A; Nyborg, J K

    1998-02-01

    Efficient human T-cell leukemia virus type 1 (HTLV-1) replication and viral gene expression are dependent upon the virally encoded oncoprotein Tax. To activate HTLV-1 transcription, Tax interacts with the cellular DNA binding protein cyclic AMP-responsive element binding protein (CREB) and recruits the coactivator CREB binding protein (CBP), forming a nucleoprotein complex on the three viral cyclic AMP-responsive elements (CREs) in the HTLV-1 promoter. Short stretches of dG-dC-rich (GC-rich) DNA, immediately flanking each of the viral CREs, are essential for Tax recruitment of CBP in vitro and Tax transactivation in vivo. Although the importance of the viral CRE-flanking sequences is well established, several studies have failed to identify an interaction between Tax and the DNA. The mechanistic role of the viral CRE-flanking sequences has therefore remained enigmatic. In this study, we used high resolution methidiumpropyl-EDTA iron(II) footprinting to show that Tax extended the CREB footprint into the GC-rich DNA flanking sequences of the viral CRE. The Tax-CREB footprint was enhanced but not extended by the KIX domain of CBP, suggesting that the coactivator increased the stability of the nucleoprotein complex. Conversely, the footprint pattern of CREB on a cellular CRE lacking GC-rich flanking sequences did not change in the presence of Tax or Tax plus KIX. The minor-groove DNA binding drug chromomycin A3 bound to the GC-rich flanking sequences and inhibited the association of Tax and the Tax-CBP complex without affecting CREB binding. Tax specifically cross-linked to the viral CRE in the 5'-flanking sequence, and this cross-link was blocked by chromomycin A3. Together, these data support a model where Tax interacts directly with both CREB and the minor-groove viral CRE-flanking sequences to form a high-affinity binding site for the recruitment of CBP to the HTLV-1 promoter.

  17. Estimation of the binding modes with important human cytochrome P450 enzymes, drug interaction potential, pharmacokinetics, and hepatotoxicity of ginger components using molecular docking, computational, and pharmacokinetic modeling studies

    Directory of Open Access Journals (Sweden)

    Qiu JX

    2015-02-01

    2, 2C9, 2C19, 2D6, and 3A4 mainly through hydrogen bond formation, to a lesser extent, via π–π stacking. The pharmacokinetic simulation studies showed that the [I]/[Ki] value for CYP2C9, 2C19, and 3A4 ranged from 0.0002 to 19.6 and the R value ranged from 1.0002 to 20.6 and that ginger might exhibit a high risk of drug interaction via inhibition of the activity of human CYP2C9 and CYP3A4, but a low risk of drug interaction toward CYP2C19-mediated drug metabolism. Furthermore, it has been evaluated that the 12 ginger components possessed a favorable ADMET profiles with regard to the solubility, absorption, permeability across the blood–brain barrier, interactions with CYP2D6, hepatotoxicity, and plasma protein binding. The validation results showed that there was no remarkable effect of ginger on the metabolism of warfarin in humans, whereas concurrent use of ginger and nifedipine exhibited a synergistic effect on platelet aggregation in humans. Moreover, ginger components showed a rapid half-life and no to low toxicity in humans. Taken together, this study shows that ginger components may regulate the activity and expression of various human CYPs, probably resulting in alterations in drug clearance and response. More studies are warranted to identify and confirm potential ginger–drug interactions and explore possible interactions of ginger with human CYPs and other functionally important proteins, to reduce and avoid side effects induced by unfavorable ginger–drug interactions.Keywords: CYP, drug metabolism, ginger, drug interaction, docking

  18. The 2.5 Å Structure of CD1c in Complex with a Mycobacterial Lipid Reveals an Open Groove Ideally Suited for Diverse Antigen Presentation

    Energy Technology Data Exchange (ETDEWEB)

    Scharf, Louise; Li, Nan-Sheng; Hawk, Andrew J.; Garzón, Diana; Zhang, Tejia; Fox, Lisa M.; Kazen, Allison R.; Shah, Sneha; Haddadian, Esmael J.; Gumperz, Jenny E.; Saghatelian, Alan; Faraldo-Gómez, José D.; Meredith, Stephen C.; Piccirilli, Joseph A.; Adams, Erin J. (Harvard); (UC); (MXPL-G); (UW-MED)

    2011-08-24

    CD1 molecules function to present lipid-based antigens to T cells. Here we present the crystal structure of CD1c at 2.5 {angstrom} resolution, in complex with the pathogenic Mycobacterium tuberculosis antigen mannosyl-{beta}1-phosphomycoketide (MPM). CD1c accommodated MPM's methylated alkyl chain exclusively in the A pocket, aided by a unique exit portal underneath the {alpha}1 helix. Most striking was an open F pocket architecture lacking the closed cavity structure of other CD1 molecules, reminiscent of peptide binding grooves of classical major histocompatibility complex molecules. This feature, combined with tryptophan-fluorescence quenching during loading of a dodecameric lipopeptide antigen, provides a compelling model by which both the lipid and peptide moieties of the lipopeptide are involved in CD1c presentation of lipopeptides.

  19. Probing binding hot spots at protein-RNA recognition sites.

    Science.gov (United States)

    Barik, Amita; Nithin, Chandran; Karampudi, Naga Bhushana Rao; Mukherjee, Sunandan; Bahadur, Ranjit Prasad

    2016-01-29

    We use evolutionary conservation derived from structure alignment of polypeptide sequences along with structural and physicochemical attributes of protein-RNA interfaces to probe the binding hot spots at protein-RNA recognition sites. We find that the degree of conservation varies across the RNA binding proteins; some evolve rapidly compared to others. Additionally, irrespective of the structural class of the complexes, residues at the RNA binding sites are evolutionary better conserved than those at the solvent exposed surfaces. For recognitions involving duplex RNA, residues interacting with the major groove are better conserved than those interacting with the minor groove. We identify multi-interface residues participating simultaneously in protein-protein and protein-RNA interfaces in complexes where more than one polypeptide is involved in RNA recognition, and show that they are better conserved compared to any other RNA binding residues. We find that the residues at water preservation site are better conserved than those at hydrated or at dehydrated sites. Finally, we develop a Random Forests model using structural and physicochemical attributes for predicting binding hot spots. The model accurately predicts 80% of the instances of experimental ΔΔG values in a particular class, and provides a stepping-stone towards the engineering of protein-RNA recognition sites with desired affinity. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  20. Synthesis and characterization of Cu(II)-based anticancer chemotherapeutic agent targeting topoisomerase Iα: in vitro DNA binding, pBR322 cleavage, molecular docking studies and cytotoxicity against human cancer cell lines.

    Science.gov (United States)

    Tabassum, Sartaj; Zaki, Mehvash; Afzal, Mohd; Arjmand, Farukh

    2014-03-03

    New metal-based anticancer chemotherapeutic drug candidates [Cu(phen)L](NO₃)₂ (1) and [Zn(phen)L](NO₃)₂ (2) were synthesized from ligand L (derived from pharmacophore scaffold barbituric acid and pyrazole). In vitro DNA binding studies of the L, 1 and 2 were carried out by various biophysical techniques revealing electrostatic mode. Complex 1 cleaves pBR322 DNA via oxidative pathway and recognizes major groove of DNA double helix. The molecular docking study was carried out to ascertain the mode of action towards the molecular target DNA and enzymes. The complex 1 exhibited remarkably good anticancer activity on a panel of human cancer cell lines (GI₅₀ values < 10 μg/ml), and to elucidate the mechanism of cancer inhibition, Topo-I enzymatic activity was carried out. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  1. Getting into the GROOVE: How Building Effective Education Partnerships and Promoting Authentic Student Research through the Girls' Remotely Operated Ocean Vehicle Exploration (GROOVE) Workshop.

    Science.gov (United States)

    Pelz, M.; Heesemann, M.; Hoeberechts, M.

    2017-12-01

    This presentation outlines the pilot year of Girls' Remotely Operated Ocean Vehicle Exploration or GROOVE, a hands-on learning program created collaboratively with education partners Ocean Networks Canada and St. Margaret's School (Victoria, BC, Canada). The program features student-led activities, authentic student experiences, clearly outlined learning outcomes, teacher and student self-assessment tools, and curriculum-aligned content. Presented through the lens of STEM, students build a modified Seaperch ROV and explore and research thematic scientific concepts such as buoyancy, electronic circuitry, and deep-sea exploration. Further, students learn engineering skills such as isotropic scaling, soldering, and assembly as they build their ROV. Ocean Networks Canada (ONC), an initiative of the University of Victoria, develops, operates, and maintains cabled ocean observatory systems. These include technologies developed on the world-leading NEPTUNE and VENUS observatories and the ever-expanding network of community observatories in the Arctic and coastal British Columbia. These observatories, large and small, enable communities, users, scientists, teachers, and students to monitor real-time and historical data from the local marine environment from anywhere on the globe. GROOVE, Girls' Remotely Operated Ocean Vehicle Exploration, is ONC's newest educational program and is related to their foundational program K-12 Ocean Sense educational program. This presentation will share our experiences developing, refining, and assessing our efforts to implement GROOVE using a train-the-trainer model aimed at formal and informal K-12 educators. We will highlight lessons learned from multiple perspectives (students, participants, developers, and mentors) with the intent of informing future education and outreach initiatives.

  2. Molecular dynamics simulations and free energy calculations of netropsin and distamycin binding to an AAAAA DNA binding site

    Science.gov (United States)

    Dolenc, Jožica; Oostenbrink, Chris; Koller, Jože; van Gunsteren, Wilfred F.

    2005-01-01

    Molecular dynamics simulations have been performed on netropsin in two different charge states and on distamycin binding to the minor groove of the DNA duplex d(CGCGAAAAACGCG)·d(CGCGTTTTTCGCG). The relative free energy of binding of the two non-covalently interacting ligands was calculated using the thermodynamic integration method and reflects the experimental result. From 2 ns simulations of the ligands free in solution and when bound to DNA, the mobility and the hydrogen-bonding patterns of the ligands were studied, as well as their hydration. It is shown that even though distamycin is less hydrated than netropsin, the loss of ligand–solvent interactions is very similar for both ligands. The relative mobilities of the ligands in their bound and free forms indicate a larger entropic penalty for distamycin when binding to the minor groove compared with netropsin, partially explaining the lower binding affinity of the distamycin molecule. The detailed structural and energetic insights obtained from the molecular dynamics simulations allow for a better understanding of the factors determining ligand–DNA binding. PMID:15687382

  3. Molecular dynamics simulations and free energy calculations of netropsin and distamycin binding to an AAAAA DNA binding site.

    Science.gov (United States)

    Dolenc, Jozica; Oostenbrink, Chris; Koller, Joze; van Gunsteren, Wilfred F

    2005-01-01

    Molecular dynamics simulations have been performed on netropsin in two different charge states and on distamycin binding to the minor groove of the DNA duplex d(CGCGAAAAACGCG).d(CGCGTTTTTCGCG). The relative free energy of binding of the two non-covalently interacting ligands was calculated using the thermodynamic integration method and reflects the experimental result. From 2 ns simulations of the ligands free in solution and when bound to DNA, the mobility and the hydrogen-bonding patterns of the ligands were studied, as well as their hydration. It is shown that even though distamycin is less hydrated than netropsin, the loss of ligand-solvent interactions is very similar for both ligands. The relative mobilities of the ligands in their bound and free forms indicate a larger entropic penalty for distamycin when binding to the minor groove compared with netropsin, partially explaining the lower binding affinity of the distamycin molecule. The detailed structural and energetic insights obtained from the molecular dynamics simulations allow for a better understanding of the factors determining ligand-DNA binding.

  4. Study on the Correlation Between Dynamical Behavior and Friction/Wear Mechanism Under the Effect of Grooves

    Science.gov (United States)

    Zhu, Z. Y.; Mo, J. L.; Wang, D. W.; Zhao, J.; Zhu, M. H.; Zhou, Z. R.

    2018-04-01

    In this work, the interfacial friction and wear and vibration characteristics are studied by sliding a chromium bearing steel ball (AISI 52100) over both multi-grooved and single-grooved forged steel disks (20CrMnMo) at low and high rotating speeds in order to reveal the effect mechanism of groove-textured surface on tribological behaviors. The results show that the grooves modify the contact state of the ball and the disk at the contact interface. This consequently causes variations in the normal displacement, normal force, and friction force signals. The changes in these three signals become more pronounced with increasing groove width at a low speed. The collision behavior between the ball and the groove increase the amplitude of vibration acceleration at a high speed. The test results suggest that grooves with appropriate widths could trap wear debris on the ball surface while avoiding a strong collision between the disk and the ball, resulting in an improvement in the wear states.

  5. Trial design and manufacture of double spiral grooved vacuum pump; Double neji mizoshiki shinku pump no shisaku

    Energy Technology Data Exchange (ETDEWEB)

    Iguchi, M.; Sawada, T.; Sugiyama, W. [Akita University, Akita (Japan). Faculty of Mining; Watanabe, M.

    1997-04-25

    A spiral grooved vacuum pump and a compound molecular pump (the combination of a spiral grooved pump and a turbomolecular pump) are widely used in the thin-film industry for processes such as semiconductor production. Pumping performance is high at pressures below 1 000 Pa and low at pressures above 1000 Pa when the clearance between rotor and stator is on the order of 0.1 mm, which is the practical value for industrial use. The double spiral grooved vacuum pump is thought to have better pumping performance at such high pressures than the conventional spiral grooved vacuum pump. The aim of this study is to investigate the feasibility of use of the double spiral grooved vacuum pump at pressures above 1000 Pa. A double spiral grooved vacuum pump with a rotor of 150 mm diameter and 190 mm length has been designed and manufactured. Its pumping performance has been tested by experiments. The test results show the improvement in the performance at pressures above 1000 Pa compared to the conventional spiral grooved vacuum pump. 2 refs., 12 figs., 2 tabs.

  6. Y-box-binding protein-1 (YB-1) promotes cell proliferation, adhesion and drug resistance in diffuse large B-cell lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Miao, Xiaobing; Wu, Yaxun [Department of Pathology, Affiliated Cancer Hospital of Nantong University, Nantong 226361, Jiangsu (China); Wang, Yuchan [Department of Pathogen, Medical College, Nantong University, Nantong 226001, Jiangsu (China); Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, Jiangsu (China); Zhu, Xinghua; Yin, Haibing [Department of Pathology, Affiliated Cancer Hospital of Nantong University, Nantong 226361, Jiangsu (China); He, Yunhua [Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Nantong 226001, Jiangsu (China); Li, Chunsun; Liu, Yushan; Lu, Xiaoyun; Chen, Yali; Shen, Rong [Department of Pathology, Affiliated Cancer Hospital of Nantong University, Nantong 226361, Jiangsu (China); Xu, Xiaohong, E-mail: xuxiaohongnantong@126.com [Department of Oncology, Affiliated Cancer Hospital of Nantong University, Nantong 226361, Jiangsu (China); He, Song, E-mail: hesongnt@126.com [Department of Pathology, Affiliated Cancer Hospital of Nantong University, Nantong 226361, Jiangsu (China)

    2016-08-15

    YB-1 is a multifunctional protein, which has been shown to correlate with resistance to treatment of various tumor types. This study investigated the expression and biologic function of YB-1 in diffuse large B-cell lymphoma (DLBCL). Immunohistochemical analysis showed that the expression statuses of YB-1 and pYB-1{sup S102} were reversely correlated with the clinical outcomes of DLBCL patients. In addition, we found that YB-1 could promote the proliferation of DLBCL cells by accelerating the G1/S transition. Ectopic expression of YB-1 could markedly increase the expression of cell cycle regulators cyclin D1 and cyclin E. Furthermore, we found that adhesion of DLBCL cells to fibronectin (FN) could increase YB-1 phosphorylation at Ser102 and pYB-1{sup S102} nuclear translocation. In addition, overexpression of YB-1 could increase the adhesion of DLBCL cells to FN. Intriguingly, we found that YB-1 overexpression could confer drug resistance through cell-adhesion dependent and independent mechanisms in DLBCL. Silencing of YB-1 could sensitize DLBCL cells to mitoxantrone and overcome cell adhesion-mediated drug resistance (CAM-DR) phenotype in an AKT-dependent manner. - Highlights: • The expression statuses of YB-1 and pYB-1{sup S102} are reversely correlated with outcomes of DLBCL patients. • YB-1 promotes cell proliferation by accelerating G1/S transition in DLBCL. • YB-1 confers drug resistance to mitoxantrone in DLBCL.

  7. Recognition of AT-Rich DNA Binding Sites by the MogR Repressor

    Energy Technology Data Exchange (ETDEWEB)

    Shen, Aimee; Higgins, Darren E.; Panne, Daniel; (Harvard-Med); (EMBL)

    2009-07-22

    The MogR transcriptional repressor of the intracellular pathogen Listeria monocytogenes recognizes AT-rich binding sites in promoters of flagellar genes to downregulate flagellar gene expression during infection. We describe here the 1.8 A resolution crystal structure of MogR bound to the recognition sequence 5' ATTTTTTAAAAAAAT 3' present within the flaA promoter region. Our structure shows that MogR binds as a dimer. Each half-site is recognized in the major groove by a helix-turn-helix motif and in the minor groove by a loop from the symmetry-related molecule, resulting in a 'crossover' binding mode. This oversampling through minor groove interactions is important for specificity. The MogR binding site has structural features of A-tract DNA and is bent by approximately 52 degrees away from the dimer. The structure explains how MogR achieves binding specificity in the AT-rich genome of L. monocytogenes and explains the evolutionary conservation of A-tract sequence elements within promoter regions of MogR-regulated flagellar genes.

  8. CFD Validation of Gas Injection in Flowing Mercury over Vertical Smooth and Grooved Wall

    International Nuclear Information System (INIS)

    Abdou, Ashraf A.; Wendel, Mark W.; Felde, David K.; Riemer, Bernie

    2009-01-01

    The Spallation Neutron Source (SNS) is an accelerator-based neutron source at Oak Ridge National Laboratory (ORNL). The nuclear spallation reaction occurs when a proton beam hits liquid mercury. This interaction causes thermal expansion of the liquid mercury which produces high pressure waves. When these pressure waves hit the target vessel wall, cavitation can occur and erode the wall. Research and development efforts at SNS include creation of a vertical protective gas layer between the flowing liquid mercury and target vessel wall to mitigate the cavitation damage erosion and extend the life time of the target. Since mercury is opaque, computational fluid dynamics (CFD) can be used as a diagnostic tool to see inside the liquid mercury and guide the experimental efforts. In this study, CFD simulations of three dimensional, unsteady, turbulent, two-phase flow of helium gas injection in flowing liquid mercury over smooth, vertically grooved and horizontally grooved walls are carried out with the commercially available CFD code Fluent-12 from ANSYS. The Volume of Fluid (VOF) model is used to track the helium-mercury interface. V-shaped vertical and horizontal grooves with 0.5 mm pitch and about 0.7 mm depth were machined in the transparent wall of acrylic test sections. Flow visualization data of helium gas coverage through transparent test sections is obtained with a high-speed camera at the ORNL target test facility (TTF). The helium gas mass flow rate is 8 mg/min and introduced through a 0.5 mm diameter port. The local mercury velocity is 0.9 m/s. In this paper, the helium gas flow rate and the local mercury velocity are kept constant for the three cases. Time integration of predicted helium gas volume fraction over time is done to evaluate the gas coverage and calculate the average thickness of the helium gas layer. The predicted time-integrated gas coverage over vertically grooved and horizontally grooved test sections is better than over a smooth wall. The

  9. Investigating the binding properties of porous drug delivery systems using nuclear sensors (radiotracers) and positron annihilation lifetime spectroscopy--predicting conditions for optimum performance.

    Science.gov (United States)

    Mume, Eskender; Lynch, Daniel E; Uedono, Akira; Smith, Suzanne V

    2011-06-21

    Understanding how the size, charge and number of available pores in porous material influences the uptake and release properties is important for optimising their design and ultimately their application. Unfortunately there are no standard methods for screening porous materials in solution and therefore formulations must be developed for each encapsulated agent. This study investigates the potential of a library of radiotracers (nuclear sensors) for assessing the binding properties of hollow silica shell materials. Uptake and release of Cu(2+) and Co(2+) and their respective complexes with polyazacarboxylate macrocycles (dota and teta) and a series of hexa aza cages (diamsar, sarar and bis-(p-aminobenzyl)-diamsar) from the hollow silica shells was monitored using their radioisotopic analogues. Coordination chemistry of the metal (M) species, subtle alterations in the molecular architecture of ligands (Ligand) and their resultant complexes (M-Ligand) were found to significantly influence their uptake over pH 3 to 9 at room temperature. Positively charged species were selectively and rapidly (within 10 min) absorbed at pH 7 to 9. Negatively charged species were preferentially absorbed at low pH (3 to 5). Rates of release varied for each nuclear sensor, and time to establish equilibrium varied from minutes to days. The subtle changes in design of the nuclear sensors proved to be a valuable tool for determining the binding properties of porous materials. The data support the development of a library of nuclear sensors for screening porous materials for use in optimising the design of porous materials and the potential of nuclear sensors for high through-put screening of materials.

  10. Quantum spill-out in few-nanometer metal gaps: Effect on gap plasmons and reflectance from ultrasharp groove arrays

    DEFF Research Database (Denmark)

    Skjølstrup, Enok Johannes Haahr; Søndergaard, Thomas; Pedersen, Thomas Garm

    2018-01-01

    Plasmons in ultranarrow metal gaps are highly sensitive to the electron density profile at the metal surfaces. Using a quantum mechanical approach and assuming local response, we study the effects of electron spill-out on gap plasmons and reflectance from ultrasharp metal grooves.We demonstrate...... the reflectance from arrays of ultrasharp metal grooves. These findings are explained in terms of enhanced gap plasmon absorption taking place inside the gap 1–2 °A from the walls and delocalization near the groove bottom. Reflectance calculations taking spill-out into account are shown to be in much better...

  11. Virtual Dual inhibition of COX-2 / 5-LOX enzymes based on binding properties of alpha-amyrins, the anti-inflammatory compound as a promising anti-cancer drug

    Science.gov (United States)

    Ranjbar, Mohammad Mehdi; Assadolahi, Vahideh; Yazdani, Mohsen; Nikaein, Donya; Rashidieh, Behnam

    2016-01-01

    Hydro-alcoholic fruit extract of Cordia myxa was considerably effective on curing acute inflammation in mouse model. Previous studies suggested significant anti-inflammatory activities as well as potential anticancer agent of α-amyrins in seeds. Inhibition of Cyclooxygenase-2 (COX-2) and 5-Lipooxygenase (5-LOX) is significant in cancer prevention and therapeutics although this inhibition with chemo-drugs has its own side-effects. It is shown that these enzymes pathways are related to several cancers including colon, breast and lung cancer. This study was conducted based on Cordia species' α-amyrins as a safer natural anti-cancer compound for inhibition of COX-2 and 5-LOX enzymes by molecular docking. The X-ray crystal structure of COX2 / 5-LOX enzymes and α-amyrins was retrieved and energetically minimized respectively. The binding site and surface of enzymes were detected. Docking studies were performed by AutoDock 4.2 using Lamarckian genetic algorithm (LGA). Finally drug likeness, molecular pharmacokinetic properties and toxicity of α-amyrins was calculated. Molecular Docking revealed hydrogen and hydrophobic interactions between α-amyrins with both active sites of COX-2 and 5-LOX enzymes. Interestingly, it covalently bonded to Fe cofactor of 5-LOX enzyme and chelated this molecule. Base on binding energies (∆G) α-amyrin has more inhibitory effects on 5-LOX (-10.45 Kcal/mol) than COX-2 (-8.02 Kcal/mol). Analysis of molecular pharmacokinetic parameters suggested that α-amyrins complied with most sets of Lipinski's rules, and so it could be a suitable ligand for docking studies. Eventually, bioactivity score showed α-amyrins possess considerable biological activities as nuclear receptor, enzyme inhibitor, GPCR and protease inhibitor ligand. These results clearly demonstrate that α-amyrins could act as potential highly selective COX-/5-LOX inhibitor. Also, it is a safe compound in comparison with classical non-steroidal anti-inflammatory drugs (NSAIDs

  12. Substrate-induced stable enzyme-inhibitor complex formation allows tight binding of novel 2-aminopyrimidin-4(3H)-ones to drug-resistant HIV-1 reverse transcriptase mutants.

    Science.gov (United States)

    Samuele, Alberta; Facchini, Marcella; Rotili, Dante; Mai, Antonello; Artico, Marino; Armand-Ugón, Mercedes; Esté, José A; Maga, Giovanni

    2008-09-01

    We recently reported the synthesis and biological evaluation of a novel series of 5-alkyl-2-(N,N-disubstituted)amino-6-(2,6-difluorophenylalkyl)-3,4-dihydropyrimidin-4(3H)-ones (F(2)-N,N-DABOs). These compounds are highly active against both wild-type HIV-1 and the K103N, Y181C, and Y188L mutant strains. Herein we present novel 6-(2-chloro-6-fluorophenylalkyl)-N,N-DABO (2-Cl-6-F-N,N-DABO) derivatives and investigate the molecular basis for their high-affinity binding to HIV-1 reverse transcriptase (RT). Our results show that the new compounds display higher association rates than the difluoro derivatives toward wild-type HIV-1 RT or drug-resistant RT mutant forms. We also show that they preferentially associate to either the free enzyme or the enzyme-nucleic acid binary complex, and that this binding is stabilized upon formation of the ternary complex between HIV-1 RT and both the nucleic acid and nucleotide substrates. Interestingly, one compound showed dissociation rates from the ternary complex with RT mutants K103N and Y181I 10-20-fold slower than from the corresponding complex with wild-type RT.

  13. In-vitro DNA binding and cleavage studies with pBR322 of N,N-Bis(3{beta}-acetoxy-5{alpha}-cholest-6-yl-idene)hydrazine

    Energy Technology Data Exchange (ETDEWEB)

    Tabassum, Zishan [School of Industrial Technology, Universiti Sains Malaysia, 11800 USM, Penang (Malaysia); Muddassir, Mohd [Department of Chemistry, Aligarh Muslim University, Aligarh 202002, U.P. (India); Sulaiman, Othman [School of Industrial Technology, Universiti Sains Malaysia, 11800 USM, Penang (Malaysia); Arjmand, Farukh [Department of Chemistry, Aligarh Muslim University, Aligarh 202002, U.P. (India)

    2012-08-15

    The DNA binding studies of the triterpenoid derivative, cholesterol, N,N-Bis(3{beta}-acetoxy-5{alpha}-cholest-6-yl-idene)hydrazine (L) with CT DNA were carried out by employing different optical methods viz, UV-vis and fluorescence spectroscopy. The ligand binds to DNA through hydrophobic interaction with K{sub b} value found to be 4.7 Multiplication-Sign 10{sup 3} M{sup -1}. These observations have been validated also by fluorescence spectroscopy. (L) exhibits a remarkable DNA cleavage activity with pBR322 DNA in the presence of different activators and the DNA is probably cleaved by an other than oxidative mechanism, possibly by a discernable hydrolytic pathway. In the presence of major and minor groove binding agents, (L) prefers major groove binding of the DNA. - Highlights: Black-Right-Pointing-Pointer DNA binding studies of the triterpenoid derivative, cholesterol, N,N-Bis(3{beta}-acetoxy-5{alpha}-cholest-6-yl-idene)hydrazine. Black-Right-Pointing-Pointer The ligand binds to DNA through hydrophobic interaction with K{sub b} value found to be 4.7 Multiplication-Sign 10{sup 3} M{sup -1}. Black-Right-Pointing-Pointer DNA is probably cleaved by an other than oxidative mechanism, possibly by a discernable hydrolytic pathway. Black-Right-Pointing-Pointer In the presence of major and minor groove binding agents, the (L) prefers major groove binding of the DNA.

  14. In-vitro DNA binding and cleavage studies with pBR322 of N,N-Bis(3β-acetoxy-5α-cholest-6-yl-idene)hydrazine

    International Nuclear Information System (INIS)

    Tabassum, Zishan; Muddassir, Mohd; Sulaiman, Othman; Arjmand, Farukh

    2012-01-01

    The DNA binding studies of the triterpenoid derivative, cholesterol, N,N-Bis(3β-acetoxy-5α-cholest-6-yl-idene)hydrazine (L) with CT DNA were carried out by employing different optical methods viz, UV–vis and fluorescence spectroscopy. The ligand binds to DNA through hydrophobic interaction with K b value found to be 4.7×10 3 M −1 . These observations have been validated also by fluorescence spectroscopy. (L) exhibits a remarkable DNA cleavage activity with pBR322 DNA in the presence of different activators and the DNA is probably cleaved by an other than oxidative mechanism, possibly by a discernable hydrolytic pathway. In the presence of major and minor groove binding agents, (L) prefers major groove binding of the DNA. - Highlights: ► DNA binding studies of the triterpenoid derivative, cholesterol, N,N-Bis(3β-acetoxy-5α-cholest-6-yl-idene)hydrazine. ► The ligand binds to DNA through hydrophobic interaction with K b value found to be 4.7×10 3 M −1 . ► DNA is probably cleaved by an other than oxidative mechanism, possibly by a discernable hydrolytic pathway. ► In the presence of major and minor groove binding agents, the (L) prefers major groove binding of the DNA.

  15. Performance of an inclined solar still with rectangular grooves and ridges

    International Nuclear Information System (INIS)

    Anburaj, P.; Kalidasa, Murugavel K.; Samuel Hansen, R.

    2013-01-01

    This work investigates the experimental performance of a new type inclined solar still with rectangular grooves and ridges in absorber plate. The still was fabricated and tested for various inclination angles of 25, 30 and 35 facing south with absorber plate. Performances of the still were compared with different wick materials (Black cotton cloth, Jute cloth, and Waste cotton pieces) on the absorber plate. The effect of placing porous material (Clay pot) and energy storing material (Mild steel pieces) in the grooves were studied. The results demonstrate that 30 inclination is optimum which yielded 3.77 L/day production. Compared to different wick materials, black cotton cloth helps to achieve maximum productivity of 4.21 L/day. The addition of permeable materials and energy absorbing materials also enhances the distillate output to 4.27 L/day. (authors)

  16. Palato-gingival groove: An innocuous culprit for endo-perio lesion

    Directory of Open Access Journals (Sweden)

    Rafeza Sultana

    2016-09-01

    Full Text Available This case report represents the clinical management of tooth with palato-gingival groove in a right maxillary lateral incisor with endo-perio lesion leading to dento-alveolar abscess and sinus tract. The right maxillary lateral incisor was examined clinico-radiographically. On clinical examination, the offending tooth revealed localized swelling and an intraoral draining sinus pointing on the labial gingiva without any evidence of caries, discoloration and trauma. The palatal surface of lateral incisor showed a groove with mild calculus embedded in it. The radiographic examination revealed periapical radiolucency. This case provides an evidence of morphological defect of tooth. Complete clinical and radiological examination and adequate knowledge of such morphological/ developmental defects of teeth are necessary for recognition and identification especially because of their diagnostic complexity and further consequences. 

  17. Propagation of Channel Plasmons at the Visible Regime in Aluminum V-Groove Waveguides

    DEFF Research Database (Denmark)

    Lotan, Oren; Smith, Cameron; Bar-David, Jonathan

    2016-01-01

    Aluminum plasmonics is emerging as a promising platform in particular for the ultraviolet-blue spectral band. We present the experimental results of propagating channel plasmon-polaritons (CPP) waves in aluminum coated V-shaped waveguides at the short visible wavelength regime. The V-grooves are ......Aluminum plasmonics is emerging as a promising platform in particular for the ultraviolet-blue spectral band. We present the experimental results of propagating channel plasmon-polaritons (CPP) waves in aluminum coated V-shaped waveguides at the short visible wavelength regime. The V......-grooves are fabricated by a process involving UV-photolithography, crystallographic silicon etching, and metal deposition. Polarization measurements of coupling demonstrate a preference to the TM-aligned mode, as predicted in simulations....

  18. Influence of structural parameters of deep groove ball bearings on vibration

    Science.gov (United States)

    Yu, Guangwei; Wu, Rui; Xia, Wei

    2018-04-01

    Taking 6201 bearing as the research object, a dynamic model of 4 degrees of freedom is established to solve the vibration characteristics such as the displacement, velocity and acceleration of deep groove ball bearings by MATLAB and Runge-Kutta method. By calculating the theoretical value of the frequency of the rolling element passing through the outer ring and the simulation value of the model, it can be known that the theoretical calculation value and the simulation value have good consistency. By the experiments, the measured values and simulation values are consistent. Using the mathematical model, the effect of structural parameters on vibration is obtained. The method in the paper is testified to be feasible and the results can be used as references for the design, manufacturing and testing of deep groove ball bearings.

  19. Research on Degeneration Model of Neural Network for Deep Groove Ball Bearing Based on Feature Fusion

    Directory of Open Access Journals (Sweden)

    Lijun Zhang

    2018-02-01

    Full Text Available Aiming at the pitting fault of deep groove ball bearing during service, this paper uses the vibration signal of five different states of deep groove ball bearing and extracts the relevant features, then uses a neural network to model the degradation for identifying and classifying the fault type. By comparing the effects of training samples with different capacities through performance indexes such as the accuracy and convergence speed, it is proven that an increase in the sample size can improve the performance of the model. Based on the polynomial fitting principle and Pearson correlation coefficient, fusion features based on the skewness index are proposed, and the performance improvement of the model after incorporating the fusion features is also validated. A comparison of the performance of the support vector machine (SVM model and the neural network model on this dataset is given. The research shows that neural networks have more potential for complex and high-volume datasets.

  20. Nanoscale Plasmonic V-Groove Waveguides for the Interrogation of Single Fluorescent Bacterial Cells.

    Science.gov (United States)

    Lotan, Oren; Bar-David, Jonathan; Smith, Cameron L C; Yagur-Kroll, Sharon; Belkin, Shimshon; Kristensen, Anders; Levy, Uriel

    2017-09-13

    We experimentally demonstrate the interrogation of an individual Escherichia coli cell using a nanoscale plasmonic V-groove waveguide. Several different configurations were studied. The first involved the excitation of the cell in a liquid environment because it flows on top of the waveguide nanocoupler, while the obtained fluorescence is coupled into the waveguide and collected at the other nanocoupler. The other two configurations involved the positioning of the bacterium within the nanoscale waveguide and its excitation in a dry environment either directly from the top or through waveguide modes. This is achieved by taking advantage of the waveguide properties not only for light guiding but also as a mechanical tool for trapping the bacteria within the V-grooves. The obtained results are supported by a set of numerical simulations, shedding more light on the mechanism of excitation. This demonstration paves the way for the construction of an efficient bioplasmonic chip for diverse cell-based sensing applications.

  1. Steady State Thermo-Hydrodynamic Analysis of Two-Axial groove and Multilobe Hydrodynamic Bearings

    Directory of Open Access Journals (Sweden)

    C. Bhagat

    2014-12-01

    Full Text Available Steady state thermo-hydrodynamic analysis of two axial groove and multi lobe oil journal bearings is performed in this paper. To study the steady state thermo-hydrodynamic characteristics Reynolds equation is solved simultaneously along with the energy equation and heat conduction equation in bush and shaft. The effect of groove geometry, cavitation in the fluid film, the recirculation of lubricant, shaft speed has also been taken into account. Film temperature in case of three-lobe bearing is found to be high as compared to other studied bearing configurations. The data obtained from this analysis can be used conveniently in the design of such bearings, which are presented in dimensionless form.

  2. Aptamer sensor for cocaine using minor groove binder based energy transfer.

    Science.gov (United States)

    Zhou, Jinwen; Ellis, Amanda V; Kobus, Hilton; Voelcker, Nicolas H

    2012-03-16

    We report on an optical aptamer sensor for cocaine detection. The cocaine sensitive fluorescein isothiocyanate (FITC)-labeled aptamer underwent a conformational change from a partial single-stranded DNA with a short hairpin to a double-stranded T-junction in the presence of the target. The DNA minor groove binder Hoechst 33342 selectively bound to the double-stranded T-junction, bringing the dye within the Förster radius of FITC, and therefore initiating minor groove binder based energy transfer (MBET), and reporting on the presence of cocaine. The sensor showed a detection limit of 0.2 μM. The sensor was also implemented on a carboxy-functionalized polydimethylsiloxane (PDMS) surface by covalently immobilizing DNA aptamers. The ability of surface-bound cocaine detection is crucial for the development of microfluidic sensors. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. Tube with helical grooving for a heat exchanger and its manufacturing process

    International Nuclear Information System (INIS)

    Yampolsky, J.S.

    1980-01-01

    This claim broadly concerns heat transfer tubes for heat exchangers of the kind described in the main patent specification and, in particular, a heat transfer tube and a process for manufacturing it. This tube includes a strip of metal, the opposite sides of which extend to form a certain number of longitudinal grooves of specific profile and height. This strip is helically wound and the lateral edges are joined butt to butt so as to be leak tight to fluids [fr

  4. Highly efficient absorption of visible and near infrared light in convex gold and nickel grooves

    DEFF Research Database (Denmark)

    Eriksen, René Lynge; Beermann, Jonas; Søndergaard, Thomas

    The realization of nonresonant light absorption with nanostructured metal surfaces by making practical use of nanofocusing optical energy in tapered plasmonic waveguides, is of one of the most fascinating and fundamental phenomena in plasmonics [1,2]. We recently realized broadband light absorption...... in gold via adiabatic nanofocusing of gap surface plasmon modes in well-defined geometries of ultra-sharp convex grooves and being excited by scattering off subwavelength-sized wedges [3]....

  5. Effects of Gas Rarefaction on Dynamic Characteristics of Micro Spiral-Grooved Thrust Bearing

    OpenAIRE

    Liu, Ren; Wang, Xiao-Li; Zhang, Xiao-Qing

    2012-01-01

    The effects of gas-rarefaction on dynamic characteristics of micro spiral-grooved-thrust-bearing are studied. The Reynolds equation is modified by the first order slip model, and the corresponding perturbation equations are then obtained on the basis of the linear small perturbation method. In the converted spiral-curve-coordinates system, the finite-volume-method (FVM) is employed to discrete the surface domain of micro bearing. The results show, compared with the continuum-flow model, that ...

  6. Apical groove type and molecular phylogeny suggests reclassification of Cochlodinium geminatum as Polykrikos geminatum.

    Science.gov (United States)

    Qiu, Dajun; Huang, Liangmin; Liu, Sheng; Zhang, Huan; Lin, Senjie

    2013-01-01

    Traditionally Cocholodinium and Gymnodinium sensu lato clade are distinguished based on the cingulum turn number, which has been increasingly recognized to be inadequate for Gymnodiniales genus classification. This has been improved by the combination of the apical groove characteristics and molecular phylogeny, which has led to the erection of several new genera (Takayama, Akashiwo, Karenia, and Karlodinium). Taking the apical groove characteristics and molecular phylogeny combined approach, we reexamined the historically taxonomically uncertain species Cochlodinium geminatum that formed massive blooms in Pearl River Estuary, China, in recent years. Samples were collected from a bloom in 2011 for morphological, characteristic pigment, and molecular analyses. We found that the cingulum in this species wraps around the cell body about 1.2 turns on average but can appear under the light microscopy to be >1.5 turns after the cells have been preserved. The shape of its apical groove, however, was stably an open-ended anticlockwise loop of kidney bean shape, similar to that of Polykrikos. Furthermore, the molecular phylogenetic analysis using 18S rRNA-ITS-28S rRNA gene cistron we obtained in this study also consistently placed this species closest to Polykrikos within the Gymnodinium sensu stricto clade and set it far separated from the clade of Cochlodinium. These results suggest that this species should be transferred to Polykrikos as Polykrikos geminatum. Our results reiterate the need to use the combination of apical groove morphology and molecular phylogeny for the classification of species within the genus of Cochlodinium and other Gymnodiniales lineages.

  7. Apical groove type and molecular phylogeny suggests reclassification of Cochlodinium geminatum as Polykrikos geminatum.

    Directory of Open Access Journals (Sweden)

    Dajun Qiu

    Full Text Available Traditionally Cocholodinium and Gymnodinium sensu lato clade are distinguished based on the cingulum turn number, which has been increasingly recognized to be inadequate for Gymnodiniales genus classification. This has been improved by the combination of the apical groove characteristics and molecular phylogeny, which has led to the erection of several new genera (Takayama, Akashiwo, Karenia, and Karlodinium. Taking the apical groove characteristics and molecular phylogeny combined approach, we reexamined the historically taxonomically uncertain species Cochlodinium geminatum that formed massive blooms in Pearl River Estuary, China, in recent years. Samples were collected from a bloom in 2011 for morphological, characteristic pigment, and molecular analyses. We found that the cingulum in this species wraps around the cell body about 1.2 turns on average but can appear under the light microscopy to be >1.5 turns after the cells have been preserved. The shape of its apical groove, however, was stably an open-ended anticlockwise loop of kidney bean shape, similar to that of Polykrikos. Furthermore, the molecular phylogenetic analysis using 18S rRNA-ITS-28S rRNA gene cistron we obtained in this study also consistently placed this species closest to Polykrikos within the Gymnodinium sensu stricto clade and set it far separated from the clade of Cochlodinium. These results suggest that this species should be transferred to Polykrikos as Polykrikos geminatum. Our results reiterate the need to use the combination of apical groove morphology and molecular phylogeny for the classification of species within the genus of Cochlodinium and other Gymnodiniales lineages.

  8. DNA exit ramps are revealed in the binding landscapes obtained from simulations in helical coordinates.

    Directory of Open Access Journals (Sweden)

    Ignacia Echeverria

    2015-02-01

    Full Text Available DNA molecules are highly charged semi-flexible polymers that are involved in a wide variety of dynamical processes such as transcription and replication. Characterizing the binding landscapes around DNA molecules is essential to understanding the energetics and kinetics of various biological processes. We present a curvilinear coordinate system that fully takes into account the helical symmetry of a DNA segment. The latter naturally allows to characterize the spatial organization and motions of ligands tracking the minor or major grooves, in a motion reminiscent of sliding. Using this approach, we performed umbrella sampling (US molecular dynamics (MD simulations to calculate the three-dimensional potentials of mean force (3D-PMFs for a Na+ cation and for methyl guanidinium, an arginine analog. The computed PMFs show that, even for small ligands, the free energy landscapes are complex. In general, energy barriers of up to ~5 kcal/mol were measured for removing the ligands from the minor groove, and of ~1.5 kcal/mol for sliding along the minor groove. We shed light on the way the minor groove geometry, defined mainly by the DNA sequence, shapes the binding landscape around DNA, providing heterogeneous environments for recognition by various ligands. For example, we identified the presence of dissociation points or "exit ramps" that naturally would terminate sliding. We discuss how our findings have important implications for understanding how proteins and ligands associate and slide along DNA.

  9. Genetic association analysis of ATP binding cassette protein family reveals a novel association of ABCB1 genetic variants with epilepsy risk, but not with drug-resistance.

    Directory of Open Access Journals (Sweden)

    Shabeesh Balan

    Full Text Available Epilepsy constitutes a heterogeneous group of disorders that is characterized by recurrent unprovoked seizures due to widely different etiologies. Multidrug resistance remains a major issue in clinical epileptology, where one third of patients with epilepsy continue to have seizures. Role of efflux transporters in multidrug resistant epilepsy has been attributed to drug-resistant epilepsy although, with discrepant observation in genetic studies. These discrepancies could be attributed to variety of factors such as variable definition of the anti-epileptic drug (AED-resistance, variable epilepsy phenotypes and ethnicities among the studies. In the present study we inquired the role of multidrug transporters ABCB1 and ABCG2 variants in determining AED-resistance and susceptibility to epilepsy in three well-characterized cohorts comprising of mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS (prototype for AED-resistant epilepsy; juvenile myoclonic epilepsy (JME (prototype for AED-responsive epilepsy; and healthy non-epileptic controls, in 738 subjects of Malayalam speaking south Indian ancestry. ABCB1 and ABCG2 variants were not found to be associated with drug resistance when AED-resistant and AED-responsive cohorts were compared. However, a significant association was observed between ABCB1 (C3435T rs1045642 and risk of having epilepsy (MTLE-HS and JME pooled cohort; genotypic p-value = 0.0002; allelic p-value = 0.004. This association was seen persistent with MTLE-HS (genotypic p-value = 0.0008; allelic p-value = 0.004 and also with JME (genotypic p-value = 0.01; allelic p-value = 0.05 cohort individually. In-silico functional prediction indicated that ABCB1 rs1045642 has a deleterious impact on protein coding function and in splicing regulation. We conclude that the ABCB1 and ABCG2 variants do not confer to AED-resistance in the study population. However, ABCB1 rs1045642 increases vulnerability to epilepsy with greater tendency

  10. Grooved stone tools from Calabria region (Italy: Archaeological evidence and research perspectives

    Directory of Open Access Journals (Sweden)

    Felice Larocca

    2016-10-01

    Full Text Available Since the end of the 19th century the Calabria region in southern Italy has been known for an abundance of grooved stone axes and hammers used during late prehistory. These artefacts are characterized by a wide and often pronounced groove in the middle of the implement, thought to have aided securing the head to a wooden haft. Their widespread presence is known both in prehistoric archaeological literature and in the archaeological collections of various regional and extra-regional museums. At first, scholars did not relate these tools to the rich Calabrian ore deposits and to possible ancient mining activities; they were regarded simply as a variant of ground lithic industry of Neolithic tradition. However, between 1997 and 2012, about 50 tools were discovered in the prehistoric mine of Grotta della Monaca in northern Calabria where there are outcrops of copper and iron ore. This allowed us to recognize their specific mining value and to consider them as a sort of “guide fossil” for the identification of ancient mining districts. This paper presents the results of a study involving over 150 tools from the entire region, effectively demonstrating an almost perfect co-occurrence of grooved axes and hammers with areas rich in mineral resources, especially metalliferous ores.

  11. Effective slip for Stokes flow between two grooved walls with an arbitrary phase shift

    Energy Technology Data Exchange (ETDEWEB)

    Ng, Chiu-On, E-mail: cong@hku.hk [Department of Mechanical Engineering, The University of Hong Kong, Pokfulam Road (Hong Kong)

    2017-04-15

    This work aims to determine how the effective slip length for a wall-bounded flow may depend on, among other geometrical parameters, the phase shift between patterns on the two walls. An analytical model is developed for Stokes flow through a channel bounded by walls patterned with a regular array of rectangular ribs and grooves, where the patterns on the two walls can be misaligned by any phase shift. This study incorporates several previous studies as limiting or special cases. It is shown that the phase shift can have qualitatively different effects on the flow rate and effective slip length, depending on the flow direction. In a narrow channel, increasing the phase shift may mildly decrease the flow rate and effective slip length for flow parallel to the grooves, but can dramatically increase the flow rate and effective slip length for flow transverse to the grooves. It is found that unless the channel height is much larger than the period of the wall pattern, the effect due to wall confinement has to be taken into account on evaluating the effective slip lengths. (paper)