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Sample records for drug duplex complex

  1. Phosphorus-31 NMR spectra of ethidium, quinacrine, and daunomycin complexes with poly(adenylic acid)ter dot poly(uridylic acid) RNA duplex and calf thymus DNA

    SciTech Connect

    Gorenstein, D.G.; Lai, K. )

    1989-04-04

    {sup 31}P NMR provides a convenient monitor of the phosphate ester backbone conformational changes upon binding of the intercalating drugs ethidium, quinacrine, and daunomycin to sonicated poly(A){center dot}poly(U) and calf thymus DNA. {sup 31}P chemical shifts can also be used to assess differences in the duplex unwinding angles in the presence of the drug. Thus a new {sup 31}P signal, 1.8-2.2 ppm downfield from the double-stranded helix signals, is observed in the ethidium ion-poly(A){center dot}poly(U) complex. This signal arises from phosphates which are in perturbed environments due to intercalation of the drug. This is in keeping with the hypothesis that the P-O ester torsional angle in phosphates linking the intercalated base pairs is more trans-like. Similar though smaller deshielding of the {sup 31}P signals is observed in sonicated poly(A){center dot}poly(U)-quinacrine complexes as well as in the daunomycin complexes. The effect of added ethidium ion, quinacrine, and daunomycin on the {sup 31}P spectra of sonicated calf thymus DNA is consistent with Wilson and Jones' (1982) earlier study. In these drug-DNA complexes the drug produces a gradual downfield shift in the DNA {sup 31}P signal without the appearance of a separate downfield peak. These differences are attributed to differences in the rate of chemical exchange of the drug between free and bound duplex states. The previous correlation of {sup 31}P chemical shift with drug duplex unwinding angle is confirmed for both the RNA and DNA duplexes.

  2. ATP hydrolysis Promotes Duplex DNA Release by the RecA Presynaptic Complex.

    PubMed

    Lee, Ja Yil; Qi, Zhi; Greene, Eric C

    2016-10-14

    Homologous recombination is an important DNA repair pathway that plays key roles in maintaining genome stability. Escherichia coli RecA is an ATP-dependent DNA-binding protein that catalyzes the DNA strand exchange reactions in homologous recombination. RecA assembles into long helical filaments on single-stranded DNA, and these presynaptic complexes are responsible for locating and pairing with a homologous duplex DNA. Recent single molecule studies have provided new insights into RecA behavior, but the potential influence of ATP in the reactions remains poorly understood. Here we examine how ATP influences the ability of the RecA presynaptic complex to interact with homologous dsDNA. We demonstrate that over short time regimes, RecA presynaptic complexes sample heterologous dsDNA similarly in the presence of either ATP or ATPγS, suggesting that initial interactions do not depend on ATP hydrolysis. In addition, RecA stabilizes pairing intermediates in three-base steps, and stepping energetics is seemingly unaltered in the presence of ATP. However, the overall dissociation rate of these paired intermediates with ATP is ∼4-fold higher than with ATPγS. These experiments suggest that ATP plays an unanticipated role in promoting the turnover of captured duplex DNA intermediates as RecA attempts to align homologous sequences during the early stages of recombination.

  3. Cytotoxicity of new duplex drugs linking 3'-C-ethynylcytidine and 5-fluor-2'-deoxyuridine against human melanoma cells.

    PubMed

    Schott, Sarah; Niessner, Heike; Sinnberg, Tobias; Venturelli, Sascha; Berger, Alexander; Ikenberg, Kristian; Villanueva, Jessie; Meier, Friedegund; Garbe, Claus; Busch, Christian

    2012-11-01

    Melanoma is an increasingly common and potentially fatal malignancy of the skin and some mucous membranes. As no cure exists for metastatic disease, there is an urgent need for novel drugs. 2'-Deoxy-5-fluorouridylyl-(3'-5')-3'-C-ethynylcytidine [5-FdU(3'-5')ECyd] and 3'-C-ethynylcytidinylyl-(5' → 1-O)-2-O-octadecyl-sn-glycerylyl-(3-O → 5')-2'-deoxy-5-fluorouridine [ECyd-lipid-5-FdU] represent cytostatic active duplex drugs, which can be metabolized into various active antimetabolites. We evaluated the cytotoxicity of these heterodinucleoside phosphate analogs, their corresponding monomers ECyd and 5-FdU and combinations thereof on six metastatic melanoma cell lines and six ex vivo patient-derived melanoma cells in comparison to current standard cytostatic agents and the BRAF V600E inhibitor Vemurafenib. In vitro (real-time)-proliferation assays demonstrated that 5-FdU(3'-5')ECyd and ECyd-lipid-5-FdU had a high cytotoxic efficacy causing 75% melanoma cell death at concentrations in the nanomolar and micromolar range. Cytotoxicity was conducted by induction of DNA cleavage indicating apoptotic cells. Chicken embryotoxicity demonstrated that the duplex drugs were less toxic than 5-FdU at 0.01 μM. In vivo the duplex drug 5-FdU(3'-5')ECyd was efficacious in the murine LOX IMVI melanoma xenograph model on administration of 11.2 mg/kg/injection every fourth day. Both duplex drugs are promising novel cytostatic agents for the treatment of malignant melanoma meriting clinical evaluation.

  4. Supramolecular substitution reactions between hydrazide-based molecular duplex strands: complexation induced nonsymmetry and dynamic behavior.

    PubMed

    Yang, Yong; Xiang, Jun-Feng; Xue, Min; Hu, Hai-Yu; Chen, Chuan-Feng

    2008-08-15

    Supramolecular substitution reactions between hydrazide-based oligomers 1a- c and 2a- c were systematically investigated. Each oligomer existed as hydrogen-bonding mediated molecular duplex strands or a polymeric zipper structure in apolar solvents. But when another oligomer with complementary hydrogen bonding sites was added, a heterodimer structure formed due to supramolecular substitution reaction driven by the formation of more hydrogen bonds, which was evidenced by NMR experiments, sometimes gel-sol transition. When a nonsymmetric oligomer and a symmetric oligomer were involved, complexation-induced nonsymmetry was observed. When two nonsymmetric oligomers were involved, two hydrogen-bonded isomers were observed in solution. Variable-temperature (1)H NMR experiments further revealed unique dynamic behavior for the individual oligomer and the complexes. When diacetyl-terminated oligomer 1c was involved, slides perpendicular to hydrogen bonds between two constituent molecules were observed, which led to complicated (1)H NMR spectra at lower temperature; otherwise, high selectivity was obtained. Combined with the results we reported previously, a detailed picture of the structure-property relationship for our hydrazide-based oligomers was depicted, which would provide guidelines for the design of hydrazide-based fine-tuning functional materials.

  5. Structure of human Bloom's syndrome helicase in complex with ADP and duplex DNA.

    PubMed

    Swan, Michael K; Legris, Valerie; Tanner, Adam; Reaper, Philip M; Vial, Sarah; Bordas, Rebecca; Pollard, John R; Charlton, Peter A; Golec, Julian M C; Bertrand, Jay A

    2014-05-01

    Bloom's syndrome is an autosomal recessive genome-instability disorder associated with a predisposition to cancer, premature aging and developmental abnormalities. It is caused by mutations that inactivate the DNA helicase activity of the BLM protein or nullify protein expression. The BLM helicase has been implicated in the alternative lengthening of telomeres (ALT) pathway, which is essential for the limitless replication of some cancer cells. This pathway is used by 10-15% of cancers, where inhibitors of BLM are expected to facilitate telomere shortening, leading to apoptosis or senescence. Here, the crystal structure of the human BLM helicase in complex with ADP and a 3'-overhang DNA duplex is reported. In addition to the helicase core, the BLM construct used for crystallization (residues 640-1298) includes the RecQ C-terminal (RQC) and the helicase and ribonuclease D C-terminal (HRDC) domains. Analysis of the structure provides detailed information on the interactions of the protein with DNA and helps to explain the mechanism coupling ATP hydrolysis and DNA unwinding. In addition, mapping of the missense mutations onto the structure provides insights into the molecular basis of Bloom's syndrome.

  6. Duplex ultrasound

    MedlinePlus

    Vascular ultrasound; Peripheral vascular ultrasound ... A duplex ultrasound combines: Traditional ultrasound: This uses sound waves that bounce off blood vessels to create pictures. Doppler ultrasound: This ...

  7. On the origin of the decrease in stability of the DNA hairpin d(GCGAAGC) on complexation with aromatic drugs.

    PubMed

    Kostjukov, V V; Lantushenko, A O; Davies, D B; Evstigneev, M P

    2007-08-01

    Molecular dynamics simulations of drug-DNA complexes have been carried out in order to explain the experimentally observed decrease in thermal stability of the DNA hairpin d(GCGAAGC) on binding the aromatic drug molecules, daunomycin, ethidium bromide, novantrone and proflavine. This complexation behavior is in contrast to the stabilizing effect of the same aromatic drug molecules on DNA duplexes. Analysis of the energy parameters and the hydration properties of the complexes shows that the main factor correlating with the decrease in melting temperatures of the drug-hairpin complexes is the number of water bridges, with a reduction of at least 40% on ligand binding.

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

    PubMed

    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. A study of the possible effects of repeated intracorporeal self-injection of vasoactive drugs in patients with elevated end diastolic velocity during pharmacopenile duplex ultrasonography

    PubMed Central

    Fayez, Ashraf Hasan; El-Khayat, Yasser; Hosny, Hosam; Zaki, Shady

    2013-01-01

    Introduction The aim of the work is to evaluate the effect of repeated intracavernosal self-injection of vasoactive drugs in patients with elevated End Diastolic Velocity (>5 cm/sec) during pharmacopenile duplex ultrasonography (PPDU). Methods Duplex evaluation was performed to the patients on self-injection therapy for comparison of end diastolic velocity and resistive index before and after completing the eight doses of IC self-injection. Results After the 8 trials of home therapy, 21 (52.5%) patients showed improvement in the duplex parameters regarding the end diastolic velocity, ten of them showed improvement in the EDV to the level of <5 cm/sec. The effect of different factors that may contribute to the improvement in EDV to <5 cm/sec are shown in the table 2. Age was the only predictive factor for successful response to home therapy intracavernous injection (ICI). Improvement in erectile response was assessed before and after the course of the therapy. Erection response to ICI during penile duplex improved in only six patients (E4 & E4-5)) to the point that it was sufficient for satisfactory sexual performance, 3 of them (7.5%) regained spontaneous erection and stopped using ICI (table 3). The IIEF score was 10.6 ±2.8 before the home therapy and it became 14 ±3.9 one month after completing the treatment course (P value <0.001). Conclusions Early rehabilitation of the patients with venous leakage ED using ICI may help to regain normal erection and avoid unnecessary penile prosthesis surgeries. PMID:24579031

  10. Duplex detection of the Mycobacterium tuberculosis complex and medically important non-tuberculosis mycobacteria by real-time PCR based on the rnpB gene.

    PubMed

    Abdeldaim, Guma; Svensson, Erik; Blomberg, Jonas; Herrmann, Björn

    2016-11-01

    A duplex real-time PCR based on the rnpB gene was developed for Mycobacterium spp. The assay was specific for the Mycobacterium tuberculosis complex (MTB) and also detected all 19 tested species of non-tuberculous mycobacteria (NTM). The assay was evaluated on 404 clinical samples: 290 respiratory samples and 114 from tissue and other non-respiratory body sites. M. tuberculosis was detected by culture in 40 samples and in 30 samples by the assay. The MTB assay showed a sensitivity similar to Roche Cobas Amplicor MTB-PCR (Roche Molecular Systems, Pleasanton, CA, USA). There were only nine samples with non-tuberculous mycobacteria detected by culture. Six of them were detected by the PCR assay.

  11. Positive and negative ion mode ESI-MS and MS/MS for studying drug-DNA complexes

    NASA Astrophysics Data System (ADS)

    Rosu, Frédéric; Pirotte, Sophie; Pauw, Edwin De; Gabelica, Valérie

    2006-07-01

    We report systematic investigation of duplex DNA complexes with minor groove binders (Hoechsts 33258 and 33342, netropsin and DAPI) and intercalators (daunomycin, doxorubicin, actinomycin D, ethidium, cryptolepine, neocryptolepine, m-Amsacrine, proflavine, ellipticine and mitoxantrone) by ESI-MS and ESI-MS/MS in the negative ion mode and in the positive ion mode. The apparent solution phase equilibrium binding constants can be determined by measuring relative intensities in the ESI-MS spectrum. While negative ion mode gives reliable results, positive ion mode gives a systematic underestimation of the binding constants and even a complete suppression of the complexes for intercalators lacking functional groups capable of interacting in the grooves. In the second part of the paper we systematically compare MS/MS fragmentation channels and breakdown curves in the positive and the negative modes, and discuss the possible uses and caveats of MS/MS in drug-DNA complexes. In the negative mode, the drugs can be separated in three groups: (1) those that leave the complex with no net charge; (2) those that leave the complex with a negative charge; and (3) those that remain attached on the strands upon dissociation of the duplex due to their positive charge. In the positive ion mode, all complexes fragment via the loss of protonated drug. Information on the stabilization of the complex by drug-DNA noncovalent interactions can be obtained straightforwardly only in the case of neutral drug loss. In all other cases, proton affinity (in the positive ion mode), gas-phase basicity (in the negative ion mode) and coulombic repulsion are the major factors influencing the fragmentation channel and the dissociation kinetics.

  12. Sequence specificity of mutagen-nucleic acid complexes in solution: intercalation and mutagen-base pair overlap geometries for proflavine binding to dC-dC-dG-dG and dG-dG-dC-dC self-complementary duplexes.

    PubMed

    Patel, D J; Canuel, L L

    1977-07-01

    The complex formed between the mutagen proflavine and the dC-dC-dG-dG and dG-dG-dC-dC self-complementary tetranucleotide duplexes has been monitored by proton high resolution nuclear magnetic resonance spectroscopy in 0.1 M phosphate solution at high nucleotide/drug ratios. The large upfield shifts (0.5 to 0.85 ppm) observed at all the proflavine ring nonexchangeable protons on complex formation are consistent with intercalation of the mutagen between base pairs of the tetranucleotide duplex. We have proposed an approximate overlap geometry between the proflavine ring and nearest neighbor base pairs at the intercalation site from a comparison between experimental shifts and those calculated for various stacking orientations. We have compared the binding of actinomycin D, propidium diiodide, and proflavine to self-complementary tetranucleotide sequences dC-dC-dG-dG and dG-dG-dC-dC by UV absorbance changes in the drug bands between 400 and 500 nm. Actinomycin D exhibits a pronounced specificity for sequences with dG-dC sites (dG-dG-dC-dC), while propidium diiodide and proflavine exhibit a specificity for sequences with dC-dG sites (dC-dC-dG-dG). Actinomycin D binds more strongly than propidium diiodide and proflavine to dC-dG-dC-dG (contains dC-dG and dG-dC binding sites), indicative of the additional stabilization from hydrogen bonding and hydrophobic interactions between the pentapeptide lactone rings of actinomycin D and the base pair edges and sugar-phosphate backbone of the tetranucleotide duplex.

  13. Hsp70 Protein Complexes as Drug Targets

    PubMed Central

    Assimon, Victoria A.; Gillies, Anne T.; Rauch, Jennifer N.; Gestwicki, Jason E.

    2013-01-01

    Heat shock protein 70 (Hsp70) plays critical roles in proteostasis and is an emerging target for multiple diseases. However, competitive inhibition of the enzymatic activity of Hsp70 has proven challenging and, in some cases, may not be the most productive way to redirect Hsp70 function. Another approach is to inhibit Hsp70’s interactions with important co-chaperones, such as J proteins, nucleotide exchange factors (NEFs) and tetratricopeptide repeat (TPR) domain-containing proteins. These co-chaperones normally bind Hsp70 and guide its many diverse cellular activities. Complexes between Hsp70 and co-chaperones have been shown to have specific functions, such as pro-folding, pro-degradation and pro-trafficking. Thus, a promising strategy may be to block protein-protein interactions between Hsp70 and its co-chaperones or to target allosteric sites that disrupt these contacts. Such an approach might shift the balance of Hsp70 complexes and re-shape the proteome and it has the potential to restore healthy proteostasis. In this review, we discuss specific challenges and opportunities related to those goals. By pursuing Hsp70 complexes as drug targets, we might not only develop new leads for therapeutic development, but also discover new chemical probes for use in understanding Hsp70 biology. PMID:22920901

  14. Hsp70 protein complexes as drug targets.

    PubMed

    Assimon, Victoria A; Gillies, Anne T; Rauch, Jennifer N; Gestwicki, Jason E

    2013-01-01

    Heat shock protein 70 (Hsp70) plays critical roles in proteostasis and is an emerging target for multiple diseases. However, competitive inhibition of the enzymatic activity of Hsp70 has proven challenging and, in some cases, may not be the most productive way to redirect Hsp70 function. Another approach is to inhibit Hsp70's interactions with important co-chaperones, such as J proteins, nucleotide exchange factors (NEFs) and tetratricopeptide repeat (TPR) domain-containing proteins. These co-chaperones normally bind Hsp70 and guide its many diverse cellular activities. Complexes between Hsp70 and co-chaperones have been shown to have specific functions, including roles in pro-folding, pro-degradation and pro-trafficking pathways. Thus, a promising strategy may be to block protein- protein interactions between Hsp70 and its co-chaperones or to target allosteric sites that disrupt these contacts. Such an approach might shift the balance of Hsp70 complexes and re-shape the proteome and it has the potential to restore healthy proteostasis. In this review, we discuss specific challenges and opportunities related to these goals. By pursuing Hsp70 complexes as drug targets, we might not only develop new leads for therapeutic development, but also discover new chemical probes for use in understanding Hsp70 biology.

  15. [Renal duplex: clinical usefulness].

    PubMed

    Miralles, M; Giménez, A; Cairols, M A; Riambau, V; Sáez, A

    1993-01-01

    It is the purpose of this report to focus attention on the clinical usefulness of Renal Duplex for the diagnosis of patients with vasculo-renal diseases in terms of: 1. Accuracy of Duplex/Angiography in the measurement of the renal stenosis degree. 2. Correlationship between Duplex ans Isotopic Renogram with respect to the study of the parenchyma's perfusion. 3. The effect of the inhibitors of the conversor enzyme (Captopril) on the Doppler signal of the parenchyma, comparing it with the results from the captopril test about the peripheral plasmatic renin activity and the isotopic renogram, in patients with vasculo-renal HTA. Results obtains by Duplex and Angiography were compared in 92 renal arteries from 46 patients. For both technics, three degrees of stenosis were established: 0-59%, 60-99% and occlusion. The Duplex technique identified 49/54 stenosis < 60%, 28/33 stenosis > 60% and 5/5 occlusions (Kappa 0.8). Sensibility and specificity of Duplex for the diagnosis of stenosis > 60% were, respectively, 89.5% and 90.7%; with an exactness of 90.2%. The angiographies showed stenosis > 60% in 23 patients with HTA (diastolic pressures > 100 mmHg). In all of the patients, a measurement of the plasmatic renin activity, an isotopic renogram and a Doppler of the interlobar arteries basal and post-captopril, were performed. The correlationship between Duplex and isotopic renogram with respect to the measurement of the relative renal perfusion was statistically significant (r = 0.91; p < 0.0001). The captopril test for renin and isotopic renogram were positives for 5 patients (4 with unilateral stenosis an 1 with bilateral stenosis). All of them showed severe stenosis (> 80%).(ABSTRACT TRUNCATED AT 250 WORDS)

  16. 1. VIEW OF DUPLEX (FEATURE 7). CORNER OF DUPLEX (FEATURE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. VIEW OF DUPLEX (FEATURE 7). CORNER OF DUPLEX (FEATURE 6) IS VISIBLE AT LEFT. MILL SITE IS VISIBLE IN THE BACKGROUND. FACING EAST. - Copper Canyon Camp of the International Smelting & Refining Company, Duplex, Copper Canyon, Battle Mountain, Lander County, NV

  17. Duplex tab exhaust nozzle

    NASA Technical Reports Server (NTRS)

    Gutmark, Ephraim Jeff (Inventor); Martens, Steven (nmn) (Inventor)

    2012-01-01

    An exhaust nozzle includes a conical duct terminating in an annular outlet. A row of vortex generating duplex tabs are mounted in the outlet. The tabs have compound radial and circumferential aft inclination inside the outlet for generating streamwise vortices for attenuating exhaust noise while reducing performance loss.

  18. The many roles of molecular complexity in drug discovery.

    PubMed

    Méndez-Lucio, Oscar; Medina-Franco, José L

    2017-01-01

    Molecular complexity is becoming a crucial concept in drug discovery. It has been associated with target selectivity, success in progressing into clinical development and compound safety, among other factors. Multiple metrics have been developed to quantify molecular complexity and explore complexity-property relationships. However, there is no general agreement regarding how to measure this molecular feature. Herein, we have surveyed the many roles of molecular complexity in drug discovery discussing in a critical manner different quantification methods. Through the analysis of various reference compound databases, common pitfalls and workarounds of the quantification of molecular complexity are discussed.

  19. Protein Complex Production from the Drug Discovery Standpoint.

    PubMed

    Moarefi, Ismail

    2016-01-01

    Small molecule drug discovery critically depends on the availability of meaningful in vitro assays to guide medicinal chemistry programs that are aimed at optimizing drug potency and selectivity. As it becomes increasingly evident, most disease relevant drug targets do not act as a single protein. In the body, they are instead generally found in complex with protein cofactors that are highly relevant for their correct function and regulation. This review highlights selected examples of the increasing trend to use biologically relevant protein complexes for rational drug discovery to reduce costly late phase attritions due to lack of efficacy or toxicity.

  20. Interaction of octahedral ruthenium(II) polypyridyl complex [Ru(bpy)2(PIP)](2+) with poly(U)·poly(A)*poly(U) triplex: Increasing third-strand stabilization of the triplex without affecting the stability of the duplex.

    PubMed

    Zhu, Zhiyuan; Peng, Mengna; Zhang, Jingwen; Tan, Lifeng

    2017-04-01

    Triple-helical RNA are of interest because of possible biological roles as well as the potential therapeutic uses of these structures, while the stability of triplexes is usually weaker than that of the Watson-Crick base pairing duplex strand due to the electrostatic repulsion between three polyanionic strands. Therefore, how to increase the stability of the specific sequences of triplexes are of importance. In this paper the binding of a Ru(II) complex, [Ru(bpy)2(PIP)](2+) (bpy=2.2'-bipyridine, PIP=2-phenyl-1H-imidazo[4,5-f]- [1,10]-phenanthroline), with poly(U)·poly(A)*poly(U) triplex has been investigated by spectrophotometry, spectrofluorometry, viscosimetry and circular dichroism. The results suggest that [Ru(bpy)2(PIP)](2+) as a metallointercalator can stabilize poly(U)·poly(A)*poly(U) triplex (where · denotes the Watson-Crick base pairing and * denotes the Hoogsteen base pairing),while it stabilizes third-strand with no obvious effect on the duplex of poly(U)·poly(A), reflecting the binding of this complex with the triplex is favored by the Hoogsteen paired poly(U) third strand to a great extent.

  1. Inferring drug-disease associations based on known protein complexes.

    PubMed

    Yu, Liang; Huang, Jianbin; Ma, Zhixin; Zhang, Jing; Zou, Yapeng; Gao, Lin

    2015-01-01

    Inferring drug-disease associations is critical in unveiling disease mechanisms, as well as discovering novel functions of available drugs, or drug repositioning. Previous work is primarily based on drug-gene-disease relationship, which throws away many important information since genes execute their functions through interacting others. To overcome this issue, we propose a novel methodology that discover the drug-disease association based on protein complexes. Firstly, the integrated heterogeneous network consisting of drugs, protein complexes, and disease are constructed, where we assign weights to the drug-disease association by using probability. Then, from the tripartite network, we get the indirect weighted relationships between drugs and diseases. The larger the weight, the higher the reliability of the correlation. We apply our method to mental disorders and hypertension, and validate the result by using comparative toxicogenomics database. Our ranked results can be directly reinforced by existing biomedical literature, suggesting that our proposed method obtains higher specificity and sensitivity. The proposed method offers new insight into drug-disease discovery. Our method is publicly available at http://1.complexdrug.sinaapp.com/Drug_Complex_Disease/Data_Download.html.

  2. Inferring drug-disease associations based on known protein complexes

    PubMed Central

    2015-01-01

    Inferring drug-disease associations is critical in unveiling disease mechanisms, as well as discovering novel functions of available drugs, or drug repositioning. Previous work is primarily based on drug-gene-disease relationship, which throws away many important information since genes execute their functions through interacting others. To overcome this issue, we propose a novel methodology that discover the drug-disease association based on protein complexes. Firstly, the integrated heterogeneous network consisting of drugs, protein complexes, and disease are constructed, where we assign weights to the drug-disease association by using probability. Then, from the tripartite network, we get the indirect weighted relationships between drugs and diseases. The larger the weight, the higher the reliability of the correlation. We apply our method to mental disorders and hypertension, and validate the result by using comparative toxicogenomics database. Our ranked results can be directly reinforced by existing biomedical literature, suggesting that our proposed method obtains higher specificity and sensitivity. The proposed method offers new insight into drug-disease discovery. Our method is publicly available at http://1.complexdrug.sinaapp.com/Drug_Complex_Disease/Data_Download.html. PMID:26044949

  3. Polypathology, polypharmacy, medication regimen complexity and drug therapy appropriateness.

    PubMed

    Gómez Aguirre, N; Caudevilla Martínez, A; Bellostas Muñoz, L; Crespo Avellana, M; Velilla Marco, J; Díez-Manglano, J

    2017-02-16

    Polypathological patients are usually elderly and take numerous drugs. Polypharmacy affects 85% of these individuals and is not associated with greater survival. On the contrary, polypharmacy exposes these individuals to more adverse effects, such as weight loss, falls, functional and cognitive impairment and hospitalisations. The complexity of a drug regimen covers more aspects than the simple number of drugs consumed. The galenic form, the dosage and the method for preparing the drug can impede the understanding of and compliance with prescriptions. Both polypharmacy and therapeutic complexity are associated with poorer adherence by patients. To prevent polypharmacy, reduce complexity and improve adherence, the appropriate use of drugs is needed. Proper prescribing consists of selecting drugs that have clear evidence for their use in the indication, which are appropriate for the patient's circumstances, are well tolerated and cost-effective and whose benefits outweigh the risks. To improve the drug prescription, periodic reviews of the drugs need to be conducted, especially when the patient changes doctor and during healthcare transitions. The Beers and STOPP/START (Screening Tool of Older Person's potentially inappropriate Prescriptions/Screening Tool to Alert doctors to the Right Treatment) criteria are effective tools for this improvement. Deprescription for polymedicated polypathological patients that considers their clinical circumstances, prognosis and preferences can contribute to a more appropriate use of drugs.

  4. Solution structures of antimalarial drug-heme complexes.

    PubMed

    Leed, Alison; DuBay, Kateri; Ursos, Lyann M B; Sears, Devin; De Dios, Angel C; Roepe, Paul D

    2002-08-13

    Paramagnetic metal centers [such as Fe(III) found within ferriprotoporphyrin IX heme (FPIX)] exert through space effects on the relaxation rate of nearby proton spins that depend critically on the metal-proton distance. We have measured these effects for all protons of several antimalarial drugs that bind to FPIX by systematically varying the drug:heme molar ratio in high field NMR experiments. These measurements allow us to determine precise FPIX Fe-drug H distances for the solution structures of noncovalent complexes formed between FPIX mu-oxo dimers and the antimalarial drugs chloroquine (CQ), quinine (QN), and quinidine (QD). Using these distances, we then performed distance restraint calculations to determine the lowest-energy solution structures of these complexes. Structures were solved for neutral, monoprotic (+1), and diprotic (+2) forms of the drugs. Analysis of these structures allows us to visualize for the first time the stereospecific differences between QN and QD binding to FPIX and the differences in populations of QN and QD solution structures upon changes in digestive vacuolar pH for drug resistant malarial parasites [Dzekunov, S. M., et al. (2000) Mol. Biochem. Parasitol. 110, 107-124]. The data indicate a previously unrecognized key role for the CQ aliphatic chain in stabilizing FPIX-CQ complexes, and suggest how lengthening or shortening the chain might perturb stability. We also define FPIX:drug stoichiometries of 2:1 for the complexes formed at physiological FPIX concentrations, in contrast to the 4:1 and 5:1 stoichiometries previously determined at higher FPIX concentrations [Dorn, A., et al. (1998) Biochem. Pharmacol. 55, 727-736]. These atomic resolution antimalarial drug-heme structures should help elucidate how these drugs inhibit formation of hemozoin during metabolism of heme within the malarial parasite Plasmodium falciparum and assist ongoing development of strategies for circumventing antimalarial drug resistance.

  5. Complexation of C60 fullerene with aromatic drugs.

    PubMed

    Evstigneev, Maxim P; Buchelnikov, Anatoly S; Voronin, Dmitry P; Rubin, Yuriy V; Belous, Leonid F; Prylutskyy, Yuriy I; Ritter, Uwe

    2013-02-25

    The contributions of various physical factors to the energetics of complexation of aromatic drug molecules with C(60) fullerene are investigated in terms of the calculated magnitudes of equilibrium complexation constants and the components of the net Gibbs free energy. Models of complexation are developed taking into account the polydisperse nature of fullerene solutions in terms of the continuous or discrete (fractal) aggregation of C(60) molecules. Analysis of the energetics has shown that stabilization of the ligand-fullerene complexes in aqueous solution is mainly determined by intermolecular van der Waals interactions and, to lesser extent, by hydrophobic interactions. The results provide a physicochemical basis for a potentially new biotechnological application of fullerenes as modulators of biological activity of aromatic drugs.

  6. The N domain of Argonaute drives duplex unwinding during RISC assembly.

    PubMed

    Kwak, Pieter Bas; Tomari, Yukihide

    2012-01-10

    Small RNAs, such as microRNAs and small interfering RNAs, act through Argonaute (Ago) proteins as a part of RNA-induced silencing complexes (RISCs). To make RISCs, Ago proteins bind and subsequently unwind small RNA duplexes, finally leaving one strand stably incorporated. Here we identified the N domain of human AGO2 as the initiator of duplex unwinding during RISC assembly. We discovered that a functional N domain is strictly required for small RNA duplex unwinding but not for precedent duplex loading or subsequent target cleavage. We postulate that RISC assembly is tripartite, comprising (i) RISC loading, whereby Ago undergoes conformational opening and loads a small RNA duplex, forming pre-RISC; (ii) wedging, whereby the end of the duplex is pried open through active wedging by the N domain, in preparation for unwinding; and (iii) unwinding, whereby the passenger strand is removed through slicer-dependent or slicer-independent unwinding, forming mature RISC.

  7. Dislocation substructure in fatigued duplex stainless steel

    SciTech Connect

    Polak, J. . Lab. de Mecanique de Lille Inst. of Physical Metallurgy, Brno . Academy of Sciences); Degallaix, S. . Lab. de Mecanique de Lille); Kruml, T. . Academy of Sciences)

    1993-12-15

    Cyclic plastic straining of crystalline materials results in the formation of specific dislocation structures. Considerable progress in mapping and understanding internal dislocation structures has been achieved by studying single crystal behavior: however, most structural materials have a polycrystalline structure and investigations of polycrystals in comparison to single crystal behavior of simple metals prove to be very useful in understanding more complex materials. There are some classes of materials, however, with complicated structure which do not have a direct equivalent in single crystalline form. Moreover, the specific dimensions and shapes of individual crystallites play an important role both in the cyclic stress-strain response of these materials and in the formation of their interior structure in cyclic straining. Austenitic-ferritic duplex stainless steel, which is a kind of a natural composite, is a material of this type. The widespread interest in the application of duplex steels is caused by approximately doubled mechanical properties and equal corrosion properties, when compared with classical austenitic stainless steels. Fatigue resistance of these steels as well as the surface damage evolution in cyclic straining have been studied; however, much less is known about the internal substructure development in cyclic straining. In this study the dislocation arrangement in ferritic and austenitic grains of the austenitic-ferritic duplex steel alloyed with nitrogen and cyclically strained with two strain amplitudes, is reported and compared to the dislocation arrangement found in single and polycrystals of austenitic and ferritic materials of a similar composition and with the surface relief produced in cyclic plastic straining.

  8. [Carotid duplex ultrasonography for neurosurgeons].

    PubMed

    Sadahiro, Hirokazu; Ishihara, Hideyuki; Oka, Fumiaki; Suzuki, Michiyasu

    2011-12-01

    Carotid duplex ultrasonography (CDU) is one of the most well-known imaging methods for arteriosclerosis and ischemic stroke. For neurosurgeons, it is very important for the details of carotid plaque to be thoroughly investigated by CDU. Symptomatic carotid plaque is very fragile and easily changes morphologically, and so requires frequent CDU examination. Furthermore, after carotid endarterectomy (CEA) and carotid artery stenting (CAS), restenosis is evaluated with CDU. CDU facilitates not only morphological imaging in the B mode, but also allows a flow study with color Doppler and duplex imaging. So, CDU can help assess the presence of proximal and intracranial artery lesions in spite of only having a cervical view, and the patency of the extracranial artery to intracranial artery bypass is revealed with CDU, which shows a rich velocity and low pulsatility index (PI) in duplex imaging. For the examiner, it is necessary to ponder on what duplex imaging means in examinations, and to summarize all imaging finding.

  9. Synthesis of biocompatible nanoparticle drug complexes for inhibition of mycobacteria

    NASA Astrophysics Data System (ADS)

    Bhave, Tejashree; Ghoderao, Prachi; Sanghavi, Sonali; Babrekar, Harshada; Bhoraskar, S. V.; Ganesan, V.; Kulkarni, Anjali

    2013-12-01

    Tuberculosis (TB) is one of the most critical infectious diseases affecting the world today. Current TB treatment involves six months long daily administration of four oral doses of antibiotics. Due to severe side effects and the long treatment, a patient's adherence is low and this results in relapse of symptoms causing an alarming increase in the prevalence of multi-drug resistant (MDR) TB. Hence, it is imperative to develop a new drug delivery technology wherein these effects can be reduced. Rifampicin (RIF) is one of the widely used anti-tubercular drugs (ATD). The present study discusses the development of biocompatible nanoparticle-RIF complexes with superior inhibitory activity against both Mycobacterium smegmatis (M. smegmatis) and Mycobacterium tuberculosis (M. tuberculosis). Iron oxide nanoparticles (NPs) synthesized by gas phase condensation and NP-RIF complexes were tested against M. smegmatis SN2 strain as well as M. tuberculosis H37Rv laboratory strain. These complexes showed significantly better inhibition of M. smegmatis SN2 strain at a much lower effective concentration (27.5 μg ml-1) as compared to neat RIF (125 μg ml-1). Similarly M. tuberculosis H37Rv laboratory strain was susceptible to both nanoparticle-RIF complex and neat RIF at a minimum inhibitory concentration of 0.22 and 1 μg ml-1, respectively. Further studies are underway to determine the efficacy of NPs-RIF complexes in clinical isolates of M. tuberculosis as well as MDR isolates.

  10. Characterization of a unique tomaymycin-d(CICGAATTCICG) sub 2 adduct containing two drug molecules per duplex by NMR, fluorescence, and molecular modeling studies

    SciTech Connect

    Boyd, F.L.; Stewart, D.; Hurley, L.H. ); Remers, W.A. ); Barkley, M.D. )

    1990-03-06

    Tomaymycin is a member of the pyrrolo(1,4)benzodiazepine (P(1,4)B) antitumor antibiotic group. This antibiotic is proposed to react with the exocyclic 2-amino group (N2) of guanine to form a covalent adduct that lies snugly within the minor groove of DNA. While DNA-footprinting experiments using methidiumpropyl-EDTA have revealed the favored bonding sequences for tomaymycin and related drugs on DNA, the stereochemistry at the covalent bonding site (C-11) and orientation in the minor groove were not established by these experiments. In previous studies using a combined fluorescence, high-field NMR, and molecular modeling approach, the authors have shown that for tomaymycin there are two diastereomeric species (11R and 11S) on both calf thymus DNA and d(ATGCAT){sub 2}. Although they were able to infer the identify of the two species on d(ATGCAT){sub 2}, definitive experimental evidence was lacking. They have designed and synthesized a self-complementary 12-mer (d(CICGAATTCICG){sub 2}) based on the Dickerson dodecamer (d(CGCGAATTCGCG){sub 2}) that bonds identically two tomaymycin molecules, each having a defined orientation and stereochemistry. The results presented in this study together with previous investigations show that the orientation of the drug molecule in the minor groove, and stereochemistry at the covalent linkage site, is dependent upon both the flanking sequence and drug structure. This conclusion mandates caution be used in rationalizing the biochemical and and biological effects of P(1,4)B bonding to DNA until precise structural information is established.

  11. Defined presentation of carbohydrates on a duplex DNA scaffold.

    PubMed

    Schlegel, Mark K; Hütter, Julia; Eriksson, Magdalena; Lepenies, Bernd; Seeberger, Peter H

    2011-12-16

    A new method for the spatially defined alignment of carbohydrates on a duplex DNA scaffold is presented. The use of an N-hydroxysuccinimide (NHS)-ester phosphoramidite along with carbohydrates containing an alkylamine linker allows for on-column labeling during solid-phase oligonucleotide synthesis. This modification method during solid-phase synthesis only requires the use of minimal amounts of complex carbohydrates. The covalently attached carbohydrates are presented in the major groove of the B-form duplex DNA as potential substrates for murine type II C-type lectin receptors mMGL1 and mMGL2. CD spectroscopy and thermal melting revealed only minimal disturbance of the overall helical structure. Surface plasmon resonance and cellular uptake studies with bone-marrow-derived dendritic cells were used to assess the capability of these carbohydrate-modified duplexes to bind to mMGL receptors.

  12. Synthesis, interactions, molecular structure, biological properties and molecular docking studies on Mn, Co, Zn complexes containing acetylacetone and pyridine ligands with DNA duplex.

    PubMed

    Thamilarasan, V; Sengottuvelan, N; Stalin, N; Srinivasan, P; Chakkaravarthi, G

    2016-07-01

    Three metal complexes (1-3) of the type [Mn(acac)2(py)·H2O] (1), [Co(acac)2(py)·H2O] (2) and [Zn(acac)2(py)·H2O] (3), [Where acac=acetylacetone, py=pyridine] were synthesized and characterized by spectral (UV-vis, FT-IR, ESI-mass) analysis. The structure of complex 2 has been determined by single crystal X-ray diffraction studies and the configuration of ligand-coordinated to metal(II) ion was well described as distorted octahedral coordination geometry. The interaction of the complexes with CT-DNA has been explored by absorption, fluorescence, circular dichromism spectroscopy, viscosity measurements and molecular docking studies. The intrinsic binding constant Kb of complexes 1-3 with CT-DNA obtained from UV-vis absorption spectral studies were 2.1×10(4), 2.1×10(5) and 1.98×10(4)M(-1), respectively, which revealed that the complexes could interact with CT-DNA through groove binding. The results indicated that the complexes (1-3) were able to bind to DNA with different binding affinity, in the order: 2>1>3. The interaction of the compounds with bovine serum albumins were also investigated using fluorescence methods and the gel electrophoresis assay demonstrates weak cleavage ability of the pBR322 plasmid DNA in the presence of the metal complexes (1-3) with various activators. Further, the in vitro cytotoxic effect of the complexes were examined on cancerous cell line, with human breast cancer cells MCF-7.

  13. Block ionomer complexes as prospective nanocontainers for drug delivery.

    PubMed

    Oh, Kyung T; Bronich, Tatiana K; Bromberg, Lev; Hatton, T Alan; Kabanov, Alexander V

    2006-09-28

    Nanosized environmentally responsive materials are of special interest for various applications, including drug delivery. Block ionomer complexes (BIC) composed of graft-comb copolymers of Pluronic and poly(acrylic acid) (Pluronic-PAA) and a model cationic surfactant, hexadecyltrimethylammonium bromide (HTAB), were synthesized by mixing the polymer and surfactant in aqueous media. According to TEM, the resulting BIC represented spherical particles of nanoscale size (50 to 100 nm). The stability of the BIC in the aqueous dispersion depended on the lengths of the hydrophilic poly(ethylene oxide) and hydrophobic poly(propylene oxide) chains in Pluronic molecules as well as on the surface charge of the resulting complexes. The latter was controlled by changing the ratio of the Pluronic-PAA and HTAB in the BIC and by changing the pH due to reversible ionization of the PAA chains. The acidification of the media below pH 6.0 resulted in the appearance of a strong positive charge on the BIC, which in the intracellular environment can trigger interaction of such BIC with the cell membranes. An efficient solubilization of a model hydrophobic molecule, Sudan III, and a drug, Etoposide, in such BIC was demonstrated with the loading capacities of about 6 to 15% by weight of the dispersed complex. Overall, these BIC wield a promise as environmentally responsive nanocarriers for pharmaceuticals.

  14. Self-organized nanoparticles based on drug-interpolyelectrolyte complexes as drug carriers

    NASA Astrophysics Data System (ADS)

    Palena, M. C.; Manzo, R. H.; Jimenez-Kairuz, A. F.

    2012-06-01

    Potential applications in drug delivery from nanostructures composed of two oppositely charged polymethacrylates, eudragit® L100 (EL) and eudragit® EPO (EE), loaded with three model basic drugs (D), atenolol, propranolol, and metroclopramide were evaluated. The self-organized nanoparticles based on drug-interpolyelectrolyte complexes (DIPEC), (EL-D50)-EEX, were obtained by mixing the aqueous dispersions of both polyelectrolytes at room temperature in an ultrasound bath. Dispersions of (EL-D50) neutralized with increasing proportions of EE exhibited a rise of turbidity, particle sizes in the range of 150-400 nm, and high negative zeta potential. The sign of zeta potential was shifted from negative to positive by changes in composition of DIPEC. Freeze dried DIPEC were easily redispersed in water yielding nearly the same parameters of fresh dispersions. In vitro release experiments using Franz cells showed that DIPEC systems behave as a drug reservoir that slowly releases the drug as water is placed in the receptor compartment. The release rate was raised by ionic exchange with counterions present in simulated physiological fluids placed in the receptor media. Delivery of D from DIPEC exhibited a remarkable robustness toward simulated physiological media of different pH. The DIPEC systems exhibit interesting properties to design nanoparticulate drug delivery systems for oral and/or topical routes.

  15. DNA Duplex Engineering for Enantioselective Fluorescent Sensor.

    PubMed

    Hu, Yuehua; Lin, Fan; Wu, Tao; Zhou, Yufeng; Li, Qiusha; Shao, Yong; Xu, Zhiai

    2017-02-21

    The rapid identification of biomacromolecule structure that has a specific association with chiral enantiomers especially from natural sources will be helpful in developing enantioselective sensor and in speeding up drug exploitation. Herein, owing to its existence also in living cells, apurinic/apyrimidinic site (AP site) was first engineered into ds-DNA duplex to explore its competence in enantiomer selectivity. An AP site-specific fluorophore was utilized as an enantioselective discrimination probe to develop a straightforward chiral sensor using natural tetrahydropalmatine (L- and D-THP) as enantiomer representatives. We found that only L-THP can efficiently replace the prebound fluorophore to cause a significant fluorescence increase due to its specific binding with the AP site (two orders magnitude higher in affinity than binding with D-THP). The AP site binding specificity of L-THP over D-THP was assessed via intrinsic fluorescence, isothermal titration calorimetry, and DNA stability. The enantioselective performance can be easily tuned by the sequences near the AP site and the number of AP sites. A single AP site provides a perfect binding pocket to differentiate the chiral atom-induced structure discrepancy. We expect that our work will inspire interest in engineering local structures into a ds-DNA duplex for developing novel enantioselective sensors.

  16. Duplex evaluation of venous insufficiency.

    PubMed

    Labropoulos, Nicos; Leon, Luis R

    2005-03-01

    Duplex ultrasound is the most useful examination for the evaluation of venous valvular incompetence. Multi-frequency 4 to 7-MHz linear array transducers are typically used for this assessment of superficial and deep reflux. The examination is done with the patient standing and manual compression maneuvers are used to initiate reflux. Automatic rapid inflation and deflation cuffs may be used when a standard stimulus is needed. Cutoff values for reflux have been defined. Perforating veins must be identified and flow direction during compression recorded. When ulcers are present, duplex ultrasound is used to investigate veins of the ulcerated legs. Venous outflow obstruction is also studied by duplex ultrasound and chronic changes in deep and superficial veins following deep venous thrombosis noted. The main drawback in evaluation of chronic obstruction is inability to quantify hemodynamic significance. Anatomic variations in superficial and deep veins are common and their identification is necessary. Reporting results of duplex ultrasound studies must take into consideration the proper classification of venous disease as well as the new anatomic terms that have been accepted.

  17. Consensus preferred hydration sites in six FKBP12-drug complexes.

    PubMed

    Faerman, C H; Karplus, P A

    1995-09-01

    A set of consensus hydration sites for the FK506-FKBP12 complex are derived by comparing six FKBP12-drug complexes. These hydration sites include a subset of the observed water molecules plus some sites that are occupied by neighboring protein atoms in the FK506-FKBP12 crystal structure. Two hydration prediction algorithms, AUTO-SOL and AQUARIUS2, showed significant increases in apparent efficacy using these consensus water sites, suggesting that our proposed set of consensus hydration sites is truly a better representation of the hydration properties of FKBP12 in solution. Predictably, the consensus hydration sites include all buried water molecules. Otherwise, the features of solvation sites included in the consensus list versus those discarded reveal no distinctive features that would allow them to be selected unambiguously without reference to multiple crystal forms. We suggest that analyses such as this one are a crucial prelude to any theoretical analysis aimed at understanding hydration properties.

  18. Sodium montmorillonite/amine-containing drugs complexes: new insights on intercalated drugs arrangement into layered carrier material.

    PubMed

    Bello, Murilo L; Junior, Aridio M; Vieira, Bárbara A; Dias, Luiza R S; de Sousa, Valéria P; Castro, Helena C; Rodrigues, Carlos R; Cabral, Lucio M

    2015-01-01

    Layered drug delivery carriers are current targets of nanotechnology studies since they are able to accommodate pharmacologically active substances and are effective at modulating drug release. Sodium montmorillonite (Na-MMT) is a clay that has suitable properties for developing new pharmaceutical materials due to its high degree of surface area and high capacity for cation exchange. Therefore Na-MMT is a versatile material for the preparation of new drug delivery systems, especially for slow release of protonable drugs. Herein, we describe the intercalation of several amine-containing drugs with Na-MMT so we can derive a better understanding of how these drugs molecules interact with and distribute throughout the Na-MMT interlayer space. Therefore, for this purpose nine sodium montmorillonite/amine-containing drugs complexes (Na-MMT/drug) were prepared and characterized. In addition, the physicochemical properties of the drugs molecules in combination with different experimental conditions were assessed to determine how these factors influenced experimental outcomes (e.g. increase of the interlayer spacing versus drugs arrangement and orientation). We also performed a molecular modeling study of these amine-containing drugs associated with different Na-MMT/drug complex models to analyze the orientation and arrangement of the drugs molecules in the complexes studied. Six amine-containing drugs (rivastigmine, doxazosin, 5-fluorouracil, chlorhexidine, dapsone, nystatin) were found to successfully intercalate Na-MMT. These findings provide important insights on the interlayer aspect of the molecular systems formed and may contribute to produce more efficient drug delivery nanosystems.

  19. Complexation of aromatic drugs with single-walled carbon nanotubes

    NASA Astrophysics Data System (ADS)

    Buchelnikov, Anatoly S.; Voronin, Dmitry P.; Kostjukov, Viktor V.; Deryabina, Tatyana A.; Khrapatiy, Sergii V.; Prylutskyy, Yuriy I.; Ritter, Uwe; Evstigneev, Maxim P.

    2014-07-01

    We report a detailed study of the complexation of aromatic molecules and drugs with the surface of single-walled carbon nanotubes (SWCNTs, the diameter and the length ranges are 0.5-2 nm and 1-5 μm, respectively) in terms of equilibrium binding constants, K. It is found that the binding constants have magnitudes of the order of 104-105 M-1 and that there is some ligand specificity to the SWCNT surface depending on the structure of the aromatic molecule. The observed specificity is strongly governed by the curvature of the ligand chromophore and the type of side chains, resulting in the highest K for methylene blue which closely matches the curvature of the SWCNT surface. Stabilization of the drug-SWCNT complexes is found to be mainly due to intermolecular van der Waals forces and to a lesser extent by hydrophobic interactions. The approach suggested for determination of the binding parameters may be used as an alternative, or complementary, to standard Langmuir analysis.

  20. Gallium phosphinoarylbisthiolato complexes counteract drug resistance of cancer cells.

    PubMed

    Fischer-Fodor, Eva; Vălean, Ana-Maria; Virag, Piroska; Ilea, Petru; Tatomir, Corina; Imre-Lucaci, Florica; Schrepler, Maria Perde; Krausz, Ludovic Tibor; Tudoran, Lucian Barbu; Precup, Calin George; Lupan, Iulia; Hey-Hawkins, Evamarie; Silaghi-Dumitrescu, Luminita

    2014-04-01

    In cancer therapy the platinum-based drugs are used frequently with a good clinical outcome, but besides unwanted side effects which occur, the tumour cells subjected to treatment are prone to develop tolerance or even multidrug resistance (MDR). Metal compounds with a central atom other than platinum are efficient in targeting the chemoresistant cells, therefore the biological outcome of two recently synthesized gallium phosphinoarylbisthiolato complexes was studied, having the formula [X][Ga{PPh(2-SC6H4)2-κ(3)S,S',P}{PPh(2-SC6H4)2-κ(2)S,S'}] where [X] is either the NEt3H (1) or PPh4 (2) cation. Compounds 1 and 2 display in vitro cytotoxicity against both platinum-sensitive and platinum-resistant cell lines (A2780 and A2780cis). Morphological and ultrastructural evidence points toward their capacity to impair tumour cells survival. This behaviour is based on malignant cells capacity to selectively intake gallium, and to bind to the cellular DNA. They are able to cause massive DNA damage in treated cancer cells, focusing on 7-methylguanine and 8-oxoguanine sites and oxidizing the pyrimidine bases; this leads to early apoptosis of a significant percent of treated cells. The intrinsic and extrinsic apoptotic pathways are influenced through the modulation of gene expression following the treatment with complexes 1 and 2, which accompanies the negative regulation of P-glycoprotein 1 (Pgp-1), an important cellular ABC-type transporter from the multidrug resistance (MDR) family. The studied Ga(III) compounds demonstrated the capacity to counteract the chemoresistance mechanisms in the tumours defiant to standard drug action. Compound 2 shows a good anticancer potential and it could represent an alternative to platinum-based drugs especially in the situation of standard treatment failure.

  1. Cavitation erosion of duplex and super duplex stainless steels

    SciTech Connect

    Kwok, C.T.; Man, H.C.; Cheng, F.T.

    1998-10-05

    Owing to their excellent corrosion resistance, stainless steels are widely used both in the marine, urban water, chemical and food industries. In addition to the corrosive environment, high fluid flow speeds are always encountered for components used in these industries. The cavitation characteristics of S30400 and S31600 austenitic stainless steels and duplex stainless steels were studied in detail by a number of authors. It was generally agreed that S30400 has higher cavitation erosion resistance than that of S31600 due to higher tendency of strain induced martensitic transformation under high impulse of stress. A considerable number of results on stress corrosion cracking characteristics of SDSS and duplex stainless steels have been published but data concerning their cavitation erosion property are extremely rare.

  2. Structural basis for duplex RNA recognition and cleavage by Archaeoglobus fulgidus C3PO

    PubMed Central

    Parizotto, Eneida A; Lowe, Edward D; Parker, James S

    2013-01-01

    Oligomeric complexes of Trax and Translin proteins, known as C3POs, participate in a variety of eukaryotic nucleic acid metabolism pathways including RNAi and tRNA processing. In RNAi in humans and Drosophila, C3PO activates pre-RISC by removing the passenger strand of the siRNA precursor duplex using nuclease activity present in Trax. It is not known how C3POs engage with nucleic acid substrates. Here we identify a single protein from Archaeoglobus fulgidus that assembles into an octamer with striking similarity to human C3PO. The structure in complex with duplex RNA reveals that the octamer entirely encapsulates a single thirteen base-pair RNA duplex inside a large inner cavity. Trax-like subunit catalytic sites target opposite strands of the duplex for cleavage, separated by seven base pairs. The structure provides insight into the mechanism of RNA recognition and cleavage by an archaeal C3PO-like complex. PMID:23353787

  3. Sodium Montmorillonite/Amine-Containing Drugs Complexes: New Insights on Intercalated Drugs Arrangement into Layered Carrier Material

    PubMed Central

    Vieira, Bárbara A.; Dias, Luiza R. S.; de Sousa, Valéria P.; Castro, Helena C.; Rodrigues, Carlos R.; Cabral, Lucio M.

    2015-01-01

    Layered drug delivery carriers are current targets of nanotechnology studies since they are able to accommodate pharmacologically active substances and are effective at modulating drug release. Sodium montmorillonite (Na-MMT) is a clay that has suitable properties for developing new pharmaceutical materials due to its high degree of surface area and high capacity for cation exchange. Therefore Na-MMT is a versatile material for the preparation of new drug delivery systems, especially for slow release of protonable drugs. Herein, we describe the intercalation of several amine-containing drugs with Na-MMT so we can derive a better understanding of how these drugs molecules interact with and distribute throughout the Na-MMT interlayer space. Therefore, for this purpose nine sodium montmorillonite/amine-containing drugs complexes (Na-MMT/drug) were prepared and characterized. In addition, the physicochemical properties of the drugs molecules in combination with different experimental conditions were assessed to determine how these factors influenced experimental outcomes (e.g. increase of the interlayer spacing versus drugs arrangement and orientation). We also performed a molecular modeling study of these amine-containing drugs associated with different Na-MMT/drug complex models to analyze the orientation and arrangement of the drugs molecules in the complexes studied. Six amine-containing drugs (rivastigmine, doxazosin, 5-fluorouracil, chlorhexidine, dapsone, nystatin) were found to successfully intercalate Na-MMT. These findings provide important insights on the interlayer aspect of the molecular systems formed and may contribute to produce more efficient drug delivery nanosystems. PMID:25803292

  4. Evaluation of various processes for simultaneous complexation and granulation to incorporate drug-cyclodextrin complexes into solid dosage forms.

    PubMed

    Gyanani, Vijay; Siddalingappa, Basavaraj; Betageri, Guru V

    2015-01-01

    Insoluble drugs often formulated with various excipients to enhance the dissolution. Cyclodextrins (CDs) are widely used excipients to improve dissolution profile of poorly soluble drugs. Drug-CD complexation process is complex and often requires multiple processes to produce solid dosage form. Hence, this study explored commonly used granulation processes for simultaneous complexation and granulation. Poorly soluble drugs ibuprofen and glyburide were selected as experimental drugs. Co-evaporation of drug:CD mixture from a solvent followed by wet granulation with water was considered as standard process for comparison. Spray granulation and fluid bed processing (FBP) using drug:CD solution in ethanol were evaluated as an alternative processes. The dissolution data of glyburide tablets indicated that tablets produced by spray granulation, FBP and co-evaporation-granulation have almost identical dissolution profile in water and 0.1% SLS (>70% in water and >60% in SLS versus 30 and 34%, respectively for plain tablet, in 120 min). Similarly, ibuprofen:CD tablets produced by co-evaporation-granulation and FBP displayed similar dissolution profile in 0.01 M HCl (pH 2.0) and buffer pH 5.5 (>90 and 100% versus 44 and 80% respectively for plain tablets, 120 min). Results of this study demonstrated that spray granulation is simple and cost effective process for low dose poorly soluble drugs to incorporate drug:CD complex into solid dosage form, whereas FBP is suitable for poorly soluble drugs with moderate dose.

  5. View from east to west of family housing unit (duplex; ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View from east to west of family housing unit (duplex; either #27 or #87, as only the 7 is visible). Unit #27 was three-bedroom and located on 9th Street south. Unit #87 was a two-bedroom located on 4th Street north. These housing units have been removed - Stanley R. Mickelsen Safeguard Complex, Family Housing Units, In area bounded by Tenth Street North, Avenue A, & Avenue J, Nekoma, Cavalier County, ND

  6. Duplex-Selective Ruthenium-based DNA Intercalators

    PubMed Central

    Shade, Chad M.; Kennedy, Robert D.; Rouge, Jessica L.; Rosen, Mari S.; Wang, Mary X.; Seo, Soyoung E.; Clingerman, Daniel J.

    2016-01-01

    We report the design and synthesis of small molecules that exhibit enhanced luminescence in the presence of duplex rather than single-stranded DNA. The local environment presented by a well-known [Ru(dipyrido[2,3-a:3',2'-c]phenazine)L2]2+-based DNA intercalator was modified by functionalizing the bipyridine ligands with esters and carboxylic acids. By systematically varying the number and charge of the pendant groups, it was determined that decreasing the electrostatic interaction between the intercalator and the anionic DNA backbone reduced single-strand interactions and translated to better duplex specificity. In studying this class of complexes, a single RuII complex emerged that selectively luminesces in the presence of duplex DNA with little to no background from interacting with single stranded DNA. This complex shows promise as a new dye capable of selectively staining double versus single-stranded DNA in gel electrophoresis, which cannot be done with conventional SYBR dyes. PMID:26119581

  7. A novel sustained release drug-resin complex-based microbeads of ciprofloxacin HCl.

    PubMed

    Jain, Sunil K; Prajapati, Neeraj; Rajpoot, Kuldeep; Kumar, Amrish

    2016-12-01

    Objective A novel multiparticulate system for the gastro-mucoadhesive delivery of ciprofloxacin HCl (CFN) was developed with the help of ion-exchange resin to deal with urinary tract (UT) infections effectively. Materials and methods An optimized complex (resinate) of CFN with sodium polystyrene sulfonate USP resin was prepared and entrapped within microbeads of sodium alginate and pectin. The developed systems were evaluated for drug entrapment efficiency, percentage of mucoadhesion and in vitro release patterns in simulated gastric fluid (pH 1.2). Results and discussion The interaction of the resin complex and polycation via alginate was consequently supported the formation of polyelectrolyte complex membrane. The in vitro drug release studies demonstrate that formulation without drug-resin complex (NRB) released the drug more swiftly than formulation containing drug-resin complex (DRC). This controlled release pattern of drug, resin complex containing microbeads was owed to complexation between drug and resin. Conclusion Preliminary results from the study suggested that this drug-resin complex-entrapped microbeads can be used to incorporate other antibiotic drugs and could be effective against UT infection. Such developed formulation could be subjected to in vivo studies in future in order to prove their efficacy for such type of infections.

  8. Role of complexes formation between drugs and penetration enhancers in transdermal delivery.

    PubMed

    Drakulić, Branko J; Juranić, Ivan O; Erić, Slavica; Zloh, Mire

    2008-11-03

    The use of chemical penetration enhancers (CPE) is growing due to their ability to improve drug delivery through the skin. A possible mechanism of penetration enhancement could involve the complex formation between drug and components in the pharmaceutical formulation, thus altering the physicochemical properties of the active substance. Here, modelling studies indicate that hydrocarbon and oxygen-containing terpenes (penetration enhancers) could form complexes with drugs. Satisfactory correlations have been obtained between the predicted molecular properties of enhancers and their enhancement effects.

  9. Duplex Direct Data Distribution System

    NASA Technical Reports Server (NTRS)

    Greenfield, Israel (Technical Monitor)

    2001-01-01

    The NASA Glenn Research Center (GRC) is developing and demonstrating communications and network technologies that are helping to enable the near-Earth space Internet. GRC envisions several service categories. The first of these categories is direct data distribution or D3 (pronounced "D-cubed"). Commercially provided D3 will make it possible to download a data set from a spacecraft, like the International Space Station. as easily as one can extract a file from a remote server today, using a file transfer protocol. In a second category, NASA spacecraft will make use of commercial satellite communication (SATCOM) systems. Some of those services will come from purchasing time on unused transponders that cover landmasses. While it is likely there will be gaps in service coverage, Internet services should be available using these systems. This report addresses alternative methods of implementing a full duplex enhancement of the GRC developed experimental Ka-Band Direct Data Distribution (D3) space-to-ground communication link. The resulting duplex version is called the Duplex Direct Data Distribution (D4) system. The D4 system is intended to provide high-data-rate commercial direct or internet-based communications service between the NASA spacecraft in low earth orbit (LEO) and the respective principal investigators associated with these spacecraft. Candidate commercial services were assessed regarding their near-term potential to meet NASA requirements. Candidates included Ka-band and V-band geostationary orbit and non-geostationary orbit satellite relay services and direct downlink ("LEO teleport") services. End-to-end systems concepts were examined and characterized in terms of alternative link layer architectures. Alternatives included a Direct Link, a Relay Link, a Hybrid Link, and a Dual Mode Link. The direct link assessment examined sample ground terminal placements and antenna angle issues. The SATCOM-based alternatives examined existing or proposed commercial

  10. Crystal structure of the [Mg2+-(chromomycin A3)2]-d(TTGGCCAA)2 complex reveals GGCC binding specificity of the drug dimer chelated by a metal ion.

    PubMed

    Hou, Ming-Hon; Robinson, Howard; Gao, Yi-Gui; Wang, Andrew H-J

    2004-01-01

    The anticancer antibiotic chromomycin A3 (Chro) is a DNA minor groove binding drug belonging to the aureolic family. Chro likely exerts its activity by interfering with replication and transcription. Chro forms a dimer, mediated by a divalent metal ion, which binds to G/C-rich DNA. Herein we report the first crystal structure of Chro bound to d(TTG GCCAA)2 DNA duplex solved by multiwavelength anomalous diffraction (MAD) based on the chelated Co3+ ion. The structure of the Mg2+ complex was subsequently refined at 2.15 A resolution, which revealed two complexes of metal-coordinated dimers of Chro bound to the octamer DNA duplex in the asymmetric unit. The metal ion is octahedrally coordinated to the O1 and O9 oxygen atoms of the chromophore (CPH), and two water molecules act as the fifth and sixth ligands. The two coordinated water molecules are hydrogen bonded to O2 atoms of C5 and C13 bases. The Chro dimer binds at and significantly widens the minor groove of the GGCC sequence. The long axis of each chromophore lies along and stacks over the sugar-phosphate backbone with the two attached saccharide moieties (rings A/B and C/D/E) wrapping across the minor groove. DNA is kinked by 30 degrees and 36 degrees in the two complexes, respectively. Six G-specific hydrogen bonds between Chro and DNA provide the GGCC sequence specificity. Interestingly, DNA in concert with Chro appears to act as an effective template to catalyze the deamination of Co(NH3)6(3+), as shown by circular dichroism and crystal structure data. Our results present useful structural information for designing new anticancer drug derivatives in the future.

  11. [Two complex suicidal poisonings with drugs and their medicolegal aspects].

    PubMed

    Kłys, M; Skupień, E; Bujak-Gizycka, B; Latacz, B

    2001-01-01

    The main subject of the study was a toxicological investigation of biological specimens coming from two cases of intoxication with mixture of drugs. Two young people decided to commit suicide by the use of mixture of drugs mainly analgesic in approximately equal doses. For one person the dose of drugs administered turned out to be fatal while second person survived with the symptoms of acute intoxication. The analysis carried out with the use of liquid chromatographic method with mass detection (HPLC/MS) confirmed the presence of mixture of drugs in blood of living person and in postmortem specimens of the victim in significant concentrations. The toxicological findings have delivered information for discussion in medico-legal and ethical aspects.

  12. Drug-disease association and drug-repositioning predictions in complex diseases using causal inference-probabilistic matrix factorization.

    PubMed

    Yang, Jihong; Li, Zheng; Fan, Xiaohui; Cheng, Yiyu

    2014-09-22

    The high incidence of complex diseases has become a worldwide threat to human health. Multiple targets and pathways are perturbed during the pathological process of complex diseases. Systematic investigation of complex relationship between drugs and diseases is necessary for new association discovery and drug repurposing. For this purpose, three causal networks were constructed herein for cardiovascular diseases, diabetes mellitus, and neoplasms, respectively. A causal inference-probabilistic matrix factorization (CI-PMF) approach was proposed to predict and classify drug-disease associations, and further used for drug-repositioning predictions. First, multilevel systematic relations between drugs and diseases were integrated from heterogeneous databases to construct causal networks connecting drug-target-pathway-gene-disease. Then, the association scores between drugs and diseases were assessed by evaluating a drug's effects on multiple targets and pathways. Furthermore, PMF models were learned based on known interactions, and associations were then classified into three types by trained models. Finally, therapeutic associations were predicted based upon the ranking of association scores and predicted association types. In terms of drug-disease association prediction, modified causal inference included in CI-PMF outperformed existing causal inference with a higher AUC (area under receiver operating characteristic curve) score and greater precision. Moreover, CI-PMF performed better than single modified causal inference in predicting therapeutic drug-disease associations. In the top 30% of predicted associations, 58.6% (136/232), 50.8% (31/61), and 39.8% (140/352) hit known therapeutic associations, while precisions obtained by the latter were only 10.2% (231/2264), 8.8% (36/411), and 9.7% (189/1948). Clinical verifications were further conducted for the top 100 newly predicted therapeutic associations. As a result, 21, 12, and 32 associations have been studied and

  13. The use of hairpin DNA duplexes as HIV-1 fusion inhibitors: synthesis, characterization, and activity evaluation.

    PubMed

    Xu, Liang; Jiang, Xifeng; Xu, Xiaoyu; Zheng, Baohua; Chen, Xueliang; Zhang, Tao; Gao, Fang; Cai, Lifeng; Cheng, Maosheng; Keliang Liu

    2014-07-23

    Discovery of new drugs for the treatment of AIDS that possess unique structures associated with novel mechanisms of action are of great importance due the rapidity with which drug-resistant HIV-1 strains evolve. Recently we reported on a novel class of DNA duplex-based HIV-1 fusion inhibitors modified with hydrophobic groups. The present study describes a new category of hairpin fusion inhibitor DNA duplexes bearing a 3 nucleotide loop located at either the hydrophobic or hydrophilic end. The new loop structures were designed to link 2 separate duplex-forming oligodeoxynucleotides (ODNs) to make helix-assembly easier and more thermally stable resulting in a more compact form of DNA duplex based HIV-1 fusion inhibitors. A series of new hairpin duplexes were tested for anti-HIV-1 cell-cell membrane fusion activity. In addition, Tm, CD, fluorescent resonance energy transfer assays, and molecular modeling analyses were carried out to define their structural activity relationships and possible mechanisms of action.

  14. Chitosan-polycarbophil complexes in swellable matrix systems for controlled drug release.

    PubMed

    Lu, Z; Chen, W; Hamman, J H

    2007-10-01

    A prerequisite for progress in the design of novel drug delivery systems is the development of excipients that are capable of fulfilling multifunctional roles such as controlling the release of the drug according to the therapeutic needs. Although several polymers have been utilised in the development of specialised drug delivery systems, their scope in dosage form design can be enlarged through combining different polymers. When a polymer is cross-linked or complexed with an oppositely charged polyelectrolyte, a three-dimensional network is formed in which the drug can be incorporated to control its release. The swelling properties and release kinetics of two model drugs with different water solubilities (i.e. diltiazem and ibuprofen) from monolithic matrix tablets consisting of an interpolyelectrolyte complex between chitosan and polycarbophil are reported. Matrix tablets consisting of this polymeric complex without drug or excipients exhibited extremely high swelling properties that are completely reversible upon drying. The drug release from matrix systems with different formulations depended on the concentration of the chitosan-polycarbophil interpolyelectrolyte complex and approached zero order release kinetics for both model drugs. The chitosan-polycarbophil interpolyelectrolyte complex has demonstrated a high potential as an excipient for the production of swellable matrix systems with controlled drug release properties.

  15. Hypromellose-graft-chitosan and Its Polyelectrolyte Complex as Novel Systems for Sustained Drug Delivery.

    PubMed

    Lai, Wing-Fu; Shum, Ho Cheung

    2015-05-20

    Polyelectrolyte complexes formed between chitosan (CS) and anionic polymers have attracted increasing interest in drug delivery. In this study, CS is copolymerized with hypromellose via a coupling reagent-mediated approach to form a water-soluble, nontoxic CS derivative, namely hypromellose-graft-CS (HC), which is subsequently complexed with carboxymethylcellulose (CMC) to generate a polyampholytic hydrogel. When compared with conventional CS, HC is highly water-soluble across a wide pH range, and has a substantially higher pH buffering capacity to provide a pH-stable environment for delivery of drugs. In addition, the polyelectrolyte complex of HC exhibits a drug encapsulation efficiency of over 90% in all drugs tested, which is 1-2 fold higher than the efficiency attainable by the polyelectrolyte complex of conventional CS, with a 2-3 fold longer duration of sustained drug release. Our results indicate that as a novel polymer, HC has excellent promise for future pharmaceutical applications.

  16. Atomic level insights into realistic molecular models of dendrimer-drug complexes through MD simulations

    NASA Astrophysics Data System (ADS)

    Jain, Vaibhav; Maiti, Prabal K.; Bharatam, Prasad V.

    2016-09-01

    Computational studies performed on dendrimer-drug complexes usually consider 1:1 stoichiometry, which is far from reality, since in experiments more number of drug molecules get encapsulated inside a dendrimer. In the present study, molecular dynamic (MD) simulations were implemented to characterize the more realistic molecular models of dendrimer-drug complexes (1:n stoichiometry) in order to understand the effect of high drug loading on the structural properties and also to unveil the atomistic level details. For this purpose, possible inclusion complexes of model drug Nateglinide (Ntg) (antidiabetic, belongs to Biopharmaceutics Classification System class II) with amine- and acetyl-terminated G4 poly(amidoamine) (G4 PAMAM(NH2) and G4 PAMAM(Ac)) dendrimers at neutral and low pH conditions are explored in this work. MD simulation analysis on dendrimer-drug complexes revealed that the drug encapsulation efficiency of G4 PAMAM(NH2) and G4 PAMAM(Ac) dendrimers at neutral pH was 6 and 5, respectively, while at low pH it was 12 and 13, respectively. Center-of-mass distance analysis showed that most of the drug molecules are located in the interior hydrophobic pockets of G4 PAMAM(NH2) at both the pH; while in the case of G4 PAMAM(Ac), most of them are distributed near to the surface at neutral pH and in the interior hydrophobic pockets at low pH. Structural properties such as radius of gyration, shape, radial density distribution, and solvent accessible surface area of dendrimer-drug complexes were also assessed and compared with that of the drug unloaded dendrimers. Further, binding energy calculations using molecular mechanics Poisson-Boltzmann surface area approach revealed that the location of drug molecules in the dendrimer is not the decisive factor for the higher and lower binding affinity of the complex, but the charged state of dendrimer and drug, intermolecular interactions, pH-induced conformational changes, and surface groups of dendrimer do play an

  17. PCR hot-start using duplex primers.

    PubMed

    Kong, Deming; Shen, Hanxi; Huang, Yanping; Mi, Huaifeng

    2004-02-01

    A new technique of PCR hot-start using duplex primers has been developed which can decrease the undesirable products arising throughout PCR amplification thereby giving better results than a manual hot-start method.

  18. Gang Membership and Drug Involvement: Untangling the Complex Relationship

    ERIC Educational Resources Information Center

    Bjerregaard, Beth

    2010-01-01

    Previous research has consistently demonstrated a relationship between gang membership and involvement in illegal substances. In addition, researchers have noted that gang members are frequently more heavily involved in drug sales, which often lead to increases in violent behaviors. Most of this research, however, is either cross-sectional or…

  19. Unravelling the complex drug-drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein.

    PubMed

    Ledwitch, Kaitlyn V; Barnes, Robert W; Roberts, Arthur G

    2016-01-28

    Drug-drug interactions (DDIs) and associated toxicity from cardiovascular drugs represents a major problem for effective co-administration of cardiovascular therapeutics. A significant amount of drug toxicity from DDIs occurs because of drug interactions and multiple cardiovascular drug binding to the efflux transporter P-glycoprotein (Pgp), which is particularly problematic for cardiovascular drugs because of their relatively low therapeutic indexes. The calcium channel antagonist, verapamil and the cardiac glycoside, digoxin, exhibit DDIs with Pgp through non-competitive inhibition of digoxin transport, which leads to elevated digoxin plasma concentrations and digoxin toxicity. In the present study, verapamil-induced ATPase activation kinetics were biphasic implying at least two verapamil-binding sites on Pgp, whereas monophasic digoxin activation of Pgp-coupled ATPase kinetics suggested a single digoxin-binding site. Using intrinsic protein fluorescence and the saturation transfer double difference (STDD) NMR techniques to probe drug-Pgp interactions, verapamil was found to have little effect on digoxin-Pgp interactions at low concentrations of verapamil, which is consistent with simultaneous binding of the drugs and non-competitive inhibition. Higher concentrations of verapamil caused significant disruption of digoxin-Pgp interactions that suggested overlapping and competing drug-binding sites. These interactions correlated to drug-induced conformational changes deduced from acrylamide quenching of Pgp tryptophan fluorescence. Also, Pgp-coupled ATPase activity kinetics measured with a range of verapamil and digoxin concentrations fit well to a DDI model encompassing non-competitive and competitive inhibition of digoxin by verapamil. The results and previous transport studies were combined into a comprehensive model of verapamil-digoxin DDIs encompassing drug binding, ATP hydrolysis, transport and conformational changes.

  20. About Complexity and Self-Similarity of Chemical Structures in Drug Discovery

    NASA Astrophysics Data System (ADS)

    von Korff, Modest; Sander, Thomas

    A new method is introduced to calculate the complexity of organic molecules in drug discovery. The complexity is calculated by taking the number of unique connected subgraphs u as basis c = f(a, b, p, u). With a and b are the number of atoms and bonds, respectively and p is the ratio of covered bonds by redundant fragments. A set of five datasets with 50 molecules each was analyzed. The datasets were compiled from bioactive natural products, approved drugs, highly bioactive molecules, commercially available compounds for high throughput screening and artificial generated molecules. Comparing the median of c for the five datasets showed a significant increase in the following order: commercially available compounds < bioactive molecules < approved drugs < natural products < artificial molecules. With the introduced complexity value c a meaningful figure of merit was developed to assess automatically the complexity of single compounds and compound libraries in drug discovery.

  1. Sequence-specific interactions of drugs interfering with the topoisomerase-DNA cleavage complex.

    PubMed

    Palumbo, Manlio; Gatto, Barbara; Moro, Stefano; Sissi, Claudia; Zagotto, Giuseppe

    2002-07-18

    DNA-processing enzymes, such as the topoisomerases (tops), represent major targets for potent anticancer (and antibacterial) agents. The drugs kill cells by poisoning the enzymes' catalytic cycle. Understanding the molecular details of top poisoning is a fundamental requisite for the rational development of novel, more effective antineoplastic drugs. In this connection, sequence-specific recognition of the top-DNA complex is a key step to preferentially direct the action of the drugs onto selected genomic sequences. In fact, the (reversible) interference of drugs with the top-DNA complex exhibits well-defined preferences for DNA bases in the proximity of the cleavage site, each drug showing peculiarities connected to its structural features. A second level of selectivity can be observed when chemically reactive groups are present in the structure of the top-directed drug. In this case, the enzyme recognizes or generates a unique site for covalent drug-DNA binding. This will further subtly modulate the drug's efficiency in stimulating DNA damage at selected sites. Finally, drugs can discriminate not only among different types of tops, but also among different isoenzymes, providing an additional level of specific selection. Once the molecular basis for DNA sequence-dependent recognition has been established, the above-mentioned modes to generate selectivity in drug poisoning can be rationally exploited, alone or in combination, to develop tailor-made drugs targeted at defined loci in cancer cells.

  2. Duplex sampling apparatus and method

    DOEpatents

    Brown, Paul E.; Lloyd, Robert

    1992-01-01

    An improved apparatus is provided for sampling a gaseous mixture and for measuring mixture components. The apparatus includes two sampling containers connected in series serving as a duplex sampling apparatus. The apparatus is adapted to independently determine the amounts of condensable and noncondensable gases in admixture from a single sample. More specifically, a first container includes a first port capable of selectively connecting to and disconnecting from a sample source and a second port capable of selectively connecting to and disconnecting from a second container. A second container also includes a first port capable of selectively connecting to and disconnecting from the second port of the first container and a second port capable of either selectively connecting to and disconnecting from a differential pressure source. By cooling a mixture sample in the first container, the condensable vapors form a liquid, leaving noncondensable gases either as free gases or dissolved in the liquid. The condensed liquid is heated to drive out dissolved noncondensable gases, and all the noncondensable gases are transferred to the second container. Then the first and second containers are separated from one another in order to separately determine the amount of noncondensable gases and the amount of condensable gases in the sample.

  3. Different duplex/quadruplex junctions determine the properties of anti-thrombin aptamers with mixed folding.

    PubMed

    Russo Krauss, Irene; Spiridonova, Vera; Pica, Andrea; Napolitano, Valeria; Sica, Filomena

    2016-01-29

    Mixed duplex/quadruplex oligonucleotides have attracted great interest as therapeutic targets as well as effective biomedical aptamers. In the case of thrombin-binding aptamer (TBA), the addition of a duplex motif to the G-quadruplex module improves the aptamer resistance to biodegradation and the affinity for thrombin. In particular, the mixed oligonucleotide RE31 is significantly more effective than TBA in anticoagulation experiments and shows a slower disappearance rate in human plasma and blood. In the crystal structure of the complex with thrombin, RE31 adopts an elongated structure in which the duplex and quadruplex regions are perfectly stacked on top of each other, firmly connected by a well-structured junction. The lock-and-key shape complementarity between the TT loops of the G-quadruplex and the protein exosite I gives rise to the basic interaction that stabilizes the complex. However, our data suggest that the duplex motif may have an active role in determining the greater anti-thrombin activity in biological fluids with respect to TBA. This work gives new information on mixed oligonucleotides and highlights the importance of structural data on duplex/quadruplex junctions, which appear to be varied, unpredictable, and fundamental in determining the aptamer functional properties.

  4. Ultrasensitive Detection of RNA and DNA Viruses Simultaneously Using Duplex UNDP-PCR Assay.

    PubMed

    Huang, Yong; Xing, Na; Wang, Zengguo; Zhang, Xiujuan; Zhao, Xiaomin; Du, Qian; Chang, Lingling; Tong, Dewen

    2015-01-01

    Mixed infection of multiple viruses is common in modern intensive pig rearing. However, there are no methods available to detect DNA and RNA viruses in the same reaction system in preclinical level. In this study, we aimed to develop a duplex ultrasensitive nanoparticle DNA probe-based PCR assay (duplex UNDP-PCR) that was able to simultaneously detect DNA and RNA viruses in the same reaction system. PCV2 and TGEV are selected as representatives of the two different types of viruses. PCV2 DNA and TGEV RNA were simultaneously released from the serum sample by boiling with lysis buffer, then magnetic beads and gold nanoparticles coated with single and/or duplex specific probes for TGEV and PCV2 were added to form a sandwich-like complex with nucleic acids released from viruses. After magnetic separation, DNA barcodes specific for PCV2 and TGEV were eluted using DTT and characterized by specific PCR assay for specific DNA barcodes subsequently. The duplex UNDP-PCR showed similar sensitivity as that of single UNDP-PCR and was able to detect 20 copies each of PCV2 and TGEV in the serum, showing approximately 250-fold more sensitivity than conventional duplex PCR/RT-PCR assays. No cross-reaction was observed with other viruses. The positive detection rate of single MMPs- and duplex MMPs-based duplex UNDP-PCR was identical, with 29.6% for PCV2, 9.3% for TGEV and 3.7% for PCV2 and TGEV mixed infection. This duplex UNDP-PCR assay could detect TGEV (RNA virus) and PCV2 (DNA virus) from large-scale serum samples simultaneously without the need for DNA/RNA extraction, purification and reverse transcription of RNA, and showed a significantly increased positive detection rate for PCV2 (29%) and TGEV (11.7%) preclinical infection than conventional duplex PCR/RT-PCR. Therefore, the established duplex UNDP-PCR is a rapid and economical detection method, exhibiting high sensitivity, specificity and reproducibility.

  5. Investigation of the complexation of the anti-cancer drug novantrone with the hairpin structure of the deoxyheptanucleotide 5‧-d(GpCpGpApApGpC)

    NASA Astrophysics Data System (ADS)

    Kostjukov, V. V.; Pahomov, V. I.; Andrejuk, D. D.; Davies, D. B.; Evstigneev, M. P.

    2007-10-01

    In aqueous solution the deoxyheptanucleotide, 5'-d(GpCpGpApApGpC), exists as a very stable hairpin structure in equilibrium with small proportions of the single-stranded and duplex forms. Complexation of the anti-cancer drug novantrone (mitoxantrone) with the DNA heptamer was investigated by one- and two-dimensional 500 MHz 1H NMR spectroscopy (2M-TOCSY, 2M-NOESY) and molecular dynamics simulations. The proton chemical shifts of NOV in mixed solutions with the heptamer were measured as a function of concentration and temperature and the equilibrium association parameters were determined for complexation of NOV with the three forms of the heptamer. The spatial structure of the complex of the antibiotic with the hairpin form of the heptamer was built on the basis of 2D-NOE data. The conformational dynamics of the complex and its interaction with the water environment were investigated by molecular dynamics methods. The results suggest that NOV complexes with the hairpin form of the heptamer in solution by intercalation. Complexation of NOV with the hairpin stem results in a disruption of about one half of the intramolecular water bridges of the hairpin, which is considered to be the main reason for the observed decrease in the thermodynamical stability of the hairpin on binding with the ligand.

  6. Biocompatible Double-Membrane Hydrogels from Cationic Cellulose Nanocrystals and Anionic Alginate as Complexing Drugs Codelivery.

    PubMed

    Lin, Ning; Gèze, Annabelle; Wouessidjewe, Denis; Huang, Jin; Dufresne, Alain

    2016-03-23

    A biocompatible hydrogel with a double-membrane structure is developed from cationic cellulose nanocrystals (CNC) and anionic alginate. The architecture of the double-membrane hydrogel involves an external membrane composed of neat alginate, and an internal composite hydrogel consolidates by electrostatic interactions between cationic CNC and anionic alginate. The thickness of the outer layer can be regulated by the adsorption duration of neat alginate, and the shape of the inner layer can directly determine the morphology and dimensions of the double-membrane hydrogel (microsphere, capsule, and filmlike shapes). Two drugs are introduced into the different membranes of the hydrogel, which will ensure the complexing drugs codelivery and the varied drugs release behaviors from two membranes (rapid drug release of the outer hydrogel, and prolonged drug release of the inner hydrogel). The double-membrane hydrogel containing the chemically modified cellulose nanocrystals (CCNC) in the inner membrane hydrogel can provide the sustained drug release ascribed to the "nano-obstruction effect" and "nanolocking effect" induced by the presence of CCNC components in the hydrogels. Derived from natural polysaccharides (cellulose and alginate), the novel double-membrane structure hydrogel material developed in this study is biocompatible and can realize the complexing drugs release with the first quick release of one drug and the successively slow release of another drug, which is expected to achieve the synergistic release effects or potentially provide the solution to drug resistance in biomedical application.

  7. Characterization of latex-antineoplastic drug complexes by differential scanning calorimetry and microphotography.

    PubMed

    Gallardo, V; Ruiz, M A; Morales, E; Zouaki, J; Campos, J; Conejo-García, A; Gallo, M A; Espinosa, A

    2006-12-01

    Choline kinase inhibitors have recently been identified as potentially useful antitumoral agents. Here we determine the best conditions for obtaining drug-polymer complexes with 5-fluorouracil (5-FU), and JCR791B, a new drug representing a significant advance in the development of new molecules to inhibit tumour proliferation. As polymers we used the cellulose derivatives Aquacoat and Aquateric. The variables in the adsorption process measured were time to adsorbent-adsorbate equilibrium, pH and concentration. The drug-polymer complexes were characterized by differential scanning calorimetry and microphotography. Our results show that adsorption of 5-FU and JCR was similar with both polymers although slightly greater with Aquacoat. The chemical structure of the drug and its solubility in water and oil are fundamental characteristics that determine the performance of polymers as drug carriers able to provide controlled release.

  8. Supramolecular Complexation of Carbohydrates for the Bioavailability Enhancement of Poorly Soluble Drugs.

    PubMed

    Cho, Eunae; Jung, Seunho

    2015-10-27

    In this review, a comprehensive overview of advances in the supramolecular complexes of carbohydrates and poorly soluble drugs is presented. Through the complexation process, poorly soluble drugs could be efficiently delivered to their desired destinations. Carbohydrates, the most abundant biomolecules, have diverse physicochemical properties owing to their inherent three-dimensional structures, hydrogen bonding, and molecular recognition abilities. In this regard, oligosaccharides and their derivatives have been utilized for the bioavailability enhancement of hydrophobic drugs via increasing the solubility or stability. By extension, polysaccharides and their derivatives can form self-assembled architectures with poorly soluble drugs and have shown increased bioavailability in terms of the sustained or controlled drug release. These supramolecular systems using carbohydrate will be developed consistently in the field of pharmaceutical and medical application.

  9. Dialkyl bisphosphonate platinum(II) complex as a potential drug for metastatic bone tumor.

    PubMed

    Nakatake, Hidetoshi; Ekimoto, Hisao; Aso, Mariko; Ogawa, Atsushi; Yamaguchi, Asami; Suemune, Hiroshi

    2011-01-01

    Bisphosphonates have high affinity for hydroxyapatite (HA), which is abundantly present in bone. Also, platinum complexes are known that have a wide spectrum of antitumor activities. The conjugate of bisphosphonate and a platinum complex might have HA affinity and antitumor activity, and become a drug for metastatic bone tumor. In this study, the authors synthesized platinum complexes that had dialkyl bisphosphonic acid as a ligand, and evaluated the possibility of the synthesized complexes as a drug for metastatic bone tumor. The synthesized dialkyl bisphosphonate platinum(II) complex was characterized, and its stability in an aqueous solution was also confirmed. The synthesized platinum complex showed higher HA affinity than other platinum complexes such as cisplatin and carboplatin in an experiment of adsorption to HA. In vitro, the platinum complex showed tumor growth inhibitory effect stronger than or equal to cisplatin, which is the most commonly used antitumor agent. Moreover, the platinum complex showed a bone absorption inhibitory effect on the osteoclast. These results suggest potential of dialkyl bisphosphonate platinum(II) complexes as a drug for metastatic bone tumor.

  10. Polyelectrolyte Complexes: A Review of their Applicability in Drug Delivery Technology

    PubMed Central

    Lankalapalli, S.; Kolapalli, V. R. M.

    2009-01-01

    Over the past several years, great advances have been made towards novel drug delivery systems. The phenomena of interpolymer interactions and formation of polyelectrolyte complexes have been the focus of intensive fundamental and applied research. Interpolyelectrolyte complexes combine unique physicochemical properties with high biocompatibility. Studies have been carried out on many different polymer blends and types. Such combinations may possess unique properties that are different from those of individual component. The present review emphasizes on the applicability of polyelectrolyte complexes in drug delivery technology. PMID:20502564

  11. Heat treatment temperature influence on ASTM A890 GR 6A super duplex stainless steel microstructure

    SciTech Connect

    Martins, Marcelo; E-mail: marcelo.martins@sulzer.com; Casteletti, Luiz Carlos

    2005-09-15

    Duplex and super duplex stainless steels are ferrous alloys with up to 26% chromium, 8% nickel, 5% molybdenum and 0.3% nitrogen, which are largely used in applications in media containing ions from the halogen family, mainly the chloride ion (Cl{sup -}). The emergence of this material aimed at substituting Copper-Nickel alloys (Cupro-Nickel) that despite presenting good corrosion resistance, has mechanical properties quite inferior to steel properties. The metallurgy of duplex and super duplex stainless steel is complex due to high sensitiveness to sigma phase precipitation that becomes apparent, due to the temperatures they are exposed on cooling from solidification as well as from heat treatment processes. The objective of this study was to verify the influence of heat treating temperatures on the microstructure and hardness of ASTM A890/A890M Gr 6A super duplex stainless steel type. Microstructure control is of extreme importance for castings, as the chemical composition and cooling during solidification inevitably provide conditions for precipitation of sigma phase. Higher hardness in these materials is directly associated to high sigma phase concentration in the microstructure, precipitated in the ferrite/austenite interface. While heat treatment temperature during solution treatment increases, the sigma phase content in the microstructure decreases and consequently, the material hardness diminishes. When the sigma phase was completely dissolved by the heat treatment, the material hardness was influenced only due to ferrite and austenite contents in the microstructure.

  12. FACILITY 810, REAR OF DUPLEX SHOWING COURTYARD BETWEEN WINGS, OBLIQUE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    FACILITY 810, REAR OF DUPLEX SHOWING COURTYARD BETWEEN WINGS, OBLIQUE VIEW FACING EAST. - Schofield Barracks Military Reservation, Duplex Housing Type with Corner Entries, Between Hamilton & Tidball Streets near Williston Avenue, Wahiawa, Honolulu County, HI

  13. 3. VIEW OF DUPLEX (FEATURE 7), FACING NORTH. OFFICE (FEATURE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    3. VIEW OF DUPLEX (FEATURE 7), FACING NORTH. OFFICE (FEATURE 11) VISIBLE IN BACKGROUND. - Copper Canyon Camp of the International Smelting & Refining Company, Duplex, Copper Canyon, Battle Mountain, Lander County, NV

  14. 1. VIEW OF DUPLEX (FEATURE 9), FACING NORTHEAST. MILL SITE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. VIEW OF DUPLEX (FEATURE 9), FACING NORTHEAST. MILL SITE IS SHOWN IN UPPER RIGHT CORNER OF PHOTOGRAPH. - Copper Canyon Camp of the International Smelting & Refining Company, Duplex, Copper Canyon, Battle Mountain, Lander County, NV

  15. Extensional duplex in the Purcell Mountains of southeastern British Columbia

    SciTech Connect

    Root, K.G. )

    1990-05-01

    An extensional duplex consisting of fault-bounded blocks (horses) located between how-angle normal faults is exposed in Proterozoic strata in the Purcell Mountains of British Columbia, Canada. This is one of the first documented extensional duplexes, and it is geometrically and kinematically analogous to duplexes developed in contractional and strike-slip fault systems. The duplex formed within an extensional fault with a ramp and flat geometry when horses were sliced from the ramp and transported within the fault system.

  16. Full-duplex optical communication system

    NASA Technical Reports Server (NTRS)

    Shay, Thomas M. (Inventor); Hazzard, David A. (Inventor); Horan, Stephen (Inventor); Payne, Jason A. (Inventor)

    2004-01-01

    A method of full-duplex electromagnetic communication wherein a pair of data modulation formats are selected for the forward and return data links respectively such that the forward data electro-magnetic beam serves as a carrier for the return data. A method of encoding optical information is used wherein right-hand and left-hand circular polarizations are assigned to optical information to represent binary states. An application for an earth to low earth orbit optical communications system is presented which implements the full-duplex communication and circular polarization keying modulation format.

  17. mTOR complex 1: a key player in neuroadaptations induced by drugs of abuse.

    PubMed

    Neasta, Jeremie; Barak, Segev; Hamida, Sami Ben; Ron, Dorit

    2014-07-01

    The mammalian (or mechanistic) target of rapamycin (mTOR) complex 1 (mTORC1) is a serine and threonine kinase that regulates cell growth, survival, and proliferation. mTORC1 is a master controller of the translation of a subset of mRNAs. In the central nervous system mTORC1 plays a crucial role in mechanisms underlying learning and memory by controlling synaptic protein synthesis. Here, we review recent evidence suggesting that the mTORC1 signaling pathway promotes neuroadaptations following exposure to a diverse group of drugs of abuse including stimulants, cannabinoids, opiates, and alcohol. We further describe potential molecular mechanisms by which drug-induced mTORC1 activation may alter brain functions. Finally, we propose that mTORC1 is a focal point shared by drugs of abuse to mediate drug-related behaviors such as reward seeking and excessive drug intake, and offer future directions to decipher the contribution of the kinase to mechanisms underlying addiction. Recent studies suggesting that exposure to diverse classes of drugs of abuse as well as exposure to drug-associated memories lead to mTORC1 kinase activation in the limbic system. In turn, mTORC1 controls the onset and the maintenance of pathological neuroadaptions that underlie several features of drug addiction such as drug seeking and relapse. Therefore, we propose that targeting mTORC1 and its effectors is a promising strategy to treat drug disorders.

  18. Binding stability of a cross-linked drug: Calculation of an anticancer drug cisplatin-DNA complex

    NASA Astrophysics Data System (ADS)

    Chen, Y. Z.; Zhang, Yong-Li; Prohofsky, E. W.

    1997-05-01

    One of the binding modes of anticancer and antibiotic drugs bound to DNA is the formation of a cross link, i.e., binding is made through the formation of covalent bonds between a binding drug and DNA. In this work we present a computational method to calculate the binding stability of a drug cross linked to DNA. Our method is based on the modified self-consistent harmonic approach in which the disruption probabil- ity of the cross-linked bonds as well as hydrogen bonds is calculated from a statistical analysis of micro- scopic thermal fluctuational motions. A Morse potential with appropriate parameters is used to model the cross-linked covalent bonds. Our method is applied to an anticancer drug cisplatin-DNA oligomer d(CTCTAGTGCTCAC).d(GTGAGCACTAGAG) complex. We calculated the equilibrium binding constant of a cisplatin bound to this DNA oligomer. Our method can also be used to analyze the effect of drug binding on DNA base-pair thermal stability. We find that, despite the disruption of certain interbase H bonds, the thermal fluctuational opening probability Pop of base pairs in the cisplatin binding region is enhanced by the formation of non-Watson-Crick H bonds as well as cross-linked covalent bonds. Although the entire DNA helix is bent by cisplatin binding, the stability of the base pairs outside the binding region is only slightly affected by this deformation.

  19. Aromatic oligomers that form hetero duplexes in aqueous solution.

    PubMed

    Gabriel, Gregory J; Iverson, Brent L

    2002-12-25

    The electron-deficient 1,4,5,8-naphthalenetetracarboxylic diimide (Ndi) and electron-rich 1,5-dialkoxynaphthalene (Dan) have been shown to complex strongly with each other in water due to the hydrophobic effect as modulated through the electrostatic complementarity of the stacked dimer. Previously, oligomers of alternating Ndi and Dan units, termed aedamers, were the first foldamers to employ intramolecular aromatic stacking to effect the formation of secondary structure of nonnatural chains in aqueous solution. Described here is the use of this aromatic-aromatic (or pi-pi) interaction, this time in an intermolecular format, to demonstrate the self-assembly of stable hetero duplexes from a set of molecular strands (1a-4a) and (1b-4b) incorporating Ndi and Dan units, respectively. A 1-to-1 binding stoichiometry was determined from NMR and isothermal titration calorimetry (ITC) investigations, and these experiments indicated that association is enthalpically favored with the tetra-Ndi (4a) and tetra-Dan (4b) strands forming hetero duplexes (4a:4b) with a stability constant of 350 000 M-1 at T = 318 K. Polyacrylamide gel electrophoresis (PAGE) also illustrated the strong interaction between 4a and 4b and support a 1-to-1 binding mode even when one component is in slight excess. Overall, this system is the first to utilize complementary aromatic units to drive discrete self-assembly in aqueous solution. This new approach for designing assemblies is encouraging for future development of duplex systems with highly programmable modes of binding in solution or on surfaces.

  20. Counterion effects on nano-confined metal-drug-DNA complexes.

    PubMed

    Biswas, Nupur; Chakraborty, Sreeja; Datta, Alokmay; Sarkar, Munna; Mukhopadhyay, Mrinmay K; Bera, Mrinal K; Seto, Hideki

    2016-01-01

    We have explored morphology of DNA molecules bound with Cu complexes of piroxicam (a non-steroidal anti-inflammatory drug) molecules under one-dimensional confinement of thin films and have studied the effect of counterions present in a buffer. X-ray reflectivity at and away from the Cu K absorption edge and atomic force microscopy studies reveal that confinement segregates the drug molecules preferentially in a top layer of the DNA film, and counterions enhance this segregation.

  1. Nanodiamond–Mitoxantrone Complexes Enhance Drug Retention in Chemoresistant Breast Cancer Cells

    PubMed Central

    2015-01-01

    Chemoresistance is a prevalent issue that accounts for the vast majority of treatment failure outcomes in metastatic cancer. Among the mechanisms of resistance that markedly decrease treatment efficacy, the efflux of drug compounds by ATP-binding cassette (ABC) transporter proteins can impair adequate drug retention by cancer cells required for therapeutic cytotoxic activity. Of note, ABC transporters are capable of effluxing several classes of drugs that are clinical standards, including the anthracyclines such as doxorubicin, as well as anthracenediones such as mitoxantrone. To address this challenge, a spectrum of nanomaterials has been evaluated for improved drug retention and enhanced efficacy. Nanodiamonds (NDs) are emerging as a promising nanomaterial platform because they integrate several important properties into a single agent. These include a uniquely faceted truncated octahedral architecture that enables potent drug binding and dispersibility in water, scalably processed ND particles with uniform diameters of approximately 5 nm, and a demonstrated ability to improve drug tolerance while delaying tumor growth in multiple preclinical models, among others. This work describes a ND–mitoxantrone complex that can be rapidly synthesized and mediates marked improvements in drug efficacy. Comprehensive complex characterization reveals a complex with favorable drug delivery properties that is capable of improving drug retention and efficacy in an MDA-MB-231-luc-D3H2LN (MDA-MB-231) triple negative breast cancer cell line that was lentivirally transduced for resistance against mitoxantrone. Findings from this study support the further evaluation of ND–MTX in preclinical dose escalation and safety studies toward potentially clinical validation. PMID:24867631

  2. Baicalein-phospholipid complex: a novel drug delivery technology for phytotherapeutics.

    PubMed

    Rawat, Devendra Singh; Thakur, Bandana K; Semalty, Mona; Semalty, Ajay; Badoni, Prabhakar; Rawat, Mohan Singh Maniyari

    2013-09-01

    Flavonoids are a group of low-molecular-weight polyphenolic compounds of plant origin. They exhibit a variety of biological activities such as anti-inflammatory, antioxidant, antiviral, and antitumor etc. Baicalein, is a bioactive flavone constituent of Scutellariae radix with a wide range of beneficial activities. But the poor solubility and dissolution rate limit its oral intestinal absorption and bioavailability. The aim of this study was to develop an amphiphilic phytophospholipid complex in order to enhance the delivery of poorly soluble drug (baicalein). The baicalein-phospholipid complex (Ba-PLc) was prepared and evaluated for various physico-chemical parameters like drug loading, infrared absorption (FT-IR), differential scanning calorimetry (DSC), X-ray powder diffractometry (X-RPD), scanning electron microscopy (SEM), aqueous/ n-octanol solubility and dissolution study. In the SEM, phospholipid complex (Ba-PLc) was found fluffy and porous with rough surface morphology. FT-IR, DSC and X-RPD data confirmed the formation of phospholipid complex. The water/ n-octanol solubility of baicalein was improved significantly in the complex. Improved dissolution was shown by the phospholipid complex. The results of the study concluded that the phospholipid complex may be considered as a promising drug delivery system for improving the absorption and overall bioavailability of the baicalein molecule.

  3. An extremely stable, self-complementary hydrogen-bonded duplex

    SciTech Connect

    Zeng, Huang; Yang, Xiaowu; Brown, A L.; Martinovic, Suzana; Smith, Richard D.; Gong, Bing

    2003-07-30

    This paper describes the design, synthesis and characterization of a self-complementary six-H-bonded duplex with an association constant greater than 10{sup 9}/M in CHCl3. Numerous unnatural self-assembly systems have been developed in recent years. Most of these previously described systems are case-dependent, i.e., the individual components carry the information that defines only the formation of the specific assembly. An alternative approach involves the design of highly specific and highly stable recognition units (modules)that are compatible with a variety of structural components. Such recognition modules or ''molecular glues'' then direct the assembly of these structural components. In this regard,hydrogen-bonded complexes based on rigid heterocycles with multiple H-bonding donor (D) and acceptor (A) sites have received the most attention in recent years. Other complexes, most based on H-bonding interactions, have also been reported. Highly stable, self-complementary H-bonded complexes are particularly attractive for developing supramolecular homopolymers of very high molecular weights. In spite of the intriguing perspective, only a very small number of self-complementary H-bonded complexes with high stabilities are known. The best known examples involve two pairs of quadruply H-bonded, self-complementary complexes, both based on the AADD-DDAA array, and with association constants greater than 10{sup 7}/M. We report here the design and characterization of our first six-H-bonded, self-complementary duplex that contains the AADADD-DDADAA array.

  4. Structural, electronic, and optical properties of metallo base pairs in duplex DNA: a theoretical insight.

    PubMed

    Samanta, Pralok K; Manna, Arun K; Pati, Swapan K

    2012-11-01

    Using density functional theory calculations, we investigated the structural, energetic, electronic, and optical properties of recently synthesized duplex DNA containing metal-mediated base pairs. The studied duplex DNA consists of three imidazole (Im) units linked through metal (Im-M-Im, M = metal) and four flanking A:T base pairs (two on each side). We examined the role of artificial base pairing in the presence of two distinctive metal ions, diamagnetic Ag(+) and magnetic Cu(2+) ions, on the stability of duplex DNA. We found that metal-mediated base pairs form stable duplex DNA by direct metal ion coordination to the Im bases. Our results suggest a higher binding stability of base pairing mediated by Cu(2+) ions than by Ag(+) ions, which is attributed to a larger extent of orbital hybridization. We furthermore found that DNA modified with Im-Ag(+)-Im shows the low-energy optical absorption characteristic of π-π*orbital transition of WC A:T base pairs. On the other hand, we found that the low-energy optical absorption peaks for DNA modified with Im-Cu(2+)-Im originate from spin-spin interactions. Additionally, this complex exhibits weak ferromagnetic coupling between Cu(2+) ions and strong spin polarization, which could be used for memory devices. Moreover, analyzing the role of counter ions (Na(+)) and the presence of explicit water molecules on the structural stability and electronic properties of the DNA duplex modified with Im-Ag(+)-Im, we found that the impact of these two factors is negligible. Our results are fruitful for understanding the experimental data and suggest a potential route for constructing effective metal-mediated base pairs in duplex DNA for optoelectronic applications.

  5. Structural, Dynamical, and Electronic Transport Properties of Modified DNA Duplexes Containing Size-Expanded Nucleobases

    SciTech Connect

    Fuentes-Cabrera, Miguel A; Orozco, Modesto; Luque, Javier; Sumpter, Bobby G; Blas, Jose; Ordejon, Pablo J; Huertas, Oscar; Tabares, Carolina

    2011-01-01

    Among the distinct strategies proposed to expand the genetic alphabet, sizeexpanded nucleobases are promising for the development of modified DNA duplexes with improved biotechnological properties. In particular, duplexes built up by replacing canonical bases with the corresponding benzo-fused counterparts could be valuable as molecular nanowires. In this context, this study reports the results of classical molecular dynamics simulations carried out to examine the structural and dynamical features of size-expanded DNAs, including both hybrid duplexes containing mixed pairs of natural and benzo-fused bases (xDNA) and pure size-expanded (xxDNA) duplexes. Furthermore, the electronic structure of both natural and size-expanded duplexes is examined by means of density functional computations. The results confirm that the structural and flexibility properties of the canonical DNA are globally little affected by the presence of benzo-fused bases. Themost relevant differences are found in the enhanced size of the grooves, and the reduction in the twist. However, the analysis also reveals subtle structural effects related to the nature and sequence of benzo-fused bases in the duplex. On the other hand, electronic structure calculations performed for xxDNAs confirm the reduction in the HOMOLUMO gap predicted from the analysis of the natural bases and their size-expanded counterparts, which suggests that pure size-expanded DNAs can be good conductors. A more complex situation is found for xDNAs, where fluctuations in the electrostatic interaction between base pairs exerts a decisive influence on the modulation of the energy gap.

  6. Drug Release Kinetics and Front Movement in Matrix Tablets Containing Diltiazem or Metoprolol/λ-Carrageenan Complexes

    PubMed Central

    Bonferoni, Maria Cristina; Colombo, Paolo; Zanelotti, Laura; Caramella, Carla

    2014-01-01

    In this work we investigated the moving boundaries and the associated drug release kinetics in matrix tablets prepared with two complexes between λ-carrageenan and two soluble model drugs, namely, diltiazem HCl and metoprolol tartrate aiming at clarifying the role played by drug/polymer interaction on the water uptake, swelling, drug dissolution, and drug release performance of the matrix. The two studied complexes released the drug with different mechanism indicating two different drug/polymer interaction strengths. The comparison between the drug release behaviour of the complexes and the relevant physical mixtures indicates that diltiazem gave rise to a less soluble and more stable complex with carrageenan than metoprolol. The less stable metoprolol complex afforded an erodible matrix, whereas the stronger interaction between diltiazem and carrageenan resulted in a poorly soluble, slowly dissolving matrix. It was concluded that the different stability of the studied complexes affords two distinct drug delivery systems: in the case of MTP, the dissociation of the complex, as a consequence of the interaction with water, affords a classical soluble matrix type delivery system; in the case of DTZ, the dissolving/diffusing species is the complex itself because of the very strong interaction between the drug and the polymer. PMID:25045689

  7. Nanoscale Reaction Vessels Designed for Synthesis of Copper-Drug Complexes Suitable for Preclinical Development

    PubMed Central

    Wehbe, Mohamed; Anantha, Malathi; Backstrom, Ian; Leung, Ada; Chen, Kent; Malhotra, Armaan; Edwards, Katarina; Bally, Marcel B.

    2016-01-01

    The development of copper-drug complexes (CDCs) is hindered due to their very poor aqueous solubility. Diethyldithiocarbamate (DDC) is the primary metabolite of disulfiram, an approved drug for alcoholism that is being repurposed for cancer. The anticancer activity of DDC is dependent on complexation with copper to form copper bis-diethyldithiocarbamate (Cu(DDC)2), a highly insoluble complex that has not been possible to develop for indications requiring parenteral administration. We have resolved this issue by synthesizing Cu(DDC)2 inside liposomes. DDC crosses the liposomal lipid bilayer, reacting with the entrapped copper; a reaction that can be observed through a colour change as the solution goes from a light blue to dark brown. This method is successfully applied to other CDCs including the anti-parasitic drug clioquinol, the natural product quercetin and the novel targeted agent CX-5461. Our method provides a simple, transformative solution enabling, for the first time, the development of CDCs as viable candidate anticancer drugs; drugs that would represent a brand new class of therapeutics for cancer patients. PMID:27055237

  8. Counter-ion complexes for enhanced drug loading in nanocarriers: Proof-of-concept and beyond.

    PubMed

    Günday Türeli, Nazende; Türeli, Akif E; Schneider, Marc

    2016-09-25

    Enhanced drug loading is an important prerequisite of nanomedicines, to reach administration dose while reducing the amount of excipient. Considering biocompatible and biodegradable polymers such as PLGA, pH dependent solubility characteristics along with limited organic solvent solubility of the drug hampers nanoparticle (NP) preparation. To improve loading of such molecules, a method based on using counter ions for complex formation is proposed. Formed complex alters the intrinsic solubility of active substance via electrostatic interaction without chemical modification. A proof-of-concept study was conducted with sodium dodecyl sulfate as counter-ion to fluoroquinolone antibiotic ciprofloxacin. Complex formation resulted in suppressed pH dependent solubility over pH 1.2-9.0 and an additional -80 fold increase in organic solubility was achieved. In consequence, NPs prepared by microjet reactor technology have shown enhanced drug loading efficiencies (-78%) and drug loading of 14%. Moreover, the counter-ion concept was also demonstrated with another class of antibiotics, water soluble aminoglycosides gentamycin and tobramycin. In addition, the counter ion was substituted by degradable excipients such as phosphatidic acid derivatives. Successful implementation has proven the counter-ion concept to be a platform concept that can be successfully implemented for a variety of active substances and counter-ions to enhance drug loading in nanocarriers.

  9. Analytical studies on the charge transfer complexes of loperamide hydrochloride and trimebutine drugs. Spectroscopic and thermal characterization of CT complexes.

    PubMed

    Elqudaby, Hoda M; Mohamed, Gehad G; El-Din, Ghada M G

    2014-08-14

    Charge transfer complexes of loperamide hydrochloride (LOP.HCl) and trimebutine (TB) drugs as electron donor with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), tetracyanoethylene (TCNE) and 7,7,8,8-tetracyanoquinodimethane (TCNQ) as π-acceptors in acetonitrile were investigated spectrophotometrically to determine the cited drugs in pure and dosage forms. The reaction gives highly coloured complex species which are measured spectrophotometrically at 460, 415 and 842nm in case of LOP.HCl and at 455, 414 and 842nm in case of TB using DDQ, TCNE and TCNQ reagents, respectively. The optimum experimental conditions have been studied carefully and optimized. Beer's law was obeyed over the concentration ranges of 47.70-381.6, 21.50-150.5 and 10.00-100.0μgmL(-1) for LOP.HCl and 37.85-264.9, 38.75-310.0 and 7.75-155.0μgmL(-1) for TB using DDQ, TCNE and TCNQ reagents, respectively. Sandell sensitivity, standard deviation, relative standard deviation, limit of detection and quantification were calculated. The obtained data refer to high accuracy and precision of the proposed method. These results are also confirmed by inter and intra-day precision with percent recovery of 99.18-101.1% and 99.32-101.4% in case of LOP.HCl and 98.00-102.0% and 97.50-101.4% in case of TB using DDQ, TCNE and TCNQ reagents for intra- and inter-day, respectively. These data were compared with those obtained using official methods for the determination of the cited drugs. The stability constants of the CT complexes were determined. The final products of the reaction were isolated and characterized using FT-IR, (1)H NMR, elemental analysis and thermogravimetric analysis (TG). The stoichiometry and apparent formation constant of the complexes formed were determined by applying the conventional spectrophotometric molar ratio method.

  10. EEG complexity drug-induced changes in disorders of consciousness: a preliminary report.

    PubMed

    Valenza, G; Carboncini, M C; Virgillito, A; Creatini, I; Bonfiglio, L; Rossi, B; Lanatà, A; Scilingo, E P

    2011-01-01

    The goal of this work is to investigate EEG (ElectroEncephaloGram) dynamics after drug intake in patients being in states of Disorders Of Consciousness (DOC) after brain injury. Four patients were involved in the study. All the patients exhibit cerebral lesions located in the same anatomical region. Two nonlinear indexes, such as Lempel-Ziv Complexity (LZC) and Approximate Entropy (ApEn), along with power spectra, were calculated for EEG signals gathered from electrodes placed on both injured and non-injured regions. Experimental results show that after drug administration the two nonlinear indexes calculated from EEG taken from injured regions increase (p < 0.001) while power spectra decrease or remain unchanged. These results do not pretend to draw conclusions about consciousness level either suggest promising therapeutical treatments, but represent only an experimental evidence about the change in the EEG complexity after drug administration.

  11. Tri-partite complex for axonal transport drug delivery achieves pharmacological effect

    PubMed Central

    2010-01-01

    Background Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior. Results We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle. Conclusion Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise

  12. Mapping of drug-like chemical universe with reduced complexity molecular frameworks.

    PubMed

    Kontijevskis, Aleksejs

    2017-03-28

    The emergence of DNA-encoded chemical libraries (DEL) field in past decade has attracted attention of pharmaceutical industry as a powerful mechanism for the discovery of novel drug-like hits for various biological targets. Nuevolution Chemetics technology enables DNA encoded synthesis of billions of chemically diverse drug-like small molecule compounds, and the efficient screening and optimization of these, facilitating effective identification of drug candidates at an unprecedented speed and scale. Although many approaches have been developed by the cheminformatics community for the analysis and visualization of drug-like chemical space, most of them are restricted to the analysis of maximum few millions of compounds and cannot handle collections of 10(8)-10(12) compounds typical for DELs. To address this big chemical data challenge, we developed Reduced Complexity Molecular (RCM) frameworks methodology as an abstract and very general way of representing chemical structures. By further introducing RCM framework descriptors we constructed a global framework map of drug-like chemical space and demonstrate how chemical space occupied by multi-million-member drug-like Chemetics DNA-encoded libraries and virtual combinatorial libraries with >10(12) members could be analysed and mapped without a need for library enumeration. We further validate the approach by performing RCM framework-based searches in drug-like chemical universe and mapping Chemetics library selection outputs for LSD1 target on a global framework chemical space map.

  13. Osmium complex binding to mismatched methylcytosine: effect of adjacent bases.

    PubMed

    Nomura, Akiko; Tainaka, Kazuki; Okamoto, Akimitsu

    2009-01-01

    We investigated the efficiency of osmium complex formation at 5-methylcytosine in mismatched DNA duplexes. Osmium complexation was not observed in fully matched duplexes, whereas the complexation site and efficiency in mismatched duplexes depended on the 5'-neighboring base of the 5-methylcytosine. In particular, when the base adjacent to the 5' side of the mismatched base pair was thymine, a unique side reaction was observed. However, the mismatched base pairs did not influence the selectivity of osmium complexation with methylated DNA.

  14. RNA chaperones stimulate formation and yield of the U3 snoRNA-pre-rRNA duplexes needed for eukaryotic ribosome biogenesis

    PubMed Central

    Gérczei, Tímea; Shah, Binal N.; Manzo, Anthony J.; Walter, Nils G.; Correll, Carl C.

    2010-01-01

    To satisfy the high demand for ribosome synthesis in rapidly growing eukaryotic cells, short duplexes between the U3 small nucleolar RNA (snoRNA) and the precursor ribosomal RNA (pre-rRNA) must form quickly and with high yield. These interactions, designated the U3-ETS and U3-18S duplexes, are essential to initiate the processing of small subunit rRNA. Previously, we showed in vitro that duplexes corresponding to those in Saccharomyces cerevisiae are only observed after addition of one of two proteins: Imp3p or Imp4p. Here, we used fluorescence-based and other in vitro assays to determine whether these proteins possess RNA chaperone activities and to assess whether these activities are sufficient to satisfy the duplex yield and rate requirements expected in vivo. Assembly of both proteins with the U3 snoRNA into a chaperone complex destabilizes a U3-stem structure, apparently to expose its 18S base-pairing site. As a result, the chaperone complex accelerates formation of the U3-18S duplex from an undetectable rate to one comparable to the intrinsic rate observed for hybridizing short duplexes. The chaperone complex also stabilizes the U3-ETS duplex by 2.7 kcal/mol. These chaperone activities provide high U3-ETS duplex yield and rapid U3-18S duplex formation over a broad concentration range to help ensure that the U3-pre-rRNA interactions limit neither ribosome biogenesis nor rapid cell growth. The thermodynamic and kinetic framework used is general and thus suitable to investigate the mechanism of action of other RNA chaperones. PMID:19482034

  15. Usefulness of charge-transfer complexation for the assessment of sympathomimetic drugs: Spectroscopic properties of drug ephedrine hydrochloride complexed with some π-acceptors

    NASA Astrophysics Data System (ADS)

    Refat, Moamen S.; Ibrahim, Omar B.; Saad, Hosam A.; Adam, Abdel Majid A.

    2014-05-01

    Recently, ephedrine (Eph) assessment in food products, pharmaceutical formulations, human fluids of athletes and detection of drug toxicity and abuse, has gained a growing interest. To provide basic data that can be used to assessment of Eph quantitatively based on charge-transfer (CT) complexation, the CT complexes of Eph with 7‧,8,8‧-tetracyanoquinodimethane (TCNQ), dichlorodicyanobenzoquinone (DDQ), 1,3-dinitrobenzene (DNB) or tetrabromothiophene (TBT) were synthesized and spectroscopically investigated. The newly synthesized complexes have been characterized via elemental analysis, IR, Raman, 1H NMR, and UV-visible spectroscopy. The formation constant (KCT), molar extinction coefficient (εCT) and other spectroscopic data have been determined using the Benesi-Hildebrand method and its modifications. The sharp, well-defined Bragg reflections at specific 2θ angles have been identified from the powder X-ray diffraction patterns. Thermal decomposition behavior of these complexes was also studied, and their kinetic thermodynamic parameters were calculated with Coats-Redfern and Horowitz-Metzger equations.

  16. Mixed micelles loaded with silybin-polyene phosphatidylcholine complex improve drug solubility

    PubMed Central

    Duan, Rui-ling; Sun, Xun; Liu, Jie; Gong, Tao; Zhang, Zhi-rong

    2011-01-01

    Aim: To prepare a novel formulation of phosphatidylcholine (PC)-bile salts (BS)-mixed micelles (MMs) loaded with silybin (SLB)-PC complex for parenteral applications. Methods: SLB-PC-BS-MMs were prepared using the co-precipitation method. Differential scanning calorimetry (DSC) analysis was used to confirm the formation of the complex and several parameters were optimized to obtain a high quality formulation. The water-solubility, drug loading, particle size, zeta potential, morphology and in vivo properties of the SLB-PC-BS-MMs were determined. Results: The solubility of SLB in water was increased from 40.83±1.18 μg/mL to 10.14±0.36 mg/mL with a high drug loading (DL) of 14.43%±0.44% under optimized conditions. The SLB-PC-BS-MMs were observed by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) and showed spherical shapes. The particle size and zeta potential, as measured by photon correlation spectroscopy (PCS), were about 30±4.8 nm and −39±5.0 mV, respectively. In vivo studies showed that incorporation of the SLB-PC complex into PC-BS-MMs led to a prolonged circulation time of the drug. Conclusion: This novel formulation appears to be a good candidate for drug substances that exhibit poor solubility for parenteral administration. PMID:21170082

  17. Separation of drug stereoisomers by the formation of. beta. -cyclodextrin inclusion complexes

    SciTech Connect

    Armstrong, D.W.; Ward, T.J.; Armstrong, R.D.; Beesley, T.E.

    1986-05-30

    For many drugs, only racemic mixtures are available for clinical use. Because different stereoisomers of drugs often cause different physiological responses, the use of pure isomers could elicit more exact therapeutic effects. Differential complexation of a variety of drug stereoisomers by immobilized ..beta..-cyclodextrin was investigated. Chiral recognition and racemic resolution were observed with a number of compounds from such clinically useful classes as ..beta..-blockers, calcium-channel blockers, sedative hypnotics, antihistamines, anticonvulsants, diuretics, and synthetic opiates. Separation of the diastereomers of the cardioactive and antimalarial cinchona alkaloids and of two antiestrogens was demonstrated as well. Three dimensional projections of ..beta..-cyclodextrin complexes of propanol, which is resolved by this technique, and warfarin, which is not, are compared. These studies have improved the understanding and application of the chiral interactions of ..beta..-cyclodextrin, and they have demonstrated a means to measure optical purity and to isolate or produce pure enantiomers of drugs. In addition, this highly specific technique could also be used in the pharmacological evaluation of enantiometric drugs. 27 references, 3 figures, 2 tables.

  18. Siderophore-drug complexes: potential medicinal applications of the 'Trojan horse' strategy.

    PubMed

    Górska, Agnieszka; Sloderbach, Anna; Marszałł, Michał Piotr

    2014-09-01

    The ability of bacteria to develop resistance to antimicrobial agents poses problems in the treatment of numerous bacterial infections. One method to circumvent permeability-mediated drug resistance involves the employment of the 'Trojan horse' strategy. The Trojan horse concept involves the use of bacterial iron uptake systems to enter and kill bacteria. The siderophore-drug complex is recognized by specific siderophore receptors and is then actively transported across the outer membrane. The recently identified benefits of this strategy have led to the synthesis of a series of siderophore-based antibiotics. Several studies have shown that siderophore-drug conjugates make it possible to design antibiotics with improved cell transport and reduce the frequency of resistance mutants. Growing interest in siderophore-drug conjugates for the treatment of human diseases including iron overload, cancer, and malaria has driven the search for new siderophore-drug complexes. This strategy may have special importance for the development of iron oxide nanoparticle-based therapeutics.

  19. Chitosan Based Polyelectrolyte Complexes as Potential Carrier Materials in Drug Delivery Systems

    PubMed Central

    Hamman, Josias H.

    2010-01-01

    Chitosan has been the subject of interest for its use as a polymeric drug carrier material in dosage form design due to its appealing properties such as biocompatibility, biodegradability, low toxicity and relatively low production cost from abundant natural sources. However, one drawback of using this natural polysaccharide in modified release dosage forms for oral administration is its fast dissolution rate in the stomach. Since chitosan is positively charged at low pH values (below its pKa value), it spontaneously associates with negatively charged polyions in solution to form polyelectrolyte complexes. These chitosan based polyelectrolyte complexes exhibit favourable physicochemical properties with preservation of chitosan’s biocompatible characteristics. These complexes are therefore good candidate excipient materials for the design of different types of dosage forms. It is the aim of this review to describe complexation of chitosan with selected natural and synthetic polyanions and to indicate some of the factors that influence the formation and stability of these polyelectrolyte complexes. Furthermore, recent investigations into the use of these complexes as excipients in drug delivery systems such as nano- and microparticles, beads, fibers, sponges and matrix type tablets are briefly described. PMID:20479980

  20. Helical molecular duplex strands: multiple hydrogen-bond-mediated assembly of self-complementary oligomeric hydrazide derivatives.

    PubMed

    Yang, Yong; Yang, Zhi-Yong; Yi, Yuan-Ping; Xiang, Jun-Feng; Chen, Chuan-Feng; Wan, Li-Jun; Shuai, Zhi-Gang

    2007-06-22

    Careful examination of the X-ray structure of a ditopic hydrazide derivative 7 led to the concept that with malonyl groups as interhydrazide linkers hydrogen-bonding-mediated molecular duplex strands might be obtained. Complexation studies between 7, 8, and 9 confirmed this hypothesis. Two quadruple hydrogen-bonded heterodimers formed, in which spectator repulsive secondary electrostatic interaction was found to play an important role in determining the stability of the complexes. Extensive studies on 1-4 indicated that the hydrogen-bonding mode could persist in longer oligomeric hydrazide derivatives with chain extension from monomer to tetramer. Molecular duplex strands via two to fourteen interstrand hydrogen bonds were obtained. In addition to affecting the stability of the duplex strands, spectator repulsive secondary electrostatic interaction also played an important role in determining dynamic behavior of the duplex strands as exemplified by variable temperature (1)H NMR experiments. IR studies confirmed stronger hydrogen bonding in the longer oligomers. The assemblies of 1-4 on HOPG were also studied by STM technology. Molecular mechanical calculations further revealed double-helical structures for the longer oligomers. The results provide new opportunities for development of polymeric helical duplexes with well-defined structures.

  1. Characterization of thermal aging of duplex stainless steel by SQUID

    SciTech Connect

    Isobe, Y.; Kamimura, A.; Aoki, K.; Nakayasu, F.

    1995-08-01

    Thermal aging is a growing concern for long-term-aged duplex stainless steel piping in nuclear power plants. Superconducting QUantum Interference Device (SQUID) was used for the detection of thermal aging of SUS329 rolled duplex stainless steel and SCS16 cast duplex stainless steel. It was found that the SQUID output signal pattern in the presence of AC magnetic field applied to the specimen was sensitive to the changes in electromagnetic properties due to thermal aging.

  2. Analytical studies on the charge transfer complexes of loperamide hydrochloride and trimebutine drugs. Spectroscopic and thermal characterization of CT complexes

    NASA Astrophysics Data System (ADS)

    Elqudaby, Hoda M.; Mohamed, Gehad G.; El-Din, Ghada M. G.

    2014-08-01

    Charge transfer complexes of loperamide hydrochloride (LOP.HCl) and trimebutine (TB) drugs as electron donor with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), tetracyanoethylene (TCNE) and 7,7,8,8-tetracyanoquinodimethane (TCNQ) as π-acceptors in acetonitrile were investigated spectrophotometrically to determine the cited drugs in pure and dosage forms. The reaction gives highly coloured complex species which are measured spectrophotometrically at 460, 415 and 842 nm in case of LOP.HCl and at 455, 414 and 842 nm in case of TB using DDQ, TCNE and TCNQ reagents, respectively. The optimum experimental conditions have been studied carefully and optimized. Beer’s law was obeyed over the concentration ranges of 47.70-381.6, 21.50-150.5 and 10.00-100.0 μg mL-1 for LOP.HCl and 37.85-264.9, 38.75-310.0 and 7.75-155.0 μg mL-1 for TB using DDQ, TCNE and TCNQ reagents, respectively. Sandell sensitivity, standard deviation, relative standard deviation, limit of detection and quantification were calculated. The obtained data refer to high accuracy and precision of the proposed method. These results are also confirmed by inter and intra-day precision with percent recovery of 99.18-101.1% and 99.32-101.4% in case of LOP.HCl and 98.00-102.0% and 97.50-101.4% in case of TB using DDQ, TCNE and TCNQ reagents for intra- and inter-day, respectively. These data were compared with those obtained using official methods for the determination of the cited drugs. The stability constants of the CT complexes were determined. The final products of the reaction were isolated and characterized using FT-IR, 1H NMR, elemental analysis and thermogravimetric analysis (TG). The stoichiometry and apparent formation constant of the complexes formed were determined by applying the conventional spectrophotometric molar ratio method.

  3. Social epidemiology and complex system dynamic modelling as applied to health behaviour and drug use research.

    PubMed

    Galea, Sandro; Hall, Chris; Kaplan, George A

    2009-05-01

    A social epidemiologic perspective considers factors at multiple levels of influence (e.g., social networks, neighbourhoods, states) that may individually or jointly affect health and health behaviour. This provides a useful lens through which to understand the production of health behaviours in general, and drug use in particular. However, the analytic models that are commonly applied in population health sciences limit the inference we are able to draw about the determination of health behaviour by factors, likely interrelated, across levels of influence. Complex system dynamic modelling techniques may be useful in enabling the adoption of a social epidemiologic approach in health behaviour and drug use research. We provide an example of a model that aims to incorporate factors at multiple levels of influence in understanding drug dependence. We conclude with suggestions about future directions in the field and how such models may serve as virtual laboratories for policy experiments aimed at improving health behaviour.

  4. Antitumor drug nogalamycin binds DNA in both grooves simultaneously: molecular structure of nogalamycin-DNA complex.

    PubMed

    Liaw, Y C; Gao, Y G; Robinson, H; van der Marel, G A; van Boom, J H; Wang, A H

    1989-12-26

    The three-dimensional molecular structures of the complexes between an interesting antitumor drug, nogalamycin, and two DNA hexamers, d[CGT(pS)ACG] and d[m5CGT(pS)Am5CG], were determined at high resolution by X-ray diffraction analyses. Two nogalamycins bind to the DNA double helix in a 2:1 ratio with the aglycon chromophore intercalated between the CpG steps at both ends of the helix. The nogalose and aminoglucose sugars lie in the minor and major grooves, respectively, of the distorted B-DNA double helix. The binding of nogalamycin to DNA requires that the base pairs in DNA open up transiently to allow the bulky sugars to go through. Specific hydrogen bonds are found in the complex between the drug and guanine bases. We suggest that nogalamycin may prefer GC sequences embedded in a stretch of AT sequences.

  5. Phospholipid complex enriched micelles: A novel drug delivery approach for promoting the antidiabetic effect of repaglinide.

    PubMed

    Kassem, Ahmed Alaa; Abd El-Alim, Sameh Hosam; Basha, Mona; Salama, Abeer

    2017-03-01

    To enhance the oral antidiabetic effect of repaglinide (RG), a newly emerging approach, based on the combination of phospholipid complexation and micelle techniques, was employed. Repaglinide-phospholipid complex (RG-PLC) was prepared by the solvent-evaporation method then characterized using Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR) and X-ray powder diffraction (XPRD). The results revealed obvious disappearance of the characteristic peaks of the prepared RG-PLCs confirming the formation of drug-phospholipid complex. RG-PLC enriched micelles (RG-PLC-Ms) were prepared by the solvent-evaporation technique employing poloxamer 188 as surfactant. The prepared RG-PLC-Ms showed high drug encapsulation efficiencies (93.81-99.38%), with nanometric particle diameters (500.61-665.32nm) of monodisperse distribution and high stability (Zeta potential < -29.8mV). The in vitro release of RG from RG-PLC-Ms was pH-dependant according to the release media. A higher release pattern was reported in pH=1.2 compared to a more retarded release in pH=6.8 owing to two different kinetics of drug release. Oral antidiabetic effect of two optimized RG-PLC-M formulations was evaluated in an alloxan-induced diabetic rat model for 7-day treatment protocol. The two investigated formulations depicted normal blood glucose, serum malondialdehyde and insulin levels as well as an improved lipid profile, at the end of daily oral treatment, in contrast to RG marketed tablets implying enhanced antidiabetic effect of the drug. Hence, phospholipid-complex enriched micelles approach holds a promising potential for promoting the antidiabetic effect of RG.

  6. Structural basis and anticancer properties of ruthenium-based drug complexed with human serum albumin.

    PubMed

    Zhang, Yao; Ho, Andy; Yue, Jiping; Kong, Linlin; Zhou, Zuping; Wu, Xiaoyang; Yang, Feng; Liang, Hong

    2014-10-30

    Ruthenium-based anticancer complexes have become increasingly popular for study over the last two decades. Although ruthenium complexes are currently being investigated in clinical trials, there are still some difficulties with their delivery and associated side effects. Human serum albumin (HSA)-based delivery systems are promising for improving anticancer drug targeting and reducing negative side effects. However, there have been few studies regarding the HSA delivery system for metal-based anticancer compounds and no mention of its structural mechanism. Therefore, we studied the structure and anticancer properties of the ruthenium-based compound [RuCl5(ind)](2-) in complex with HSA. The structure revealed that [RuCl5(ind)](2-) has two binding sites in HSA. In the IB subdomain, [RuCl5(ind)](2-) binds to a new sub-site by coordinating with His-146. In the IIA subdomain, ruthenium (III) of [RuCl5(ind)](2-) binds to the hydrophobic cavity and forms coordination bonds by replacing chlorine atoms with the His-242 and Lys-199 residues of HSA. Interestingly, [RuCl5(ind)](2-), together with HSA, can enhance cytotoxicity by two to five times in cancer cells but has no effect on normal cells in vitro. Compared with unbound drug, the HSA-[RuCl5(ind)](2-) complex promotes MGC-803 cell apoptosis and also has a stronger capacity for cell cycle arrest at the G2 phase in MGC-803. In conclusion, this study will guide the rational design and development of ruthenium-containing or ruthenium-centered drugs and an HSA delivery system for ruthenium-based drugs.

  7. Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis.

    PubMed

    Mészáros, Bálint; Tóth, Judit; Vértessy, Beáta G; Dosztányi, Zsuzsanna; Simon, István

    2011-07-01

    Lengthy co-evolution of Homo sapiens and Mycobacterium tuberculosis, the main causative agent of tuberculosis, resulted in a dramatically successful pathogen species that presents considerable challenge for modern medicine. The continuous and ever increasing appearance of multi-drug resistant mycobacteria necessitates the identification of novel drug targets and drugs with new mechanisms of action. However, further insights are needed to establish automated protocols for target selection based on the available complete genome sequences. In the present study, we perform complete proteome level comparisons between M. tuberculosis, mycobacteria, other prokaryotes and available eukaryotes based on protein domains, local sequence similarities and protein disorder. We show that the enrichment of certain domains in the genome can indicate an important function specific to M. tuberculosis. We identified two families, termed pkn and PE/PPE that stand out in this respect. The common property of these two protein families is a complex domain organization that combines species-specific regions, commonly occurring domains and disordered segments. Besides highlighting promising novel drug target candidates in M. tuberculosis, the presented analysis can also be viewed as a general protocol to identify proteins involved in species-specific functions in a given organism. We conclude that target selection protocols should be extended to include proteins with complex domain architectures instead of focusing on sequentially unique and essential proteins only.

  8. Characterization of Mouse Models of Mycobacterium avium Complex Infection and Evaluation of Drug Combinations

    PubMed Central

    Almeida, Deepak V.; Tyagi, Sandeep; Converse, Paul J.; Ammerman, Nicole C.; Grosset, Jacques H.

    2015-01-01

    The Mycobacterium avium complex is the most common cause of nontuberculous mycobacterial lung disease worldwide; yet, an optimal treatment regimen for M. avium complex infection has not been established. Clarithromycin is accepted as the cornerstone drug for treatment of M. avium lung disease; however, good model systems, especially animal models, are needed to evaluate the most effective companion drugs. We performed a series of experiments to evaluate and use different mouse models (comparing BALB/c, C57BL/6, nude, and beige mice) of M. avium infection and to assess the anti-M. avium activity of single and combination drug regimens, in vitro, ex vivo, and in mice. In vitro, clarithromycin and moxifloxacin were most active against M. avium, and no antagonism was observed between these two drugs. Nude mice were more susceptible to M. avium infection than the other mouse strains tested, but the impact of treatment was most clearly seen in M. avium-infected BALB/c mice. The combination of clarithromycin-ethambutol-rifampin was more effective in all infected mice than moxifloxacin-ethambutol-rifampin; the addition of moxifloxacin to the clarithromycin-containing regimen did not increase treatment efficacy. Clarithromycin-containing regimens are the most effective for M. avium infection; substitution of moxifloxacin for clarithromycin had a negative impact on treatment efficacy. PMID:25624335

  9. [Analysis of Conformational Features of Watson-Crick Duplex Fragments by Molecular Mechanics and Quantum Mechanics Methods].

    PubMed

    Poltev, V I; Anisimov, V M; Sanchez, C; Deriabina, A; Gonzalez, E; Garcia, D; Rivas, F; Polteva, N A

    2016-01-01

    It is generally accepted that the important characteristic features of the Watson-Crick duplex originate from the molecular structure of its subunits. However, it still remains to elucidate what properties of each subunit are responsible for the significant characteristic features of the DNA structure. The computations of desoxydinucleoside monophosphates complexes with Na-ions using density functional theory revealed a pivotal role of DNA conformational properties of single-chain minimal fragments in the development of unique features of the Watson-Crick duplex. We found that directionality of the sugar-phosphate backbone and the preferable ranges of its torsion angles, combined with the difference between purines and pyrimidines. in ring bases, define the dependence of three-dimensional structure of the Watson-Crick duplex on nucleotide base sequence. In this work, we extended these density functional theory computations to the minimal' fragments of DNA duplex, complementary desoxydinucleoside monophosphates complexes with Na-ions. Using several computational methods and various functionals, we performed a search for energy minima of BI-conformation for complementary desoxydinucleoside monophosphates complexes with different nucleoside sequences. Two sequences are optimized using ab initio method at the MP2/6-31++G** level of theory. The analysis of torsion angles, sugar ring puckering and mutual base positions of optimized structures demonstrates that the conformational characteristic features of complementary desoxydinucleoside monophosphates complexes with Na-ions remain within BI ranges and become closer to the corresponding characteristic features of the Watson-Crick duplex crystals. Qualitatively, the main characteristic features of each studied complementary desoxydinucleoside monophosphates complex remain invariant when different computational methods are used, although the quantitative values of some conformational parameters could vary lying within the

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

    PubMed

    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.

  11. Hydrophilic drug encapsulation in shell-core microcarriers by two stage polyelectrolyte complexation method.

    PubMed

    Dalmoro, Annalisa; Sitenkov, Alexander Y; Cascone, Sara; Lamberti, Gaetano; Barba, Anna Angela; Moustafine, Rouslan I

    2017-02-25

    In this study a protocol exploiting the combination of the ultrasonic atomization and the complexation between polyelectrolytes was developed to efficiently encapsulate a hydrophilic chemotherapeutic agent essentially used in the treatment of colon cancer, 5-fluorouracil, in enteric shell-core alginate-based microcarriers. The atomization assisted by ultrasound allowed to obtain small droplets by supplying low energy and avoiding drug degradation. In particular microcarriers were produced in a home-made apparatus where both the core (composed of alginate, drug, and Pluronic F127) and shell (composed of only alginate) feed were separately sent to the coaxial ultrasonic atomizer where they were nebulized and placed in contact with the complexation bulk. With the aim to obtain microstructured particles of alginate encapsulating 5-fluorouracil, different formulations of the first complexation bulk were tested; at last an emulsion made of a calcium chloride aqueous solution and dichloromethane allowed to reach an encapsulation efficiency of about 50%. This result can be considered very interesting considering that in literature similar techniques gave 5-fluorouracil encapsulation efficiencies of about 10%. Since a single complexation stage was not able to assure microcarriers gastroresistance, the formulation of a second complexation bulk was evaluated. The solution of cationic and pH-insoluble Eudragit® RS 100 in dichloromethane was chosen as bulk of second-stage complexation obtaining good enteric properties of shell-core microcarriers, i.e. a 5-FU cumulative release at pH 1 (simulating gastric pH) lower than 35%. The formation of interpolyelectrolyte complex (IPEC) between countercharged polymers and the chemical stability of 5-FU in microcarriers were confirmed by FTIR analysis, the presence of an amorphous dispersion of 5-FU in prepared microparticles was also confirmed by DSC. Finally, shell-core enteric coated microcarriers encapsulating 5-fluorouracil were used

  12. Full Duplex, Spread Spectrum Radio System

    NASA Technical Reports Server (NTRS)

    Harvey, Bruce A.

    2000-01-01

    The goal of this project was to support the development of a full duplex, spread spectrum voice communications system. The assembly and testing of a prototype system consisting of a Harris PRISM spread spectrum radio, a TMS320C54x signal processing development board and a Zilog Z80180 microprocessor was underway at the start of this project. The efforts under this project were the development of multiple access schemes, analysis of full duplex voice feedback delays, and the development and analysis of forward error correction (FEC) algorithms. The multiple access analysis involved the selection between code division multiple access (CDMA), frequency division multiple access (FDMA) and time division multiple access (TDMA). Full duplex voice feedback analysis involved the analysis of packet size and delays associated with full loop voice feedback for confirmation of radio system performance. FEC analysis included studies of the performance under the expected burst error scenario with the relatively short packet lengths, and analysis of implementation in the TMS320C54x digital signal processor. When the capabilities and the limitations of the components used were considered, the multiple access scheme chosen was a combination TDMA/FDMA scheme that will provide up to eight users on each of three separate frequencies. Packets to and from each user will consist of 16 samples at a rate of 8,000 samples per second for a total of 2 ms of voice information. The resulting voice feedback delay will therefore be 4 - 6 ms. The most practical FEC algorithm for implementation was a convolutional code with a Viterbi decoder. Interleaving of the bits of each packet will be required to offset the effects of burst errors.

  13. Discovery of Antischistosomal Drug Leads Based on Tetraazamacrocyclic Derivatives and Their Metal Complexes

    PubMed Central

    Keiser, Jennifer; Amoyaw, P. N. A.; Hossain, Mohammad F.; Vargas, Mireille; Le, Justin G.; Simpson, Natalie C.; Roewe, Kimberly D.; Freeman, TaRynn N. Carder; Hasley, Travis R.; Maples, Randall D.; Archibald, Stephen J.

    2016-01-01

    Praziquantel (PZQ) is the only drug available for the treatment of schistosomiasis, and since its large-scale use might be associated with the onset of resistance, new antischistosomal drugs should be developed. A series of 26 synthetic tetraazamacrocyclic derivatives and their metal complexes were synthesized, characterized, and screened for antischistosomal activity by application of a phased screening program. The compounds were first screened against newly transformed schistosomula (NTS) of harvested Schistosoma mansoni cercariae, then against adult worms, and finally, in vivo using the mouse model of S. mansoni infection. At a concentration of 33 μM, incubation with a total of 12 compounds resulted in the mortality of NTS at the 62% to 100% level. Five of these showing 100% inhibition of viability of NTS at 10 μM were selected for further screening for determination of the 50 inhibitory concentrations (IC50s) against both NTS and adult worms. Against NTS, all 5 compounds showed IC50s comparable to the IC50 of the standard drug, PZQ (0.87 to 9.65 μM for the 5 compounds versus 2.20 μM for PZQ). Three of these, which are the bisquinoline derivative of cyclen and its Fe2+ and Mn2+ complexes, showed micromolar IC50s (1.62 μM, 1.34 μM, and 4.12 μM, respectively, versus 0.10 μM for PZQ) against adult worms. In vivo, the worm burden reductions were 12.3%, 88.4%, and 74.5%, respectively, at a single oral dose of 400 mg/kg of body weight. The Fe2+ complex exhibited activity in vivo comparable to that of PZQ, pointing to the discovery of a novel drug lead for schistosomiasis. PMID:27324765

  14. Insights into the mechanism of drug resistance. X-ray structure analysis of multi-drug resistant HIV-1 protease ritonavir complex

    SciTech Connect

    Liu, Zhigang; Yedidi, Ravikiran S.; Wang, Yong; Dewdney, Tamaria G.; Reiter, Samuel J.; Brunzelle, Joseph S.; Kovari, Iulia A.; Kovari, Ladislau C.

    2013-01-08

    Ritonavir (RTV) is a first generation HIV-1 protease inhibitor with rapidly emerging drug resistance. Mutations at residues 46, 54, 82 and 84 render the HIV-1 protease drug resistant against RTV. We report the crystal structure of multi-drug resistant (MDR) 769 HIV-1 protease (carrying resistant mutations at residues 10, 36, 46, 54, 62, 63, 71, 82, 84 and 90) complexed with RTV and the in vitro enzymatic IC50 of RTV against MDR HIV-1 protease. The structural and functional studies demonstrate significant drug resistance of MDR HIV-1 protease against RTV, arising from reduced hydrogen bonds and Van der Waals interactions between RTV and MDR HIV-1 protease.

  15. Preparation and spectroscopic studies on charge-transfer complexes of famciclovir drug with different electron acceptors

    NASA Astrophysics Data System (ADS)

    Gaballa, Akmal S.; Teleb, Said M.; Nour, El-Metwally

    2012-09-01

    The CT-interaction of electron acceptors such as chloranilic acid (H2CA), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and and 7,7',8,8'-tetracyano-p-quinodimethane (TCNQ) with the antiviral drug famciclovir (FCV) have been investigated spectrophotometrically in the defined solvent. The data indicate the formation of CT-complexes with the general formula [(FCV)(acceptor)]. The 1:1 stoichiometry of the (FCV)-acceptors were based on elemental analysis, IR spectra and thermogravimetric analysis of the solid CT-complexes along with the photometric titration measurements for the reactions. The formation constants (KCT) for the CT-complexes are shown to be strongly dependent on the type and structure of the electron acceptor. Factors affecting the CT-processes such as redox potentials and steric hinderance of reactants are discussed.

  16. Duplex unwinding with DEAD-box proteins.

    PubMed

    Jankowsky, Eckhard; Putnam, Andrea

    2010-01-01

    DEAD-box proteins, which comprise the largest helicase family, are involved in virtually all aspects of RNA metabolism. DEAD-box proteins catalyze diverse ATP-driven functions including the unwinding of RNA secondary structures. In contrast to many well-studied DNA and viral RNA helicases, DEAD-box proteins do not rely on translocation on one of the nucleic acid strands for duplex unwinding, but directly load onto helical regions and then locally pry the strands apart in an ATP-dependent fashion. In this chapter, we outline substrate design and unwinding protocols for DEAD-box proteins and focus on the quantitative evaluation of their unwinding activity.

  17. Mechanisms of cell death pathway activation following drug-induced inhibition of mitochondrial complex I

    PubMed Central

    Imaizumi, Naoki; Kwang Lee, Kang; Zhang, Carmen; Boelsterli, Urs A.

    2015-01-01

    Respiratory complex I inhibition by drugs and other chemicals has been implicated as a frequent mode of mitochondria-mediated cell injury. However, the exact mechanisms leading to the activation of cell death pathways are incompletely understood. This study was designed to explore the relative contributions to cell injury of three distinct consequences of complex I inhibition, i.e., impairment of ATP biosynthesis, increased formation of superoxide and, hence, peroxynitrite, and inhibition of the mitochondrial protein deacetylase, Sirt3, due to imbalance of the NADH/NAD+ ratio. We used the antiviral drug efavirenz (EFV) to model drug-induced complex I inhibition. Exposure of cultured mouse hepatocytes to EFV resulted in a rapid onset of cell injury, featuring a no-effect level at 30 µM EFV and submaximal effects at 50 µM EFV. EFV caused a concentration-dependent decrease in cellular ATP levels. Furthermore, EFV resulted in increased formation of peroxynitrite and oxidation of mitochondrial protein thiols, including cyclophilin D (CypD). This was prevented by the superoxide scavenger, Fe-TCP, or the peroxynitrite decomposition catalyst, Fe-TMPyP. Both ferroporphyrins completely protected from EFV-induced cell injury, suggesting that peroxynitrite contributed to the cell injury. Finally, EFV increased the NADH/NAD+ ratio, inhibited Sirt3 activity, and led to hyperacetylated lysine residues, including those in CypD. However, hepatocytes isolated from Sirt3-null mice were protected against 40 µM EFV as compared to their wild-type controls. In conclusion, these data are compatible with the concept that chemical inhibition of complex I activates multiple pathways leading to cell injury; among these, peroxynitrite formation may be the most critical. PMID:25625582

  18. Criteria for the Segmentation of Vowels on Duplex Oscillograms.

    ERIC Educational Resources Information Center

    Naeser, Margaret A.

    This paper develops criteria for the segmentation of vowels on duplex oscillograms. Previous vowel duration studies have primarily used sound spectrograms. The use of duplex oscillograms, rather than sound spectrograms, permits faster production (real time) at less expense (adding machine paper may be used). The speech signal can be more spread…

  19. 52. Photocopy of copy of original Officers' Duplex Quarters drawing ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    52. Photocopy of copy of original Officers' Duplex Quarters drawing by Copeland, 7 April 1932 (Original in possession of Veterans Administration, Wichita, Kansas, copy at Ablah Library, Wichita State University). Heating - Veterans Administration Center, Officers Duplex Quarters, 5302 East Kellogg (Legal Address); 5500 East Kellogg (Common Address), Wichita, Sedgwick County, KS

  20. 53. Photocopy of copy of original Officers' Duplex Quarters drawing ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    53. Photocopy of copy of original Officers' Duplex Quarters drawing by A.G.D., 7 April 1932 (original in possession of Veterans Administration, Wichita, Kansas, copy at Ablah Library, Wichita State University). Electrical - Veterans Administration Center, Officers Duplex Quarters, 5302 East Kellogg (Legal Address); 5500 East Kellogg (Common Address), Wichita, Sedgwick County, KS

  1. Methods And Devices For Characterizing Duplex Nucleic Acid Molecules

    DOEpatents

    Akeson, Mark; Vercoutere, Wenonah; Haussler, David; Winters-Hilt, Stephen

    2005-08-30

    Methods and devices are provided for characterizing a duplex nucleic acid, e.g., a duplex DNA molecule. In the subject methods, a fluid conducting medium that includes a duplex nucleic acid molecule is contacted with a nanopore under the influence of an applied electric field and the resulting changes in current through the nanopore caused by the duplex nucleic acid molecule are monitored. The observed changes in current through the nanopore are then employed as a set of data values to characterize the duplex nucleic acid, where the set of data values may be employed in raw form or manipulated, e.g., into a current blockade profile. Also provided are nanopore devices for practicing the subject methods, where the subject nanopore devices are characterized by the presence of an algorithm which directs a processing means to employ monitored changes in current through a nanopore to characterize a duplex nucleic acid molecule responsible for the current changes. The subject methods and devices find use in a variety of applications, including, among other applications, the identification of an analyte duplex DNA molecule in a sample, the specific base sequence at a single nulceotide polymorphism (SNP), and the sequencing of duplex DNA molecules.

  2. First insights into circulating Mycobacterium tuberculosis complex lineages and drug resistance in Guinea.

    PubMed

    Ejo, Mebrat; Gehre, Florian; Barry, Mamadou Dian; Sow, Oumou; Bah, Nene Mamata; Camara, Mory; Bah, Boubacar; Uwizeye, Cecile; Nduwamahoro, Elie; Fissette, Kristina; De Rijk, Pim; Merle, Corinne; Olliaro, Piero; Burgos, Marcos; Lienhardt, Christian; Rigouts, Leen; de Jong, Bouke C

    2015-07-01

    In this study we assessed first-line anti-tuberculosis drug resistance and the genotypic distribution of Mycobacterium tuberculosis complex (MTBC) isolates that had been collected from consecutive new tuberculosis patients enrolled in two clinical trials conducted in Guinea between 2005 and 2010. Among the total 359 MTBC strains that were analyzed in this study, 22.8% were resistant to at least one of the first line anti-tuberculosis drugs, including 2.5% multidrug resistance and 17.5% isoniazid resistance, with or without other drugs. In addition, further characterization of isolates from a subset of the two trials (n = 184) revealed a total of 80 different spoligotype patterns, 29 "orphan" and 51 shared patterns. We identified the six major MTBC lineages of human relevance, with predominance of the Euro-American lineage. In total, 132 (71.7%) of the strains were genotypically clustered, and further analysis (using the DESTUS model) suggesting significantly faster spread of LAM10_CAM family (p = 0.00016). In conclusion, our findings provide a first insight into drug resistance and the population structure of the MTBC in Guinea, with relevance for public health scientists in tuberculosis control programs.

  3. Helix-Dependent Spin Filtering through the DNA Duplex.

    PubMed

    Zwang, Theodore J; Hürlimann, Sylvia; Hill, Michael G; Barton, Jacqueline K

    2016-12-07

    Recent work suggests that electrons can travel through DNA and other chiral molecules in a spin-selective manner, but little is known about the origin of this spin selectivity. Here we describe experiments on magnetized DNA-modified electrodes to explore spin-selective electron transport through hydrated duplex DNA. Our results show that the two spins migrate through duplex DNA with a different yield and that spin selectivity requires charge transport through the DNA duplex. Significantly, shifting the same duplex DNA between right-handed B- and left-handed Z-forms leads to a diode-like switch in spin selectivity; which spin moves more efficiently through the duplex depends upon the DNA helicity. With DNA, the supramolecular organization of chiral moieties, rather than the chirality of the individual monomers, determines the selectivity in spin, and thus a conformational change can switch the spin selectivity.

  4. Eddy Current Assessment of Duplex Metallic Coatings

    NASA Astrophysics Data System (ADS)

    Krzywosz, K. J.

    2004-02-01

    EPRI is involved in a multi-year program with the Department of Energy to test, evaluate, and develop a field-deployable eddy current NDE system for life assessment of blade coatings for advanced gas turbines. The coatings evaluated from these advanced GE engines include CoCrAlY (GT 29) and NiCoCrAlY (GT 33) bond coats followed by top aluminide overlay coatings. These duplex metallic coatings commonly referred to as GT 29+ and GT 33+ coatings, respectively. In general, during cycling and continuous operation at higher operating temperature, coatings fail due to spallation of protective oxide layers, leading to consumption of protective coating by oxidation and to eventual failure of blades. To extend service life of these critical rotating components, an inspection-based condition assessment program has been initiated to help establish more optimum inspection intervals that are not dependent on time-in-service maintenance approach. This paper summarizes the latest results obtained to date using the state-of-the-art frequency-scanning eddy current tester with a built-in three-layer inversion analysis algorithm. Significant progress has been made in assessing and discriminating the duplex metallic coatings as normal, degraded, and/or cracked. In addition, quantitative assessment was conducted by estimating various coating and substrate conductivity values.

  5. Spermine Condenses DNA, but Not RNA Duplexes

    SciTech Connect

    Katz, Andrea M.; Tolokh, Igor S.; Pabit, Suzette A.; Baker, Nathan; Onufriev, Alexey V.; Pollack, Lois

    2017-01-01

    Interactions between the polyamine spermine and nucleic acids drive important cellular processes. Spermine condenses DNA, and some RNAs such as poly(rA):poly(rU). A large fraction of the spermine present in cells is bound to RNA, but apparently does not condense it. Here, we study the effect of spermine binding to short duplex RNA and DNA and compare our findings with predictions of molecular dynamics simulations. When small numbers of spermine are introduced, RNA with a designed sequence, containing a mixture of 14 GC pairs and 11 AU pairs, resists condensation relative to DNA of an equivalent sequence or to 25 base pair poly(rA):poly(rU) RNA. Comparison of wide-angle x-ray scattering profiles with simulation suggests that spermine is sequestered deep within the major groove of mixed sequence RNA, preventing condensation by limiting opportunities to bridge to other molecules as well as stabilizing the RNA by locking it into a particular conformation. In contrast, for DNA, simulations suggest that spermine binds external to the duplex, offering opportunities for intermolecular interaction. The goal of this study is to explain how RNA can remain soluble, and available for interaction with other molecules in the cell, despite the presence of spermine at concentrations high enough to precipitate DNA.

  6. Antipsychotics reverse abnormal EEG complexity in drug-naïve schizophrenia: A multiscale entropy analysis

    PubMed Central

    Takahashi, Tetsuya; Cho, Raymond Y.; Mizuno, Tomoyuki; Kikuchi, Mitsuru; Murata, Tetsuhito; Takahashi, Koichi; Wada, Yuji

    2010-01-01

    Multiscale entropy (MSE) analysis is a novel entropy-based approach for measuring dynamical complexity in physiological systems over a range of temporal scales. To evaluate this analytic approach as an aid to elucidating the pathophysiologic mechanisms in schizophrenia, we examined MSE in EEG activity in drug-naïve schizophrenia subjects pre- and post-treatment with antipsychotics in comparison with traditional EEG analysis. We recorded eyes-closed resting state EEG from frontal, temporal, parietal and occipital regions in drug-naïve 22 schizophrenia and 24 age-matched healthy control subjects. Fifteen patients were re-evaluated within 2–8 weeks after the initiation of antipsychotic treatment. For each participant, MSE was calculated on one continuous 60 second epoch for each experimental session. Schizophrenia subjects showed significantly higher complexity at higher time scales (lower frequencies), than that of healthy controls in fronto-centro-temporal, but not in parieto-occipital regions. Post-treatment, this higher complexity decreased to healthy control subject levels selectively in fronto-central regions, while the increased complexity in temporal sites remained higher. Comparative power analysis identified spectral slowing in frontal regions in pre-treatment schizophrenia subjects, consistent with previous findings, whereas no antipsychotic treatment effect was observed. In summary, multiscale entropy measures identified abnormal dynamical EEG signal complexity in anterior brain areas in schizophrenia that normalized selectively in fronto-central areas with antipsychotic treatment. These findings show that entropy-based analytic methods may serve as a novel approach for characterizing and understanding abnormal cortical dynamics in schizophrenia, and elucidating the therapeutic mechanisms of antipsychotics. PMID:20149880

  7. 1H NMR study of the complexation of aromatic drugs with dimethylxanthine derivatives

    NASA Astrophysics Data System (ADS)

    Hernandez Santiago, A. A.; Gonzalez Flores, M.; Rosas Castilla, S. A.; Cervantes Tavera, A. M.; Gutierrez Perez, R.; Khomich, V. V.; Ovchinnikov, D. V.; Parkes, H. G.; Evstigneev, M. P.

    2012-02-01

    With an aim of searching efficient interceptors of aromatic drugs, the self- and hetero-association of dimethylxanthine derivatives with different structures, selected according to Strategy 1 (variation of the position of methyl groups) and Strategy 2 (variation of the length of sbnd (CH2)nsbnd COOH group), with aromatic drug molecules: Ethidium Bromide, Proflavine and Daunomycin, were studied using 1H NMR spectroscopy. It was found that the association proceeds in a form of stacking-type complexation and its energetics is relatively independent on the structure of the dimethylxanthines. However, on average, the dimethylxanthines possess higher hetero-association constant and, hence, higher interceptor ability as compared to the trimethylxanthine, Caffeine, used during the past two decades as a typical interceptor molecule.

  8. Basic butylated methacrylate copolymer/kappa-carrageenan interpolyelectrolyte complex: preparation, characterization and drug release behaviour.

    PubMed

    Prado, H J; Matulewicz, M C; Bonelli, P; Cukierman, A L

    2008-09-01

    The formation of a novel interpolyelectrolyte complex (IPEC) between basic butylated methacrylate copolymer and kappa-carrageenan was investigated and the product formed was characterized. Turbidity measurements and elemental analyses pointed to a 1:1 interaction of the repeating units. These results and FT-IR confirmed IPEC formation. Electronic microscopy images, particle size determination by image analysis and N(2) (77K) adsorption measurements were consistent with a porous material. This IPEC formed presented very good flowability and compactibility. Two maxima were observed in the swelling behaviour as a function of pH. The performance of the IPEC as a matrix for controlled release of drugs was evaluated, using ibuprofen as a model drug. Release profiles were properly represented by a mathematical model, which indicates that the system releases ibuprofen in a zero-order manner. These profiles could be controlled by conveniently modifying the proportion of the IPEC in the tablets.

  9. How to regulate nonbiological complex drugs (NBCD) and their follow-on versions: points to consider.

    PubMed

    Schellekens, Huub; Stegemann, Sven; Weinstein, Vera; de Vlieger, Jon S B; Flühmann, Beat; Mühlebach, Stefan; Gaspar, Rogério; Shah, Vinod P; Crommelin, Daan J A

    2014-01-01

    The aim of this critical review is to reach a global consensus regarding the introduction of follow-on versions of nonbiological complex drugs (NBCD). A nonbiological complex drug is a medicinal product, not being a biological medicine, where the active substance is not a homo-molecular structure, but consists of different (closely related and often nanoparticulate) structures that cannot be isolated and fully quantitated, characterized and/or described by state of the art physicochemical analytical means and where the clinical meaning of the differences is not known. The composition, quality and in vivo performance of NBCD are highly dependent on manufacturing processes of both the active ingredient as well as in most cases the formulation. The challenges posed by the development of follow-on versions of NBCD are illustrated in this paper by discussing the 'families' of liposomes, iron-carbohydrate ('iron-sugar') drugs and glatiramoids. It is proposed that the same principles for the marketing authorization of copies of NBCD as for biosimilars be used: the need for animal and/or clinical data and the need to show similarity in quality, safety and efficacy. The regulatory approach of NBCD will have to take into consideration the specific characteristics of the drugs, their formulation and manufacturing process and the resulting critical attributes to achieve their desired quality, safety and efficacy. As with the biosimilars, for the NBCD product, family-specific methods should be evaluated and applied where scientifically proven, including sophisticated quality methods, pharmacodynamic markers and animal models. Concerning substitution and interchangeability of NBCD, it is also advisable to take biosimilars as an example, i.e. (1) substitution without the involvement of a healthcare professional should be discouraged to ensure traceability of the treatment of individual patients, (2) keep an individual patient on a specific treatment if the patient is doing well

  10. Multivalent IDP assemblies: Unique properties of LC8-associated, IDP duplex scaffolds.

    PubMed

    Clark, Sarah A; Jespersen, Nathan; Woodward, Clare; Barbar, Elisar

    2015-09-14

    A wide variety of subcellular complexes are composed of one or more intrinsically disordered proteins (IDPs) that are multivalent, flexible, and characterized by dynamic binding of diverse partner proteins. These multivalent IDP assemblies, of broad functional diversity, are classified here into five categories distinguished by the number of IDP chains and the arrangement of partner proteins in the functional complex. Examples of each category are summarized in the context of the exceptional molecular and biological properties of IDPs. One type - IDP duplex scaffolds - is considered in detail. Its unique features include parallel alignment of two IDP chains, formation of new self-associated domains, enhanced affinity for additional bivalent ligands, and ubiquitous binding of the hub protein LC8. For two IDP duplex scaffolds, dynein intermediate chain IC and nucleoporin Nup159, these duplex features, together with the inherent flexibility of IDPs, are central to their assembly and function. A new type of IDP-LC8 interaction, distributed binding of LC8 among multiple IDP recognition sites, is described for Nup159 assembly.

  11. N-heterocyclic carbene metal complexes as bio-organometallic antimicrobial and anticancer drugs.

    PubMed

    Patil, Siddappa A; Patil, Shivaputra A; Patil, Renukadevi; Keri, Rangappa S; Budagumpi, Srinivasa; Balakrishna, Geetha R; Tacke, Matthias

    2015-01-01

    Late transition metal complexes that bear N-heterocyclic carbene (NHC) ligands have seen a speedy growth in their use as both, metal-based drug candidates and potentially active homogeneous catalysts in a plethora of C-C and C-N bond forming reactions. This review article focuses on the recent developments and advances in preparation and characterization of NHC-metal complexes (metal: silver, gold, copper, palladium, nickel and ruthenium) and their biomedical applications. Their design, syntheses and characterization have been reviewed and correlated to their antimicrobial and anticancer efficacies. All these initial discoveries help validate the great potential of NHC-metal derivatives as a class of effective antimicrobial and anticancer agents.

  12. Breast Cancer Stem Cell Potent Copper(II)-Non-Steroidal Anti-Inflammatory Drug Complexes.

    PubMed

    Boodram, Janine N; Mcgregor, Iain J; Bruno, Peter M; Cressey, Paul B; Hemann, Michael T; Suntharalingam, Kogularamanan

    2016-02-18

    The breast cancer stem cell (CSC) potency of a series of copper(II)-phenanthroline complexes containing the nonsteroidal anti-inflammatory drug (NSAID), indomethacin, is reported. The most effective copper(II) complex in this series, 4, selectivity kills breast CSC-enriched HMLER-shEcad cells over breast CSC-depleted HMLER cells. Furthermore, 4 reduces the formation, size, and viability of mammospheres, to a greater extent than salinomycin, a potassium ionophore known to selectively inhibit CSCs. Mechanistic studies revealed that the CSC-specificity observed for 4 arises from its ability to generate intracellular reactive oxygen species (ROS) and inhibit cyclooxygenase-2 (COX-2), an enzyme that is overexpressed in breast CSCs. The former induces DNA damage, activates JNK and p38 pathways, and leads to apoptosis.

  13. The similarity question for biologicals and non-biological complex drugs.

    PubMed

    Crommelin, Daan J A; Shah, Vinod P; Klebovich, Imre; McNeil, Scott E; Weinstein, Vera; Flühmann, Beat; Mühlebach, Stefan; de Vlieger, Jon S B

    2015-08-30

    For small - low molecular weight - molecule medicines a robust regulatory system has evolved over the years. This system guarantees high and constant quality of our (generic) medicines. Pharmaceutical equivalence and bioequivalence assessment are the pillars under that system. But there are complex medicines where the question of equivalence is more challenging to answer. For biologicals the paradigm of similarity rather than equality (the emergence of 'biosimilars') was developed in the past decade. This has been a program where an evolutionary, science based approach has been chosen by the frontrunner regulatory body, the EMA, with a 'learn and confirm' character. In addition, there is another group of complex drugs, the non-biological complex drugs, NBCDs, where the generic paradigm can be challenged as well. The NBCDs are defined as: 1. consisting of a complex multitude of closely related structures; 2. the entire multitude is the active pharmaceutical ingredient; 3. the properties cannot be fully characterized by physicochemical analysis and 4. the consistent, tightly controlled manufacturing process is fundamental to reproduce the product. NBCDs encompass product families such as the glatiramoids, liposomes, iron-carbohydrate colloids and many candidates of the group of the upcoming nanoparticulate systems. Following the main principles of regulatory pathways for biologicals (with appropriate product-by-product adjustments), instead of that for small molecules, would be the more logical strategy for these NBCDs. The status and outstanding regulatory issues for biosimilars and NBCD-similars/follow on versions were discussed at a conference in Budapest, Hungary (October 2014) and this commentary touches upon the issues brought up in the presentations, deliberations and conclusions.

  14. Zinc complexes of the antibacterial drug oxolinic acid: structure and DNA-binding properties.

    PubMed

    Tarushi, Alketa; Psomas, George; Raptopoulou, Catherine P; Kessissoglou, Dimitris P

    2009-06-01

    The neutral mononuclear zinc complexes with the quinolone antibacterial drug oxolinic acid in the absence or presence of a nitrogen donor heterocyclic ligand 2,2'-bipyridine or 1,10-phenanthroline have been synthesized and characterized. The experimental data suggest that oxolinic acid is on deprotonated mode acting as a bidentate ligand coordinated to the metal ion through the ketone and one carboxylato oxygen atoms. The crystal structures of (chloro)(oxolinato)(2,2'-bipyridine)zinc(II), 2, and bis(oxolinato)(1,10-phenanthroline)zinc(II), 3, have been determined with X-ray crystallography. The biological activity of the complexes has been evaluated by examining their ability to bind to calf-thymus DNA (CT DNA) with UV and fluorescence spectroscopies. UV studies of the interaction of the complexes with DNA have shown that they can bind to CT DNA and the DNA-binding constants have been calculated. Competitive studies with ethidium bromide (EB) have shown that complex 3 exhibits the ability to displace the DNA-bound EB indicating that it binds to DNA in strong competition with EB.

  15. Thermo-sensitive complex micelles from sodium alginate-graft-poly(N-isopropylacrylamide) for drug release.

    PubMed

    Yu, Nana; Li, Guiying; Gao, Yurong; Jiang, Hua; Tao, Qian

    2016-05-01

    Polymer micelles with environmentally sensitive properties have potential applications in biomedicine. In this paper, thermo-sensitive complex micelles assembled from biocompatible graft copolymers sodium alginate-graft-poly(N-isopropylacrylamide) (SA-g-PNIPAM) and divalent metal ions were prepared for controlled drug release. The polymer micelles had core-corona structure, which was constituted by metal ions (Ba(2+), Zn(2+), Co(2+)) cross-linked sodium alginate as the core and thermo-sensitive PNIPAM chains as the corona. Formation of polymer micelles was determined by Fourier-transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and dynamic light scattering (DLS). The polymer micelles were observed as regular spheres with good polydispersity and excellent performance on drug encapsulation and release ability. The cumulative release of 5-fluorouracil (5-FU) from micelles was controlled by pH, ionic strength or temperature of surroundings. The superior properties of sensitive polymer micelles induced by metal ions are expected to be utilized in controlled drug delivery systems.

  16. Structural Basis of Resistance to Anti-Cytochrome bc1 Complex Inhibitors: Implication for Drug Improvement

    PubMed Central

    Esser, Lothar; Yu, Chang-An; Xia, Di

    2016-01-01

    The emergence of drug resistance has devastating economic and social consequences, a testimonial of which is the rise and fall of inhibitors against the respiratory component cytochrome bc1 complex, a time tested and highly effective target for disease control. Unfortunately, the mechanism of resistance is a multivariate problem, including primarily mutations in the gene of the cytochrome b subunit but also activation of alternative pathways of ubiquinol oxidation and pharmacokinetic effects. There is a considerable interest in designing new bc1 inhibitors with novel modes of binding and lower propensity to induce the development of resistance. The accumulation of crystallographic data of bc1 complexes with and without inhibitors bound provides the structural basis for rational drug design. In particular, the cytochrome b subunit offers two distinct active sites that can be targeted for inhibition - the quinol oxidation site and the quinone reduction site. This review brings together available structural information of inhibited bc1 by various quinol oxidation- and reduction-site inhibitors, the inhibitor binding modes, conformational changes upon inhibitor binding of side chains in the active site and large scale domain movements of the iron-sulfur protein subunit. Structural data analysis provides a clear understanding of where and why existing inhibitors fail and points towards promising alternatives. PMID:23688079

  17. Huperzine A-phospholipid complex-loaded biodegradable thermosensitive polymer gel for controlled drug release.

    PubMed

    Cai, Xiaoqing; Luan, Yuxia; Jiang, Yue; Song, Aixin; Shao, Wei; Li, Zhonghao; Zhao, Zhongxi

    2012-08-20

    The huperzine A-phospholipid complex loaded biodegradable thermosensitive PLGA-PEG-PLGA polymer gel was studied as injectable implant system for controlled release of huperzine-A (HA). First, HA molecules were successfully incorporated into the soybean phosphatidylcholine (SP) molecules to form the huperzine-A-soybean phosphatidylcholine complexes (HA-SPC), which was proved by FT-IR, DSC, XRD, solubility study, TEM, etc. The results indicated that hydrogen bonds and electrostatic interaction between HA and SP molecules play an important role in the formation of HA-SPC. Secondly, the HA-SPC was loaded into biodegradable PLGA-PEG-PLGA thermosensitive gel as injectable implant material to control the release of HA. The in vitro and in vivo drug release behaviors of the prepared products were studied. The in vitro release studies demonstrated that the HA-SPC-loaded gel significantly reduced the initial burst of drug release and extended the release period to about 2 weeks. The in vivo pharmacokinetics study of HA-SPC-loaded gel in rabbits showed that plasma concentration of HA (2.54-0.15ng/mL) was detected for nearly 2 weeks from delivery systems upon single subcutaneous injection. What's more, the in vitro release pattern correlated well with the in vivo pharmacokinetics profile. The present study indicates that HA-SPC loaded PLGA-PEG-PLGA thermal gel may be an attractive candidate vehicle for controlled HA release.

  18. Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance

    PubMed Central

    Brooun, Alexei; Gajiwala, Ketan S.; Deng, Ya-Li; Liu, Wei; Bolaños, Ben; Bingham, Patrick; He, You-Ai; Diehl, Wade; Grable, Nicole; Kung, Pei-Pei; Sutton, Scott; Maegley, Karen A.; Yu, Xiu; Stewart, Al E.

    2016-01-01

    Polycomb repressive complex 2 (PRC2) mediates gene silencing through chromatin reorganization by methylation of histone H3 lysine 27 (H3K27). Overexpression of the complex and point mutations in the individual subunits of PRC2 have been shown to contribute to tumorigenesis. Several inhibitors of the PRC2 activity have shown efficacy in EZH2-mutated lymphomas and are currently in clinical development, although the molecular basis of inhibitor recognition remains unknown. Here we report the crystal structures of the inhibitor-bound wild-type and Y641N PRC2. The structures illuminate an important role played by a stretch of 17 residues in the N-terminal region of EZH2, we call the activation loop, in the stimulation of the enzyme activity, inhibitor recognition and the potential development of the mutation-mediated drug resistance. The work presented here provides new avenues for the design and development of next-generation PRC2 inhibitors through establishment of a structure-based drug design platform. PMID:27122193

  19. Immunogenicity to Biotherapeutics – The Role of Anti-drug Immune Complexes

    PubMed Central

    Krishna, Murli; Nadler, Steven G.

    2016-01-01

    Biological molecules are increasingly becoming a part of the therapeutics portfolio that has been either recently approved for marketing or those that are in the pipeline of several biotech and pharmaceutical companies. This is largely based on their ability to be highly specific relative to small molecules. However, by virtue of being a large protein, and having a complex structure with structural variability arising from production using recombinant gene technology in cell lines, such therapeutics run the risk of being recognized as foreign by a host immune system. In the context of immune-mediated adverse effects that have been documented to biological drugs thus far, including infusion reactions, and the evolving therapeutic platforms in the pipeline that engineer different functional modules in a biotherapeutic, it is critical to understand the interplay of the adaptive and innate immune responses, the pathophysiology of immunogenicity to biological drugs in instances where there have been immune-mediated adverse clinical sequelae and address technical approaches for their laboratory evaluation. The current paradigm in immunogenicity evaluation has a tiered approach to the detection and characterization of anti-drug antibodies (ADAs) elicited in vivo to a biotherapeutic; alongside with the structural, biophysical, and molecular information of the therapeutic, these analytical assessments form the core of the immunogenicity risk assessment. However, many of the immune-mediated adverse effects attributed to ADAs require the formation of a drug/ADA immune complex (IC) intermediate that can have a variety of downstream effects. This review will focus on the activation of potential immunopathological pathways arising as a consequence of circulating as well as cell surface bound drug bearing ICs, risk factors that are intrinsic either to the therapeutic molecule or to the host that might predispose to IC-mediated effects, and review the recent literature on

  20. Neomycin-neomycin dimer: an all-carbohydrate scaffold with high affinity for AT-rich DNA duplexes.

    PubMed

    Kumar, Sunil; Xue, Liang; Arya, Dev P

    2011-05-18

    A dimeric neomycin-neomycin conjugate 3 with a flexible linker, 2,2'-(ethylenedioxy)bis(ethylamine), has been synthesized and characterized. Dimer 3 can selectively bind to AT-rich DNA duplexes with high affinity. Biophysical studies have been performed between 3 and different nucleic acids with varying base composition and conformation by using ITC (isothermal calorimetry), CD (circular dichroism), FID (fluorescent intercalator displacement), and UV (ultraviolet) thermal denaturation experiments. A few conclusions can be drawn from this study: (1) FID assay with 3 and polynucleotides demonstrates the preference of 3 toward AT-rich sequences over GC-rich sequences. (2) FID assay and UV thermal denaturation experiments show that 3 has a higher affinity for the poly(dA)·poly(dT) DNA duplex than for the poly(dA)·2poly(dT) DNA triplex. Contrary to neomycin, 3 destabilizes poly(dA)·2poly(dT) triplex but stabilizes poly(dA)·poly(dT) duplex, suggesting the major groove as the binding site. (3) UV thermal denaturation studies and ITC experiments show that 3 stabilizes continuous AT-tract DNA better than DNA duplexes with alternating AT bases. (4) CD and FID titration studies show a DNA binding site size of 10-12 base pairs/drug, depending upon the structure/sequence of the duplex for AT-rich DNA duplexes. (5) FID and ITC titration between 3 and an intramolecular DNA duplex [d(5'-A(12)-x-T(12)-3'), x = hexaethylene glycol linker] results in a binding stoichiometry of 1:1 with a binding constant ∼10(8) M(-1) at 100 mM KCl. (6) FID assay using 3 and 512 hairpin DNA sequences that vary in their AT base content and placement also show a higher binding selectivity of 3 toward continuous AT-rich than toward DNA duplexes with alternate AT base pairs. (7) Salt-dependent studies indicate the formation of three ion pairs during binding of the DNA duplex d[5'-A(12)-x-T(12)-3'] and 3. (8) ITC-derived binding constants between 3 and DNA duplexes have the following order: AT

  1. In vitro evaluation of a new drug combination against clinical isolates belonging to the Mycobacterium abscessus complex.

    PubMed

    Singh, S; Bouzinbi, N; Chaturvedi, V; Godreuil, S; Kremer, L

    2014-12-01

    The in vitro susceptibility profile to amikacin, linezolid, clarithromycin, imipenem, cefoxitin, clofazimine and tigecycline was established for 67 strains belonging to the Mycobacterium abscessus complex. Clofazimine and tigecycline were among the most effective drugs, prompting us to assess the effect of a clofazimine and tigecycline combination. Synergistic activity was found in 42% of the 19 isolates tested. The clinical impact of this new drug combination against the M. abscessus complex, as an alternative or sequential medication for the treatment of drug-resistant strains, remains to be addressed.

  2. Reliability analysis of a repairable duplex system

    NASA Astrophysics Data System (ADS)

    Vanderperre, E. J.; Makhanov, S. S.

    2014-09-01

    We analyse the survival time of a repairable duplex system characterised by cold standby and by a pre-emptive priority rule. We allow general probability distributions for failure and repair. Moreover, an important realistic feature of the system is the general assumption that the non-priority unit has a memory. This combination of features has not been analysed in the previous literature. Our (new) methodology is based on a concatenation of a Cauchy-type integral representation of the modified Heaviside unit-step function and a two-sided stochastic inequality. Finally, we introduce a security interval related to a security level and a suitable risk-criterion based on the survival function of the system. As a practical application, we analyse some particular cases of the survival function jointly with the security interval corresponding to a security level of 90.

  3. Structural basis for RNA-duplex recognition and unwinding by the DEAD-box helicase Mss116p.

    PubMed

    Mallam, Anna L; Del Campo, Mark; Gilman, Benjamin; Sidote, David J; Lambowitz, Alan M

    2012-10-04

    DEAD-box proteins are the largest family of nucleic acid helicases, and are crucial to RNA metabolism throughout all domains of life. They contain a conserved 'helicase core' of two RecA-like domains (domains (D)1 and D2), which uses ATP to catalyse the unwinding of short RNA duplexes by non-processive, local strand separation. This mode of action differs from that of translocating helicases and allows DEAD-box proteins to remodel large RNAs and RNA-protein complexes without globally disrupting RNA structure. However, the structural basis for this distinctive mode of RNA unwinding remains unclear. Here, structural, biochemical and genetic analyses of the yeast DEAD-box protein Mss116p indicate that the helicase core domains have modular functions that enable a novel mechanism for RNA-duplex recognition and unwinding. By investigating D1 and D2 individually and together, we find that D1 acts as an ATP-binding domain and D2 functions as an RNA-duplex recognition domain. D2 contains a nucleic-acid-binding pocket that is formed by conserved DEAD-box protein sequence motifs and accommodates A-form but not B-form duplexes, providing a basis for RNA substrate specificity. Upon a conformational change in which the two core domains join to form a 'closed state' with an ATPase active site, conserved motifs in D1 promote the unwinding of duplex substrates bound to D2 by excluding one RNA strand and bending the other. Our results provide a comprehensive structural model for how DEAD-box proteins recognize and unwind RNA duplexes. This model explains key features of DEAD-box protein function and affords a new perspective on how the evolutionarily related cores of other RNA and DNA helicases diverged to use different mechanisms.

  4. Oligonucleotides with "clickable" sugar residues: synthesis, duplex stability, and terminal versus central interstrand cross-linking of 2'-O-propargylated 2-aminoadenosine with a bifunctional azide.

    PubMed

    Pujari, Suresh S; Leonard, Peter; Seela, Frank

    2014-05-16

    Duplex DNA with terminal and internal sugar cross-links were synthesized by the CuAAC reaction from oligonucleotides containing 2'-O-propargyl-2-aminoadenosine as a clickable site and a bifunctional azide (4). Stepwise click chemistry was employed to introduce cross-links at internal and terminal positions. Copper turnings were used as catalyst, reducing the copper load of the reaction mixture and avoiding complexing agents. For oligonucleotide building block synthesis, a protecting group strategy was developed for 2'-O-propargyl-2-aminoadenosine owing to the rather different reactivities of the two amino groups. Phosphoramidites were synthesized bearing clickable 2'-O-propargyl residues (14 and 18) as well as a 2'-deoxyribofuranosyl residue (10). Hybridization experiments of non-cross-linked oligonucleotides with 2,6-diaminopurine as nucleobase showed no significant thermal stability changes over those containing adenine. Surprisingly, an isobutyryl group protecting the 2-amino function has no negative impact on the stability of DNA-DNA and DNA-RNA duplexes. Oligonucleotide duplexes with cross-linked 2'-O-propargylated 2-aminoadenosine (1) and 2'-O-propargylated adenosine (3) at terminal positions are significantly stabilized (ΔT(m) = +29 °C). The stability results from a molecularity change from duplex to hairpin melting and is influenced by the ligation position. Terminal ligation led to higher melting duplexes than corresponding hairpins, while duplexes with central ligation sites were less stable.

  5. Dinuclear Pt(II)-bisphosphonate complexes: a scaffold for multinuclear or different oxidation state platinum drugs.

    PubMed

    Piccinonna, Sara; Margiotta, Nicola; Pacifico, Concetta; Lopalco, Antonio; Denora, Nunzio; Fedi, Serena; Corsini, Maddalena; Natile, Giovanni

    2012-08-28

    Geminal bisphosphonates (BPs), used in the clinic for the treatment of hypercalcaemia and skeletal metastases, have been also exploited for promoting the specific accumulation of platinum antitumor drugs in bone tissue. In this work, the platinum dinuclear complex [{Pt(en)}(2)(μ-AHBP-H(2))](+) (1) (the carbon atom bridging the two phosphorous atoms carrying a 2-ammonioethyl and a hydroxyl group, AHBP-H(2)) has been used as scaffold for the synthesis of a Pt(II) trinuclear complex, [{Pt(en)}(3)(μ-AHBP)](+) (2), and a Pt(IV) adamantane-shaped dinuclear complex featuring an oxo-bridge, [{Pt(IV)(en)Cl}(2)(μ-O)(μ-AHBP-H(2))](+) (3) (X-ray structure). Compound 2 undergoes a reversible, pH dependent, rearrangement with a neat switch point around pH = 5.4. Compound 3 undergoes a one-step electrochemical reduction at E(pc) = -0.84 V affording compound 1. Such a potential is far lower than that of glutathione (-0.24 V), nevertheless compound 3 can undergo chemical reduction to 1 by GSH, most probably through a different (inner-sphere) mechanism. In vitro cytotoxicity of the new compounds, tested against murine glioma (C6) and human cervix (HeLa) and hepatoma (HepG2) cell lines, has shown that, while the Pt(IV) dimer 3 is inactive up to a concentration of 50 μM, the two Pt(II) polynuclear compounds 1 and 2 have a cytotoxicity comparable to that of cisplatin with the trinuclear complex 2 generally more active than the dinuclear complex 1.

  6. Gold(III) complexes with ONS-Tridentate thiosemicarbazones: Toward selective trypanocidal drugs.

    PubMed

    Rettondin, Andressa R; Carneiro, Zumira A; Gonçalves, Ana C R; Ferreira, Vanessa F; Oliveira, Carolina G; Lima, Angélica N; Oliveira, Ronaldo J; de Albuquerque, Sérgio; Deflon, Victor M; Maia, Pedro I S

    2016-09-14

    Tridentate thiosemicarbazone ligands with an ONS donor set, H2L(R) (R = Me and Et) were prepared by reactions of 1-phenyl-1,3-butanedione with 4-R-3-thiosemicarbazides. H2L(R) reacts with Na[AuCl4]·2H2O in MeOH in a 1:1 M ratio under formation of green gold(III) complexes of composition [AuCl(L(R))]. These compounds represent the first examples of gold(III) complexes with ONS chelate-bonded thiosemicarbazones. The in vitro anti-Trypanosoma cruzi activity against both trypomastigote and amastigote forms (IC50try/ama) of CL Brener strains as well as the cytotoxicity against LLC-MK2 cells of the free ligands and complexes was evaluated. The complex [AuCl(L(Me))] was found to be more active and more selective than its precursor ligand and the standard drug benznidazole with a SItry/ama value higher than 200, being considered as a lead candidate for Chagas disease treatment. Moreover the in vitro activity against the replicative amastigote form (IC50ama) of T. cruzi was additionally investigated revealing that [AuCl(L(Me))] was also more potent than benznidazole still with a similar selectivity index. Finally, docking studies showed that free ligands and complexes interact with the same residues of the parasite protease cruzain but with different intensities, suggesting that this protease could be a possible target for the trypanocidal action of the obtained compounds.

  7. Cyclodextrin complexes of reduced bromonoscapine in guar gum microspheres enhance colonic drug delivery.

    PubMed

    Madan, Jitender; Gundala, Sushma R; Baruah, Bharat; Nagaraju, Mulpuri; Yates, Clayton; Turner, Timothy; Rangari, Vijay; Hamelberg, Donald; Reid, Michelle D; Aneja, Ritu

    2014-12-01

    Here, we report improved solubility and enhanced colonic delivery of reduced bromonoscapine (Red-Br-Nos), a cyclic ether brominated analogue of noscapine, upon encapsulation of its cyclodextrin (CD) complexes in bioresponsive guar gum microspheres (GGM). Phase-solubility analysis suggested that Red-Br-Nos complexed with β-CD and methyl-β-CD in a 1:1 stoichiometry, with a stability constant (Kc) of 2.29 × 10(3) M(-1) and 4.27 × 10(3) M(-1). Fourier transforms infrared spectroscopy indicated entrance of an O-CH₂ or OCH₃-C₆H₄-OCH₃ moiety of Red-Br-Nos in the β-CD or methyl-β-CD cavity. Furthermore, the cage complex of Red-Br-Nos with β-CD and methyl-β-CD was validated by several spectral techniques. Rotating frame Overhauser enhancement spectroscopy revealed that the Ha proton of the OCH₃-C₆H₄-OCH₃ moiety was closer to the H₅ proton of β-CD and the H₃ proton of the methyl-β-CD cavity. The solubility of Red-Br-Nos in phosphate buffer saline (PBS, pH ∼ 7.4) was improved by ∼10.7-fold and ∼21.2-fold when mixed with β-CD and methyl-β-CD, respectively. This increase in solubility led to a favorable decline in the IC₅₀ by ∼2-fold and ∼3-fold for Red-Br-Nos-β-CD-GGM and Red-Br-Nos-methyl-β-CD-GGM formulations respectively, compared to free Red-Br-Nos-β-CD and Red-Br-Nos-methyl-β-CD in human colon HT-29 cells. GGM-bearing drug complex formulations were found to be highly cytotoxic to the HT-29 cell line and further effective with simultaneous continuous release of Red-Br-Nos from microspheres. This is the first study to showing the preparation of drug-complex loaded GGMS for colon delivery of Red-Br-Nos that warrants preclinical assessment for the effective management of colon cancer.

  8. Cyclodextrin Complexes of Reduced Bromonoscapine in Guar Gum Microspheres Enhance Colonic Drug Delivery

    PubMed Central

    2015-01-01

    Here, we report improved solubility and enhanced colonic delivery of reduced bromonoscapine (Red-Br-Nos), a cyclic ether brominated analogue of noscapine, upon encapsulation of its cyclodextrin (CD) complexes in bioresponsive guar gum microspheres (GGM). Phase–solubility analysis suggested that Red-Br-Nos complexed with β-CD and methyl-β-CD in a 1:1 stoichiometry, with a stability constant (Kc) of 2.29 × 103 M–1 and 4.27 × 103 M–1. Fourier transforms infrared spectroscopy indicated entrance of an O–CH2 or OCH3–C6H4–OCH3 moiety of Red-Br-Nos in the β-CD or methyl-β-CD cavity. Furthermore, the cage complex of Red-Br-Nos with β-CD and methyl-β-CD was validated by several spectral techniques. Rotating frame Overhauser enhancement spectroscopy revealed that the Ha proton of the OCH3–C6H4–OCH3 moiety was closer to the H5 proton of β-CD and the H3 proton of the methyl-β-CD cavity. The solubility of Red-Br-Nos in phosphate buffer saline (PBS, pH ∼ 7.4) was improved by ∼10.7-fold and ∼21.2-fold when mixed with β-CD and methyl-β-CD, respectively. This increase in solubility led to a favorable decline in the IC50 by ∼2-fold and ∼3-fold for Red-Br-Nos−β-CD-GGM and Red-Br-Nos–methyl-β-CD-GGM formulations respectively, compared to free Red-Br-Nos−β-CD and Red-Br-Nos–methyl-β-CD in human colon HT-29 cells. GGM-bearing drug complex formulations were found to be highly cytotoxic to the HT-29 cell line and further effective with simultaneous continuous release of Red-Br-Nos from microspheres. This is the first study to showing the preparation of drug-complex loaded GGMS for colon delivery of Red-Br-Nos that warrants preclinical assessment for the effective management of colon cancer. PMID:25350222

  9. In vitro susceptibility testing of Mycobacterium tuberculosis complex strains isolated from seals to antituberculosis drugs.

    PubMed

    Bernardelli, Amelia; Morcillo, Nora; Loureiro, Julio; Quse, Viviana; Davenport, Silvana

    2004-06-01

    Mycobacteria strains belonging to the Mycobacterium tuberculosis complex were isolated from seals found in the South Atlantic. The animals were received in Mundo Marino installations and treated for Mycobacterium tuberculosis complex by conventional therapy of intensive care and enriched food supply; however, in all cases treatment failed. Necropsies of all animals revealed extensive lesions compatible with tuberculosis involving lungs, liver, spleen and lymphatic nodes. Classical biochemical methods as well as molecular techniques using the IS6110 probes were performed for mycobacterial identification. Furthermore, the LCx M. tuberculosis assay (Abbott Laboratories) identified all strains as Mycobacterium tuberculosis complex members. The in vitro susceptibility pattern was examined in mycobacterial strains isolated from seven seals and in 3 reference strains--BCG, H37Rv (M. tuberculosis) and AN5 (Mycobacterium bovis)--to 4 medications--isoniazid, rifampin, streptomycin and ethambutol. Minimal inhibitory drug concentrations were determined by the Mycobacterial Growth Indicator Tube (BD Argentina) method and a microdilution and colorimetric assay using 3-(4-5 dimethyltiazol-2)-2,5 diphenyltetrazolium bromide. All the isolates and the reference strains BCG and AN5 were inhibited by MIC values similar to those of H37Rv with good agreement obtained by both techniques. These findings suggest that a therapeutic regimen aimed to seals diagnosed with tuberculosis play an important role in the prevention of tuberculosis transmission from infected animals to humans that are in routine contact with them.

  10. [Ultrasound duplex scanning in the assessment of the effectiveness of gravitation therapy and conservative treatment of patients with atherosclerosis obliterans of the lower extremities].

    PubMed

    Galkin, R A; Makarov, I V; Preobrazhenskaia, N M

    2004-01-01

    Ultrasound duplex scanning was used to compare the results of the treatment of 162 patients suffering from atherosclerosis obliterans of the lower extremities. It is to be noted that 50 patients were administered only gravitation therapy, 72 patients underwent a complex of treatment measures including, in addition to gravitation therapy, physiotherapy and drug treatment, and 40 patients received conservative treatment alone. The assessment criteria were the maximal systolic velocity of blood flow (V(max)), end diastolic mean, velocity (V(min)), mean maximal velocity (V(mean)), volume velocity of blood flow (V(vol)), ankle/brachial index (ABI), and index of regional perfusion (IRP), proposed by us and representing the percent ratio of the volume velocity of blood flow to the minute heart volume (MHV). It has been revealed in the course of the treatment that the best clinical outcome was recorded in patients who received a complex of treatment measures. The use of gravitation therapy alone provided better treatment results as compared to those obtained in patients administered standard conservative therapy. Of all the indicators used, only V(mean), V(vol), ABI and IRP are of the clinical significance. However, the most significant information on the segmental blood flow was obtained on the assessment of the IRP whose values did not depend on the changes in central hemodynamics. In contrast to the ABI, the advantage of the IRP lies in the possibility of blood flow assessment in different segments and arteries of the extremities. So, the use of the quantitative indicators of ultrasound duplex scanning and, first of all, of the IRP, allows an objective evaluation of the segmental blood flow and may serve one of the significant criteria of the treatment effectiveness.

  11. The structure and duplex context of DNA interstrand crosslinks affects the activity of DNA polymerase η

    PubMed Central

    Roy, Upasana; Mukherjee, Shivam; Sharma, Anjali; Frank, Ekaterina G.; Schärer, Orlando D.

    2016-01-01

    Several important anti-tumor agents form DNA interstrand crosslinks (ICLs), but their clinical efficiency is counteracted by multiple complex DNA repair pathways. All of these pathways require unhooking of the ICL from one strand of a DNA duplex by nucleases, followed by bypass of the unhooked ICL by translesion synthesis (TLS) polymerases. The structures of the unhooked ICLs remain unknown, yet the position of incisions and processing of the unhooked ICLs significantly influence the efficiency and fidelity of bypass by TLS polymerases. We have synthesized a panel of model unhooked nitrogen mustard ICLs to systematically investigate how the state of an unhooked ICL affects pol η activity. We find that duplex distortion induced by a crosslink plays a crucial role in translesion synthesis, and length of the duplex surrounding an unhooked ICL critically affects polymerase efficiency. We report the synthesis of a putative ICL repair intermediate that mimics the complete processing of an unhooked ICL to a single crosslinked nucleotide, and find that it provides only a minimal obstacle for DNA polymerases. Our results raise the possibility that, depending on the structure and extent of processing of an ICL, its bypass may not absolutely require TLS polymerases. PMID:27257072

  12. A nanoscale duplex precipitation approach for improving the properties of Fe-base alloys

    SciTech Connect

    Zhang, Zhongwu; Liu, C T; Wang, Xun-Li; Wen, Y. R.; Fujita, T.; Hirata, A.; Chen, M.W.; Miller, Michael K; Chen, Guang; Chin, Bryan

    2013-01-01

    The precipitate size and number density are important factors for tailoring the mechanical behaviors of nanoscale precipitate-hardened alloys. However during thermal aging, the precipitate size and number density change leading to either poor strength or high strength but significantly reduced ductility. Here we demonstrate, by producing nanoprecipitates with unusual duplex structures in a composition-optimized multicomponent precipitation-hardened alloy, a unique approach to improve the stability of the alloy against the effects of thermal aging and consequently change in the mechanical properties. Our study provides compelling experimental evidence that these nanoscale precipitates consist of a duplex structures with a Cu-enriched bcc core that is partially encased by a B2-ordered Ni(Mn,Al) phase. This duplex structure enables the precipitate size and number density to be independently optimized, provides a more complex obstacle for dislocation movement due to the ordering and an additional interphase interface, and yields a high yield strength alloy without sacrificing the ductility.

  13. Binding specificity and stability of duplexes formed by modified oligonucleotides with a 4096-hexanucleotide microarray

    PubMed Central

    Timofeev, Edward; Mirzabekov, Andrei

    2001-01-01

    The binding of oligodeoxynucleotides modified with adenine 2′-O-methyl riboside, 2,6-diaminopurine 2′-O-methyl riboside, cytosine 2′-O-methyl riboside, 2,6-diaminopurine deoxyriboside or 5-bromodeoxyuridine was studied with a microarray containing all possible (4096) polyacrylamide-bound hexadeoxynucleotides (a generic microchip). The generic microchip was manufactured by using reductive immobilization of aminooligonucleotides in the activated copolymer of acrylamide, bis-acrylamide and N-(2,2-dimethoxyethyl) acrylamide. The binding of the fluorescently labeled modified octanucleotides to the array was analyzed with the use of both melting profiles and the fluorescence distribution at selected temperatures. Up to three substitutions of adenosines in the octamer sequence by adenine 2′-O-methyl ribosides (Am), 2,6-diaminopurine 2′-O-methyl ribosides (Dm) or 2,6-diaminopurine deoxyribosides (D) resulted in increased mismatch discrimination measured at the melting temperature of the corresponding perfect duplex. The stability of complexes formed by 2′-O-methyl-adenosine-modified oligodeoxynucleotides was slightly decreased with every additional substitution, yielding ∼4°C of total loss in melting temperature for three modifications, as followed from microchip thermal denaturation experiments. 2,6-Diaminopurine 2′-O-methyl riboside modifications led to considerable duplex stabilization. The cytosine 2′-O-methyl riboside and 5-bromodeoxyuridine modifications generally did not change either duplex stability or mismatch resolution. Denaturation experiments conducted with selected perfect duplexes on microchips and in solution showed similar results on thermal stabilities. Some hybridization artifacts were observed that might indicate the formation of parallel DNA. PMID:11410672

  14. Unravelling the complex drug–drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein

    PubMed Central

    Ledwitch, Kaitlyn V.; Barnes, Robert W.; Roberts, Arthur G.

    2016-01-01

    Drug–drug interactions (DDIs) and associated toxicity from cardiovascular drugs represents a major problem for effective co-administration of cardiovascular therapeutics. A significant amount of drug toxicity from DDIs occurs because of drug interactions and multiple cardiovascular drug binding to the efflux transporter P-glycoprotein (Pgp), which is particularly problematic for cardiovascular drugs because of their relatively low therapeutic indexes. The calcium channel antagonist, verapamil and the cardiac glycoside, digoxin, exhibit DDIs with Pgp through non-competitive inhibition of digoxin transport, which leads to elevated digoxin plasma concentrations and digoxin toxicity. In the present study, verapamil-induced ATPase activation kinetics were biphasic implying at least two verapamil-binding sites on Pgp, whereas monophasic digoxin activation of Pgp-coupled ATPase kinetics suggested a single digoxin-binding site. Using intrinsic protein fluorescence and the saturation transfer double difference (STDD) NMR techniques to probe drug–Pgp interactions, verapamil was found to have little effect on digoxin–Pgp interactions at low concentrations of verapamil, which is consistent with simultaneous binding of the drugs and non-competitive inhibition. Higher concentrations of verapamil caused significant disruption of digoxin–Pgp interactions that suggested overlapping and competing drug-binding sites. These interactions correlated to drug-induced conformational changes deduced from acrylamide quenching of Pgp tryptophan fluorescence. Also, Pgp-coupled ATPase activity kinetics measured with a range of verapamil and digoxin concentrations fit well to a DDI model encompassing non-competitive and competitive inhibition of digoxin by verapamil. The results and previous transport studies were combined into a comprehensive model of verapamil–digoxin DDIs encompassing drug binding, ATP hydrolysis, transport and conformational changes. PMID:26823559

  15. Thermoacoustic Duplex Technology for Cooling and Powering a Venus Lander

    NASA Astrophysics Data System (ADS)

    Walker, A. R.; Haberbusch, M. S.; Sasson, J.

    2015-04-01

    A Thermoacoustic Stirling Heat Engine (TASHE) is directly coupled to a Pulse Tube Refrigerator (PTR) in a duplex configuration, providing simultaneous cooling and electrical power, thereby suiting the needs of a long-lived Venus lander.

  16. 43. View of station from southwest side with duplex keepers' ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    43. View of station from southwest side with duplex keepers' dwelling to the left. USLHB photo by Herbert Bamber, June 9, 1893. - Bodie Island Light Station, Off Highway 12, Nags Head, Dare County, NC

  17. 1. VIEW OF STAFF HOUSE (FEATURE 10), FACING SOUTHWEST. DUPLEX ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. VIEW OF STAFF HOUSE (FEATURE 10), FACING SOUTHWEST. DUPLEX (FEATURE 7) IS VISIBLE IN THE BACKGROUND AT RIGHT. - Copper Canyon Camp of the International Smelting & Refining Company, Staff House, Copper Canyon, Battle Mountain, Lander County, NV

  18. 1. VIEW OF RESIDENCE (FEATURE 12), FACING SOUTHWEST. DUPLEX (FEATURE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    1. VIEW OF RESIDENCE (FEATURE 12), FACING SOUTHWEST. DUPLEX (FEATURE 9) IS VISIBLE IN THE BACKGROUND. - Copper Canyon Camp of the International Smelting & Refining Company, Residence, Copper Canyon, Battle Mountain, Lander County, NV

  19. Duplex ultrasound assessment of femorodistal grafts: correlation with angiography.

    PubMed

    McShane, M D; Gazzard, V M; Clifford, P C; Hacking, C N; Fairhurst, J J; Humphries, K N; Birch, S J; Webster, J H; Chant, A D

    1987-12-01

    Fifty-eight grafts have been assessed using duplex scanning and ankle brachial pressure indices. This assessment is compared with the findings by angiography. Eighteen grafts were occluded and 40 patent. Duplex scanning defined graft status with a greater accuracy than pressure indices. Pressure indices alone would not differentiate "satisfactory" grafts from those with localised, haemodynamically significant disease. Only 55% of those grafts with localised stenoses demonstrated a fall of greater than 0.2 in ankle brachial pressure index after exercise. When the information obtained using pressure indices and duplex scanning was combined non-invasive assessment had a sensitivity of 86% and specificity of 94% for detection of localised, haemodynamically significant disease in patent grafts. Haemodynamically significant disease, as defined by angiography, can be detected and localised with duplex scanning complementing the use of pressure indices in graft assessment.

  20. Rapid drug susceptibility of Mycobacterium avium complex using a fluorescence quenching method.

    PubMed

    Marone, P; Bono, L; Carretto, E; Barbarini, D; Telecco, S

    1997-08-01

    Mycobacteria Growth Indicator Tube (MGIT) is a recently introduced rapid growth detection method which uses an oxygen quenched fluorescent indicator. The present study evaluated the ability of this new method to determine the drug susceptibility of Mycobacterium avium complex (MAC). Thirty strains recovered from patients with AIDS were tested for susceptibility to clarithromycin, rifabutin, ciprofloxacin, azithromycin and amikacin using MGIT. Results were compared to susceptibilities determined by the agar dilution method. The results obtained showed a 100% correlation between MGIT and the agar dilution method for rifabutin and clarithromycin. There was a 100% correlation between the two methods for azithromycin against 27 strains. MGIT was well correlated with the agar dilution method for detecting resistance to clarithromycin, rifabutin and azithromycin in 4 days, but the correlation was poor when susceptibilities to ciprofloxacin and amikacin were determined. This rapid method is non-radiometric, noninvasive and does not require any special instruments.

  1. The Origins of Microtexture in Duplex Ti Alloys (Preprint)

    DTIC Science & Technology

    2008-06-01

    To) June 2008 Journal Article Preprint 4 . TITLE AND SUBTITLE THE ORIGINS OF MICROTEXTURE IN DUPLEX Ti ALLOYS (PREPRINT) 5a. CONTRACT NUMBER In...house 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 62102F 6 . AUTHOR(S) M.G. Glavic (UES, Inc.) B.B. Bartha (United Technologies Corporation...applicable to duplex alpha/beta titanium microstructures. The crystallographic coherency of the primary and secondary alpha phase with the prior beta

  2. Extended Outcomes of Complex Coronary Disease in the Drug Eluting Stent Era

    PubMed Central

    Desrosiers, Kevin P.; Brown, Jeremiah R.; Langner, Craig A.; Sidhu, Mandeep S.; Robb, John F.; Hearne, Michael J.; Lee, Peter M. Ver; Kellett, Mirle A.; Ryan, Thomas J.; O’Meara, John R.; Dauerman, Harold L.; Silver, M. Theodore; Thompson, Craig A.; Malenka, David J.

    2011-01-01

    Background Several randomized trials comparing bare-metal stents to Drug-Eluting Stents (DES) have demonstrated a significant reduction in Target Vessel Revascularization (TVR) and Target Lesion Revascularization (TLR) exists with the use of drug-eluting stents, without compromising survival. These conclusions are based on restricted inclusion criteria for patients and lesion. It is unknown if these results can be generalized to an unselected patient population and more complex disease. The objective of this study was to determine to what extent the availability of DES has impacted survival, TVR, and TLR in a large regional experience without the restriction of on-label indications. Methods Patients registered with the Northern New England Cardiovascular Disease Study Group’s PCI registry with single vessel coronary disease undergoing a first PCI were sorted according to the Bare-Metal stent (BMS) era (2001 - 2002) or the Drug-Eluting stent (DES) era (2004 - 2005) based on the time period their first PCI took place. Totally, 6,093 BMS and 5,651 DES patients were identified. Outcomes of survival, TLR and TVR were measured after one year. Results After 1 year, survival was comparable, TLR was reduced by 4.9% (absolute) and TVR was reduced by 5.4% (absolute) in the DES era compared to the BMS era. The TLR/TVR differences remained significant after propensity matching in the DES era vs BMS era (Mortality: HR 1.00, 95% CI: 0.83 - 1.28; TLR: HR 0.40, 95% CI 0.32 - 0.46; TVR: HR 0.44, 95% CI 0.38 - 0.51). Conclusions In large regional experience with a consecutive series of patients representing the contemporary practice of PCI, including both on and off label use, the frequent use of DES reduces the risk of TVR and TLR without compromising survival.

  3. Benznidazole drug delivery by binary and multicomponent inclusion complexes using cyclodextrins and polymers.

    PubMed

    Soares-Sobrinho, José L; Santos, Fabiana L A; Lyra, Magaly A M; Alves, Lariza D S; Rolim, Larissa A; Lima, Adley A N; Nunes, Lívio C C; Soares, Monica F R; Rolim-Neto, Pedro J; Torres-Labandeira, Juan J

    2012-06-20

    Benznidazole (BNZ) is the drug of choice for Chagas disease treatment, which affects about 9.8 million people worldwide. It has low solubility and high toxicity. The present study aimed to develop and characterize inclusion complexes (IC) in binary systems (BS) with BNZ and randomly methylated-β-cyclodextrin (RMβCD) and in ternary systems (TS) with BNZ, RMβCD and hydrophilic polymers. The results showed that the solid BS had a large increase in dissolution rate (Q>80%). For the solid IC obtained, the kneading method, in ratio of 1:0.17 (77.8% in 60 min), appeared to be the most suitable for the development of a solid oral pharmaceutical product, with possible industrial scale-up and low concentration of CD. The solid TS containing 0.1% of hydroxypropylmethylcellulose (HPMC) showed no significant advantages compared to the binary IC in solid state. The use of cyclodextrins proved to be a viable tool for effective, standardized and safe drug delivery.

  4. First Evidence of the Liposome-Mediated Deintercalation of Anticancer Drug Doxorubicin from the Drug-DNA Complex: A Spectroscopic Approach.

    PubMed

    Das, Anupam; Adhikari, Chandan; Nayak, Debasis; Chakraborty, Anjan

    2016-01-12

    Biocompatible liposomes were used for the first time to study the deintercalation process of a prominent anticancer drug, doxorubicin (DOX), from doxorubicin-intercalated DNA (DOX-DNA complex) under controlled experimental conditions. The study revealed that anionic liposomes (DMPG liposomes) appeared to be the most effective to bring in the highest percentage of drug release while cationic liposomes (DOTAP liposomes) scored the lowest percentage of release. The drug release was primarily attributed to the electrostatic interaction between liposomes and drug molecules. Apart from this interaction, changes in the hydrophobicity of the medium upon addition of liposomes to the DNA-drug solution accompanied by lipoplex formation between DNA and liposomes were also attributed to the observed deintercalation. The CD and the time-resolved rotational relaxation studies confirmed that lipoplex formation took place between liposomes and DNA owing to electrostatic interaction. The confocal study revealed that in the postrelease period, DOX binds with liposomes. The reason behind the binding is electrostatic interaction as well as the unique bilayer structure of liposomes which helps it to act as a "hydrophobic sink" for DOX. The study overall highlighted a novel strategy for deintercalation of drug using biocompatible liposomes, as the release of the drug can be controlled over a period of time by varying the concentration and composition of the liposomes.

  5. Computer-aided molecular modeling techniques for predicting the stability of drug cyclodextrin inclusion complexes in aqueous solutions

    NASA Astrophysics Data System (ADS)

    Faucci, Maria Teresa; Melani, Fabrizio; Mura, Paola

    2002-06-01

    Molecular modeling was used to investigate factors influencing complex formation between cyclodextrins and guest molecules and predict their stability through a theoretical model based on the search for a correlation between experimental stability constants ( Ks) and some theoretical parameters describing complexation (docking energy, host-guest contact surfaces, intermolecular interaction fields) calculated from complex structures at a minimum conformational energy, obtained through stochastic methods based on molecular dynamic simulations. Naproxen, ibuprofen, ketoprofen and ibuproxam were used as model drug molecules. Multiple Regression Analysis allowed identification of the significant factors for the complex stability. A mathematical model ( r=0.897) related log Ks with complex docking energy and lipophilic molecular fields of cyclodextrin and drug.

  6. Reaction-diffusion processes and metapopulation models on duplex networks

    NASA Astrophysics Data System (ADS)

    Xuan, Qi; Du, Fang; Yu, Li; Chen, Guanrong

    2013-03-01

    Reaction-diffusion processes, used to model various spatially distributed dynamics such as epidemics, have been studied mostly on regular lattices or complex networks with simplex links that are identical and invariant in transferring different kinds of particles. However, in many self-organized systems, different particles may have their own private channels to keep their purities. Such division of links often significantly influences the underlying reaction-diffusion dynamics and thus needs to be carefully investigated. This article studies a special reaction-diffusion process, named susceptible-infected-susceptible (SIS) dynamics, given by the reaction steps β→α and α+β→2β, on duplex networks where links are classified into two groups: α and β links used to transfer α and β particles, which, along with the corresponding nodes, consist of an α subnetwork and a β subnetwork, respectively. It is found that the critical point of particle density to sustain reaction activity is independent of the network topology if there is no correlation between the degree sequences of the two subnetworks, and this critical value is suppressed or extended if the two degree sequences are positively or negatively correlated, respectively. Based on the obtained results, it is predicted that epidemic spreading may be promoted on positive correlated traffic networks but may be suppressed on networks with modules composed of different types of diffusion links.

  7. Beamforming Based Full-Duplex for Millimeter-Wave Communication.

    PubMed

    Liu, Xiao; Xiao, Zhenyu; Bai, Lin; Choi, Jinho; Xia, Pengfei; Xia, Xiang-Gen

    2016-07-21

    In this paper, we study beamforming based full-duplex (FD) systems in millimeter-wave (mmWave) communications. A joint transmission and reception (Tx/Rx) beamforming problem is formulated to maximize the achievable rate by mitigating self-interference (SI). Since the optimal solution is difficult to find due to the non-convexity of the objective function, suboptimal schemes are proposed in this paper. A low-complexity algorithm, which iteratively maximizes signal power while suppressing SI, is proposed and its convergence is proven. Moreover, two closed-form solutions, which do not require iterations, are also derived under minimum-mean-square-error (MMSE), zero-forcing (ZF), and maximum-ratio transmission (MRT) criteria. Performance evaluations show that the proposed iterative scheme converges fast (within only two iterations on average) and approaches an upper-bound performance, while the two closed-form solutions also achieve appealing performances, although there are noticeable differences from the upper bound depending on channel conditions. Interestingly, these three schemes show different robustness against the geometry of Tx/Rx antenna arrays and channel estimation errors.

  8. Beamforming Based Full-Duplex for Millimeter-Wave Communication

    PubMed Central

    Liu, Xiao; Xiao, Zhenyu; Bai, Lin; Choi, Jinho; Xia, Pengfei; Xia, Xiang-Gen

    2016-01-01

    In this paper, we study beamforming based full-duplex (FD) systems in millimeter-wave (mmWave) communications. A joint transmission and reception (Tx/Rx) beamforming problem is formulated to maximize the achievable rate by mitigating self-interference (SI). Since the optimal solution is difficult to find due to the non-convexity of the objective function, suboptimal schemes are proposed in this paper. A low-complexity algorithm, which iteratively maximizes signal power while suppressing SI, is proposed and its convergence is proven. Moreover, two closed-form solutions, which do not require iterations, are also derived under minimum-mean-square-error (MMSE), zero-forcing (ZF), and maximum-ratio transmission (MRT) criteria. Performance evaluations show that the proposed iterative scheme converges fast (within only two iterations on average) and approaches an upper-bound performance, while the two closed-form solutions also achieve appealing performances, although there are noticeable differences from the upper bound depending on channel conditions. Interestingly, these three schemes show different robustness against the geometry of Tx/Rx antenna arrays and channel estimation errors. PMID:27455256

  9. Phase Transformations in Cast Duplex Stainless Steels

    SciTech Connect

    Kim, Yoon-Jun

    2004-01-01

    Duplex stainless steels (DSS) constitute both ferrite and austenite as a matrix. Such a microstructure confers a high corrosion resistance with favorable mechanical properties. However, intermetallic phases such as σ and χ can also form during casting or high-temperature processing and can degrade the properties of the DSS. This research was initiated to develop time-temperature-transformation (TTT) and continuous-cooling-transformation (CCT) diagrams of two types of cast duplex stainless steels, CD3MN (Fe-22Cr-5Ni-Mo-N) and CD3MWCuN (Fe-25Cr-7Ni-Mo-W-Cu-N), in order to understand the time and temperature ranges for intermetallic phase formation. The alloys were heat treated isothermally or under controlled cooling conditions and then characterized using conventional metallographic methods that included tint etching, and also using electron microscopy (SEM, TEM) and wavelength dispersive spectroscopy (WDS). The kinetics of intermetallic-phase (σ + χ) formation were analyzed using the Johnson-Mehl-Avrami (MA) equation in the case of isothermal transformations and a modified form of this equation in the case of continuous cooling transformations. The rate of intermetallic-phase formation was found to be much faster in CD3MWCuN than CD3MN due mainly to differences in the major alloying contents such as Cr, Ni and Mo. To examine in more detail the effects of these elements of the phase stabilities; a series of eight steel castings was designed with the Cr, Ni and Mo contents systematically varied with respect to the nominal composition of CD3MN. The effects of varying the contents of alloying additions on the formation of intermetallic phases were also studied computationally using the commercial thermodynamic software package, Thermo-Calc. In general, σ was stabilized with increasing Cr addition and χ by increasing Mo addition. However, a delicate balance among Ni and other minor elements such as N and Si also exists. Phase equilibria in DSS can be affected by

  10. Host-Guest Complexes of Carboxylated Pillar[n]arenes With Drugs.

    PubMed

    Wheate, Nial J; Dickson, Kristie-Ann; Kim, Ryung Rae; Nematollahi, Alireza; Macquart, René B; Kayser, Veysel; Yu, Guocan; Church, W Bret; Marsh, Deborah J

    2016-12-01

    Pillar[n]arenes are a new family of nanocapsules that have shown application in a number of areas, but because of their poor water solubility their biomedical applications are limited. Recently, a method of synthesizing water-soluble pillar[n]arenes was developed. In this study, carboxylated pillar[n]arenes (WP[n], n = 6 or 7) have been examined for their ability to form host-guest complexes with compounds relevant to drug delivery and biodiagnostic applications. Both pillar[n]arenes form host-guest complexes with memantine, chlorhexidine hydrochloride, and proflavine by (1)H nuclear magnetic resonance and modeling. Binding is stabilized by hydrophobic effects within the cavities, and hydrogen bonding and electrostatic interactions at the portals. Encapsulation within WP[6] results in the complete and efficient quenching of proflavine fluorescence, giving rise to "on" and "off" states that have potential in biodiagnostics. The toxicity of the pillar[n]arenes was examined using in vitro growth assays with the OVCAR-3 and HEK293 cell lines. The pillar[n]arenes are relatively nontoxic to cells except at high doses and after prolonged continuous exposure. Overall, the results show that there could be a potentially large range of medical applications for carboxylated pillar[n]arene nanocapsules.

  11. Molecular structure and spectroscopic properties of novel manganese(II) complex with sulfamethazine drug

    NASA Astrophysics Data System (ADS)

    Mansour, Ahmed M.

    2013-03-01

    [MnLCl(H2O)3]·H2O complex (HL = 4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzenesulfonamide, sulfamethazine) has been synthesized and characterized by elemental analysis, TG/DTA, MS, FT-IR, UV-Vis, magnetic, electrochemical, and X-ray powder diffraction. The experimental studies were complemented by quantum chemical calculations at DFT/B3LYP level of theory. Sulfamethazine behaves as a mono-negatively bidentate ligand and interacts with Mn(II) ion through sulfonamidic (N15) and pyrimidic (N23) nitrogen atoms. Electronic structures were investigated using TD-DFT method and the descriptions of frontier molecular orbitals and the relocation of the electron density were determined. The voltammogram of NaL shows one irreversible one-electron process due to oxidation of p-amino group, and one anodic peak characteristic of reduction of sbnd SO2 group. The synthesized complex, in comparison to the parent drug, was screened for its antibacterial activity.

  12. Detecting drug-induced prolongation of the QRS complex: New insights for cardiac safety assessment

    SciTech Connect

    Cros, C.; Skinner, M.; Moors, J.; Lainee, P.; Valentin, J.P.

    2012-12-01

    Background: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I{sub Na}) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I{sub Na}, this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation. Methods: Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1 h period from 1 h pre-dose to 5 h post-dose. Results: Compared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (E{sub max} 13% and 20% respectively, P < 0.01–0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of + 0.7 ± 0.5 ms (quinidine, NS), + 1.8 ± 0.8 ms (mexiletine, P < 0.05) and + 2.8 ± 0.8 ms (flecainide, P < 0.01) (calculated as QRS at basal HR-QRS at high HR). Conclusion: Electrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function. -- Highlights: ► We aimed to improve detection of drug-induced QRS prolongation in safety screening. ► We used telemetered dogs to test class I antiarrhythmics at low and high heart rate. ► At low heart rate only quinidine and flecainide induced an increase in QRS duration. ► At high heart rate the effects of two

  13. Endonuclease cleavage of blocked replication forks: An indirect pathway of DNA damage from antitumor drug-topoisomerase complexes

    NASA Astrophysics Data System (ADS)

    Hong, George; Kreuzer, Kenneth N.

    2003-04-01

    The cytotoxicity of several important antitumor drugs depends on formation of the covalent topoisomerase-DNA cleavage complex. However, cellular processes such as DNA replication are necessary to convert the cleavage complex into a cytotoxic lesion, but the molecular mechanism of this conversion and the precise nature of the cytotoxic lesion are unknown. Using a bacteriophage T4 model system, we have previously shown that antitumor drug-induced cleavage complexes block replication forks in vivo. In this report, we show that these blocked forks can be cleaved by T4 endonuclease VII to create overt DNA breaks. The accumulation of blocked forks increased in endonuclease VII-deficient infections, suggesting that endonuclease cleavage contributes to fork processing in vivo. Furthermore, purified endonuclease VII cleaved the blocked forks in vitro close to the branch points. These results suggest that an indirect pathway of branched-DNA cleavage contributes to the cytotoxicity of antitumor drugs that target DNA topoisomerases.

  14. Predicting drugs and proteins in parasite infections with topological indices of complex networks: theoretical backgrounds, applications, and legal issues.

    PubMed

    González-Díaz, Humberto; Romaris, Fernanda; Duardo-Sanchez, Aliuska; Pérez-Montoto, Lázaro G; Prado-Prado, Francisco; Patlewicz, Grace; Ubeira, Florencio M

    2010-01-01

    Quantitative Structure-Activity Relationship (QSAR) models have been used in Pharmaceutical design and Medicinal Chemistry for the discovery of anti-parasite drugs. QSAR models predict biological activity using as input different types of structural parameters of molecules. Topological Indices (TIs) are a very interesting class of these parameters. We can derive TIs from graph representations based on only nodes (atoms) and edges (chemical bonds). TIs are not time-consuming in terms of computational resources because they depend only on atom-atom connectivity information. This information expressed in the molecular graphs can be tabulated in the form of adjacency matrices easy to manipulate with computers. Consequently, TIs allow the rapid collection, annotation, retrieval, comparison and mining of molecular structures within large databases. The interest in TIs has exploded because we can use them to describe also macromolecular and macroscopic systems represented by complex networks of interactions (links) between the different parts of a system (nodes) such as: drug-target, protein-protein, metabolic, host-parasite, brain cortex, parasite disease spreading, Internet, or social networks. In this work, we review and comment on the following topics related to the use of TIs in anti-parasite drugs and target discovery. The first topic reviewed was: Topological Indices and QSAR for antiparasitic drugs. This topic included: Theoretical Background, QSAR for anti-malaria drugs, QSAR for anti-Toxoplasma drugs. The second topic was: TOMO-COMD approach to QSAR of antiparasitic drugs. We included in this topic: TOMO-COMD theoretical background and TOMO-COMD models for antihelmintic activity, Trichomonas, anti-malarials, anti-trypanosome compounds. The third section was inserted to discuss Topological Indices in the context of Complex Networks. The last section is devoted to the MARCH-INSIDE approach to QSAR of antiparasitic drugs and targets. This begins with a theoretical

  15. Underplating process from melange formation to duplexing: Example from the Cretaceous Shimanto Belt, Kii Peninsula, southwest Japan

    NASA Astrophysics Data System (ADS)

    Hashimoto, Y.; Kimura, G.

    1999-02-01

    Accretionary complexes are considered to form through off scraping and underplating, which results in the lateral and vertical growth of an accretionary prism. Accretion of the upper part of the oceanic crust and the formation of melange are important components of the accretionary process, although the origin of melange is considered controversial. In order to better understand the origin of melange and its role in accretion, in particular during underplating, we have studied the relationship between the formation of melange and duplexing in the Miyama Assemblage. Here the melange is composed dominantly of shale, basalt, chert, and sandstone. This study stresses the following features: (1) the structure of the Miyama Assemblage appears to be a composite suite of landward and seaward dipping duplexes; (2) the melange fabric displays a systematic asymmetry, which may have resulted through shearing along the decollement; and (3) facing of horses within duplexes changes from north to south, coinciding with a change in the sense of shear inferred from the melange fabric, which suggests that it formed prior to duplexing.

  16. Synthesis, characterization and thermal studies on metal complexes of new azo compounds derived from sulfa drugs

    NASA Astrophysics Data System (ADS)

    Mohamed, Gehad G.; Gad-Elkareem, Mohamed A. M.

    2007-12-01

    Four new azo ligands, L1 and HL2-4, of sulfa drugs have been prepared and characterized. [MX 2(L1)(H 2O) m]· nH 2O; [(MX 2) 2(HL2 or HL3)(H 2O) m]· nH 2O and [M 2X 3(L4)(H 2O)]· nH 2O; M = Co(II), Ni(II) and Cu(II) (X = Cl) and Zn(II) (X = AcO); m = 0-4 and n = 0-3, complexes were prepared. Elemental and thermal analyses (TGA and DTA), IR, solid reflectance spectra, magnetic moment and molar conductance measurements have accomplished characterization of the complexes. The IR data reveal that HL1 and HL2-3 ligands behave as a bidentate neutral ligands while HL4 ligand behaves as a bidentate monoionic ligand. They coordinated to the metal ions via the carbonyl O, enolic sulfonamide sbnd S(O)OH, pyrazole or thiazole N and azo N groups. The molar conductance data reveal that the chelates are non-electrolytes. From the solid reflectance spectra and magnetic moment data, the complexes were found to have octahedral, tetrahedral and square planar geometrical structures. The thermal behaviour of these chelates shows that the water molecules (hydrated and coordinated) and the anions are removed in a successive two steps followed immediately by decomposition of the ligand in the subsequent steps. The activation thermodynamic parameters, such as, E*, Δ H*, Δ S* and Δ G* are calculated from the TG curves applying Coats-Redfern method.

  17. Model of complex chiral drug metabolic systems and numerical simulation of the remaining chirality toward analysis of dynamical pharmacological activity.

    PubMed

    Ogino, Yoshiyuki; Asahi, Toru

    2015-05-21

    In this study, systems of complicated pathways involved in chiral drug metabolism were investigated. The development of chiral drugs resulted in significant improvement in the remedies available for the treatment of various severe sicknesses. Enantiopure drugs undergo various biological transformations that involve chiral inversion and thus result in the generation of multiple enantiomeric metabolites. Identification of the specific active substances determining a given drug׳s efficacy among such a mixture of different metabolites remains a challenge. To comprehend this complexity, we constructed a mathematical model representing the complicated metabolic pathways simultaneously involving chiral inversion. Moreover, this model is applied to the metabolism of thalidomide, which has recently been revived as a potentially effective prescription drug for a number of intractable diseases. The numerical simulation results indicate that retained chirality in the metabolites reflects the original chirality of the unmetabolized drug, and a higher level of enantiomeric purity is preserved during spontaneous degradation. In addition, chirality remaining after equilibration is directly related to the rate constant not only for chiral inversion but also for generation and degradation. Furthermore, the retention of chirality is quantitatively predictable using this combination of kinetic parameters. Our simulation results well explain the behavior of thalidomide in the practical biological experimental data. Therefore, this model promises a comprehensive understanding of dynamic metabolic systems involving chiral drugs that express multiple enantiospecific drug efficacies.

  18. Terahertz absorption of DNA decamer duplex.

    PubMed

    Li, Xiaowei; Globus, Tatiana; Gelmont, Boris; Salay, Luiz C; Bykhovski, Alexei

    2008-11-27

    This work combines experimental and theoretical approaches to investigate terahertz absorption spectra of the DNA formed by the sequence oligomer 5'-CCGGCGCCGG-3'. The three-dimensional structure of this self-complimentary DNA decamer has been well-studied, permitting us to perform direct identification of the low-frequency phonon modes associated with specific conformation and to conduct comprehensive computer simulations. Two modeling techniques, normal-mode analysis and nanosecond molecular dynamics with explicit solvent molecules, were employed to extract the low-frequency vibrational modes based on which the absorption spectra were calculated. The absorption spectra of the DNA decamer in aqueous solution were measured in the frequency range 10-25 cm(-1) using the terahertz Fourier transform infrared spectroscopy. Multiple well-resolved and reproducible resonance modes were observed. When calculated and experimental spectra were compared, the spectrum based on molecular dynamics simulations showed a better correlation with the experimental spectra than the one based on normal-mode analysis. These results demonstrate that there exist a considerable number of active low-frequency phonon modes in this short DNA duplex.

  19. Principal physicochemical methods used to characterize dendrimer molecule complexes used as genetic therapy agents, nanovaccines or drug carriers.

    PubMed

    Alberto, Rodríguez Fonseca Rolando; Joao, Rodrigues; de Los Angeles, Muñoz-Fernández María; Alberto, Martínez Muñoz; Jonathan, Fragoso Vázquez Manuel; José, Correa Basurto

    2017-02-20

    Nanomedicine is the application of nanotechnology to medicine. This field is related to the study of nanodevices and nanomaterials applied to various medical uses, such as in improving the pharmacological properties of different molecules. Dendrimers are synthetic nanoparticles whose physicochemical properties vary according to their chemical structure. These molecules have been extensively investigated as drug nanocarriers to improve drug solubility and as sustained-release systems. New therapies such as gene therapy and the development of nanovaccines can be improved by the use of dendrimers. The biophysical and physicochemical characterization of nucleic acid/peptide-dendrimer complexes is crucial to identify their functional properties prior to biological evaluation. In that sense, it is necessary to first identify whether the peptide-dendrimer or nucleic acid-dendrimer complexes can be formed and whether the complex can dissociate under the appropriate conditions at the target cells. In addition, biophysical and physicochemical characterization is required to determine how long the complexes remain stable, what proportion of peptide or nucleic acid is required to form the complex or saturate the dendrimer, and the size of the complex formed. In this review, we present the latest information on characterization systems for dendrimer-nucleic acid, dendrimer-peptide and dendrimer-drug complexes with several biotechnological and pharmacological applications.

  20. A novel method to enhance the efficiency of drug transdermal iontophoresis delivery by using complexes of drug and ion-exchange fibers.

    PubMed

    Xin, Che; Li-hong, Wang; Yue, Yuan; Ya-nan, Gao; Qi-fang, Wang; Yang, Yang; San-ming, Li

    2012-05-30

    The main reason for generally low efficiency of the transdermal iontophoretic drug delivery is that the fraction of the total current contributed by the drug ions is very small. The objective of this study was to find a method to increase the fraction of the total current contributed by the drug ions so as to enhance the drug's iontophoretic delivery. Iontophoretic transport of diclofenac solution and diclofenac assisted by ion exchange materials, including ion-exchange resin, ion-exchange membrane and ion-exchange fiber, across the rat skin were investigated. Both in vitro and in vivo iontophoretic transport experiments showed the amount of diclofenac permeated across rat skin from the diclofenac-fibers was highest among those from the diclofenac simple solutions and ion exchange materials complexes. The results of this study suggested that there is an enhancement of drug across rat skin by ion-exchange fibers in ion-exchange fibers assisted iontophoresis. The present study has demonstrated the potential of a new approach using ion-exchange fibers to enhance transdermal iontophoretic transport of an ionizable drug.

  1. ES and H-compatible lubrication for duplex bearings

    SciTech Connect

    Steinhoff, R.G.

    1997-10-01

    Two ES and H-compatible lubricants (environment, safety, and health) for duplex bearing applications and one hybrid material duplex bearing were evaluated and compared against duplex bearings with trichlorotrifluoroethane (Freon) deposition of low molecular weight polytetrafluoroethylene (PTFE) bearing lubricant extracted from Vydax{trademark}. Vydax is a product manufactured by DuPont consisting of various molecular weights of PTFE suspended in trichlorotrifluoroethane (Freon), which is an ozone-depleting solvent. Vydax has been used as a bearing lubricant in strong link mechanisms since 1974. Hybrid duplex bearings with silicon nitride balls and molded glass-nylon-Teflon retainers, duplex bearings lubricated with sputtered MoS{sub 2} on races and retainers, and duplex bearings lubricated with electrophoretic deposited MoS{sub 2} were evaluated. Bearings with electrophoretic deposited MoS{sub 2} performed as well as bearings with Freon deposition of PTFE from Freon-based Vydax. Hybrid bearings with silicon nitride balls performed worse than bearings lubricated with Vydax, but their performance would still be acceptable for most applications. Bearings lubricated with sputtered MoS{sub 2} on the races and retainers had varying amounts of film on the bearings. This affected the performance of the bearings. Bearings with a uniform coating performed to acceptable levels, but bearings with no visible MoS{sub 2} on the races and retainers did not perform as well as bearings with the other coatings. Unless process controls are incorporated in the sputtering process or the bearings are screened, they do not appear to be acceptable for duplex bearing applications.

  2. Drugs.

    ERIC Educational Resources Information Center

    Hurst, Hunter, Ed.; And Others

    1984-01-01

    This document contains the third volume of "Today's Delinquent," an annual publication of the National Center for Juvenile Justice. This volume deals with the issue of drugs and includes articles by leading authorities in delinquency and substance abuse who share their views on causes and cures for the drug problem among youth in this country.…

  3. Mycobacterium tuberculosis Complex Genotype Diversity and Drug Resistance Profiles in a Pediatric Population in Mexico

    PubMed Central

    Macías Parra, Mercedes; Kumate Rodríguez, Jesús; Arredondo García, José Luís; López-Vidal, Yolanda; Castañón-Arreola, Mauricio; Balandrano, Susana; Rastogi, Nalin; Gutiérrez Castrellón, Pedro

    2011-01-01

    The aim of this study was to determine the frequency of drug resistance and the clonality of genotype patterns in M. tuberculosis clinical isolates from pediatric patients in Mexico (n = 90 patients from 19 states; time period—January 2002 to December 2003). Pulmonary disease was the most frequent clinical manifestation (71%). Children with systemic tuberculosis (TB) were significantly younger compared to patients with localized TB infections (mean 7.7 ± 6.2 years versus 15 ± 3.4 years P = 0.001). Resistance to any anti-TB drug was detected in 24/90 (26.7%) of the isolates; 21/90 (23.3%) and 10/90 (11.1%) were resistant to Isoniazid and Rifampicin, respectively, and 10/90 (11.1%) strains were multidrug-resistant (MDR). Spoligotyping produced a total of 55 different patterns; 12/55 corresponded to clustered isolates (n = 47, clustering rate of 52.2%), and 43/55 to unclustered isolates (19 patterns were designated as orphan by the SITVIT2 database). Database comparison led to designation of 36 shared types (SITs); 32 SITs (n = 65 isolates) matched a preexisting shared type in SITVIT2, whereas 4 SITs (n = 6 isolates) were newly created. Lineage classification based on principal genetic groups (PGG) revealed that 10% of the strains belonged to PGG1 (Bovis and Manu lineages). Among PGG2/3 group, the most predominant clade was the Latin-American and Mediterranean (LAM) in 27.8% of isolates, followed by Haarlem and T lineages. The number of single drug-resistant (DR) and multidrug-resistant (MDR-TB) isolates in this study was similar to previously reported in studies from adult population with risk factors. No association between the spoligotype, age, region, or resistance pattern was observed. However, contrary to a study on M. tuberculosis spoligotyping in Acapulco city that characterized a single cluster of SIT19 corresponding to the EAI2-Manila lineage in 70 (26%) of patients, not a single SIT19 isolate was found in our pediatric patient population. Neither did we

  4. Investigating the Interaction Pattern and Structural Elements of a Drug-Polymer Complex at the Molecular Level.

    PubMed

    Nie, Haichen; Mo, Huaping; Zhang, Mingtao; Song, Yang; Fang, Ke; Taylor, Lynne S; Li, Tonglei; Byrn, Stephen R

    2015-07-06

    Strong associations between drug and polymeric carriers are expected to contribute to higher drug loading capacities and better physical stability of amorphous solid dispersions. However, molecular details of the interaction patterns and underlying mechanisms are still unclear. In the present study, a series of amorphous solid dispersions of clofazimine (CLF), an antileprosy drug, were prepared with different polymers by applying the solvent evaporation method. When using hypromellose phthalate (HPMCP) as the carrier, the amorphous solid dispersion system exhibits not only superior drug loading capacity (63% w/w) but also color change due to strong drug-polymer association. In order to further explain these experimental observations, the interaction between CLF and HPMCP was investigated in a nonpolar volatile solvent system (chloroform) prior to forming the solid dispersion. We observed significant UV/vis and (1)H NMR spectral changes suggesting the protonation of CLF and formation of ion pairs between CLF and HPMCP in chloroform. Furthermore, nuclear Overhauser effect spectroscopy (NOESY) and diffusion order spectroscopy (DOSY) were employed to evaluate the strength of associations between drug and polymers, as well as the molecular mobility of CLF. Finally, by correlating the experimental values with quantum chemistry calculations, we demonstrate that the protonated CLF is binding to the carboxylate group of HPMCP as an ion pair and propose a possible structural model of the drug-polymer complex. Understanding the drug and carrier interaction patterns from a molecular perspective is critical for the rational design of new amorphous solid dispersions.

  5. Unified QSAR approach to antimicrobials. 4. Multi-target QSAR modeling and comparative multi-distance study of the giant components of antiviral drug-drug complex networks.

    PubMed

    Prado-Prado, Francisco J; Martinez de la Vega, Octavio; Uriarte, Eugenio; Ubeira, Florencio M; Chou, Kuo-Chen; González-Díaz, Humberto

    2009-01-15

    One limitation of almost all antiviral Quantitative Structure-Activity Relationships (QSAR) models is that they predict the biological activity of drugs against only one species of virus. Consequently, the development of multi-tasking QSAR models (mt-QSAR) to predict drugs activity against different species of virus is of the major vitally important. These mt-QSARs offer also a good opportunity to construct drug-drug Complex Networks (CNs) that can be used to explore large and complex drug-viral species databases. It is known that in very large CNs we can use the Giant Component (GC) as a representative sub-set of nodes (drugs) and but the drug-drug similarity function selected may strongly determines the final network obtained. In the three previous works of the present series we reported mt-QSAR models to predict the antimicrobial activity against different fungi [Gonzalez-Diaz, H.; Prado-Prado, F. J.; Santana, L.; Uriarte, E. Bioorg.Med.Chem.2006, 14, 5973], bacteria [Prado-Prado, F. J.; Gonzalez-Diaz, H.; Santana, L.; Uriarte E. Bioorg.Med.Chem.2007, 15, 897] or parasite species [Prado-Prado, F.J.; González-Díaz, H.; Martinez de la Vega, O.; Ubeira, F.M.; Chou K.C. Bioorg.Med.Chem.2008, 16, 5871]. However, including these works, we do not found any report of mt-QSAR models for antivirals drug, or a comparative study of the different GC extracted from drug-drug CNs based on different similarity functions. In this work, we used Linear Discriminant Analysis (LDA) to fit a mt-QSAR model that classify 600 drugs as active or non-active against the 41 different tested species of virus. The model correctly classifies 143 of 169 active compounds (specificity=84.62%) and 119 of 139 non-active compounds (sensitivity=85.61%) and presents overall training accuracy of 85.1% (262 of 308 cases). Validation of the model was carried out by means of external predicting series, classifying the model 466 of 514, 90.7% of compounds. In order to illustrate the performance of the

  6. Polyelectrolyte Complex Based Interfacial Drug Delivery System with Controlled Loading and Improved Release Performance for Bone Therapeutics

    PubMed Central

    Vehlow, David; Schmidt, Romy; Gebert, Annett; Siebert, Maximilian; Lips, Katrin Susanne; Müller, Martin

    2016-01-01

    An improved interfacial drug delivery system (DDS) based on polyelectrolyte complex (PEC) coatings with controlled drug loading and improved release performance was elaborated. The cationic homopolypeptide poly(l-lysine) (PLL) was complexed with a mixture of two cellulose sulfates (CS) of low and high degree of substitution, so that the CS and PLL solution have around equal molar charged units. As drugs the antibiotic rifampicin (RIF) and the bisphosphonate risedronate (RIS) were integrated. As an important advantage over previous PEC systems this one can be centrifuged, the supernatant discarded, the dense pellet phase (coacervate) separated, and again redispersed in fresh water phase. This behavior has three benefits: (i) Access to the loading capacity of the drug, since the concentration of the free drug can be measured by spectroscopy; (ii) lower initial burst and higher residual amount of drug due to removal of unbound drug and (iii) complete adhesive stability due to the removal of polyelectrolytes (PEL) excess component. It was found that the pH value and ionic strength strongly affected drug content and release of RIS and RIF. At the clinically relevant implant material (Ti40Nb) similar PEC adhesive and drug release properties compared to the model substrate were found. Unloaded PEC coatings at Ti40Nb showed a similar number and morphology of above cultivated human mesenchymal stem cells (hMSC) compared to uncoated Ti40Nb and resulted in considerable production of bone mineral. RIS loaded PEC coatings showed similar effects after 24 h but resulted in reduced number and unhealthy appearance of hMSC after 48 h due to cell toxicity of RIS.

  7. Investigation of drug-cyclodextrin complexes by a phase-distribution method: some theoretical and practical considerations.

    PubMed

    Másson, Már; Sigurdardóttir, Birna Vigdís; Matthíasson, Kristján; Loftsson, Thorsteinn

    2005-08-01

    The purpose of the study was to evaluate an octanol-water phase distribution method for investigation of drug/cyclodextrin (D/CD) complexes and to compare stability constant values obtained by this method to values obtained by the phase solubility method. A general equation for determination of 1 : 1 D/CD complex stability constant (K1 : 1) from the slope of a phase-distribution diagram (a diagram of the reciprocal of the apparent partition coefficient vs. the total CD concentration) was derived. The equation accounted for the possible inclusion of the organic solvent in the CD cavity and the gradual saturation of the CD binding with increasing concentration of the guest compound. This method was used to determine K1 : 1 for 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) complexes of hydrocortisone, prednisolone, diazepam, beta-estradiol and diethylstilbestrol. These values were comparable to K1 : 1 values determined by the phase-solubility method. The phase-distribution method could also be applied to determine stability constants for the neutral and ionic forms of the weakly acidic drugs, naproxen and triclosan and the weakly basic drug lidocaine. The phase-distribution method is a very versatile and fast method and has the advantage, compared to the phase-solubility method, that it only requires very small drug samples. Thus, this method would be suitable for screening of new drug candidates.

  8. 5' modification of duplex DNA with a ruthenium electron donor-acceptor pair using solid-phase DNA synthesis

    NASA Technical Reports Server (NTRS)

    Frank, Natia L.; Meade, Thomas J.

    2003-01-01

    Incorporation of metalated nucleosides into DNA through covalent modification is crucial to measurement of thermal electron-transfer rates and the dependence of these rates with structure, distance, and position. Here, we report the first synthesis of an electron donor-acceptor pair of 5' metallonucleosides and their subsequent incorporation into oligonucleotides using solid-phase DNA synthesis techniques. Large-scale syntheses of metal-containing oligonucleotides are achieved using 5' modified phosporamidites containing [Ru(acac)(2)(IMPy)](2+) (acac is acetylacetonato; IMPy is 2'-iminomethylpyridyl-2'-deoxyuridine) (3) and [Ru(bpy)(2)(IMPy)](2+) (bpy is 2,2'-bipyridine; IMPy is 2'-iminomethylpyridyl-2'-deoxyuridine) (4). Duplexes formed with the metal-containing oligonucleotides exhibit thermal stability comparable to the corresponding unmetalated duplexes (T(m) of modified duplex = 49 degrees C vs T(m) of unmodified duplex = 47 degrees C). Electrochemical (3, E(1/2) = -0.04 V vs NHE; 4, E(1/2) = 1.12 V vs NHE), absorption (3, lambda(max) = 568, 369 nm; 4, lambda(max) = 480 nm), and emission (4, lambda(max) = 720 nm, tau = 55 ns, Phi = 1.2 x 10(-)(4)) data for the ruthenium-modified nucleosides and oligonucleotides indicate that incorporation into an oligonucleotide does not perturb the electronic properties of the ruthenium complex or the DNA significantly. In addition, the absence of any change in the emission properties upon metalated duplex formation suggests that the [Ru(bpy)(2)(IMPy)](2+)[Ru(acac)(2)(IMPy)](2+) pair will provide a valuable probe for DNA-mediated electron-transfer studies.

  9. Motions of the Substrate Recognition Duplex in a Group I Intron Assessed by Site-Directed Spin Labeling

    SciTech Connect

    Grant, Gian Paola G; Boyd, Nathan; Herschlag, Daniel; Qin, Peter Z

    2009-03-11

    The Tetrahymena group I intron recognizes its oligonucleotide substrate in a two-step process. First, a substrate recognition duplex, called the P1 duplex, is formed. The P1 duplex then docks into the prefolded ribozyme core by forming tertiary contacts. P1 docking controls both the rate and the fidelity of substrate cleavage and has been extensively studied as a model for the formation of RNA tertiary structure. However, previous work has been limited to studying millisecond or slower motions. Here we investigated nanosecond P1 motions in the context of the ribozyme using site-directed spin labeling (SDSL) and electron paramagnetic resonance (EPR) spectroscopy. A nitroxide spin label (R5a) was covalently attached to a specific site of the substrate oligonucleotide, the labeled substrate was bound to a prefolded ribozyme to form the P1 duplex, and X-band EPR spectroscopy was used to monitor nitroxide motions in the 0.1-50 ns regime. Using substrates that favor the docked or the undocked states, it was established that R5a was capable of reporting P1 duplex motions. Using R5a-labeled substrates it was found that the J1/2 junction connecting P1 to the ribozyme core controls nanosecond P1 mobility in the undocked state. This may account for previous observations that J1/2 mutations weaken substrate binding and give rise to cryptic cleavage. This study establishes the use of SDSL to probe nanosecond dynamic behaviors of individual helices within large RNA and RNA/protein complexes. This approach may help in understanding the relationship between RNA structure, dynamics, and function.

  10. Animals on drugs: understanding the role of pharmaceutical companies in the animal-industrial complex.

    PubMed

    Twine, Richard

    2013-12-01

    In this paper I revisit previous critiques that I have made of much, though by no means all, bioethical discourse. These pertain to faithfulness to dualistic ontology, a taken-for-granted normative anthropocentrism, and the exclusion of a consideration of how political economy shapes the conditions for bioethical discourse (Twine Medicine, Health Care and Philosophy 8(3):285-295, 2005; International Journal of Sociology of Agriculture and Food 16(3):1-18, 2007, 2010). Part of my argument around bioethical dualist ontology is to critique the assumption of a division between the "medical" (human) and "agricultural" (nonhuman) and to show various ways in which they are interrelated. I deepen this analysis with a focus on transnational pharmaceutical companies, with specific attention to their role in enhancing agricultural production through animal drug administration. I employ the topical case of antibiotics in order to speak to current debates in not only the interdisciplinary field of bioethics but also that of animal studies. More generally, the animal-industrial complex (Twine Journal for Critical Animal Studies 10(1):12-39, 2012) is underlined as a highly relevant bioethical object that deserves more conceptual and empirical attention.

  11. Charge transfer complex of some nervous and brain drugs - Part 1: Synthesis, spectroscopic, analytical and biological studies on the reaction between haloperidol antipsychotic drugs with π-acceptors

    NASA Astrophysics Data System (ADS)

    El-Habeeb, Abeer A.; Al-Saif, Foziah A.; Refat, Moamen S.

    2013-02-01

    Donor-acceptor interactions between the electron donor haloperidol (HPL) and π-acceptors like 7,7,8,8-tetracyanoquinodimethane (TCNQ) and picric acid (PA) have been studied spectrophotometrically in CH3OH solvent. The donor-acceptor (charge transfer complexes) were discussed in terms of formation constant (KCT), molar extinction coefficient (ɛCT), standard free energy (ΔGo), oscillator strength (ƒ), transition dipole moment (μ), resonance energy (RN) and ionization potential (ID). The stoichiometry of these complexes was found to be 1:1 M ratio and having the formulas [(HPL)(TCNQ)] and [(HPL)(PA)], respectively. The charge transfer interaction was successfully applied to determine of HPL drug using mentioned common π-acceptors also, the results obtained herein are satisfactory for estimation of HPL compound in the pharmaceutical form. The formed solid charge-transfer complexes were also isolated and characterized using elemental analysis, conductivity, (infrared, Raman, and 1H NMR) spectra and X-ray powder diffraction (XRD). The experimental data of elemental analyses are in agreement with calculated data. The infrared spectra of both HPL complexes are confirming the participation of sbnd OH of 4-hydroxy-1-piperidyl moiety in the donor-acceptor chelation. The morphological surface of the resulted charge transfer complexes were investigated using scanning electron microscopy (SEM). The thermogravimetric analysis (TG/DTG) and differential scanning calorimetry (DSC) techniques were performed to give knowledge about the thermal stability behavior of the synthesized charge transfer complexes. Thermodynamic parameters were computed from the thermal decomposition data. These complexes were also tested for their antimicrobial activity against six different microorganisms, and the results were compared with the parent drug.

  12. A Single-Stranded Junction Modulates Nanosecond Motional Ordering of the Substrate Recognition Duplex of a Group I Ribozyme

    PubMed Central

    Nguyen, Phuong; Shi, Xuesong; Sigurdsson, Snorri Th.; Herschlag, Daniel

    2013-01-01

    Rigid spinning: Site-directed spin-labeling studies using a rigid nitroxide spin label (Ç) reveal that both length and sequence of a single-stranded junction (J1/2) modulate nanosecond motional ordering of the substrate-recognition duplex (P1) of the 120 kD group I ribozyme. The studies demonstrate an approach for experimental measurements of nanosecond dynamics in high-molecular-weight RNA complexes. PMID:23900919

  13. A comparison of colour duplex ultrasonography after transurethral alprostadil and intracavernous alprostadil in the assessment of erectile dysfunction.

    PubMed

    Ahn, H S; Lee, S W; Yoon, S J; Hann, H J; Hong, J M

    2004-01-01

    This study aimed to investigate whether transurethral alprostadil could be used for the diagnosis of erectile dysfunction using colour duplex ultrasound. The ultrasonography results were compared after transurethral and intracavernous alprostadil administration in 20 patients with erectile dysfunction. There were no significant differences in the mean peak systolic velocities (PSVs) between the two routes of administration, but the mean end diastolic velocities (EDVs) showed significant differences, with patients treated with transurethral alprostadil having higher EDVs. Linear regression analysis of the PSVs reached following the two routes of administration showed a moderate relationship, but linear regression analysis of the EDVs showed no relationship. We concluded that transurethral alprostadil was an inappropriate vasoactive drug to use with colour duplex ultrasonography for the evaluation of patients with erectile dysfunction because it required a longer scan time and it was less effective and less reliable than intracavernous alprostadil at stimulating complete corporeal smooth muscle relaxation.

  14. Chronic exposure of rats to cognition enhancing drugs produces a neuroplastic response identical to that obtained by complex environment rearing.

    PubMed

    Murphy, Keith J; Foley, Andrew G; O'connell, Alan W; Regan, Ciaran M

    2006-01-01

    Recent data suggest that Alzheimer's patients who discontinue treatment with cholinesterase inhibitors have a significantly delayed cognitive decline as compared to patients receiving placebo. Such observations suggest cholinesterase inhibitors to provide a disease-modifying effect as well as symptomatic relief and, moreover, that this benefit remains after drug withdrawal. Consistent with this suggestion, we now demonstrate that chronic administration of tacrine, nefiracetam, and deprenyl, drugs that augment cholinergic function, increases the basal frequency of dentate polysialylated neurons in a manner similar to the enhanced neuroplasticity achieved through complex environment rearing. While both drug-treated and complex environment reared animals continue to exhibit memory-associated activation of hippocampal polysialylated neurons, the magnitude is significantly reduced suggesting that such interventions induce a more robust memory pathway that can acquire and consolidate new information more efficiently. This hypothesis is supported by our findings of improved learning behavior and enhanced resistance to cholinergic deficits seen following either intervention. Furthermore, the level of enhancement of basal neuroplastic status achieved by either drug or environmental intervention correlates directly with improved spatial learning ability. As a combination of both interventions failed to further increase basal polysialylated cell frequency, complex environment rearing and chronic drug regimens most likely enhanced cognitive performance by the same mechanism(s). These findings suggest that improved memory-associated synaptic plasticity may be the fundamental mechanism underlying the disease modifying action of drugs such as cholinesterase inhibitors. Moreover, the molecular and cellular events underpinning neuroplastic responses are identified as novel targets in the search for interventive drug strategies for the treatment of neurodegenerative and

  15. Investigation of connexin 43 uncoupling and prolongation of the cardiac QRS complex in preclinical and marketed drugs

    PubMed Central

    Burnham, M P; Sharpe, P M; Garner, C; Hughes, R; Pollard, C E; Bowes, J

    2014-01-01

    Background and Purpose Prolongation of the cardiac QRS complex is linked to increased mortality and may result from drug-induced inhibition of cardiac sodium channels (hNaV1.5). There has been no systematic evaluation of preclinical and marketed drugs for their additional potential to cause QRS prolongation via gap junction uncoupling. Experimental Approach Using the human cardiac gap junction connexin 43 (hCx43), a dye transfer ‘parachute’ assay to determine IC50 values for compound ranking was validated with compounds known to uncouple gap junctions. Uncoupling activity (and hNaV1.5 inhibition by automated patch clamp) was determined in a set of marketed drugs and preclinical candidate drugs, each with information regarding propensity to prolong QRS. Key Results The potency of known gap junction uncouplers to uncouple hCx43 was ranked (according to IC50) as phorbol ester>digoxin>meclofenamic acid>carbenoxolone>heptanol. Among the drugs associated with QRS prolongation, 29% were found to uncouple hCx43 (IC50 < 50 μM), whereas no uncoupling activity was observed in drugs not associated with QRS prolongation. In preclinical candidate drugs, hCx43 and hNaV1.5 IC50 values were similar (within threefold). No consistent margin over preclinical Cmax (free) was apparent for QRS prolongation associated with Cx43 inhibition. However, instances were found of QRS prolonging compounds that uncoupled hCx43 with significantly less activity at hNaV1.5. Conclusion and Implications These results demonstrate that off-target uncoupling activity is apparent in drug and drug-like molecules. Although the full ramifications of Cx inhibition remain to be established, screening for hCx43 off-target activity could reduce the likelihood of developing candidate drugs with a risk of causing QRS prolongation. PMID:24328991

  16. Stepwise assembly of functional C-terminal REST/NRSF transcriptional repressor complexes as a drug target.

    PubMed

    Inui, Ken; Zhao, Zongpei; Yuan, Juan; Jayaprakash, Sakthidasan; Le, Le T M; Drakulic, Srdja; Sander, Bjoern; Golas, Monika M

    2017-02-20

    In human cells, thousands of predominantly neuronal genes are regulated by the repressor element 1 (RE1)-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF). REST/NRSF represses transcription of these genes in stem cells and non-neuronal cells by tethering corepressor complexes. Aberrant REST/NRSF expression and intracellular localization are associated with cancer and neurodegeneration in humans. To date, detailed molecular analyses of REST/NRSF and its C-terminal repressor complex have been hampered largely by the lack of sufficient amounts of purified REST/NRSF and its complexes. Therefore, the aim of this study was to express and purify human REST/NRSF and its C-terminal interactors in a baculovirus multiprotein expression system as individual proteins and coexpressed complexes. All proteins were enriched in the nucleus, and REST/NRSF was isolated as a slower migrating form, characteristic of nuclear REST/NRSF in mammalian cells. Both REST/NRSF alone and its C-terminal repressor complex were functionally active in histone deacetylation and histone demethylation and bound to RE1/neuron-restrictive silencer element (NRSE) sites. Additionally, the mechanisms of inhibition of the small-molecule drugs 4SC-202 and SP2509 were analyzed. These drugs interfered with the viability of medulloblastoma cells, where REST/NRSF has been implicated in cancer pathogenesis. Thus, a resource for molecular REST/NRSF studies and drug development has been established.

  17. Carboxymethyl and hydrazide functionalized β-cyclodextrin derivatives: a systematic investigation of complexation behaviours with the model hydrophobic drug dexamethasone.

    PubMed

    Mateen, Rabia; Hoare, Todd

    2014-09-10

    Cyclodextrins (CDs) are typically functionalized to increase their solubility or provide reactive functional groups suitable for grafting onto polymer supports designed for controlled release applications. In this work, a systematic investigation was performed on the binding behaviour of the model drug dexamethasone with βCD derivatives functionalized with a small, negatively charged moiety (carboxyl groups, CM) and a large, neutral, reactive moiety (hydrazide groups, Hzd), both free and grafted to dextran. Solubilization capacities and thermodynamic parameters were examined through phase solubility analysis, the method of continuous variation, and isothermal titration calorimetry. Alternate mechanisms of solubilization were also investigated by probing aggregation of both free and complexed βCD derivatives using nanoparticle tracking analysis. CM/βCD and Hzd/βCD derivatives exhibited similar complexation behaviours with dexamethasone: 1:1 stoichiometry, linear phase solubility profiles, and consistent binding enthalpies. Increased functionalization reduced the complex stability constant as well as the complexation efficiency, while polymer grafting resulted in no significant change in binding properties. CM/βCD derivatives complexed with dexamethasone formed more and larger aggregates, while Hzd/βCD derivatives formed significantly fewer, smaller aggregates and dextran-grafted βCD did not aggregate. Such characterization of βCD derivatives provides a framework for designing βCDs as pharmaceutical excipients or drug binding sites in drug delivery vehicles.

  18. Cavitation Erosion of Sensitized UNS S31803 Duplex Stainless Steels

    NASA Astrophysics Data System (ADS)

    Mitelea, Ion; Micu, Lavinia Mădălina; Bordeaşu, Ilare; Crăciunescu, Corneliu Marius

    2016-05-01

    During processing or use, duplex steels can be subjected to heating at high temperatures that can affect their behavior. This work aims to correlate the influence of the sensitization treatment on the ultrasonic cavitation erosion behavior of a UNS S31803 (X2CrNiMoN22-5-3) duplex stainless steel. Duplex stainless steels, formed as a result of rapid cooling after solution annealing, are sensitized at temperatures of 475 and 850 °C, respectively, leading to hardening and embrittlement due to the spinodal decomposition of the ferrite and the precipitation of secondary phases. The ultrasonic cavitation erosion experiments showed that the sensitization at 850 °C reduced the mean depth of erosion by about 11% and the mean depth of erosion rate by 28%. By contrast, the sensitization at 475 °C deteriorates the cavitation erosion resistance, increasing the erosion parameters by up to 22%, compared to the solution annealed state.

  19. CMOS serial link for fully duplexed data communication

    NASA Astrophysics Data System (ADS)

    Lee, Kyeongho; Kim, Sungjoon; Ahn, Gijung; Jeong, Deog-Kyoon

    1995-04-01

    This paper describes a CMOS serial link allowing fully duplexed 500 Mbaud serial data communication. The CMOS serial link is a robust and low-cost solution to high data rate requirements. A central charge pump PLL for generating multiphase clocks for oversampling is shared by several serial link channels. Fully duplexed serial data communication is realized in the bidirectional bridge by separating incoming data from the mixed signal on the cable end. The digital PLL accomplishes process-independent data recovery by using a low-ratio oversampling, a majority voting, and a parallel data recovery scheme. Mostly, digital approach could extend its bandwidth further with scaled CMOS technology. A single channel serial link and a charge pump PLL are integrated in a test chip using 1.2 micron CMOS process technology. The test chip confirms upto 500 Mbaud unidirectional mode operation and 320 Mbaud fully duplexed mode operation with pseudo random data patterns.

  20. Determination of association constant of host-guest supramolecular complex (molecular recognition of carbamazepine, antiseizure drug, with calix(4)arene).

    PubMed

    Meenakshi, C; Jayabal, P; Ramakrishnan, V

    2015-12-05

    The thermodynamic property of the host-guest, inclusion complex formed between p-t-butyl calix(4)arene which is a supramolecule, and the antiseizure drug, carbamazepine was studied. p-t-Butyl calix(4)arene has been used as a host molecule and carbamazepine as a guest molecule. Optical absorption spectral studies were carried out to investigate the molecular recognition properties of p-t-butyl calix(4)arene with carbamazepine. The stochiometry of the host-guest complexes formed and the association constant were determined. An interesting 1:2 stochiometric host-guest complex was formed. Job's continuous method of variation and Benesi-Hildebrand expression were used for the determination of binding constant and the stochiometry of the host-guest complex formed. Molecular dimension of the host molecule plays a vital role in the formation of the host-guest stochiometric complexes.

  1. On the thermomechanical deformation behavior of duplex-type materials

    NASA Astrophysics Data System (ADS)

    Siegmund, T.; Werner, E.; Fischer, F. D.

    1995-04-01

    Two-phase duplex-type materials possess microstructures containing roughly the same amounts of the constituent phases whose grains form interwoven networks. Duplex stainless steels are typical representatives of this material group. In these steels the constituent phases austenite and ferrite have different coefficients of thermal expansion. On pure thermal loading or thermomechanical loading the yield strength of the phases can be exceeded. Specimens of a forged duplex steel with a uniaxially anisotropic micro-structure deform irreversibly even under pure thermal cycling conditions with a monotonic accumulation of strain. The results of a systematic finite element based micromechanical analysis of the thermomechanical deformation behavior of duplex steels are presented and discussed. The analysis is based on a quantitative characterization of both the real and model microstructures. Additionally, an extended constitutive material law for the thermomechanical loading of the duplex steel is proposed. For dual-phase materials this description incorporates an additional thermomechanical strain increment as a very important contribution to the total strain increment. Both the micromechanical model and the analytical model are used to analyse the experimental findings from dilatometer tests. The micromechanical approach allows the evolution of the irreversible strains in the two phases generated in a thermal cycle to be modeled. It is shown that the matrix-phase is always more deformed than the inclusion-phase, irrespective of which of the two phases (austenite or ferrite) forms the matrix. This prediction is confirmed by electron microscopic observations of a thermally cycled duplex steel. Based on these results a mechanism driving the ratchet effect is proposed.

  2. A new type of DNA "light-switch": a dual photochemical sensor and metalating agent for duplex and G-quadruplex DNA.

    PubMed

    Wachter, Erin; Howerton, Brock S; Hall, Emily C; Parkin, Sean; Glazer, Edith C

    2014-01-11

    Ru(bpy)2dppz, a well studied "light-switch" metal complex, transforms into a photochemical "light-switch" and DNA damaging agent by incorporating structural strain. This distorted compound is photoreactive and ejects a ligand upon binding duplex and G-quadruplex DNA, producing a reactive metal center that metalates the DNA.

  3. Small molecule-mediated duplex formation of nucleic acids with 'incompatible' backbones.

    PubMed

    Cafferty, Brian J; Musetti, Caterina; Kim, Keunsoo; Horowitz, Eric D; Krishnamurthy, Ramanarayanan; Hud, Nicholas V

    2016-04-07

    Proflavine, a known intercalator of DNA and RNA, promotes duplex formation by nucleic acids with natural and non-natural backbones that otherwise form duplexes with low thermal stability, and even some that show no sign of duplex formation in the absence of proflavine. These findings demonstrate the potential for intercalators to be used as cofactors for the assembly of rationally designed nucleic acid structures, and could provide fundamental insights regarding intercalation of natural nucleic acid duplexes.

  4. Evaluation of Gallium as a Tracer of Exogenous Hemoglobin-Haptoglobin Complexes for Targeted Drug Delivery Applications

    NASA Astrophysics Data System (ADS)

    Xu, Shengsheng; Kaltashov, Igor A.

    2016-12-01

    Haptoglobin (Hp) is a plasma glycoprotein that generates significant interest in the drug delivery community because of its potential for delivery of antiretroviral medicines with high selectivity to macrophages and monocytes, the latent reservoirs of human immunodeficiency virus. As is the case with other therapies that exploit transport networks for targeted drug delivery, the success of the design and optimization of Hp-based therapies will critically depend on the ability to accurately localize and quantitate Hp-drug conjugates on the varying and unpredictable background of endogenous proteins having identical structure. In this work, we introduce a new strategy for detecting and quantitating exogenous Hp and Hp-based drugs with high sensitivity in complex biological samples using gallium as a tracer of this protein and inductively coupled plasma mass spectrometry (ICP MS) as a method of detection. Metal label is introduced by reconstituting hemoglobin (Hb) with gallium(III)-protoporphyrin IX followed by its complexation with Hp. Formation of the Hp/Hb assembly and its stability are evaluated with native electrospray ionization mass spectrometry. Both stable isotopes of Ga give rise to an abundant signal in ICP MS of a human plasma sample spiked with the metal-labeled Hp/Hb complex. The metal label signal exceeds the spectral interferences' contributions by more than an order of magnitude even with the concentration of the exogenous protein below 10 nM, the level that is more than adequate for the planned pharmacokinetic studies of Hp-based therapeutics.

  5. Force measurements reveal how small binders perturb the dissociation mechanisms of DNA duplex sequences

    NASA Astrophysics Data System (ADS)

    Burmistrova, Anastasia; Fresch, Barbara; Sluysmans, Damien; de Pauw, Edwin; Remacle, Françoise; Duwez, Anne-Sophie

    2016-06-01

    The force-driven separation of double-stranded DNA is crucial to the accomplishment of cellular processes like genome transactions. Ligands binding to short DNA sequences can have a local stabilizing or destabilizing effect and thus severely affect these processes. Although the design of ligands that bind to specific sequences is a field of intense research with promising biomedical applications, so far, their effect on the force-induced strand separation has remained elusive. Here, by means of AFM-based single molecule force spectroscopy, we show the co-existence of two different mechanisms for the separation of a short DNA duplex and demonstrate how they are perturbed by small binders. With the support of Molecular Dynamics simulations, we evidence that above a critical pulling rate one of the dissociation pathways becomes dominant, with a dramatic effect on the rupture forces. Around the critical threshold, we observe a drop of the most probable rupture forces for ligand-stabilized duplexes. Our results offer a deep understanding of how a stable DNA-ligand complex behaves under force-driven strand separation.The force-driven separation of double-stranded DNA is crucial to the accomplishment of cellular processes like genome transactions. Ligands binding to short DNA sequences can have a local stabilizing or destabilizing effect and thus severely affect these processes. Although the design of ligands that bind to specific sequences is a field of intense research with promising biomedical applications, so far, their effect on the force-induced strand separation has remained elusive. Here, by means of AFM-based single molecule force spectroscopy, we show the co-existence of two different mechanisms for the separation of a short DNA duplex and demonstrate how they are perturbed by small binders. With the support of Molecular Dynamics simulations, we evidence that above a critical pulling rate one of the dissociation pathways becomes dominant, with a dramatic effect

  6. Synthesis, spectroscopic, structural and thermal characterizations of vanadyl(IV) adenine complex prospective as antidiabetic drug agent.

    PubMed

    El-Megharbel, Samy M; Hamza, Reham Z; Refat, Moamen S

    2015-01-25

    The vanadyl(IV) adenine complex; [VO(Adn)2]⋅SO4; was synthesized and characterized. The molar conductivity of this complex was measured in DMSO solution that showed an electrolyte nature. Spectroscopic investigation of the green solid complex studied here indicate that the adenine acts as a bidentate ligand, coordinated to vanadyl(IV) ions through the nitrogen atoms N7 and nitrogen atom of amino group. Thus, from the results presented the vanadyl(IV) complex has square pyramid geometry. Further characterizations using thermal analyses and scanning electron techniques was useful. The aim of this paper was to introduce a new drug model for the diabetic complications by synthesized a novel mononuclear vanadyl(IV) adenine complex to mimic insulin action and reducing blood sugar level. The antidiabetic ability of this complex was investigated in STZ-induced diabetic mice. The results suggested that VO(IV)/adenine complex has antidiabetic activity, it improved the lipid profile, it improved liver and kidney functions, also it ameliorated insulin hormone and blood glucose levels. The vanadyl(IV) complex possesses an antioxidant activity and this was clear through studying SOD, CAT, MDA, GSH and methionine synthase. The current results support the therapeutic potentiality of vanadyl(IV)/adenine complex for the management and treatment of diabetes.

  7. Synthesis, spectroscopic, structural and thermal characterizations of vanadyl(IV) adenine complex prospective as antidiabetic drug agent

    NASA Astrophysics Data System (ADS)

    El-Megharbel, Samy M.; Hamza, Reham Z.; Refat, Moamen S.

    2015-01-01

    The vanadyl(IV) adenine complex; [VO(Adn)2]ṡSO4; was synthesized and characterized. The molar conductivity of this complex was measured in DMSO solution that showed an electrolyte nature. Spectroscopic investigation of the green solid complex studied here indicate that the adenine acts as a bidentate ligand, coordinated to vanadyl(IV) ions through the nitrogen atoms N7 and nitrogen atom of amino group. Thus, from the results presented the vanadyl(IV) complex has square pyramid geometry. Further characterizations using thermal analyses and scanning electron techniques was useful. The aim of this paper was to introduce a new drug model for the diabetic complications by synthesized a novel mononuclear vanadyl(IV) adenine complex to mimic insulin action and reducing blood sugar level. The antidiabetic ability of this complex was investigated in STZ-induced diabetic mice. The results suggested that VO(IV)/adenine complex has antidiabetic activity, it improved the lipid profile, it improved liver and kidney functions, also it ameliorated insulin hormone and blood glucose levels. The vanadyl(IV) complex possesses an antioxidant activity and this was clear through studying SOD, CAT, MDA, GSH and methionine synthase. The current results support the therapeutic potentiality of vanadyl(IV)/adenine complex for the management and treatment of diabetes.

  8. Synthesis, thermal and spectroscopic behaviors of metal-drug complexes: La(III), Ce(III), Sm(III) and Y(III) amoxicillin trihydrate antibiotic drug complexes.

    PubMed

    Refat, Moamen S; Al-Maydama, Hussein M A; Al-Azab, Fathi M; Amin, Ragab R; Jamil, Yasmin M S

    2014-07-15

    The metal complexes of Amoxicillin trihydrate with La(III), Ce(III), Sm(III) and Y(III) are synthesized with 1:1 (metal:Amox) molar ratio. The suggested formula structures of the complexes are based on the results of the elemental analyses, molar conductivity, (infrared, UV-visible and fluorescence) spectra, effective magnetic moment in Bohr magnetons, as well as the thermal analysis (TG), and characterized by X-ray powder diffraction (XRD) and scanning electron microscopy (SEM). The results obtained suggested that Amoxicillin reacted with metal ions as tridentate ligands, coordinating the metal ion through its amino, imino, and β-lactamic carbonyl. The kinetic thermodynamic parameters such as: Ea, ΔH(*), ΔS(*) and ΔG(*) were estimated from the DTG curves.

  9. On the relationship between block of the cardiac Na+ channel and drug-induced prolongation of the QRS complex

    PubMed Central

    Harmer, AR; Valentin, J-P; Pollard, CE

    2011-01-01

    BACKGROUND AND PURPOSE Inhibition of the human cardiac Na+ channel (hNav1.5) can prolong the QRS complex and has been associated with increased mortality in patients with underlying cardiovascular disease. The safety implications of blocking hNav1.5 channels suggest the need to test for this activity early in drug discovery in order to design out any potential liability. However, interpretation of hNav1.5 blocking potency requires knowledge of how hNav1.5 block translates into prolongation of the QRS complex. EXPERIMENTAL APPROACH We tested Class I anti-arrhythmics, other known QRS prolonging drugs and drugs not reported to prolong the QRS complex. Their block of hNav1.5 channels (as IC50 values) was measured in an automated electrophysiology-based assay. These IC50 values were compared with published reports of the corresponding unbound (free) plasma concentrations attained during clinical use (fCmax) to provide an IC50 : fCmax ratio. KEY RESULTS For 42 Class I anti-arrhythmics and other QRS prolonging drugs, 67% had IC50 : fCmax ratios <30. For 55 non-QRS prolonging drugs tested, 72% had ratios >100. Finally, we determined the relationship between the IC50 value and the free drug concentration associated with prolongation of the QRS complex in humans. For 37 drugs, QRS complex prolongation was observed at free plasma concentrations that were about 15-fold lower than the corresponding IC50 at hNav1.5 channels. CONCLUSIONS AND IMPLICATIONS A margin of 30- to 100-fold between hNav1.5 IC50 and fCmax appears to confer an acceptable degree of safety from QRS prolongation. QRS prolongation occurs on average at free plasma levels 15-fold below the IC50 at hNav1.5 channels. LINKED ARTICLE This article is commented on by Gintant et al., pp. 254–259 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01433.x PMID:21480866

  10. Ultrasound/Magnetic Targeting with SPIO-DOX-Microbubble Complex for Image-Guided Drug Delivery in Brain Tumors

    PubMed Central

    Fan, Ching-Hsiang; Cheng, Yu-Hang; Ting, Chien-Yu; Ho, Yi-Ju; Hsu, Po-Hung; Liu, Hao-Li; Yeh, Chih-Kuang

    2016-01-01

    One of the greatest challenges in the deployment of chemotherapeutic drugs against brain tumors is ensuring that sufficient drug concentrations reach the tumor, while minimizing drug accumulation at undesired sites. Recently, injection of therapeutic agents following blood-brain barrier (BBB) opening by focused ultrasound (FUS) with microbubbles (MBs) has been shown to enhance drug delivery in targeted brain regions. Nevertheless, the distribution and quantitative deposition of agents delivered to the brain are still hard to estimate. Based on our previous work on superparamagnetic iron oxide (SPIO)-loaded MBs, we present a novel theranostic complex of SPIO-Doxorubicin (DOX)-conjugated MB (SD-MB) for drug delivery to the brain. Magnetic labeling of the drug enables direct visualization via magnetic resonance imaging, and also facilitates magnetic targeting (MT) to actively enhance targeted deposition of the drug. In a rat glioma model, we demonstrated that FUS sonication can be used with SD-MBs to simultaneously facilitate BBB opening and allow dual ultrasound/magnetic targeting of chemotherapeutic agent (DOX) delivery. The accumulation of SD complex within brain tumors can be significantly enhanced by MT (25.7 fold of DOX, 7.6 fold of SPIO). The change in relaxation rate R2 (1/T2) within tumors was highly correlated with SD deposition as quantified by high performance liquid chromatography (R2 = 0.93) and inductively coupled plasma-atomic emission spectroscopy (R2 = 0.94), demonstrating real-time monitoring of DOX distribution. Our results suggest that SD-MBs can serve as multifunction agents to achieve advanced molecular theranostics. PMID:27446489

  11. Structural analysis using thrust-fault hanging-wall sequence diagrams: Ogden duplex, Wasatch Range, Utah

    SciTech Connect

    Schirmer, T.W.

    1988-05-01

    Detailed mapping and cross-section traverses provide the control for structural analysis and geometric modeling of the Ogden duplex, a complex thrust system exposed in the Wasatch Mountains, east of Ogden, Utah. The structures consist of east-dipping folded thrust faults, basement-cored horses, lateral ramps and folds, and tear faults. The sequence of thrusting determined by means of lateral overlap of horses, thrust-splay relationships, and a top-to-bottom piggyback development is Willard thrust, Ogden thrust, Weber thrust, and Taylor thrust. Major decollement zones occur in the Cambrian shales and limestones. The Tintic Quartzite is the marker for determining gross geometries of horses. This exposed duplex serves as a good model to illustrate the method of constructing a hanging-wall sequence diagram - a series of longitudinal cross sections that move forward in time and space, and show how a thrust system formed as it moved updip over various footwall ramps. A hanging wall sequence diagram also shows the complex lateral variations in a thrust system and helps to locate lateral ramps, lateral folds, tear faults, and other features not shown on dip-oriented cross sections. 8 figures.

  12. Hybrid Percutaneous Coronary Intervention With Bioresorbable Vascular Scaffolds in Combination With Drug-Eluting Stents or Drug-Coated Balloons for Complex Coronary Lesions.

    PubMed

    Tanaka, Akihito; Jabbour, Richard J; Mitomo, Satoru; Latib, Azeem; Colombo, Antonio

    2017-03-27

    Bioresorbable vascular scaffolds (BVS) have become an attractive option in the percutaneous coronary intervention field due to the potential advantages associated with the complete resorption process that occurs within a few years. However, current-generation BVS have several limitations including thicker struts, reduced radial strength, and limited expansion capability when compared with drug-eluting stents (DES). As a result, complex coronary disease often contains BVS-inappropriate/unfavorable segments. This does not necessarily mean that BVS use must be completely avoided, and minimizing the length of permanent metallic caging may still be advantageous. Operators should fully understand the limitations of current BVS, and when to consider a hybrid strategy of BVS in combination with DES or drug-coated balloons.

  13. MiRduplexSVM: A High-Performing MiRNA-Duplex Prediction and Evaluation Methodology

    PubMed Central

    Karathanasis, Nestoras; Tsamardinos, Ioannis; Poirazi, Panayiota

    2015-01-01

    We address the problem of predicting the position of a miRNA duplex on a microRNA hairpin via the development and application of a novel SVM-based methodology. Our method combines a unique problem representation and an unbiased optimization protocol to learn from mirBase19.0 an accurate predictive model, termed MiRduplexSVM. This is the first model that provides precise information about all four ends of the miRNA duplex. We show that (a) our method outperforms four state-of-the-art tools, namely MaturePred, MiRPara, MatureBayes, MiRdup as well as a Simple Geometric Locator when applied on the same training datasets employed for each tool and evaluated on a common blind test set. (b) In all comparisons, MiRduplexSVM shows superior performance, achieving up to a 60% increase in prediction accuracy for mammalian hairpins and can generalize very well on plant hairpins, without any special optimization. (c) The tool has a number of important applications such as the ability to accurately predict the miRNA or the miRNA*, given the opposite strand of a duplex. Its performance on this task is superior to the 2nts overhang rule commonly used in computational studies and similar to that of a comparative genomic approach, without the need for prior knowledge or the complexity of performing multiple alignments. Finally, it is able to evaluate novel, potential miRNAs found either computationally or experimentally. In relation with recent confidence evaluation methods used in miRBase, MiRduplexSVM was successful in identifying high confidence potential miRNAs. PMID:25961860

  14. Kinematic model for out-of-sequence thrusting: Motion of two ramp-flat faults and the production of upper plate duplex systems

    NASA Astrophysics Data System (ADS)

    Pavlis, Terry L.

    2013-06-01

    the models some fault segments place younger rocks on older rocks which could be easily misinterpreted as normal fault systems. In some models younger-on-older juxtapositions are significant and if scaled to crustal scale would produce core-complex style structures that would be difficult to recognize as contractional features. Collectively, these observations imply that many areas where simultaneous contraction and extension are inferred may be entirely contractional with younger-on-older relationships generated by out-of-sequence thrust systems. Examples where this process may have occurred are in southwestern North America and the Moine thrust system and future studies should evaluate these systems in light of these models. Distinguishing upper plate duplex from conventional duplex is potentially important in economic evaluations of thrust systems because fluid migration paths would be very different in the two alternatives. The process may also be important in seismogenic mechanisms, particularly in subduction megathrusts, because faults warping faults could produce fault irregularities that would form transient asperities along the fault.

  15. Exposure of the Lesser Himalayan Duplex in Central Nepal

    NASA Astrophysics Data System (ADS)

    Robinson, Delores; Martin, Aaron

    2013-04-01

    In central Nepal, between the Main Central thrust and the Main Boundary thrust, only Lesser Himalayan rock is exposed in structurally complex relationships; whereas in other regions of Nepal, Lesser Himalayan rocks are buried under klippen of Greater Himalayan rock. Thus, central Nepal along the Modi Khola south through the Kali Gandaki River and the village of Tansen is one of the few locations along the Himalayan thrust belt where the entire Lesser Himalayan duplex is exposed. This location is critical to determining the kinematics of the thrust belt. The purpose of this study is to determine the structural architecture of central Nepal using the collected structural data, incorporating available age data, drawing and balancing cross sections and testing variations in shortening given different stratigraphic assumptions. The two balanced cross sections are constructed from the same topography but have different underlying assumptions and decisions made during the development. We tested whether major changes in the stratigraphy and simplifications regarding the evolution of the Lesser Himalayan duplex affected the amount of shortening. Cross section 1 has a shortening estimate from the Main Central thrust to the Main Boundary thrust, including motion on the Main Central thrust, of 359 km or 77.8%. Cross section 2 has a shortening estimate of 371 km or 78.4% over the same region. These shortening estimates do not include meso-scale and micro-scale shortening in the Lesser and Greater Himalayan rocks nor do they include intra-Greater Himalayan faults. The percentage of shortening between the two cross sections is the same and the amount of shortening is not significantly different. These are striking outcomes given the different choices made when constructing the cross sections especially with regards to the stratigraphy. This suggests that the different choices made when drawing a cross section may be fairly unimportant for the estimate of shortening and percentage

  16. Compartmentalized accumulation of cAMP near complexes of multidrug resistance protein 4 (MRP4) and cystic fibrosis transmembrane conductance regulator (CFTR) contributes to drug-induced diarrhea.

    PubMed

    Moon, Changsuk; Zhang, Weiqiang; Ren, Aixia; Arora, Kavisha; Sinha, Chandrima; Yarlagadda, Sunitha; Woodrooffe, Koryse; Schuetz, John D; Valasani, Koteswara Rao; de Jonge, Hugo R; Shanmukhappa, Shiva Kumar; Shata, Mohamed Tarek M; Buddington, Randal K; Parthasarathi, Kaushik; Naren, Anjaparavanda P

    2015-05-01

    Diarrhea is one of the most common adverse side effects observed in ∼7% of individuals consuming Food and Drug Administration (FDA)-approved drugs. The mechanism of how these drugs alter fluid secretion in the gut and induce diarrhea is not clearly understood. Several drugs are either substrates or inhibitors of multidrug resistance protein 4 (MRP4), such as the anti-colon cancer drug irinotecan and an anti-retroviral used to treat HIV infection, 3'-azido-3'-deoxythymidine (AZT). These drugs activate cystic fibrosis transmembrane conductance regulator (CFTR)-mediated fluid secretion by inhibiting MRP4-mediated cAMP efflux. Binding of drugs to MRP4 augments the formation of MRP4-CFTR-containing macromolecular complexes that is mediated via scaffolding protein PDZK1. Importantly, HIV patients on AZT treatment demonstrate augmented MRP4-CFTR complex formation in the colon, which defines a novel paradigm of drug-induced diarrhea.

  17. Inhibition of lung tumor growth by complex pulmonary delivery of drugs with oligonucleotides as suppressors of cellular resistance.

    PubMed

    Garbuzenko, Olga B; Saad, Maha; Pozharov, Vitaly P; Reuhl, Kenneth R; Mainelis, Gediminas; Minko, Tamara

    2010-06-08

    Development of cancer cell resistance, low accumulation of therapeutic drug in the lungs, and severe adverse treatment side effects represent main obstacles to efficient chemotherapy of lung cancer. To overcome these difficulties, we propose inhalation local delivery of anticancer drugs in combination with suppressors of pump and nonpump cellular resistance. To test this approach, nanoscale-based delivery systems containing doxorubicin as a cell death inducer, antisense oligonucleotides targeted to MRP1 mRNA as a suppressor of pump resistance and to BCL2 mRNA as a suppressor of nonpump resistance, were developed and examined on an orthotopic murine model of human lung carcinoma. The experimental results show high antitumor activity and low adverse side effects of proposed complex inhalatory treatment that cannot be achieved by individual components applied separately. The present work potentially contributes to the treatment of lung cancer by describing a unique combinatorial local inhalation delivery of drugs and suppressors of pump and nonpump cellular resistance.

  18. Computer Maintenance Operations Center (CMOC), showing duplexed cyber 170174 computers ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Computer Maintenance Operations Center (CMOC), showing duplexed cyber 170-174 computers - Beale Air Force Base, Perimeter Acquisition Vehicle Entry Phased-Array Warning System, Techinical Equipment Building, End of Spencer Paul Road, north of Warren Shingle Road (14th Street), Marysville, Yuba County, CA

  19. FRONT VIEW OF FACILITY 561, WHICH WAS ORIGINALLY A DUPLEX. ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    FRONT VIEW OF FACILITY 561, WHICH WAS ORIGINALLY A DUPLEX. PHOTO SHOWS THE ONLY UNIT REMAINING, UNIT B (UNIT A WAS DEMOLISHED AFTER A FIRE). VIEW FACING NORTH - Camp H.M. Smith and Navy Public Works Center Manana Title VII (Capehart) Housing, Intersection of Acacia Road and Brich Circle, Pearl City, Honolulu County, HI

  20. Self nanoemulsifying drug delivery system of stabilized ellagic acid–phospholipid complex with improved dissolution and permeability

    PubMed Central

    Avachat, Amelia M.; Patel, Vijay G.

    2014-01-01

    Ellagic acid (EA), a plant polyphenol known for its wide-range of health benefits has limited use due to its low oral bioavailability. In this study, a new self-nanoemulsifying drug delivery system (SNEDDS), based on the phospholipid complex technique, was developed to improve the oral bioavailability of ellagic acid. Ellagic acid–phospholipid complex was prepared by an anti-solvent method and characterized. Enhanced lipophilicity after the formation of ellagic acid–phospholipid complex was verified through solubility studies. Preliminary screening was carried out to select oil, surfactant and co-surfactant. Ternary phase diagrams were constructed to identify the area of nanoemulsification. Formulations were optimized on the basis of globule size, cloud point and robustness to dilution. The optimized SNEDDS of ellagic acid–phospholipid complex showed mean globule size of 106 ± 0.198 nm and cloud point at 83–85 °C. The in vitro drug release from SNEDDS was found to be higher compared to EA suspension and complex, while ex vivo studies showed increased permeation from SNEDDS compared to EA suspension. Moreover, SNEDDS overcome the food effect which was shown by EA suspension. Thus, SNEDDS were found to be influential in improving the release performance of EA, indicating their potential to improve the oral bioavailability of EA. PMID:26106276

  1. Chitosan-polycarbophil interpolyelectrolyte complex as an excipient for bioadhesive matrix systems to control macromolecular drug delivery.

    PubMed

    Lu, Zhilei; Chen, Weiyang; Hamman, Josias H; Ni, Jian; Zhai, Xiaoling

    2008-01-01

    The in vitro performance of monolithic matrix systems containing the interpolyelectrolyte complex between chitosan and polycarbophil as excipient was evaluated in terms of their swelling, bioadhesive, and drug release properties. The different matrix systems showed excellent swelling properties without erosion, except for the formulation containing the highest quantity chitosan-polycarbophil complex that exhibited surface erosion in addition to swelling. All the different matrix systems exhibited significantly higher bioadhesive properties than the control group. Furthermore, they showed controlled insulin release without an initial burst release effect. However, only the matrix system that exhibited surface erosion in combination with swelling approached zero-order release.

  2. Deformability Calculation for Estimation of the Relative Stability of Chemically Modified RNA Duplexes.

    PubMed

    Masaki, Yoshiaki; Sekine, Mitsuo; Seio, Kohji

    2017-03-02

    Chemical modification of RNA duplexes alters their stability. We have attempted to develop a computational approach to estimate the thermal stability of chemically modified duplexes. These studies revealed that the deformability of chemically modified RNA duplexes, calculated from molecular dynamics simulations, could be used as a good indicator for estimating the effect of chemical modification on duplex thermal stability. This unit describes how deformability calculation can be applied to estimate the relative stability of chemically modified RNA duplexes. © 2017 by John Wiley & Sons, Inc.

  3. A review of semi-synthetic biopolymer complexes: modified polysaccharide nano-carriers for enhancement of oral drug bioavailability.

    PubMed

    Sithole, Mduduzi N; Choonara, Yahya E; du Toit, Lisa C; Kumar, Pradeep; Pillay, Viness

    2017-03-01

    Semi-synthetic biopolymer complexes (SSBCs) have potential as nano-carriers for oral drug delivery due to their exceptional properties obtained by merging the properties of synthetic (e.g. good thermal and mechanical properties) with natural polymers (e.g. biocompatibility); thus, forming a new class of biopolymer materials incorporating the best of both worlds. Despite development in drug delivery systems, oral administration of therapeutic agent is still preferred. Several nano-polymeric systems has been prepared and characterized based on both synthetic polymers and natural polymers, each with its limitations and advantages. Among natural polymers, alginate, chitosan, and hyaluronic acid (HA) have been studied broadly for the fabrication of nanoparticles systems. This review discusses a newly investigated class of polymer called SSBCs as oral drug nano-carriers. It also discusses certain significant structural and functional attributes or effects which are essential to be taken into consideration when an oral drug delivery system is developed. The review is aimed at describing complexation of few natural polymers (e.g. polysaccharides) with selected synthetic polymers or synthetic chemicals to indicate some of the factors that influence preparation, solubility, formation, and stability of these SSBCs.

  4. Structure comparison of native and mutant human recombinant FKBP12 complexes with the immunosuppressant drug FK506 (tacrolimus).

    PubMed Central

    Itoh, S.; Navia, M. A.

    1995-01-01

    The consequences of site-directed mutagenesis experiments are often anticipated by empirical rules regarding the expected effects of a given amino acid substitution. Here, we examine the effects of "conservative" and "nonconservative" substitutions on the X-ray crystal structures of human recombinant FKBP12 mutants in complex with the immunosuppressant drug FK506 (tacrolimus). R42K and R42I mutant complexes show 110-fold and 180-fold decreased calcineurin (CN) inhibition, respectively, versus the native complex, yet retain full peptidyl prolyl isomerase (PPIase) activity, FK506 binding, and FK506-mediated PPIase inhibition. Interestingly, the structure of the R42I mutant complex is better conserved than that of the R42K mutant complex when compared to the native complex structure, within both the FKBP12 protein and FK506 ligand regions of the complexes, and with respect to temperature factors and RMS coordinate differences. This is due to compensatory interactions mediated by two newly ordered water molecules in the R42I complex structure, molecules that act as surrogates for the missing arginine guanidino nitrogens of R42. The absence of such surrogate solvent interactions in the R42K complex leads to some disorder in the so-called "40s loop" that encompasses the substituent. One rationalization proposed for the observed loss in CN inhibition in these R42 mutant complexes invokes indirect effects leading to a misorientation of FKBP12 and FK506 structural elements that normally interact with calcineurin. Our results with the structure of the R42I complex in particular suggest that the observed loss of CN inhibition might also be explained by the loss of a specific R42-mediated interaction with CN that cannot be mimicked effectively by the solvent molecules that otherwise stabilize the conformation of the 40s loop in that structure. PMID:8563622

  5. Characterization and evaluation of a folic acid receptor-targeted cyclodextrin complex as an anticancer drug delivery system.

    PubMed

    Xu, Jiaojiao; Xu, Beihua; Shou, Dan; Qin, Fuhua; Xu, Yong; Hu, Ying

    2016-02-15

    To improve the water solubility and tumor targeting ability of docetaxel (DTX), and thus enhance the drug's antitumor efficacy and safety, a novel folate receptor (FR)-targeted cyclodextrin drug delivery vehicle (FA-CD) was successfully synthesized. The synthesis of the designed cyclodextrin was confirmed by Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (1H NMR), and differential scanning calorimetry (DSC). The in vitro cytotoxicity was investigated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the results showed that no significant differences (p>0.05) appeared in cytotoxicity between the different cyclodextrins in the different cell lines. Besides, the DTX/FA-CD inclusion complex was prepared. The cellular uptake and competition assays were examined using the HepG2, HeLa, and KB cell lines, which have different levels of folate receptor expression. Interestingly, the Cy5.5/FA-CD complex had higher uptake in the HepG2, HeLa, and KB cells, compared with non-targeted Cy5.5/CD complex (p<0.001). The time-dependent drug uptake into KB cells observed by LSCM confirmed the drug delivery via endocytic routes. Data from the competition assays, especially in KB cells, showed that a significant inhibitory effect (p<0.001) was obtained when the concentration of FA was increased, and suggested that the Cy5.5/FA-CD was internalized through a FR-mediated mechanism. Moreover, the in vitro bioactivity assay also demonstrated efficient antitumor activity, and the order of the cell viabilities (% of control) was OB>HepG2>HeLa>KB for DTX/FA-CD (p<0.001). For DTX/CD, however, it displayed minimum antitumor behavior in all cell types. An apoptosis study by FCM and LSCM also revealed that the FA-modified complexes were more effective in inducing apoptosis in FR-expressing cells. Finally, an in vivo biodistribution study in KB-bearing healthy mice revealed that the DTX/FA-CD complex has enhanced tumor

  6. Free energy estimation of short DNA duplex hybridizations

    PubMed Central

    2010-01-01

    Background Estimation of DNA duplex hybridization free energy is widely used for predicting cross-hybridizations in DNA computing and microarray experiments. A number of software programs based on different methods and parametrizations are available for the theoretical estimation of duplex free energies. However, significant differences in free energy values are sometimes observed among estimations obtained with various methods, thus being difficult to decide what value is the accurate one. Results We present in this study a quantitative comparison of the similarities and differences among four published DNA/DNA duplex free energy calculation methods and an extended Nearest-Neighbour Model for perfect matches based on triplet interactions. The comparison was performed on a benchmark data set with 695 pairs of short oligos that we collected and manually curated from 29 publications. Sequence lengths range from 4 to 30 nucleotides and span a large GC-content percentage range. For perfect matches, we propose an extension of the Nearest-Neighbour Model that matches or exceeds the performance of the existing ones, both in terms of correlations and root mean squared errors. The proposed model was trained on experimental data with temperature, sodium and sequence concentration characteristics that span a wide range of values, thus conferring the model a higher power of generalization when used for free energy estimations of DNA duplexes under non-standard experimental conditions. Conclusions Based on our preliminary results, we conclude that no statistically significant differences exist among free energy approximations obtained with 4 publicly available and widely used programs, when benchmarked against a collection of 695 pairs of short oligos collected and curated by the authors of this work based on 29 publications. The extended Nearest-Neighbour Model based on triplet interactions presented in this work is capable of performing accurate estimations of free energies

  7. Letermovir and inhibitors of the terminase complex: a promising new class of investigational antiviral drugs against human cytomegalovirus

    PubMed Central

    Melendez, Dante P; Razonable, Raymund R

    2015-01-01

    Infection with cytomegalovirus is prevalent in immunosuppressed patients. In solid organ transplant and hematopoietic stem cell transplant recipients, cytomegalovirus infection is associated with high morbidity and preventable mortality. Prevention and treatment of cytomegalovirus with currently approved antiviral drugs is often associated with side effects that sometimes preclude their use. Moreover, cytomegalovirus has developed mutations that confer resistance to standard antiviral drugs. During the last decade, there have been calls to develop novel antiviral drugs that could provide better options for prevention and treatment of cytomegalovirus. Letermovir (AIC246) is a highly specific antiviral drug that is currently undergoing clinical development for the management of cytomegalovirus infection. It acts by inhibiting the viral terminase complex. Letermovir is highly potent in vitro and in vivo against cytomegalovirus. Because of a distinct mechanism of action, it does not exhibit cross-resistance with other antiviral drugs. It is predicted to be active against strains that are resistant to ganciclovir, foscarnet, and cidofovir. To date, early-phase clinical trials suggest a very low incidence of adverse effects. Herein, we present a comprehensive review on letermovir, from its postulated novel mechanism of action to the results of most recent clinical studies. PMID:26345608

  8. Computational repositioning of ethno medicine elucidated gB-gH-gL complex as novel anti herpes drug target

    PubMed Central

    2013-01-01

    Background Herpes viruses are important human pathogens that can cause mild to severe lifelong infections with high morbidity. They remain latent in the host cells and can cause recurrent infections that might prove fatal. These viruses are known to infect the host cells by causing the fusion of viral and host cell membrane proteins. Fusion is achieved with the help of conserved fusion machinery components, glycoproteins gB, heterodimer gH-gL complex along with other non-conserved components. Whereas, another important glycoprotein gD without which viral entry to the cell is not possible, acts as a co-activator for the gB-gH-gL complex formation. Thus, this complex formation interface is the most promising drug target for the development of novel anti-herpes drug candidates. In the present study, we propose a model for binding of gH-gL to gB glycoprotein leading from pre to post conformational changes during gB-gH-gL complex formation and reported the key residues involved in this binding activity along with possible binding site locations. To validate the drug targetability of our proposed binding site, we have repositioned some of the most promising in vitro, in vivo validated anti-herpes molecules onto the proposed binding site of gH-gL complex in a computational approach. Methods Hex 6.3 standalone software was used for protein-protein docking studies. Arguslab 4.0.1 and Accelrys® Discovery Studio 3.1 Visualizer softwares were used for semi-flexible docking studies and visualizing the interactions respectively. Protein receptors and ethno compounds were retrieved from Protein Data Bank (PDB) and Pubchem databases respectively. Lipinski’s Filter, Osiris Property Explorer and Lazar online servers were used to check the pharmaceutical fidelity of the drug candidates. Results Through protein-protein docking studies, it was identified that the amino acid residues VAL342, GLU347, SER349, TYR355, SER388, ASN395, HIS398 and ALA387 of gH-gL complex play an active

  9. Ab initio study of the phase stability in paramagnetic duplex steel alloys

    NASA Astrophysics Data System (ADS)

    Pitkänen, H.; Alatalo, M.; Puisto, A.; Ropo, M.; Kokko, K.; Punkkinen, M. P. J.; Olsson, P.; Johansson, B.; Hertzman, S.; Vitos, L.

    2009-01-01

    Duplex stainless steels have many superior properties compared to conventional steels, this being mainly due to their microstructure containing approximately equal amount of ferrite and austenite phases formed by iron, chromium (or Cr equivalent), and nickel (or Ni equivalent). Using computational methods based on first-principles theories, the phase stability of paramagnetic Fe1-c-nCrcNin alloys ( 0.12≤c≤0.32 and 0.04≤n≤0.32 ) at high temperatures (≳1000K) is addressed. It is shown that the stabilization of the ferrite-austenite two-phase field in duplex steels is a result of complex interplay of several competing phenomena. Taking into account only the formation energies yields a complete phase separation, strongly overestimating the two-phase region. The formation energies are calculated to be lower for the austenite than for the ferrite, meaning that the configurational entropy has a more significant impact on the stability field of the austenitic phase. The magnetic and vibrational free energies have opposite effects on the phase stability. Namely, the magnetic entropy favors the ferrite phase, whereas the vibrational free energy stabilizes the austenite phase. Combining the formation energies with the magnetic, vibrational, and configurational free energies, a region of coexistence between the two phases is obtained, in line with former thermodynamic assessments as well as with experimental observations.

  10. Specific DNA duplex formation at an artificial lipid bilayer: fluorescence microscopy after Sybr Green I staining.

    PubMed

    Werz, Emma; Rosemeyer, Helmut

    2014-01-01

    The article describes the immobilization of different probe oligonucleotides (4, 7, 10) carrying each a racemic mixture of 2,3-bis(hexadecyloxy)propan-1-ol (1a) at the 5'-terminus on a stable artificial lipid bilayer composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). The bilayer separates two compartments (cis/trans channel) of an optical transparent microfluidic sample carrier with perfusion capabilities. Injection of unlabeled target DNA sequences (6, 8, or 9), differing in sequence and length, leads in the case of complementarity to the formation of stable DNA duplexes at the bilayer surface. This could be verified by Sybr Green I double strand staining, followed by incubation periods and thorough perfusions, and was visualized by single molecule fluorescence spectroscopy and microscopy. The different bilayer-immobilized complexes consisting of various DNA duplexes and the fluorescent dye were studied with respect to the kinetics of their formation as well as to their stability against perfusion.

  11. Excess electron trapping in duplex DNA: long range transfer via stacked adenines.

    PubMed

    Black, Paul J; Bernhard, William A

    2012-11-08

    An understanding of charge transfer (CT) in DNA lies at the root of assessing the risks and benefits of exposure to ionizing radiation. Energy deposition by high-energy photons and fast-charged particles creates holes and excess electrons (EEs) in DNA, and the subsequent reactions determine the complexity of DNA damage and ultimately the risk of disease. Further interest in CT comes from the possibility that hole transfer, excess electron transfer (EET), or both in DNA might be used to develop nanoscale circuits. To study EET in DNA, EPR spectroscopy was used to determine the distribution of EE trapping by oligodeoxynucleotides irradiated and observed at 4 K. Our results indicate that stretches of consecutive adenine bases on the same strand serve as an ideal conduit for intrastrand EET in duplex DNA at 4 K. Specifically, we show that A is an efficient trap for EE at 4 K if, and only if, the A strand of the duplex does not contain one of the other three bases. If there is a T, C, or G on the A strand, then trapping occurs at T or C instead of A. This holds true for stretches up to 32 A's. Whereas T competes effectively against A for the EE, it does not compete effectively against C. Long stretches of T pass the majority of EE to C. Our results show that AT stretches channel EE to cytosine, an end point with significance to both radiation damage and the photochemical repair of pyrimidine dimers.

  12. Initiation of the microgene polymerization reaction with non-repetitive homo-duplexes

    SciTech Connect

    Itsko, Mark Zaritsky, Arieh; Rabinovitch, Avinoam; Ben-Dov, Eitan

    2008-04-11

    Microgene Polymerization Reaction (MPR) is used as an experimental system to artificially simulate evolution of short, non-repetitive homo-duplex DNA into multiply-repetitive products that can code for functional proteins. Blunt-end ligation by DNA polymerase is crucial in expansion of homo-duplexes (HDs) into head-to-tail multiple repeats in MPR. The propagation mechanism is known, but formation of the initial doublet (ID) by juxtaposing two HDs and polymerization through the gap has been ambiguous. Initiation events with pairs of HDs using Real-Time PCR were more frequent at higher HD concentrations and slightly below the melting temperature. A process molecularity of about 3.1, calculated from the amplification efficiency and the difference in PCR cycles at which propagation was detected at varying HD concentrations, led to a simple mechanism for ID formation: the gap between two HDs is bridged by a third. Considering thermodynamic aspects of the presumed intermediate 'nucleation complex' can predict relative propensity for the process with other HDs.

  13. Hardware Impairments Aware Transceiver for Full-Duplex Massive MIMO Relaying

    NASA Astrophysics Data System (ADS)

    Xia, Xiaochen; Zhang, Dongmei; Xu, Kui; Ma, Wenfeng; Xu, Youyun

    2015-12-01

    This paper studies the massive MIMO full-duplex relaying (MM-FDR), where multiple source-destination pairs communicate simultaneously with the help of a common full-duplex relay equipped with very large antenna arrays. Different from the traditional MM-FDR protocol, a general model where sources/destinations are allowed to equip with multiple antennas is considered. In contrast to the conventional MIMO system, massive MIMO must be built with low-cost components which are prone to hardware impairments. In this paper, the effect of hardware impairments is taken into consideration, and is modeled using transmit/receive distortion noises. We propose a low complexity hardware impairments aware transceiver scheme (named as HIA scheme) to mitigate the distortion noises by exploiting the statistical knowledge of channels and antenna arrays at sources and destinations. A joint degree of freedom and power optimization algorithm is presented to further optimize the spectral efficiency of HIA based MM-FDR. The results show that the HIA scheme can mitigate the "ceiling effect" appears in traditional MM-FDR protocol, if the numbers of antennas at sources and destinations can scale with that at the relay.

  14. Mussel-Inspired Protein Nanoparticles Containing Iron(III)-DOPA Complexes for pH-Responsive Drug Delivery.

    PubMed

    Kim, Bum Jin; Cheong, Hogyun; Hwang, Byeong Hee; Cha, Hyung Joon

    2015-06-15

    A novel bioinspired strategy for protein nanoparticle (NP) synthesis to achieve pH-responsive drug release exploits the pH-dependent changes in the coordination stoichiometry of iron(III)-3,4-dihydroxyphenylalanine (DOPA) complexes, which play a major cross-linking role in mussel byssal threads. Doxorubicin-loaded polymeric NPs that are based on Fe(III)-DOPA complexation were thus synthesized with a DOPA-modified recombinant mussel adhesive protein through a co-electrospraying process. The release of doxorubicin was found to be predominantly governed by a change in the structure of the Fe(III)-DOPA complexes induced by an acidic pH value. It was also demonstrated that the fabricated NPs exhibited effective cytotoxicity towards cancer cells through efficient cellular uptake and cytosolic release. Therefore, it is anticipated that Fe(III)-DOPA complexation can be successfully utilized as a new design principle for pH-responsive NPs for diverse controlled drug-delivery applications.

  15. NMR studies on the binding of antitumor drug nogalamycin to DNA hexamer d(CGTACG).

    PubMed

    Robinson, H; Liaw, Y C; van der Marel, G A; van Boom, J H; Wang, A H

    1990-08-25

    The interactions between a novel antitumor drug nogalamycin with the self-complementary DNA hexamer d(CGTACG) have been studied by 500 MHz two dimensional proton nuclear magnetic resonance spectroscopy. When two nogalamycins are mixed with the DNA hexamer duplex in a 2:1 ratio, a symmetrical complex is formed. All non-exchangeable proton resonances (except H5' & H5") of this complex have been assigned using 2D-COSY and 2D-NOESY methods at pH 7.0. The observed NOE cross peaks are fully consistent with the 1.3 A resolution x-ray crystal structure (Liaw et al., Biochemistry 28, 9913-9918, 1989) in which the elongated aglycone chromophore is intercalated between the CpG steps at both ends of the helix. The aglycone 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. The binding conformation suggests that specific hydrogen bonds exist in the complex between the drug and guanine-cytosine bases in both grooves of the helix. When only one drug per DNA duplex is present in solution, there are three molecular species (free DNA, 1:1 complex and 2:1 complex) in slow exchange on the NMR time scale. This equilibrium is temperature dependent. At high temperature the free DNA hexamer duplex and the 1:1 complex are completely destabilized such that at 65 degrees C only free single-stranded DNA and the 2:1 complex co-exist. At 35 degrees C the equilibrium between free DNA and the 1:1 complex is relatively fast, while that between the 1:1 complex and the 2:1 complex is slow. This may be rationalized by the fact that the binding of nogalamycin to DNA requires that the base pairs in DNA open up transiently to allow the bulky sugars to go through. A separate study of the 2:1 complex at low pH showed that the terminal GC base pair is destabilized.

  16. Interaction of drug based copper(II) complexes with Herring Sperm DNA and their biological activities

    NASA Astrophysics Data System (ADS)

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

    2012-11-01

    Square pyramidal Cu(II) complexes with NS donor ligand and ciprofloxacin have been synthesized and characterized using analytical and spectral techniques. The synthesized complexes have been tested for their antimicrobial activity using double dilution technique in terms of minimum inhibitory concentration (MIC) and colony forming unit (CFU). The DNA binding ability of the complexes with Sperm Herring DNA has been performed using absorption titration and viscosity measurement. The nuclease activity of complexes with plasmid DNA (pUC19) has been carried out using agarose gel electrophoresis technique. Synthesized complexes have been tested for their SOD mimic activity using NBT/NADH/PMS system. The cytotoxic properties of metal complexes have been evaluated using brine shrimp lethality bioassay.

  17. Capturing tumor complexity in vitro: Comparative analysis of 2D and 3D tumor models for drug discovery

    PubMed Central

    Stock, Kristin; Estrada, Marta F.; Vidic, Suzana; Gjerde, Kjersti; Rudisch, Albin; Santo, Vítor E.; Barbier, Michaël; Blom, Sami; Arundkar, Sharath C.; Selvam, Irwin; Osswald, Annika; Stein, Yan; Gruenewald, Sylvia; Brito, Catarina; van Weerden, Wytske; Rotter, Varda; Boghaert, Erwin; Oren, Moshe; Sommergruber, Wolfgang; Chong, Yolanda; de Hoogt, Ronald; Graeser, Ralph

    2016-01-01

    Two-dimensional (2D) cell cultures growing on plastic do not recapitulate the three dimensional (3D) architecture and complexity of human tumors. More representative models are required for drug discovery and validation. Here, 2D culture and 3D mono- and stromal co-culture models of increasing complexity have been established and cross-comparisons made using three standard cell carcinoma lines: MCF7, LNCaP, NCI-H1437. Fluorescence-based growth curves, 3D image analysis, immunohistochemistry and treatment responses showed that end points differed according to cell type, stromal co-culture and culture format. The adaptable methodologies described here should guide the choice of appropriate simple and complex in vitro models. PMID:27364600

  18. DNA interaction studies of a platinum (II) complex containing an antiviral drug, ribavirin: the effect of metal on DNA binding.

    PubMed

    Shahabadi, Nahid; Mirzaei kalar, Zeinab; Moghadam, Neda Hosseinpour

    2012-10-01

    The water-soluble Pt (II) complex, [PtCl (DMSO)(N(4)N(7)-ribavirin)]· H(2)O (ribavirin is an antiviral drug) has been synthesized and characterized by physico-chemical and spectroscopic methods. The binding interactions of this complex with calf thymus DNA (CT-DNA) were investigated using fluorimetry, spectrophotometry, circular dichroism and viscosimetry. The complex binds to CT-DNA in an intercalative mode. The calculated binding constant, K(b), was 7.2×10(5) M(-1). In fluorimetric studies, the enthalpy (ΔH<0) and entropy (ΔS>0) changes of the reaction between the Pt (II) complex with CT-DNA showed hydrophobic interaction. In addition, CD study showed stabilization of the right-handed B form of CT-DNA. All these results prove that the complex interacts with CT-DNA via intercalative mode of binding. In comparison with the previous study of the DNA interaction with ribavirin, these results show that platinum complex has greater affinity to CT-DNA.

  19. Chirality- and sequence-selective successive self-sorting via specific homo- and complementary-duplex formations

    PubMed Central

    Makiguchi, Wataru; Tanabe, Junki; Yamada, Hidekazu; Iida, Hiroki; Taura, Daisuke; Ousaka, Naoki; Yashima, Eiji

    2015-01-01

    Self-recognition and self-discrimination within complex mixtures are of fundamental importance in biological systems, which entirely rely on the preprogrammed monomer sequences and homochirality of biological macromolecules. Here we report artificial chirality- and sequence-selective successive self-sorting of chiral dimeric strands bearing carboxylic acid or amidine groups joined by chiral amide linkers with different sequences through homo- and complementary-duplex formations. A mixture of carboxylic acid dimers linked by racemic-1,2-cyclohexane bis-amides with different amide sequences (NHCO or CONH) self-associate to form homoduplexes in a completely sequence-selective way, the structures of which are different from each other depending on the linker amide sequences. The further addition of an enantiopure amide-linked amidine dimer to a mixture of the racemic carboxylic acid dimers resulted in the formation of a single optically pure complementary duplex with a 100% diastereoselectivity and complete sequence specificity stabilized by the amidinium–carboxylate salt bridges, leading to the perfect chirality- and sequence-selective duplex formation. PMID:26051291

  20. Targeting the Cytochrome bc1 Complex of Leishmania Parasites for Discovery of Novel Drugs.

    PubMed

    Ortiz, Diana; Forquer, Isaac; Boitz, Jan; Soysa, Radika; Elya, Carolyn; Fulwiler, Audrey; Nilsen, Aaron; Polley, Tamsen; Riscoe, Michael K; Ullman, Buddy; Landfear, Scott M

    2016-08-01

    Endochin-like quinolones (ELQs) are potent and specific inhibitors of cytochrome bc1 from Plasmodium falciparum and Toxoplasma gondii and show promise for novel antiparasitic drug development. To determine whether the mitochondrial electron transport chain of Leishmania parasites could be targeted similarly for drug development, we investigated the activity of 134 structurally diverse ELQs. A cohort of ELQs was selectively toxic to amastigotes of Leishmania mexicana and L. donovani, with 50% inhibitory concentrations (IC50s) in the low micromolar range, but the structurally similar hydroxynaphthoquinone buparvaquone was by far the most potent inhibitor of electron transport, ATP production, and intracellular amastigote growth. Cytochrome bc1 is thus a promising target for novel antileishmanial drugs, and further improvements on the buparvaquone scaffold are warranted for development of enhanced therapeutics.

  1. Targeting the Cytochrome bc1 Complex of Leishmania Parasites for Discovery of Novel Drugs

    PubMed Central

    Ortiz, Diana; Forquer, Isaac; Boitz, Jan; Soysa, Radika; Elya, Carolyn; Fulwiler, Audrey; Nilsen, Aaron; Polley, Tamsen; Riscoe, Michael K.; Ullman, Buddy

    2016-01-01

    Endochin-like quinolones (ELQs) are potent and specific inhibitors of cytochrome bc1 from Plasmodium falciparum and Toxoplasma gondii and show promise for novel antiparasitic drug development. To determine whether the mitochondrial electron transport chain of Leishmania parasites could be targeted similarly for drug development, we investigated the activity of 134 structurally diverse ELQs. A cohort of ELQs was selectively toxic to amastigotes of Leishmania mexicana and L. donovani, with 50% inhibitory concentrations (IC50s) in the low micromolar range, but the structurally similar hydroxynaphthoquinone buparvaquone was by far the most potent inhibitor of electron transport, ATP production, and intracellular amastigote growth. Cytochrome bc1 is thus a promising target for novel antileishmanial drugs, and further improvements on the buparvaquone scaffold are warranted for development of enhanced therapeutics. PMID:27297476

  2. Synthesis and studies on the effect of 2-thiouridine and 4-thiouridine on sugar conformation and RNA duplex stability.

    PubMed Central

    Kumar, R K; Davis, D R

    1997-01-01

    In order to understand the effect of 2-thiouridine (s2U) substitution on RNA structure and the potential for stabilization of tRNA codon-anticodon interactions through s2U-34 modification, a pentamer RNA sequence, Gs2UUUC, was synthesized and characterized by NMR spectroscopy. The single strand contains the UUU anticodon sequence of tRNALys with flanking GCs to increase duplex stability. Regiochemical effects of uridine thiolation were determined by comparing the structure and stability of the 2-thiouridine containing oligonucleotide with an identical sequence containing 4-thiouridine (s4U) and also the normal uridine nucleoside. Circular dichroism spectrum indicated an A-form helical conformation for Gs2UUUC which was further confirmed by 2D ROESY NMR experiments. The duplex stability of the three pentamers complexed with a 2'-O-methyl-ribonucleotide complementary strand, GmAmAmAmCm, was determined by UV thermal melting studies and by 1H NMR spectroscopy. The duplex containing s2U has a T m of 30.7 degrees C compared to 19. 0 degrees C for the unmodified control and 14.5 degrees C for the s4U containing duplex. The results from UV experiments were corroborated by imino proton NMR studies that show proton exchange rates, chemical shift differences, and NH proton linewidths indicative of the stability order s2U >U >s4U. The magnitude of the effect of s2U in our model system is comparable to the 20 degrees C stabilization observed by Grosjean and co-workers for 2-thiolation in a codon-anticodon model system composed of two tRNAs with complementary anticodon sequences [Houssier, C., Degee, P., Nicoghosian, K. and Grosjean, H. (1988) J. Biomol. Struct. Dyn., 5, 1259-1266]. PMID:9092639

  3. The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design.

    PubMed

    Stevaert, Annelies; Naesens, Lieve

    2016-11-01

    Influenza viruses cause seasonal epidemics and pandemic outbreaks associated with significant morbidity and mortality, and a huge cost. Since resistance to the existing anti-influenza drugs is rising, innovative inhibitors with a different mode of action are urgently needed. The influenza polymerase complex is widely recognized as a key drug target, given its critical role in virus replication and high degree of conservation among influenza A (of human or zoonotic origin) and B viruses. We here review the major progress that has been made in recent years in unravelling the structure and functions of this protein complex, enabling structure-aided drug design toward the core regions of the PA endonuclease, PB1 polymerase, or cap-binding PB2 subunit. Alternatively, inhibitors may target a protein-protein interaction site, a cellular factor involved in viral RNA synthesis, the viral RNA itself, or the nucleoprotein component of the viral ribonucleoprotein. The latest advances made for these diverse pharmacological targets have yielded agents in advanced (i.e., favipiravir and VX-787) or early clinical testing, besides several experimental inhibitors in various stages of development, which are all covered here.

  4. The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

    PubMed Central

    Stevaert, Annelies

    2016-01-01

    Abstract Influenza viruses cause seasonal epidemics and pandemic outbreaks associated with significant morbidity and mortality, and a huge cost. Since resistance to the existing anti‐influenza drugs is rising, innovative inhibitors with a different mode of action are urgently needed. The influenza polymerase complex is widely recognized as a key drug target, given its critical role in virus replication and high degree of conservation among influenza A (of human or zoonotic origin) and B viruses. We here review the major progress that has been made in recent years in unravelling the structure and functions of this protein complex, enabling structure‐aided drug design toward the core regions of the PA endonuclease, PB1 polymerase, or cap‐binding PB2 subunit. Alternatively, inhibitors may target a protein–protein interaction site, a cellular factor involved in viral RNA synthesis, the viral RNA itself, or the nucleoprotein component of the viral ribonucleoprotein. The latest advances made for these diverse pharmacological targets have yielded agents in advanced (i.e., favipiravir and VX‐787) or early clinical testing, besides several experimental inhibitors in various stages of development, which are all covered here. PMID:27569399

  5. Validated spectroflurimetric determination of some H1 receptor antagonist drugs in pharmaceutical preparations through charge transfer complexation.

    PubMed

    el-Din, Mohie K Sharaf; Ibrahim, Fawzia; Eid, Manal I; Wahba, Mary E K

    2012-01-01

    A validated simple, rapid, and selective spectrofluorimetric method was developed for the determination of some antihistaminic H(1) receptor antagonist drugs namely ebastine (EBS), cetirizine dihydrochloride (CTZ), and fexofenadine hydrochloride (FXD). The method is based on the reaction of the cited drugs with some Π acceptors namely p-chloranilic acid (CLA), tetracyanoethylene (TCNE), and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) to give highly fluorescent derivatives. The fluorescence intensity-concentration plots were rectilinear over the concentration ranges of 0.2-3.0, 0.2-2.5 and 0.15-2.0 μg/ml for EBS with CLA, DDQ, and TCNE respectively; 0.5-7.0, 0.5-6.0, and 0.2-4.0 μg/ml for CTZ with the previously mentioned reagents, and 0.2-3.5, 0.5-6.0, and 0.2-3.5 μg/ml for FXD. The factors affecting the formation of the reaction products were carefully studied and optimized. The method was applied for the determination of the studied drugs in their dosage forms. The results obtained were in good agreement with those obtained by the comparison methods. Reactions Stoichiometries of the complexes formed between the studied drugs and Π acceptors were defined by the Job's method of the continuous variation and found in 1:1 in all cases.

  6. Insights on novel particulate self-assembled drug delivery beads based on partial inclusion complexes between triglycerides and cyclodextrins.

    PubMed

    Aburahma, Mona Hassan

    2016-09-01

    Most of the newly designed drug molecules are lipophilic in nature and often encounter erratic absorption and low bioavailability after oral administration. Finding ways to enhance the absorption and bioavailability of these lipophilic drugs is one of the major challenges that face pharmaceutical industry nowadays. In view of that, the purpose of this review is to shed some light on a novel particulate self-assembling system named "beads" than can act as a safe carrier for delivering lipophilic drugs. The beads are prepared simply by mixing oils with cyclodextrin (CD) aqueous solution in mild conditions. A unique interaction between oil components and CD molecules occurs to form in situ surface-active complexes which are prerequisites for beads formation. This review mainly focuses on the fundamentals of beads preparation through reviewing present, yet scarce, literature. The key methods used for beads characterization are discussed in details. Also, the potential mechanisms by which beads increase the bioavailability of lipophilic drugs are illustrated. Finally, the related research areas that needs to be addressed in future for optimizing this promising delivery system are briefly outlined.

  7. Fluorescence Spectroscopic Studies on the Complexation of Antidiabetic Drugs with Glycosylated Serum Albumin

    NASA Astrophysics Data System (ADS)

    Seedher, N.; Kanojia, M.

    2013-11-01

    Glycosylation decreases the association constant values and hence the binding affinity of human serum albumin (HSA) for the antidiabetic drugs under study. The percentage of HAS-bound drug at physiological temperature was only about 21-38 % as compared to 46-74 % for non-glycosylated HSA. Thus the percentage of free drug available for an antihyperglycemic effect was about double (62-79 %) compared to the values for non-glycosylated HSA. Much higher free drug concentrations available for pharmacological effect can lead to the risk of hypoglycemia. Hydrophobic interactions were predominantly involved in the binding. In the binding of gliclazide, hydrogen bonding and electrostatic interactions were involved. Site specificity for glycosylated HSA was the same as that for non-glycosylated HSA; gliclazide and repaglinide bind only at site II whereas glimepiride and glipizide bind at both sites I and II. Glycosylation, however, caused conformational changes in albumin, and the binding region within site II was different for glycosylated and non-glycosylated albumin. Stern-Volmer analysis also indicated the conformational changes in albumin as a result of glycosylation and showed that the dynamic quenching mechanism was valid for fluorescence of both glycosylated and non-glycosylated HSA.

  8. Studies on Cu(II) ternary complexes involving an aminopenicillin drug and imidazole containing ligands

    NASA Astrophysics Data System (ADS)

    Regupathy, Sthanumoorthy; Nair, Madhavan Sivasankaran

    2010-02-01

    Equilibrium studies on the ternary complex systems involving ampicillin (amp) as ligand (A) and imidazole containing ligands viz., imidazole (Him), benzimidazole (Hbim), histamine (Hist) and histidine (His) as ligands (B) at 37 °C and I = 0.15 mol dm -3 (NaClO 4) show the presence of CuABH, CuAB and CuAB 2. The proton in the CuABH species is attached to ligand A. In the ternary complexes the ligand, amp(A) binds the metal ion via amino nitrogen and carbonyl oxygen atom. The CuAB (B = Hist/His)/CuAB 2 (B = Him/Hbim) species have also been isolated and the analytical data confirmed its formation. Non-electrolytic behavior and monomeric type of chelates have been assessed from their low conductance and magnetic susceptibility values. The electronic and vibrational spectral results were interpreted to find the mode of binding of ligands to metal and geometry of the complexes. This is also supported by the g tensor values calculated from ESR spectra. The thermal behaviour of complexes were studied by TGA/DTA. The redox behavior of the complexes has been studied by cyclic voltammetry. The antimicrobial activity and CT DNA cleavage study of the complexes show higher activity for ternary complexes.

  9. Haemolytic uraemic syndrome and accumulation of haemoglobin-haptoglobin complexes in plasma in serum sickness caused by penicillin drugs.

    PubMed

    Brandslund, I; Petersen, P H; Strunge, P; Hole, P; Worth, V

    1980-01-01

    2 patients treated with penicillin and ampicillin, respectively, suffered from haemorrhagic diathesis, haemolysis, cerebral symptoms and renal insufficiency, resembling a haemolytic-uraemic syndrome. Their plasma was red due to the presence during several days of haemoglobin-haptoglobin complexes, the P-haemoglobin being 2.8 and 1.6 g/l, respectively. Coagulation tests showed an unusual pattern with prolonged activated partial thromboplastin times, an extremely long thrombin time and very high levels of fibrinogen degradation products. Repeated transfusion had no effect. The patients were considered to have developed a drug-induced serum sickness associated with insufficient function of the reticuloendothelial system, and secondary to this an accumulation of haemoglobin-haptoglobin complexes in plasma. When the penicillin drugs were discontinued, all measured variables rapidly normalised and the patients recovered completely. Thus, the haemolyticuraemic syndrome seemed to be caused by the serum sickness, possibly via circulating or cell-associated immune complexes. The possibility of a type III allergic reaction should be considered in patients with haemolytic-uraemic-like syndromes.

  10. Current drug design to target the Semaphorin/Neuropilin/Plexin complexes

    PubMed Central

    Meyer, Lionel A. T.; Fritz, Justine; Pierdant-Mancera, Marie; Bagnard, Dominique

    2016-01-01

    ABSTRACT The Semaphorin/Neuropilin/Plexin (SNP) complexes control a wide range of biological processes. Consistently, activity deregulation of these complexes is associated with many diseases. The increasing knowledge on SNP had in turn validated these molecular complexes as novel therapeutic targets. Targeting SNP activities by small molecules, antibodies and peptides or by soluble semaphorins have been proposed as new therapeutic approach. This review is focusing on the latest demonstration of this potential and discusses some of the key questions that need to be addressed before translating SNP targeting into clinically relevant approaches. PMID:27906605

  11. Propolis: A Complex Natural Product with a Plethora of Biological Activities That Can Be Explored for Drug Development

    PubMed Central

    Silva-Carvalho, Ricardo; Baltazar, Fátima; Almeida-Aguiar, Cristina

    2015-01-01

    The health industry has always used natural products as a rich, promising, and alternative source of drugs that are used in the health system. Propolis, a natural resinous product known for centuries, is a complex product obtained by honey bees from substances collected from parts of different plants, buds, and exudates in different geographic areas. Propolis has been attracting scientific attention since it has many biological and pharmacological properties, which are related to its chemical composition. Several in vitro and in vivo studies have been performed to characterize and understand the diverse bioactivities of propolis and its isolated compounds, as well as to evaluate and validate its potential. Yet, there is a lack of information concerning clinical effectiveness. The goal of this review is to discuss the potential of propolis for the development of new drugs by presenting published data concerning the chemical composition and the biological properties of this natural compound from different geographic origins. PMID:26106433

  12. Propolis: A Complex Natural Product with a Plethora of Biological Activities That Can Be Explored for Drug Development.

    PubMed

    Silva-Carvalho, Ricardo; Baltazar, Fátima; Almeida-Aguiar, Cristina

    2015-01-01

    The health industry has always used natural products as a rich, promising, and alternative source of drugs that are used in the health system. Propolis, a natural resinous product known for centuries, is a complex product obtained by honey bees from substances collected from parts of different plants, buds, and exudates in different geographic areas. Propolis has been attracting scientific attention since it has many biological and pharmacological properties, which are related to its chemical composition. Several in vitro and in vivo studies have been performed to characterize and understand the diverse bioactivities of propolis and its isolated compounds, as well as to evaluate and validate its potential. Yet, there is a lack of information concerning clinical effectiveness. The goal of this review is to discuss the potential of propolis for the development of new drugs by presenting published data concerning the chemical composition and the biological properties of this natural compound from different geographic origins.

  13. NMR spectroscopy of RNA duplexes containing pseudouridine in supercooled water.

    PubMed

    Schroeder, Kersten T; Skalicky, Jack J; Greenbaum, Nancy L

    2005-07-01

    We have performed NMR experiments in supercooled water in order to decrease the temperature-dependent exchange of protons in RNA duplexes. NMR spectra of aqueous samples of RNA in bundles of narrow capillaries that were acquired at temperatures as low as -18 degrees C reveal resonances of exchangeable protons not seen at higher temperatures. In particular, we detected the imino protons of terminal base pairs and the imino proton of a non-base-paired pseudouridine in a duplex representing the eukaryotic pre-mRNA branch site helix. Analysis of the temperature dependence of chemical shift changes (thermal coefficients) for imino protons corroborated hydrogen bonding patterns observed in the NMR-derived structural model of the branch site helix. The ability to observe non-base-paired imino protons of RNA is of significant value in structure determination of RNA motifs containing loop and bulge regions.

  14. Microstructure, Properties and Weldability of Duplex Stainless Steel 2101

    NASA Astrophysics Data System (ADS)

    Ma, Li; Hu, Shengsun; Shen, Junqi

    2017-01-01

    The continuous development of duplex stainless steels (DSSs) is due to their excellent corrosion resistance in aggressive environments and their mechanical strength, which is usually twice of conventional austenitic stainless steels (ASSs). In this paper, a designed lean duplex stainless steel 2101, with the alloy design of reduced nickel content and increased additions of manganese and nitrogen, is studied by being partly compared with typical ASS 304L steels. The microstructure, mechanical properties, impact toughness, corrosion resistance and weldability of the designed DSS 2101 were conducted. The results demonstrated that both 2101 steel and its weldment show excellent mechanical properties, impact toughness and corrosion resistance, so DSS 2101 exhibits good comprehensive properties and can be used to replace 304L in numerous applications.

  15. Investigation of plastic deformation heterogeneities in duplex steel by EBSD

    SciTech Connect

    Wronski, S.; Tarasiuk, J.; Bacroix, B.; Baczmanski, A.; Braham, C.

    2012-11-15

    An EBSD analysis of a duplex steel (austeno-ferritic) deformed in tension up to fracture is presented. The main purpose of the paper is to describe, qualitatively and quantitatively, the differences in the behavior of the two phases during plastic deformation. In order to do so, several topological maps are measured on the deformed state using the electron backscatter diffraction technique. Distributions of grain size, misorientation, image quality factor and texture are then analyzed in detail. - Highlights: Black-Right-Pointing-Pointer Heterogeneities in duplex steel is studied. Black-Right-Pointing-Pointer The behavior of the two phases during plastic deformation is studied. Black-Right-Pointing-Pointer IQ factor distribution and misorientation characteristics are examined using EBSD.

  16. Direct surface-enhanced Raman scattering analysis of DNA duplexes.

    PubMed

    Guerrini, Luca; Krpetić, Željka; van Lierop, Danny; Alvarez-Puebla, Ramon A; Graham, Duncan

    2015-01-19

    The exploration of the genetic information carried by DNA has become a major scientific challenge. Routine DNA analysis, such as PCR, still suffers from important intrinsic limitations. Surface-enhanced Raman spectroscopy (SERS) has emerged as an outstanding opportunity for the development of DNA analysis, but its application to duplexes (dsDNA) has been largely hampered by reproducibility and/or sensitivity issues. A simple strategy is presented to perform ultrasensitive direct label-free analysis of unmodified dsDNA with the means of SERS by using positively charged silver colloids. Electrostatic adhesion of DNA promotes nanoparticle aggregation into stable clusters yielding intense and reproducible SERS spectra at nanogram level. As potential applications, we report the quantitative recognition of hybridization events as well as the first examples of SERS recognition of single base mismatches and base methylations (5-methylated cytosine and N6-methylated Adenine) in duplexes.

  17. Laser Safety Method For Duplex Open Loop Parallel Optical Link

    DOEpatents

    Baumgartner, Steven John; Hedin, Daniel Scott; Paschal, Matthew James

    2003-12-02

    A method and apparatus are provided to ensure that laser optical power does not exceed a "safe" level in an open loop parallel optical link in the event that a fiber optic ribbon cable is broken or otherwise severed. A duplex parallel optical link includes a transmitter and receiver pair and a fiber optic ribbon that includes a designated number of channels that cannot be split. The duplex transceiver includes a corresponding transmitter and receiver that are physically attached to each other and cannot be detached therefrom, so as to ensure safe, laser optical power in the event that the fiber optic ribbon cable is broken or severed. Safe optical power is ensured by redundant current and voltage safety checks.

  18. Herpes Zoster Duplex Unilateralis: Two Cases and Brief Literature Review

    PubMed Central

    Son, Jee Hee; Chung, Bo Young; Kim, Hye One; Cho, Hee Jin

    2016-01-01

    Cases involving dermatomal herpes zoster in two or more locations are rare, especially in immunocompetent patients. When two noncontiguous dermatomes are involved, if affected unilaterally, it is called herpes zoster duplex unilateralis; if bilaterally, bilateralis. Here, we report two cases of herpes zoster duplex unilateralis. A 66-year-old man presented with painful erythematous grouped vesicles on his left scalp, forehead, trunk, and back (left [Lt.] V1, Lt. T8). Histologic findings were consistent with herpetic infection. A 33-year-old woman presented with painful erythematous grouped vesicles and crust on her left forehead and neck (Lt. V1, Lt. C5). Both patients were treated with oral administration of famcyclovir 750 mg/day for seven days. PMID:27904277

  19. Smectic phase in suspensions of gapped DNA duplexes

    NASA Astrophysics Data System (ADS)

    Salamonczyk, Miroslaw; Zhang, Jing; Portale, Giuseppe; Zhu, Chenhui; Kentzinger, Emmanuel; Gleeson, James T.; Jakli, Antal; de Michele, Cristiano; Dhont, Jan K. G.; Sprunt, Samuel; Stiakakis, Emmanuel

    2016-11-01

    Smectic ordering in aqueous solutions of monodisperse stiff double-stranded DNA fragments is known not to occur, despite the fact that these systems exhibit both chiral nematic and columnar mesophases. Here, we show, unambiguously, that a smectic-A type of phase is formed by increasing the DNA's flexibility through the introduction of an unpaired single-stranded DNA spacer in the middle of each duplex. This is unusual for a lyotropic system, where flexibility typically destabilizes the smectic phase. We also report on simulations suggesting that the gapped duplexes (resembling chain-sticks) attain a folded conformation in the smectic layers, and argue that this layer structure, which we designate as smectic-fA phase, is thermodynamically stabilized by both entropic and energetic contributions to the system's free energy. Our results demonstrate that DNA as a building block offers an exquisitely tunable means to engineer a potentially rich assortment of lyotropic liquid crystals.

  20. Smectic phase in suspensions of gapped DNA duplexes

    PubMed Central

    Salamonczyk, Miroslaw; Zhang, Jing; Portale, Giuseppe; Zhu, Chenhui; Kentzinger, Emmanuel; Gleeson, James T.; Jakli, Antal; De Michele, Cristiano; Dhont, Jan K. G.; Sprunt, Samuel; Stiakakis, Emmanuel

    2016-01-01

    Smectic ordering in aqueous solutions of monodisperse stiff double-stranded DNA fragments is known not to occur, despite the fact that these systems exhibit both chiral nematic and columnar mesophases. Here, we show, unambiguously, that a smectic-A type of phase is formed by increasing the DNA's flexibility through the introduction of an unpaired single-stranded DNA spacer in the middle of each duplex. This is unusual for a lyotropic system, where flexibility typically destabilizes the smectic phase. We also report on simulations suggesting that the gapped duplexes (resembling chain-sticks) attain a folded conformation in the smectic layers, and argue that this layer structure, which we designate as smectic-fA phase, is thermodynamically stabilized by both entropic and energetic contributions to the system's free energy. Our results demonstrate that DNA as a building block offers an exquisitely tunable means to engineer a potentially rich assortment of lyotropic liquid crystals. PMID:27845332

  1. Charge transfer complex studies between some non-steroidal anti-inflammatory drugs and π-electron acceptors

    NASA Astrophysics Data System (ADS)

    Duymus, Hulya; Arslan, Mustafa; Kucukislamoglu, Mustafa; Zengin, Mustafa

    2006-12-01

    Charge transfer (CT) complexes of some non-steroidal anti-inflammatory drugs, naproxen and etodolac which are electron donors with some π-acceptors, such as tetracyanoethylene (TCNE), 2,3-dichloro-5,6-dicyano- p-benzoquinone (DDQ), p-chloranil ( p-CHL), have been investigated spectrophotometrically in chloroform at 21 °C. The coloured products are measured spectrophotometrically at different wavelength depending on the electronic transition between donors and acceptors. Beer's law is obeyed and colours were produced in non-aqueous media. All complexes were stable at least 2 h except for etodolac with DDQ stable for 5 min. The equilibrium constants of the CT complexes were determined by the Benesi-Hildebrand equation. The thermodynamic parameters Δ H, Δ S, Δ G° were calculated by Van't Hoff equation. Stochiometries of the complexes formed between donors and acceptors were defined by the Job's method of the continuous variation and found in 1:1 complexation with donor and acceptor at the maximum absorption bands in all cases.

  2. Compact, precision duplex bearing mount for high vibration environments

    NASA Technical Reports Server (NTRS)

    Bouzakis, George Elias (Inventor); Bowman, James Edward (Inventor); Devine, Edward J. (Inventor); Joffe, Benjamin (Inventor); Segal, Kenneth Neal (Inventor); Webb, Merritt J. (Inventor)

    2002-01-01

    A duplex bearing mount including at least one duplex bearing having an inner race and an outer race, the inner race disposed within the outer race and being rotatable relative to the outer race about an axis, the inner race having substantially no relative movement relative to the outer race in at least one direction along the axis, the inner and outer races each having first and second axial faces which are respectively located at the same axial end of the duplex bearing. The duplex bearing is radially supported by a housing, and a shaft extends through the inner race, the shaft radially and axially supported by the inner race. A first retainer is connected to the housing and engages the first axial surface of a bearing race, the movement of which race in a first direction along the axis being constrained by the first retainer. A second, resilient retainer is connected to the housing or the shaft and is deflected through engagement with the second axial face of a bearing race, the movement of which race in a second direction along the axis, opposite to the first direction, being constrained by the deflected second retainer. The bearing is preloaded by its being clamped between the first and second retainers, and the second retainer forms at least a portion of a spring having the characteristic of a substantially constant force value correlating to a range of various deflection values, whereby the preload of the bearing is substantially unaffected by variations in the deflection of the second retainer.

  3. Integrated optic broadband duplexer made by ion exchange

    NASA Astrophysics Data System (ADS)

    Ghibaudo, E.; Broquin, J.-E.; Benech, P.

    2003-02-01

    The development of optical amplification and bidirectional traffic in local and wide area networks requires broadband multiplexers which are able to treat the signal of an entire telecommunication window. A device made by ion exchange and answering to these needs is proposed in this letter. Its working principle, based on a leaky structure is first explained. An experimental result confirming a good broadband spectral behavior is then presented. Its spectral response displays two duplexing bands of at least 100 nm.

  4. Investigation of hot cracking resistance of 2205 duplex steel

    NASA Astrophysics Data System (ADS)

    Adamiec, J.; Ścibisz, B.

    2010-02-01

    Austenitic duplex steel of the brand 2205 according to Avesta Sheffield is used for welded constructions (pipelines, tanks) in the petrol industry, chemical industry and food industry. It is important to know the range of high-temperature brittleness in designing welding technology for constructions made of this steel type. There is no data in literature concerning this issue. High-temperature brittleness tests using the simulator of heat flow device Gleeble 3800 were performed. The tests results allowed the evaluation of the characteristic temperatures in the brittleness temperature range during the joining of duplex steels, specifically the nil-strength temperature (NST) and nil-ductility temperatures (NDT) during heating, the strength and ductility recovery temperatures (DRT) during cooling, the Rfparameter (Rf = (Tliquidus - NDT)/NDT) describing the duplex steel inclination for hot cracking, and the brittleness temperature range (BTR). It has been stated that, for the examined steel, this range is wide and amounts to ca. 90 °C. The joining of duplex steels with the help of welding techniques creates a significant risk of hot cracks. After analysis of the DTA curves a liquidus temperature of TL = 1465 °C and a solidus temperature of TS = 1454 °C were observed. For NST a mean value was assumed, in which the cracks appeared for six samples; the temperature was 1381 °C. As the value of the NDT temperature 1367 °C was applied while for DRT the assumed temperature was 1375 °C. The microstructure of the fractures was observed using a Hitachi S-3400N scanning electron microscope (SEM). The analyses of the chemical composition were performed using an energy-dispersive X-ray spectrometer (EDS), Noran System Six of Thermo Fisher Scientific. Essential differences of fracture morphology type over the brittle temperature range were observed and described.

  5. All-atom crystal simulations of DNA and RNA duplexes

    PubMed Central

    Liu, Chunmei; Janowski, Pawel A.; Case, David A.

    2014-01-01

    Background Molecular dynamics simulations can complement experimental measures of structure and dynamics of biomolecules. The quality of such simulations can be tested by comparisons to models refined against experimental crystallographic data. Methods We report simulations of a DNA and RNA duplex in their crystalline environment. The calculations mimic the conditions for PDB entries 1D23 [d(CGATCGATCG)2] and 1RNA [(UUAUAUAUAUAUAA)2], and contain 8 unit cells, each with 4 copies of the Watson-Crick duplex; this yields in aggregate 64 µs of duplex sampling for DNA and 16 µs for RNA. Results The duplex structures conform much more closely to the average structure seen in the crystal than do structures extracted from a solution simulation with the same force field. Sequence-dependent variations in helical parameters, and in groove widths, are largely maintained in the crystal structure, but are smoothed out in solution. However, the integrity of the crystal lattice is slowly degraded in both simulations, with the result that the interfaces between chains become heterogeneous. This problem is more severe for the DNA crystal, which has fewer inter-chain hydrogen bond contacts than does the RNA crystal. Conclusions Crystal simulations using current force fields reproduce many features of observed crystal structures, but suffer from a gradual degradation of the integrity of the crystal lattice. General significance The results offer insights into force-field simulations that tests their ability to preserve weak interactions between chains, which will be of importance also in non-crystalline applications that involve binding and recognition. PMID:25255706

  6. Metal complexes of the fourth generation quinolone antimicrobial drug gatifloxacin: Synthesis, structure and biological evaluation

    NASA Astrophysics Data System (ADS)

    Sadeek, Sadeek A.; El-Shwiniy, Walaa H.

    2010-08-01

    Three metal complexes of the fourth generation quinolone antimicrobial agent gatifloxacin (GFLX) with Y(ΙΙΙ), Zr(ΙV) and U(VΙ) have been prepared and characterized with physicochemical and spectroscopic techniques. In these complexes, gatifloxacin acts as a bidentate deprotonated ligand bound to the metal through the ketone oxygen and a carboxylato oxygen. The complexes are six-coordinated with distorted octahedral geometry. The kinetic parameters for gatifloxacin and the three prepared complexes have been evaluated from TGA curves by using Coats-Redfern (CR) and Horowitz-Metzeger (HM) methods. The calculated bond length and force constant, F(U dbnd O), for the UO 2 bond in uranyl complex are 1.7522 Å and 639.46 N m -1. The antimicrobial activity of the complexes has been tested against microorganisms, three bacterial species, such as Staphylococcus aureus ( S. aureus), Escherichia coli ( E. coli) and Pseudomonas aeruginosa ( P. aeruginosa) and two fungi species, penicillium ( P. rotatum) and trichoderma ( T. sp.), showing that they exhibit higher activity than free ligand.

  7. Binding of tobamovirus replication protein with small RNA duplexes.

    PubMed

    Kurihara, Yukio; Inaba, Naoko; Kutsuna, Natsumaro; Takeda, Atsushi; Tagami, Yuko; Watanabe, Yuichiro

    2007-08-01

    The sequence profiles of small interfering RNAs (siRNAs) in Arabidopsis infected with the crucifer tobamovirus tobacco mosaic virus (TMV)-Cg were determined by using a small RNA cloning technique. The majority of TMV-derived siRNAs were 21 nt in length. The size of the most abundant endogenous small RNAs in TMV-infected plants was 21 nt, whilst in mock-inoculated plants, it was 24 nt. Northern blot analysis revealed that some microRNAs (miRNAs) accumulated more in TMV-infected plants than in mock-inoculated plants. The question of whether the TMV-Cg-encoded 126K replication protein, an RNA-silencing suppressor, caused small RNA enrichment was examined. Transient expression of the replication protein did not change the pattern of miRNA processing. However, miRNA, miRNA* (the opposite strand of the miRNA duplex) and hairpin-derived siRNA all co-immunoprecipitated with the replication protein. Gel mobility-shift assays indicated that the replication protein binds small RNA duplexes. These results suggest that the tobamovirus replication protein functions as a silencing suppressor by binding small RNA duplexes, changing the small RNA profile in infected plants.

  8. Nano-structured complexes of reserpine and quinidine drugs with chloranilic acid based on intermolecular H-bond: Spectral and surface morphology studies

    NASA Astrophysics Data System (ADS)

    Adam, Abdel Majid A.

    2014-06-01

    The study of the drug-acceptor interaction may be useful in understanding the drug-receptor interactions and the mechanism of drug action. Here, complexes of reserpine (Res) and quinidine (Qui) drugs with chloranilic acid (CLA) have been synthesized. Then, these complexes were characterized chemically and structurally using CHN elemental analysis, infrared (IR) and electronic absorption spectroscopy, X-ray diffraction (XRD) and scanning electron microscopy (SEM). The stoichiometry of the H-bonded complex was found to have a 1:1 ratio, so these complexes can be formulated as [(Drug)(CLA)]. IR measurements confirmed the presence of intermolecular H-bond. Application of Debye-Scherrer equation indicates that the formed complexes are in the range of nano-size. The Res complex exhibits a remarkable crystalline morphology. It was also found that the particle size of Res complex is 1.533 time higher than that of Qui complex. Interestingly, free Res molecular weight is higher than that of free Qui by the same ratio (precisely; 1.525).

  9. Hydrodynamic interactions for complex-shaped nanocarriers in targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Wang, Yaohong; Eckmann, David; Radhakrishnan, Ravi; Ayyaswamy, Portonovo

    2014-11-01

    Nanocarrier motion in a blood vessel involves hydrodynamic and Brownian interactions, which collectively dictate the efficacy in targeted drug delivery. The shape of nanocarriers plays a crucial role in drug delivery. In order to quantify the flow and association properties of elliptical nanoparticles, we have developed an arbitrary Lagrangian-Eulerian framework with capabilities to simulate the hydrodynamic motion of nanoparticles of arbitrary shapes. We introduce the quaternions for rotational motion, and two collision models, namely, (a) an impulse-based model for wall-particle collision, and (b) the short-range repulsive Gay-Berne potential for particle-particle collision. We also study the red blood cell and nanocarrier (such as ellipsoid) interactions. We compare our results with those obtained for a hard sphere model for both RBCs and nanocarriers. Supported by NIH through grant U01-EB016027.

  10. Bypassing Fluoroquinolone Resistance with Quinazolinediones: Studies of Drug–Gyrase–DNA Complexes Having Implications for Drug Design

    PubMed Central

    2015-01-01

    Widespread fluoroquinolone resistance has drawn attention to quinazolinediones (diones), fluoroquinolone-like topoisomerase poisons that are unaffected by common quinolone-resistance mutations. To better understand differences between quinolones and diones, we examined their impact on the formation of cleaved complexes (drug–topoisomerase–DNA complexes in which the DNA moiety is broken) with gyrase, one of two bacterial targets of the drugs. Formation of cleaved complexes, measured by linearization of a circular DNA substrate, required lower concentrations of quinolone than dione. The reverse reaction, detected as resealing of DNA breaks in cleaved complexes, required higher temperatures and EDTA concentrations for quinolones than diones. The greater stability of quinolone-containing complexes was attributed to the unique ability of the quinolone C3/C4 keto acid to complex with magnesium and form a previously described drug–magnesium–water bridge with GyrA-Ser83 and GyrA-Asp87. A nearby substitution in GyrA (G81C) reduced activity differences between quinolone and dione, indicating that resistance due to this variation derives from perturbation of the magnesium–water bridge. To increase dione activity, we examined a relatively small, flexible C-7-3-(aminomethyl)pyrrolidinyl substituent, which is distal to the bridging C3/C4 keto acid substituent of quinolones. The 3-(aminomethyl)pyrrolidinyl group at position C-7 was capable of forming binding interactions with GyrB-Glu466, as indicated by inspection of crystal structures, computer-aided docking, and measurement of cleaved-complex formation with mutant and wild-type GyrB proteins. Thus, modification of dione C-7 substituents constitutes a strategy for obtaining compounds active against common quinolone-resistant mutants. PMID:25310082

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

    SciTech Connect

    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.

  12. Structures of BmrR-drug complexes reveal a rigid multidrug binding pocket and transcription activation through tyrosine expulsion.

    PubMed

    Newberry, Kate J; Huffman, Joy L; Miller, Marshall C; Vazquez-Laslop, Nora; Neyfakh, Alex A; Brennan, Richard G

    2008-09-26

    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. Preparation, structure and microbial evaluation of metal complexes of the second generation quinolone antibacterial drug lomefloxacin

    NASA Astrophysics Data System (ADS)

    Sadeek, Sadeek A.; El-Shwiniy, Walaa H.

    2010-09-01

    Lomefloxacinate of Y(III), Zr(IV) and U(VI) were isolated as solids with the general formula; [Y(LFX) 2Cl 2]Cl·12H 2O, [ZrO(LFX) 2Cl]Cl·15H 2O and [UO 2(LFX) 3](NO 3) 2·4H 2O. The new synthesized complexes were characterized with physicochemical and diverse spectroscopic techniques (IR, UV-Vis. and 1H NMR spectroscopies) as well as thermal analyses. In these complexes lomefloxacin act as bidentate ligand bound to the metal ions through the pyridone oxygen and one carboxylate oxygen. The kinetic parameters of thermogravimetric (TGA) and its differential (DTG), such as entropy of activation, activation energy, enthalpy of activation and Gibbs free energy evaluated by using Coats- Redfern and Horowitz- Metzger equations for free lomefloxacin and three complexes were carried out. The bond stretching force constant and length of the U dbnd O bond for the [UO 2(LFX) 3](NO 3) 2·4H 2O complex were calculated. The antimicrobial activity of lomefloxacin and its metal complexes was tested against different bacterial species, such as Staphylococcus aureus ( S. aureus), Escherichia coli ( E. coli) and Pseudomonas aeruginosa ( P. aeruginosa) as Gram-positive and Gram-negative bacterial species and also against two species of antifungal, penicillium ( P. rotatum) and trichoderma ( T. sp.). The three complexes are of a good action against three bacterial species but the Y(III) complex exhibit excellent activity against Pseudomonas aeruginosa ( P. aeruginosa), when compared to the free lomefloxacin.

  14. Complex subtype diversity of HIV-1 among drug users in major Kenyan cities.

    PubMed

    Gounder, Kamini; Oyaro, Micah; Padayachi, Nagavelli; Zulu, Thando Mbali; de Oliveira, Tulio; Wylie, John; Ndung'u, Thumbi

    2017-01-09

    Drug users are increasingly recognized as a key population driving HIV spread in sub-Saharan Africa. To determine HIV-1 subtypes circulating in this population group and explore possible geographic differences, we analyzed HIV-1 sequences among drug users from Nairobi, Mombasa and Kisumu in Kenya. We sequenced gag and env from 55 drug users. Subtype analysis from 220 gag clonal sequences from 54/55 participants (median=4/participant) showed that 44.4% were A, 16.7% were C, 3.7% were D and 35.2% were intersubtype recombinants. Of 156 env clonal sequences from 48/55 subjects (median=3/participant), 45.8% were subtype A, 14.6% were C, 6.3% were D and 33.3% were recombinants. Comparative analysis of both genes showed that 30 (63.8%) participants had concordant subtypes while 17 (36.2%) were discordant. We identified one genetically-linked transmission pair and 2 cases of dual infection. These data are indicative of extensive HIV-1 intersubtype recombination in Kenya and suggest decline in subtype D prevalence.

  15. The physical determinants of the DNA conformational landscape: an analysis of the potential energy surface of single-strand dinucleotides in the conformational space of duplex DNA

    PubMed Central

    Elsawy, Karim M.; Hodgson, Michael K.; Caves, Leo S. D.

    2005-01-01

    A multivariate analysis of the backbone and sugar torsion angles of dinucleotide fragments was used to construct a 3D principal conformational subspace (PCS) of DNA duplex crystal structures. The potential energy surface (PES) within the PCS was mapped for a single-strand dinucleotide model using an empirical energy function. The low energy regions of the surface encompass known DNA forms and also identify previously unclassified conformers. The physical determinants of the conformational landscape are found to be predominantly steric interactions within the dinucleotide backbone, with medium-dependent backbone-base electrostatic interactions serving to tune the relative stability of the different local energy minima. The fidelity of the PES to duplex DNA properties is validated through a correspondence to the conformational distribution of duplex DNA crystal structures and the reproduction of observed sequence specific propensities for the formation of A-form DNA. The utility of the PES is demonstrated through its succinct and accurate description of complex conformational processes in simulations of duplex DNA. The study suggests that stereochemical considerations of the nucleic acid backbone play a role in determining conformational preferences of DNA which is analogous to the role of local steric interactions in determining polypeptide secondary structure. PMID:16214808

  16. Europium coordination complexes as potential anticancer drugs: their partitioning and permeation into lipid bilayers as revealed by pyrene fluorescence quenching.

    PubMed

    Trusova, Valeriya; Yudintsev, Andrey; Limanskaya, Ludmila; Gorbenko, Galyna; Deligeorgiev, Todor

    2013-01-01

    The present study was undertaken to evaluate the membrane-associating properties of a series of novel antitumor agents, Eu(III) coordination complexes (EC), using the pyrene fluorescence quenching as an analytical instrument. Analysis of EC-induced decrease in pyrene fluorescence intensity in terms of partition and solubility-diffusion models allowed us to evaluate the partition and permeation coefficients of the examined compounds into the lipid vesicles prepared from zwitterionic lipid phosphatidylcholine (PC) and its mixtures with cholesterol (Chol) and anionic lipid cardiolipin (CL). The drug-lipid interactions were found to have the complex nature determined by both EC structure and lipid bilayer composition. High values of the obtained partition and permeation coefficients create the background for the development of EC liposomal formulations.

  17. Characterization of microstructure and texture across dissimilar super duplex/austenitic stainless steel weldment joint by super duplex filler metal

    SciTech Connect

    Eghlimi, Abbas; Shamanian, Morteza; Eskandarian, Masoomeh; Zabolian, Azam; Szpunar, Jerzy A.

    2015-08-15

    In the present paper, microstructural changes across an as-welded dissimilar austenitic/duplex stainless steel couple welded by a super duplex stainless steel filler metal using gas tungsten arc welding process is characterized with optical microscopy and electron back-scattered diffraction techniques. Accordingly, variations of microstructure, texture, and grain boundary character distribution of base metals, heat affected zones, and weld metal were investigated. The results showed that the weld metal, which was composed of Widmanstätten austenite side-plates and allotriomorphic grain boundary austenite morphologies, had the weakest texture and was dominated by low angle boundaries. The welding process increased the ferrite content but decreased the texture intensity at the heat affected zone of the super duplex stainless steel base metal. In addition, through partial ferritization, it changed the morphology of elongated grains of the rolled microstructure to twinned partially transformed austenite plateaus scattered between ferrite textured colonies. However, the texture of the austenitic stainless steel heat affected zone was strengthened via encouraging recrystallization and formation of annealing twins. At both interfaces, an increase in the special character coincident site lattice boundaries of the primary phase as well as a strong texture with <100> orientation, mainly of Goss component, was observed. - Graphical abstract: Display Omitted - Highlights: • Weld metal showed local orientation at microscale but random texture at macroscale. • Intensification of <100> orientated grains was observed adjacent to the fusion lines. • The austenite texture was weaker than that of the ferrite in all duplex regions. • Welding caused twinned partially transformed austenites to form at SDSS HAZ. • At both interfaces, the ratio of special CSL boundaries of the primary phase increased.

  18. Visualizing transient Watson-Crick-like mispairs in DNA and RNA duplexes.

    PubMed

    Kimsey, Isaac J; Petzold, Katja; Sathyamoorthy, Bharathwaj; Stein, Zachary W; Al-Hashimi, Hashim M

    2015-03-19

    Rare tautomeric and anionic nucleobases are believed to have fundamental biological roles, but their prevalence and functional importance has remained elusive because they exist transiently, in low abundance, and involve subtle movements of protons that are difficult to visualize. Using NMR relaxation dispersion, we show here that wobble dG•dT and rG•rU mispairs in DNA and RNA duplexes exist in dynamic equilibrium with short-lived, low-populated Watson-Crick-like mispairs that are stabilized by rare enolic or anionic bases. These mispairs can evade Watson-Crick fidelity checkpoints and form with probabilities (10(-3) to 10(-5)) that strongly imply a universal role in replication and translation errors. Our results indicate that rare tautomeric and anionic bases are widespread in nucleic acids, expanding their structural and functional complexity beyond that attainable with canonical bases.

  19. Visualizing transient Watson-Crick-like mispairs in DNA and RNA duplexes

    NASA Astrophysics Data System (ADS)

    Kimsey, Isaac J.; Petzold, Katja; Sathyamoorthy, Bharathwaj; Stein, Zachary W.; Al-Hashimi, Hashim M.

    2015-03-01

    Rare tautomeric and anionic nucleobases are believed to have fundamental biological roles, but their prevalence and functional importance has remained elusive because they exist transiently, in low abundance, and involve subtle movements of protons that are difficult to visualize. Using NMR relaxation dispersion, we show here that wobble dG•dT and rG•rU mispairs in DNA and RNA duplexes exist in dynamic equilibrium with short-lived, low-populated Watson-Crick-like mispairs that are stabilized by rare enolic or anionic bases. These mispairs can evade Watson-Crick fidelity checkpoints and form with probabilities (10-3 to 10-5) that strongly imply a universal role in replication and translation errors. Our results indicate that rare tautomeric and anionic bases are widespread in nucleic acids, expanding their structural and functional complexity beyond that attainable with canonical bases.

  20. Complexity.

    PubMed

    Gómez-Hernández, J Jaime

    2006-01-01

    It is difficult to define complexity in modeling. Complexity is often associated with uncertainty since modeling uncertainty is an intrinsically difficult task. However, modeling uncertainty does not require, necessarily, complex models, in the sense of a model requiring an unmanageable number of degrees of freedom to characterize the aquifer. The relationship between complexity, uncertainty, heterogeneity, and stochastic modeling is not simple. Aquifer models should be able to quantify the uncertainty of their predictions, which can be done using stochastic models that produce heterogeneous realizations of aquifer parameters. This is the type of complexity addressed in this article.

  1. Cytotoxic, antibacterial, DNA interaction and superoxide dismutase like activities of sparfloxacin drug based copper(II) complexes with nitrogen donor ligands.

    PubMed

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

    2013-03-01

    The novel neutral mononuclear copper(II) complexes with fluoroquinolone antibacterial drug, sparfloxacin and nitrogen donor heterocyclic ligand have been synthesized and characterized. An antimicrobial efficiency of the complexes has been tested against five different microorganisms and showed diverse biological activity. The interaction of complex with Herring sperm (HS) DNA was investigated using viscosity titration and absorption titration techniques. The results indicate that the complexes bind to DNA by intercalative mode and have rather high DNA-binding constants. DNA cleavage study showed better cleaving ability of the complexes compare to metal salt and standard drug. All the complexes showed good cytotoxic activity with LC(50) values ranging from 4.89 to 11.94 μg mL(-1). Complexes also exhibit SOD-like activity with their IC(50) values ranging from 0.717 to 1.848 μM.

  2. Cytotoxic, antibacterial, DNA interaction and superoxide dismutase like activities of sparfloxacin drug based copper(II) complexes with nitrogen donor ligands

    NASA Astrophysics Data System (ADS)

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

    2013-03-01

    The novel neutral mononuclear copper(II) complexes with fluoroquinolone antibacterial drug, sparfloxacin and nitrogen donor heterocyclic ligand have been synthesized and characterized. An antimicrobial efficiency of the complexes has been tested against five different microorganisms and showed diverse biological activity. The interaction of complex with Herring sperm (HS) DNA was investigated using viscosity titration and absorption titration techniques. The results indicate that the complexes bind to DNA by intercalative mode and have rather high DNA-binding constants. DNA cleavage study showed better cleaving ability of the complexes compare to metal salt and standard drug. All the complexes showed good cytotoxic activity with LC50 values ranging from 4.89 to 11.94 μg mL-1. Complexes also exhibit SOD-like activity with their IC50 values ranging from 0.717 to 1.848 μM.

  3. Manganese(II) complexes with the non-steroidal anti-inflammatory drug tolfenamic acid: structure and biological perspectives.

    PubMed

    Zampakou, Marianthi; Rizeq, Natalia; Tangoulis, Vassilis; Papadopoulos, Athanasios N; Perdih, Franc; Turel, Iztok; Psomas, George

    2014-02-17

    Manganese(II) complexes with the non-steroidal anti-inflammatory drug tolfenamic acid (Htolf) with the nitrogen-donor heterocyclic ligands 1,10-phenanthroline (phen), pyridine (py), or 2,2'-bipyridylamine (bipyam) and/or the oxygen-donor ligands H2O or N,N-dimethylformamide (DMF) have been synthesized and characterized. The crystal structures of complexes [Mn(tolf-O)(tolf-O,O')(phen)(H2O)], [Mn2(μ2-tolf-O,O')2(tolf-O,O')2(bipyam)2], [Mn2(μ2-H2O)(μ2-tolf-O,O')2(tolf-O)2(py)4]·1.5MeOH·py, and [Mn(μ2-tolf-O,O')2(DMF)2]n have been determined by X-ray crystallography. The interaction of the complexes with serum albumin proteins was investigated, and relative high binding constant values were calculated. The ability of the compounds to scavenge 1,1-diphenyl-picrylhydrazyl, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid), and hydroxyl radicals was evaluated, and [Mn(tolf)2(phen)(H2O)] was the most active scavenger among the compounds. The compounds have also exhibited noteworthy in vitro inhibitory activity against soybean lipoxygenase. UV titration studies of the interaction of the complexes with calf-thymus (CT) DNA have proved the binding to CT DNA with [Mn(μ2-tolf)2(DMF)2]n exhibiting the highest DNA-binding constant (Kb = 5.21 (±0.35) × 10(5) M(-1)). The complexes bind to CT DNA probably via intercalation as suggested by DNA-viscosity measurements and competitive studies with ethidium bromide (EB), which revealed the ability of the complexes to displace the DNA-bound EB.

  4. Multistimuli-responsive supramolecular vesicles based on water-soluble pillar[6]arene and SAINT complexation for controllable drug release.

    PubMed

    Cao, Yu; Hu, Xiao-Yu; Li, Yan; Zou, Xiaochun; Xiong, Shuhan; Lin, Chen; Shen, Ying-Zhong; Wang, Leyong

    2014-07-30

    Supramolecular binary vesicles based on the host-guest complexation of water-soluble pillar[6]arene (WP6) and SAINT molecule have been successfully constructed, which showed pH-, Ca(2+)-, and thermal-responsiveness. These supramolecular vesicles can efficiently encapsulate model substrate calcein, which then can be efficiently released either by adjusting the solution pH to acidic condition due to the complete disruption of vesicular structure, or particularly, by adding a certain amount of Ca(2+) due to the Ca(2+)-induced vesicle fusion and accompanied by the structure disruption. More importantly, drug loading and releasing experiments demonstrate that an anticancer drug, DOX, can be successfully encapsulated by the supramolecular vesicles, and the resulting DOX-loaded vesicles exhibit efficient release of the encapsulated DOX with the pH adjustment or the introduction of Ca(2+). Cytotoxicity experiments suggest that the resulting DOX-loaded supramolecular vesicles exhibit comparable therapeutic effect for cancer cells as free DOX and the remarkably reduced damage for normal cells as well. The present multistimuli-responsive supramolecular vesicles have great potential applications in the field of controlled drug delivery. In addition, giant supramolecular vesicles (~3 μm) with large internal volume and good stability can be achieved by increasing the temperature of WP6 ⊃ SAINT vesicular solution, and they might have potential applications for bioimaging.

  5. Bilayer Protograph Codes for Half-Duplex Relay Channels

    NASA Technical Reports Server (NTRS)

    Divsalar, Dariush; VanNguyen, Thuy; Nosratinia, Aria

    2013-01-01

    Direct to Earth return links are limited by the size and power of lander devices. A standard alternative is provided by a two-hops return link: a proximity link (from lander to orbiter relay) and a deep-space link (from orbiter relay to Earth). Although direct to Earth return links are limited by the size and power of lander devices, using an additional link and a proposed coding for relay channels, one can obtain a more reliable signal. Although significant progress has been made in the relay coding problem, existing codes must be painstakingly optimized to match to a single set of channel conditions, many of them do not offer easy encoding, and most of them do not have structured design. A high-performing LDPC (low-density parity-check) code for the relay channel addresses simultaneously two important issues: a code structure that allows low encoding complexity, and a flexible rate-compatible code that allows matching to various channel conditions. Most of the previous high-performance LDPC codes for the relay channel are tightly optimized for a given channel quality, and are not easily adapted without extensive re-optimization for various channel conditions. This code for the relay channel combines structured design and easy encoding with rate compatibility to allow adaptation to the three links involved in the relay channel, and furthermore offers very good performance. The proposed code is constructed by synthesizing a bilayer structure with a pro to graph. In addition to the contribution to relay encoding, an improved family of protograph codes was produced for the point-to-point AWGN (additive white Gaussian noise) channel whose high-rate members enjoy thresholds that are within 0.07 dB of capacity. These LDPC relay codes address three important issues in an integrative manner: low encoding complexity, modular structure allowing for easy design, and rate compatibility so that the code can be easily matched to a variety of channel conditions without extensive

  6. Effect of ultrafine grain on tensile behaviour and corrosion resistance of the duplex stainless steel.

    PubMed

    Jinlong, Lv; Tongxiang, Liang; Chen, Wang; Limin, Dong

    2016-05-01

    The ultrafine grained 2205 duplex stainless steel was obtained by cold rolling and annealing. The tensile properties were investigated at room temperature. Comparing with coarse grained stainless steel, ultrafine grained sample showed higher strength and plasticity. In addition, grain size changed deformation orientation. The strain induced α'-martensite was observed in coarse grained 2205 duplex stainless steel with large strain. However, the grain refinement inhibited the transformation of α'-martensite;nevertheless, more deformation twins improved the strength and plasticity of ultrafine grained 2205 duplex stainless steel. In addition, the grain refinement improved corrosion resistance of the 2205 duplex stainless steel in sodium chloride solution.

  7. Visualization of drug-nucleic acid interactions at atomic resolution. IX. Structures of two N,N-dimethylproflavine: 5-iodocytidylyl (3'-5') guanosine crystalline complexes

    SciTech Connect

    Bhandary, K.K.; Sakore, T.D.; Sobell, H.M.; King, D.; Gabbay, E.J.

    1984-01-01

    This paper describes two complexes containing N,N-dimethylproflavine and the dinucleoside monophosphate, 5-iodocytidylyl(3'-5')guanosine (iodoCpG). The first complex is triclinic, space group P1, with unit cell dimensions a = 11.78 A, b = 14.55 A, c = 15.50 A, ..cap alpha.. = 89.2/sup 0/, ..beta.. 86.2/sup 0/, ..gamma.. = 96.4/sup 0/. The second complex is monoclinic, space group P2/sub 1/, with a = 14.20 A, b = 19.00 A, c = 20.73 A, ..beta.. = 103.6/sup 0/. Both structures have been solved to atomic resolution and refined by Fourier and least squares methods. The first structure has been refined anisotropically to a residual of 0.09 on 5025 observed reflections using block diagonal least squares, while the second structure has been refined isotropically to a residual of 0.13 on 2888 reflections with full matrix least squares. The asymmetric unit in both structures contains two dimethylproflavine molecules and two iodoCpG molecules; the first structure has 16 water molecules (a total of 134 non-hydrogen atoms), while the second structure has 18 water molecules (a total of 136 non-hydrogen atoms). Both structures demonstrate intercalation of dimethylproflavine between base-paired iodoCpG dimers. In addition, dimethylproflavine molecules stack on either side of the intercalated duplex, being related by a unit cell translation along b and a axes, respectively. 16 references, 13 figures, 5 tables.

  8. Osmium complexation of mismatched DNA: effect of the bases adjacent to mismatched 5-methylcytosine.

    PubMed

    Nomura, Akiko; Tainaka, Kazuki; Okamoto, Akimitsu

    2009-03-18

    The efficiency of osmium complex formation at 5-methylcytosine in mismatched DNA duplexes is a key point for the design of sequence-specific detection of DNA methylation. Osmium complexation was not observed in fully matched duplexes, whereas the complexation site and efficiency in mismatched duplexes changed depending on the type of 5'-neighboring base of the 5-methylcytosine forming a mismatched base pair. In particular, when the base adjacent to the 5' side of the mismatched base pair was thymine, a unique "side reaction" was observed. However, the nature of the mismatched base pairs in the reaction site did not influence the selectivity of osmium complex formation with methylated DNA.

  9. Duplex unwinding and ATPase activities of the DEAD-box helicase eIF4A are coupled by eIF4G and eIF4B.

    PubMed

    Özeş, Ali R; Feoktistova, Kateryna; Avanzino, Brian C; Fraser, Christopher S

    2011-09-30

    Eukaryotic initiation factor (eIF) 4A is a DEAD-box helicase that stimulates translation initiation by unwinding mRNA secondary structure. The accessory proteins eIF4G, eIF4B, and eIF4H enhance the duplex unwinding activity of eIF4A, but the extent to which they modulate eIF4A activity is poorly understood. Here, we use real-time fluorescence assays to determine the kinetic parameters of duplex unwinding and ATP hydrolysis by these initiation factors. To ensure efficient duplex unwinding, eIF4B and eIF4G cooperatively activate the duplex unwinding activity of eIF4A. Our data reveal that eIF4H is much less efficient at stimulating eIF4A unwinding activity than eIF4B, implying that eIF4H is not able to completely substitute for eIF4B in duplex unwinding. By monitoring unwinding and ATPase assays under identical conditions, we demonstrate that eIF4B couples the ATP hydrolysis cycle of eIF4A with strand separation, thereby minimizing nonproductive unwinding events. Using duplex substrates with altered GC contents but similar predicted thermal stabilities, we further show that the rate of formation of productive unwinding complexes is strongly influenced by the local stability per base pair, in addition to the stability of the entire duplex. This finding explains how a change in the GC content of a hairpin is able to influence translation initiation while maintaining the overall predicted thermal stability.

  10. Clinical profiles of adverse drug reactions spontaneously reported at a single Korean hospital dedicated to children with complex chronic conditions

    PubMed Central

    Kim, Bomi; Kim, Sunwha Zara; Lee, Jin; Jung, Ae Hee; Jung, Sun-Hoi; Hahn, Hyeon-Joo; Kang, Hye Ryun

    2017-01-01

    Children with complex chronic conditions (CCC) are presumed to be vulnerable to adverse drug reactions (ADRs). The clinical profiles of ADRs in CCC are not well known. Herein, we aim to describe the ADR profiles in CCC with regard to typical presentations and vulnerable groups. We accessed the ADR yearly reports at a tertiary children's hospital whose practice is mainly dedicated to CCC and descriptively analyzed their clinical profiles according to the presence of a complex chronic condition, ADR severity, and age groups. A total of 1841 cases were analyzed, among which 1258 (68.3%) were mild, 493 (26.8%) moderate, and 90 (4.9%) cases were severe. A total of 1581 (85.9%) cases of complex chronic condition were reported. The proportion of CCC in each severity group increased as the ADR becomes more severe. In CCC, ADRs were most frequently reported by nurses in the adolescent group and in cases where the symptoms involved the gastrointestinal system. The class of antineoplastic and immunomodulating drugs was the most commonly suspected of causing an ADR, followed by one of the antibiotics. When we focus on the trend across the age groups, the ratio of severe-to-total ADRs decreased with older age. Among severe cases, the ratio of off-label prescription-related cases was the highest in the infant/toddler group and decreased as the groups aged. In conclusion, ADRs of CCCs admitted to a tertiary children’s hospital have a unique profile. These groups are vulnerable to ADRs and thus they should be monitored closely, especially when they are infants or toddlers, so that severe ADRs can be identified and treated immediately. PMID:28199420

  11. Highly structured water network in crystals of a deoxydinucleoside---drug complex.

    PubMed

    Neidle, S; Berman, H M; Shieh, H S

    1980-11-13

    X-ray diffraction analysis of crystals of the intercalative complex between the deoxyribonucleoside phosphate d(CpG) and the mutagen proflavine shows a highly structured arrangement of water molecules linked together by newtworks of hydrogen bonds to form four edge-linked pentagons per asymmetric unit. These pentagons have a general role in maximizing hydrogen bonding at 3.4-A intervals. The conformation of the deoxyribose sugar ring at the 3' end of one strand can depend on its local aqueous environment.

  12. Structural destabilization of DNA duplexes containing single-base lesions investigated by nanopore measurements.

    PubMed

    Jin, Qian; Fleming, Aaron M; Ding, Yun; Burrows, Cynthia J; White, Henry S

    2013-11-12

    The influence of DNA duplex structural destabilization introduced by a single base-pair modification was investigated by nanopore measurements. A series of 11 modified base pairs were introduced into the context of an otherwise complementary DNA duplex formed by a 17-mer and a 65-mer such that the overhanging ends comprised poly(dT)23 tails, generating a representative set of duplexes that display a range of unzipping mechanistic behaviors and kinetic stabilities. The guanine oxidation products 8-oxo-7,8-dihydroguanine (OG), guanidinohydantoin (Gh), and spiroiminodihydantoin (Sp) were paired with either cytosine (C), adenine (A), or 2,6-diaminopurine (D) to form modified base pairs. The mechanism and kinetic rate constants of duplex dissociation were determined by threading either the 3' or 5' overhangs into an α-hemolysin (α-HL) channel under an electrical field and measuring the distributions of unzipping times at constant force. In order of decreasing thermodynamic stability (as measured by duplex melting points), the rate of duplex dissociation increases, and the mechanism evolves from a first-order reaction to two sequential first-order reactions. These measurements allow us to rank the kinetic stability of lesion-containing duplexes relative to the canonical G:C base pair in which the OG:C, Gh:C, and Sp:C base pairs are, respectively, 3-200 times less stable. The rate constants also depend on whether unzipping was initiated from the 3' versus 5' side of the duplex. The kinetic stability of these duplexes was interpreted in terms of the structural destabilization introduced by the single base-pair modification. Specifically, a large distortion of the duplex backbone introduced by the presence of the highly oxidized guanine products Sp and Gh leads to a rapid two-step unzipping. The number of hydrogen bonds in the modified base pair plays a lesser role in determining the kinetics of duplex dissociation.

  13. Ladderphanes: a new type of duplex polymers.

    PubMed

    Luh, Tien-Yau

    2013-02-19

    A polymeric ladderphane is a step-like structure comprising multiple layers of linkers covalently connected to two or more polymeric backbones. The linkers can be planar aromatic, macrocyclic metal complexes, or three-dimensional organic or organometallic moieties. Structurally, a DNA molecule is a special kind of ladderphane, where the cofacially aligned base-pair pendants are linked through hydrogen bonding. A greater understanding of this class of molecules could help researchers develop new synthetic molecules capable of a similar transfer of chemical information. In this Account, we summarize our studies of the strategy, design, synthesis, characterization, replications, chemical and photophysical properties, and assembly of a range of double-stranded ladderphanes with many fascinating structures. We employed two norbornene moieties fused with N-arylpyrrolidine to connect covalently with a range of relatively rigid linkers. Ring opening metathesis polymerizations (ROMP) of these bis-norbornenes using the first-generation Grubbs ruthenium-benzylidene catalyst produced the corresponding symmetrical double-stranded ladderphanes. The N-arylpyrrolidene moiety in the linker controls the isotactic selectivity and the trans configuration for all double bonds in both single- and double-stranded polynorbornenes. The π-π interactions between these aryl pendants may contribute to the high stereoselectivity in the ROMP of these substrates. We synthesized chiral helical ladderphanes by incorporating asymmetric center(s) in the linkers. Replication protocols and sequential polymerization of a monomer that includes two different polymerizable groups offer methods for producing unsymmetical ladderphanes. These routes furnish template synthesis of daughter polymers with well-controlled chain lengths and polydispersities. The linkers in these ladderphanes are well aligned in the center along the longitudinal axis of the polymer. Fluorescence quenching, excimer formation, or

  14. Diagnostic value of three-dimensional transcranial contrast duplex sonography.

    PubMed

    Delcker, A; Turowski, B

    1997-07-01

    This study evaluated intracranial cerebral arteries using a new data acquisition system for transcranial three-dimensional (3D) ultrasonography with and without an echo contrast agent, with confirmation by cerebral angiography. Ten patients, studied with diagnostic cerebral angiography, were examined without knowledge of the angiographic results. Data acquisition through the transtemporal acoustic window was performed using a magnetic sensor system to track the spatial orientation of the ultrasound probe while scanning the volume of interest. A color transcranial duplex system with a power Doppler mode was used, and 3D data sets were acquired before and after the injection of transpulmonary-stable ultrasound contrast medium. Ipsilateral to the transducer, the anterior cerebral artery (ACA) in 90%, middle cerebral artery (MCA) in 60%, all three or more branches of the MCA in 60%, posterior cerebral artery (PCA) in 60%, and posterior communicating artery (PCoA) in 60% were successfully imaged without the echo contrast agent. With the contrast agent, the ACA, MCA, three or more branches of the MCA, PCA, and PCoA were visible in 100%. The anterior communicating artery was visualized in 40% without contrast enhancement and in 90% with contrast enhancement. Contralateral to the transducer, the ACA (60%), MCA (30%), all three or more branches of the MCA (10%), PCA (20%), and PCoA (20%) were successfully imaged without contrast. Contrast enhancement improved the imaging success rate for the ACA (90%), MCA (80%), three or more branches of the MCA (80%), PCA (100%), and PCoA (100%). A transpulmonary-stable ultrasound contrast agent used in combination with 3D transcranial duplex ultrasonography can significantly improve the success rate for transcranial color duplex imaging of intracranial arteries.

  15. Experience with duplex bearings in narrow angle oscillating applications

    NASA Technical Reports Server (NTRS)

    Phinney, D. D.; Pollard, C. L.; Hinricks, J. T.

    1988-01-01

    Duplex ball bearings are matched pairs on which the abutting faces of the rings have been accurately ground so that when the rings are clamped together, a controlled amount of interference (preload) exists across the balls. These bearings are vulnerable to radial temperature gradients, blocking in oscillation and increased sensitivity to contamination. These conditions decrease the service life of these bearings. It was decided that an accelerated thermal vacuum life test should be conducted. The test apparatus and results are described and the rationale is presented for reducing a multiyear life test on oil lubricated bearings to less than a year.

  16. Sequence Recognition in the Pairing of DNA Duplexes

    NASA Astrophysics Data System (ADS)

    Kornyshev, A. A.; Leikin, S.

    2001-04-01

    Pairing of DNA fragments with homologous sequences occurs in gene shuffling, DNA repair, and other vital processes. While chemical individuality of base pairs is hidden inside the double helix, x ray and NMR revealed sequence-dependent modulation of the structure of DNA backbone. Here we show that the resulting modulation of the DNA surface charge pattern enables duplexes longer than ~50 base pairs to recognize sequence homology electrostatically at a distance of up to several water layers. This may explain the local recognition observed in pairing of homologous chromosomes and the observed length dependence of homologous recombination.

  17. Use of duplex stainless steel castings in control valves

    SciTech Connect

    Gossett, J.L.

    1996-07-01

    Duplex stainless steels have enjoyed rapidly increasing popularity in recent years. For numerous reasons the availability of these alloys in the cast form has lagged behind the availability of the wrought form. Commercial demand for control valves in these alloys has driven development of needed information to move into production. A systematic approach was used to develop specifications, suppliers and weld procedures. Corrosion, stress corrosion cracking (SCC), sulfide stress cracking (SSC) and hardness results are also presented for several alloys including; CD3MN (UNS J92205), CD4MCu (UNS J93370) and CD7MCuN (cast UNS S32550).

  18. From QSAR models of drugs to complex networks: state-of-art review and introduction of new Markov-spectral moments indices.

    PubMed

    Riera-Fernández, Pablo; Martín-Romalde, Raquel; Prado-Prado, Francisco J; Escobar, Manuel; Munteanu, Cristian R; Concu, Riccardo; Duardo-Sanchez, Aliuska; González-Díaz, Humberto

    2012-01-01

    Quantitative Structure-Activity/Property Relationships (QSAR/QSPR) models have been largely used for different kind of problems in Medicinal Chemistry and other Biosciences as well. Nevertheless, the applications of QSAR models have been restricted to the study of small molecules in the past. In this context, many authors use molecular graphs, atoms (nodes) connected by chemical bonds (links) to represent and numerically characterize the molecular structure. On the other hand, Complex Networks are useful in solving problems in drug research and industry, developing mathematical representations of different systems. These systems move in a wide range from relatively simple graph representations of drug molecular structures (molecular graphs used in classic QSAR) to large systems. We can cite for instance, drug-target interaction networks, protein structure networks, protein interaction networks (PINs), or drug treatment in large geographical disease spreading networks. In any case, all complex networks have essentially the same components: nodes (atoms, drugs, proteins, microorganisms and/or parasites, geographical areas, drug policy legislations, etc.) and links (chemical bonds, drug-target interactions, drug-parasite treatment, drug use, etc.). Consequently, we can use the same type of numeric parameters called Topological Indices (TIs) to describe the connectivity patterns in all these kinds of Complex Networks irrespective the nature of the object they represent and use these TIs to develop QSAR/QSPR models beyond the classic frontiers of drugs small-sized molecules. The goal of this work, in first instance, is to offer a common background to all the manuscripts presented in this special issue. In so doing, we make a review of the most used software and databases, common types of QSAR/QSPR models, and complex networks involving drugs or their targets. In addition, we review both classic TIs that have been used to describe the molecular structure of drugs and

  19. Accumulate and Jam: Towards Secure Communication via A Wireless-Powered Full-Duplex Jammer

    NASA Astrophysics Data System (ADS)

    Bi, Ying; Chen, He

    2016-12-01

    This paper develops a new cooperative jamming protocol, termed accumulate-and-jam (AnJ), to improve physical layer security in wireless communications. Specifically, a full-duplex (FD) friendly jammer is deployed to secure the direct communication between source and destination in the presence of a passive eavesdropper. We consider the friendly jammer as an energy-constrained node without embedded power supply but with an energy harvesting unit and rechargeable energy storage; it can thus harvest energy from the radio frequency (RF) signals transmitted by the source, accumulate the energy in its battery, and then use this energy to perform cooperative jamming. In the proposed AnJ protocol, based on the energy status of the jammer and the channel state of source-destination link, the system operates in either dedicated energy harvesting (DEH) or opportunistic energy harvesting (OEH) mode. Thanks to the FD capability, the jammer also harvests energy from the information-bearing signal that it overhears from the source. We study the complex energy accumulation and consumption procedure at the jammer by considering a practical finite-capacity energy storage, of which the long-term stationary distribution is characterized through applying a discrete-state Markov Chain. An alternative energy storage with infinite capacity is also studied to serve as an upper bound. We further derive closed-form expressions for two secrecy metrics, i.e., secrecy outage probability and probability of positive secrecy capacity. In addition, the impact of imperfect channel state information on the performance of our proposed protocol is also investigated. Numerical results validate all theoretical analyses and reveal the merits of the proposed AnJ protocol over its half-duplex counterpart.

  20. Electron interaction with a DNA duplex: dCpdC:dGpdG.

    PubMed

    Gu, Jiande; Wang, Jing; Leszczynski, Jerzy

    2016-05-21

    Electron attachment to double-stranded cytosine-rich DNA, dCpdC:dGpdG, has been studied by density functional theory. This system represents a minimal descriptive unit of a cytosine-rich double-stranded DNA helix. A significant electron affinity for the formation of a cytosine-centered radical anion is revealed to be about 2.2 eV. The excess electron may reside on the nucleobase at the 5' position (dC˙(-)pdC:dGpdG) or at the 3' position (dCpdC˙(-):dGpdG). The inter-strand proton transfer between the radical anion centered cytosine (N3) and the paired guanine (HN1) results in the formation of radical anion center separated complexes dC1H˙pdC:dG2-H(-)pdG and dCpdC2H˙:dGpdG1-H(-). These distonic radical anions are found to be approximately 1 to 4 kcal mol(-1) more stable than the normal radical anions. Intra-strand cytosine π→π transition energies are below the electron detachment energy. Inter-strand π→π transitions of the excess electron from C to G are predicted to be less than 2.79 eV. Electron transfer might also be possible through the inter-strand base-jumping mode. An analysis of absorption visible spectra reveals the absorption bands ranging from 500 nm to 700 nm for the cytosine-rich radical anions of the DNA duplex. Electron attachment to cytidine oligomers might add color to the DNA duplex.

  1. Visualization of drug-nucleic acid interactions at atomic resolution. X. Structure of a N,N-dimethylproflavine: deoxycytidylyl(3'-5')deoxyguanosine crystalline complex

    SciTech Connect

    Sakore, T.D.; Bhandary, K.K.; Sobell, H.M.

    1984-01-01

    N,N-dimethylproflavine forms a crystalline complex with deoxycytidylyl(3'-5')deoxyguanosine (d-CpG), space group P2/sub 1/,2/sub 1/2, with a = 21.37 A, b = 34.05 A, c = 13.63 A. The structure has been solved to atomic resolution and refined by Fourier and least squares methods to a residual of 0.18 of 2032 observed reflections. The structure consists of two N,N-dimethylproflavine molecules, two deoxycytidylyl (3'-5')deoxyguanosine molecules and 16 water molecules, a total of 128 nonhydrogen atoms. As with other structures of this type, N,N-dimethylproflavine molecules intercalate between base-paired d-CpG dimers. In addition, dimethylproflavine molecules stack on either side of the intercalated duplex, being related by a unit cell translation along the c axis. Both sugar-phosphate chains demonstrate the mixed sugar puckering geometry: C3' endo (3'-5') C2' endo. The same intercalative geometry has been seen in two other complexes containing N,N-dimethylproflavine and iodoCpG, described in the accompanying paper. Taken together, these studies indicate a common intercalative geometry present in both RNA- and DNA- model systems. Again, N,N-dimethylproflavine behaves as a simple intercalator, intercalating asymmetrically between guanine-cytosine base-pairs. The free amino- group on the intercalated dimethylproflavine molecule does not hydrogen bond directly to the phosphate oxygen. Other aspects of the structure will be presented. 4 references, 5 figures, 2 tables.

  2. Evaluation of the Gibbs Free Energy Changes and Melting Temperatures of DNA/DNA Duplexes Using Hybridization Enthalpy Calculated by Molecular Dynamics Simulation.

    PubMed

    Lomzov, Alexander A; Vorobjev, Yury N; Pyshnyi, Dmitrii V

    2015-12-10

    A molecular dynamics simulation approach was applied for the prediction of the thermal stability of oligonucleotide duplexes. It was shown that the enthalpy of the DNA/DNA complex formation could be calculated using this approach. We have studied the influence of various simulation parameters on the secondary structure and the hybridization enthalpy value of Dickerson-Drew dodecamer. The optimal simulation parameters for the most reliable prediction of the enthalpy values were determined. The thermodynamic parameters (enthalpy and entropy changes) of a duplex formation were obtained experimentally for 305 oligonucleotides of various lengths and GC-content. The resulting database was studied with molecular dynamics (MD) simulation using the optimized simulation parameters. Gibbs free energy changes and the melting temperatures were evaluated using the experimental correlation between enthalpy and entropy changes of the duplex formation and the enthalpy values calculated by the MD simulation. The average errors in the predictions of enthalpy, the Gibbs free energy change, and the melting temperature of oligonucleotide complexes were 11%, 10%, and 4.4 °C, respectively. We have shown that the molecular dynamics simulation gives a possibility to calculate the thermal stability of native DNA/DNA complexes a priori with an unexpectedly high accuracy.

  3. Molecular Structure of an Anticancer Drug-DNA Complex: Daunomycin Plus d(CpGpTpApCpG)

    NASA Astrophysics Data System (ADS)

    Quigley, Gary J.; Wang, Andrew H.-J.; Ughetto, Giovanni; van der Marel, Gijs; van Boom, Jacques H.; Rich, Alexander

    1980-12-01

    The structure of the crystalline deunomycin-d(CpGpTpApCpG) complex has been solved by x-ray diffraction analysis. The DNA forms a six-base-pair right-handed double helix with two daunomycin molecules intercalated in the d(CpG) sequences. The daunomycin aglycone chromophore is oriented at right angles to the long dimension of the DNA base pairs and the cyclohexene ring rests in the minor groove. Substituents on this ring have hydrogen bonding interactions to the base pairs above and below the intercalation site. These appear to be specific for anthracycline antibiotics. The amino sugar lies in the minor groove of the double helix without bonding to the DNA. The DNA double helix is distorted in a novel manner in accommodating the drug.

  4. Examining the complex regulation and drug-induced plasticity of dopamine release and uptake using voltammetry in brain slices.

    PubMed

    Ferris, Mark J; Calipari, Erin S; Yorgason, Jordan T; Jones, Sara R

    2013-05-15

    Fast scan cyclic voltammetry in brain slices (slice voltammetry) has been used over the last several decades to increase substantially our understanding of the complex local regulation of dopamine release and uptake in the striatum. This technique is routinely used for the study of changes that occur in the dopamine system associated with various disease states and pharmacological treatments, and to study mechanisms of local circuitry regulation of dopamine terminal function. In the context of this Review, we compare the relative advantages of voltammetry using striatal slice preparations versus in vivo preparations, and highlight recent advances in our understanding of dopamine release and uptake in the striatum specifically from studies that use slice voltammetry in drug-naïve animals and animals with a history of psychostimulant self-administration.

  5. Actions of cholinergic drugs in the nematode Ascaris suum. Complex pharmacology of muscle and motorneurons

    PubMed Central

    1993-01-01

    The cholinergic agonists acetylcholine (ACh), nicotine, and pilocarpine produced depolarizations and contractions of muscle of the nematode Ascaris suum. Dose-dependent depolarization and contraction by ACh were suppressed by about two orders of magnitude by 100 microM d- tubocurarine (dTC), a nicotinic antagonist, but only about fivefold by 100 microM N-methyl-scopolamine (NMS), a muscarinic antagonist. NMS itself depolarized both normal and synaptically isolated muscle cells. The muscle depolarizing action of pilocarpine was not consistently antagonized by either NMS or dTC. ACh receptors were detected on motorneuron classes DE1, DE2, DI, and VI as ACh-induced reductions in input resistance. These input resistance changes were reversed by washing in drug-free saline or by application of dTC. NMS applied alone lowered input resistance in DE1, but not in DE2, DI, or VI motorneurons. In contrast to the effect of ACh, the action of NMS in DE1 was not reversed by dTC, suggesting that NMS-sensitive sites may not respond to ACh. Excitatory synaptic responses in muscle evoked by depolarizing current injections into DE1 and DE2 motorneurons were antagonized by dTC; however, NMS antagonized the synaptic output of only the DE1 and DE3 classes of motorneurons, an effect that was more likely to have been produced by motorneuron conduction failure than by pharmacological blockade of receptor. The concentration of NMS required to produce these changes in muscle polarization and contraction, ACh antagonism, input resistance reduction, and synaptic antagonism was 100 microM, or more than five orders of magnitude higher than the binding affinity for [3H]NMS in larval Ascaris homogenates and adult Caenorhabditis elegans (Segerberg, M. A. 1989. Ph.D. thesis. University of Wisconsin-Madison, Madison, WI). These results describe a nicotinic- like pharmacology, but muscle and motorneurons also have unusual responses to muscarinic agents. PMID:8455017

  6. Incorporating Concomitant Medications into Genome-Wide Analyses for the Study of Complex Disease and Drug Response

    PubMed Central

    Graham, Hillary T.; Rotroff, Daniel M.; Marvel, Skylar W.; Buse, John B.; Havener, Tammy M.; Wilson, Alyson G.; Wagner, Michael J.; Motsinger-Reif, Alison A.; Friedewald, W.T.

    2016-01-01

    Given the high costs of conducting a drug-response trial, researchers are now aiming to use retrospective analyses to conduct genome-wide association studies (GWAS) to identify underlying genetic contributions to drug-response variation. To prevent confounding results from a GWAS to investigate drug response, it is necessary to account for concomitant medications, defined as any medication taken concurrently with the primary medication being investigated. We use data from the Action to Control Cardiovascular Disease (ACCORD) trial in order to implement a novel scoring procedure for incorporating concomitant medication information into a linear regression model in preparation for GWAS. In order to accomplish this, two primary medications were selected: thiazolidinediones and metformin because of the wide-spread use of these medications and large sample sizes available within the ACCORD trial. A third medication, fenofibrate, along with a known confounding medication, statin, were chosen as a proof-of-principle for the scoring procedure. Previous studies have identified SNP rs7412 as being associated with statin response. Here we hypothesize that including the score for statin as a covariate in the GWAS model will correct for confounding of statin and yield a change in association at rs7412. The response of the confounded signal was successfully diminished from p = 3.19 × 10−7 to p = 1.76 × 10−5, by accounting for statin using the scoring procedure presented here. This approach provides the ability for researchers to account for concomitant medications in complex trial designs where monotherapy treatment regimens are not available. PMID:27775101

  7. Incorporating Concomitant Medications into Genome-Wide Analyses for the Study of Complex Disease and Drug Response.

    PubMed

    Graham, Hillary T; Rotroff, Daniel M; Marvel, Skylar W; Buse, John B; Havener, Tammy M; Wilson, Alyson G; Wagner, Michael J; Motsinger-Reif, Alison A

    2016-01-01

    Given the high costs of conducting a drug-response trial, researchers are now aiming to use retrospective analyses to conduct genome-wide association studies (GWAS) to identify underlying genetic contributions to drug-response variation. To prevent confounding results from a GWAS to investigate drug response, it is necessary to account for concomitant medications, defined as any medication taken concurrently with the primary medication being investigated. We use data from the Action to Control Cardiovascular Disease (ACCORD) trial in order to implement a novel scoring procedure for incorporating concomitant medication information into a linear regression model in preparation for GWAS. In order to accomplish this, two primary medications were selected: thiazolidinediones and metformin because of the wide-spread use of these medications and large sample sizes available within the ACCORD trial. A third medication, fenofibrate, along with a known confounding medication, statin, were chosen as a proof-of-principle for the scoring procedure. Previous studies have identified SNP rs7412 as being associated with statin response. Here we hypothesize that including the score for statin as a covariate in the GWAS model will correct for confounding of statin and yield a change in association at rs7412. The response of the confounded signal was successfully diminished from p = 3.19 × 10(-7) to p = 1.76 × 10(-5), by accounting for statin using the scoring procedure presented here. This approach provides the ability for researchers to account for concomitant medications in complex trial designs where monotherapy treatment regimens are not available.

  8. Comparison of duplex ultrasonography and venography in the diagnosis of deep venous thrombosis.

    PubMed

    Mitchell, D C; Grasty, M S; Stebbings, W S; Nockler, I B; Lewars, M D; Levison, R A; Wood, R F

    1991-05-01

    Sixty-five patients with suspected deep venous thrombosis (DVT) in 68 limbs were entered consecutively into a study to compare venography with duplex ultrasonography scanning. Both tests were performed on 64 limbs, venography being contraindicated in four. Overall, duplex scanning correctly identified 86 per cent of DVTs diagnosed on venography and correctly excluded 80 per cent with negative venograms. Nearly all errors arose in the diagnosis of calf DVT. In the femoral vein duplex scanning had a specificity of 100 per cent and a sensitivity of 95 per cent. In addition, duplex scanning provided data on the limb not undergoing venography. Of 55 limbs that underwent bilateral duplex scanning, five had thrombus in the femoropopliteal segment and a negative contralateral venogram. In addition, three Baker's cysts were diagnosed. Duplex scanning can be used in patients in whom venography is contraindicated and may also provide information about the contralateral limb. We regard femoropopliteal duplex scanning as sufficiently accurate that treatment can be initiated on the basis of the scan. Duplex scanning should replace venography as the standard method of diagnosing femoropopliteal DVT; radiographic studies should now be required only when the scan result is in doubt.

  9. Structures of Cytochrome P450 2B4 Complexed with the Antiplatelet Drugs Ticlopidine and Clopidogrel†‡

    PubMed Central

    Gay, Sean C.; Roberts, Arthur G.; Maekawa, Keiko; Talakad, Jyothi C.; Hong, Wen-Xu; Zhang, Qinghai; Stout, C. David; Halpert, James R.

    2010-01-01

    Prior X-ray crystal structures of rabbit cytochrome P450 2B4 (2B4) in complex with various imidazoles have demonstrated markedly different enzyme conformations depending on the size of the inhibitor occupying the active site. In this study, structures of 2B4 were solved with the antiplatelet drugs clopidogrel and ticlopidine, which were expected to have greater freedom of movement in the binding pocket. Ticlopidine could be modeled into the electron density maps in two distinct orientations, both of which are consistent with metabolic data gathered with other mammalian P450 enzymes. Results of ligand docking and heme-induced NMR relaxation of drug protons showed that ticlopidine was preferentially oriented with the chlorophenyl group closest to the heme. Because of its stereocenter, clopidogrel was easier to fit in the electron density and exhibited a single orientation, which points the chlorophenyl ring toward the heme. The Cα traces of both complexes aligned very well to each other and revealed a compact, closed structure that resembles the conformation observed in two previously solved 2B4 structures with the small molecule inhibitors 4-(4-chlorophenyl)imidazole and 1-(4-chlorophenyl)imidazole. The 2B4 active site is able to accommodate small ligands by moving only a small number of side chains, suggesting that ligand reorientation is energetically favored over protein conformational changes for binding of these similar sized molecules. Adjusting both protein conformation and ligand orientation in the active site gives 2B4 the flexibility to bind to the widest range of molecules, while also being energetically favorable. PMID:20815363

  10. Structure of Prolyl-tRNA Synthetase-Halofuginone Complex Provides Basis for Development of Drugs against Malaria and Toxoplasmosis.

    PubMed

    Jain, Vitul; Yogavel, Manickam; Oshima, Yoshiteru; Kikuchi, Haruhisa; Touquet, Bastien; Hakimi, Mohamed-Ali; Sharma, Amit

    2015-05-05

    The Chinese herb Dichroa febrifuga has traditionally treated malaria-associated fever. Its active component febrifugine (FF) and derivatives such as halofuginone (HF) are potent anti-malarials. Here, we show that FF-based derivatives arrest parasite growth by direct interaction with and inhibition of the protein translation enzyme prolyl-tRNA synthetase (PRS). Dual administration of inhibitors that target different tRNA synthetases suggests high utility of these drug targets. We reveal the ternary complex structure of PRS-HF and adenosine 5'-(β,γ-imido)triphosphate where the latter facilitates HF integration into the PRS active site. Structural analyses also highlight spaces within the PRS architecture for HF derivatization of its quinazolinone, but not piperidine, moiety. We also show a remarkable ability of HF to kill the related human parasite Toxoplasma gondii, suggesting wider HF efficacy against parasitic PRSs. Hence, our cell-, enzyme-, and structure-based data on FF-based inhibitors strengthen the case for their inclusion in anti-malarial and anti-toxoplasmosis drug development efforts.

  11. Atomistic Simulations of Complex DNA DSBs and the Interactions with Ku70/80 Heterodimer

    NASA Technical Reports Server (NTRS)

    Hu, Shaowen; Cucinotta, Francis A.

    2011-01-01

    Compared to DNA with simple DSBs, the complex lesions can enhance the hydrogen bonds opening rate at the DNA terminus, and increase the mobility of the whole duplex. Binding of Ku drastically reduces the structural disruption and flexibility caused by the complex lesions. In all complex DSBs systems, the binding of DSB terminus with Ku70 is softened while the binding of the middle duplex with Ku80 is tightened. Binding of Ku promotes the rigidity of DNA duplexes, due to the clamp structure of the inner surface of the rings of Ku70/80.

  12. RNA Editing TUTase 1: structural foundation of substrate recognition, complex interactions and drug targeting

    PubMed Central

    Rajappa-Titu, Lional; Suematsu, Takuma; Munoz-Tello, Paola; Long, Marius; Demir, Özlem; Cheng, Kevin J.; Stagno, Jason R.; Luecke, Hartmut; Amaro, Rommie E.; Aphasizheva, Inna; Aphasizhev, Ruslan; Thore, Stéphane

    2016-01-01

    Terminal uridyltransferases (TUTases) execute 3′ RNA uridylation across protists, fungi, metazoan and plant species. Uridylation plays a particularly prominent role in RNA processing pathways of kinetoplastid protists typified by the causative agent of African sleeping sickness, Trypanosoma brucei. In mitochondria of this pathogen, most mRNAs are internally modified by U-insertion/deletion editing while guide RNAs and rRNAs are U-tailed. The founding member of TUTase family, RNA editing TUTase 1 (RET1), functions as a subunit of the 3′ processome in uridylation of gRNA precursors and mature guide RNAs. Along with KPAP1 poly(A) polymerase, RET1 also participates in mRNA translational activation. RET1 is divergent from human TUTases and is essential for parasite viability in the mammalian host and the insect vector. Given its robust in vitro activity, RET1 represents an attractive target for trypanocide development. Here, we report high-resolution crystal structures of the RET1 catalytic core alone and in complex with UTP analogs. These structures reveal a tight docking of the conserved nucleotidyl transferase bi-domain module with a RET1-specific C2H2 zinc finger and RNA recognition (RRM) domains. Furthermore, we define RET1 region required for incorporation into the 3′ processome, determinants for RNA binding, subunit oligomerization and processive UTP incorporation, and predict druggable pockets. PMID:27744351

  13. The anaphase promoting complex: a critical target for viral proteins and anti-cancer drugs.

    PubMed

    Heilman, Destin W; Green, Michael R; Teodoro, Jose G

    2005-04-01

    The study of animal viruses has provided extraordinary insights into cell cycle dynamics and tumor biology. The significance of the p53 and Rb tumor suppressor proteins, for example, was discovered due to their interactions with viral oncogenes. In the past several years, investigations with four viral proteins, human immunodeficiency virus type 1 (HIV-1) vpr, adenovirus E4orf4, chicken anemia virus (CAV) apoptin and human T lymphotropic virus type I (HTLV-I) Tax, have indicated that there are also critical viral targets involved in G2/M control. In particular, recent studies with E4orf4 and apoptin have shown that they induce G2/M arrest by targeting and inhibiting the anaphase-promoting complex/cyclosome (APC/C). Notably, these two viral proteins induce apoptosis selectively in transformed cells in a p53-independent manner; thus pathways affected by these proteins are of significant therapeutic interest. Further investigation of the underlying mechanism of G2/M arrest and subsequent apoptosis induced by viral APC/C inhibitors may shed light on the mechanisms of current cancer therapies and provide the foundation for developing novel therapeutic targets.

  14. Chitosan-Carboxymethyl Tamarind Kernel Powder Interpolymer Complexation: Investigations for Colon Drug Delivery

    PubMed Central

    Kaur, Gurpreet; Jain, Subheet; Tiwary, Ashok K.

    2010-01-01

    The present study was aimed at evaluating the possible use of inter polymer complexed (IPC) films of chitosan (CH) and carboxymethyl tamarind kernel powder (CMTKP) for colon release of budesonide. Viscosity analysis of the supernatant liquid obtained after reacting CH and CMTKP in different proportions revealed 40:60 to be the optimum stoichiometric ratio. The FTIR spectra of IPC films formed from 50:50 or 40:60 ratio of CH:CMTKP did not reveal any reduction in the peaks at 1560cm−1 and 1407cm−1 after exposure to pH 1.2, suggesting resistance of the interaction between −COO− groups of CMTKP and −NH3+ groups of CH to gastric pH. Tablets containing Avicel pH 102 as diluent and coated to a weight gain of 10%, w/w with aqueous solutions of 40:60 or 50:50 ratio of CH:CMTKP did not release budesonide in pH 1.2 buffer. Histopathology of the rat colon after oral administration of these IPC film coated tablets revealed significantly greater (p<0.05) reduction in TNBS-induced ulcerative colitis as compared to that after administration of uncoated tablets. The Cmax of budesonide achieved after oral administration of these IPC film coated tablets was comparable to that observed after administration of uncoated tablets. The results strongly indicate versatility of CH-CMTKP IPC films to deliver budesonide in the colon. PMID:21179370

  15. Drug-protein interactions assessed by fluorescence measurements in the real complexes and in model dyads

    NASA Astrophysics Data System (ADS)

    Vayá, Ignacio; Pérez-Ruiz, Raúl; Lhiaubet-Vallet, Virginie; Jiménez, M. Consuelo; Miranda, Miguel A.

    2010-02-01

    In the present work, a systematic fluorescence study on supramolecular systems using two serum albumins (HSA or BSA) as hosts and the nonsteroidal antiinflammatory drugs carprofen (CPF) or naproxen (NPX) as guests has been undertaken. In parallel, model dyads containing Tyr or Trp covalently linked to CPF or NPX have also been investigated. In HSA/(S)-CPF and BSA/(S)-CPF ( λexc = 266 nm), at 1:1 M ratio, an important degree (more than 40%) of singlet-singlet energy transfer (SSET) was observed to take place. The distance ( r) calculated for energy transfer from the SAs to (S)-CPF through a FRET mechanism was found to be ca. 21 Å. In the case of HSA/(S)-NPX and BSA/(S)-NPX, energy transfer occurred to a lower extent (ca. 7%), and r was determined as ca. 24 Å. In order to investigate the possible excited state interactions between bound ligands and the relevant amino acids present in the protein binding sites, four pairs of model dyads were designed and synthesised, namely ( S, S)-TyrCPF, ( S, R)-TyrCPF, ( S, S)-TrpCPF, ( S, R)-TrpCPF, ( S, S)-TyrNPX, ( S, R)-TyrNPX, ( S, S)-TrpNPX and ( S, R)-TrpNPX. A complete SSET was observed from Tyr or Trp to CPF, since no contribution from the amino acids was present in the emission of the dyads. Likewise, a very efficient Tyr or Trp to NPX energy transfer was observed. Remarkably, in ( S, S)-TrpNPX and ( S, R)-TrpNPX a configuration-dependent reduction in the emission intensity was observed, revealing a strong and stereoselective intramolecular quenching. This effect can be attributed to exciplex formation and is dynamic in nature, as the fluorescence lifetimes were much shorter in ( S, R)- and ( S, S)-TrpNPX (1.5 and 3.1 ns, respectively) than in (S)-NPX (11 ns).

  16. Synthesis of native-like crosslinked duplex RNA and study of its properties.

    PubMed

    Onizuka, Kazumitsu; Hazemi, Madoka E; Thomas, Justin M; Monteleone, Leanna R; Yamada, Ken; Imoto, Shuhei; Beal, Peter A; Nagatsugi, Fumi

    2017-04-01

    A variety of enzymes have been found to interact with double-stranded RNA (dsRNA) in order to carry out its functions. We have endeavored to prepare the covalently crosslinked native-like duplex RNA, which could be useful for biochemical studies and RNA nanotechnology. In this study, the interstrand covalently linked duplex RNA was formed by a crosslinking reaction between vinylpurine (VP) and the target cytosine or uracil in RNA. We measured melting temperatures and CD spectra to identify the properties of the VP crosslinked duplex RNA. The crosslinking formation increased the thermodynamic stability without disturbing the natural conformation of dsRNA. In addition, a competitive binding experiment with the duplex RNA binding enzyme, ADAR2, showed the crosslinked dsRNA bound the protein with nearly the same binding affinity as the natural dsRNA, confirming that it has finely preserved the natural traits of duplex RNA.

  17. Hole Transport in A-form DNA/RNA Hybrid Duplexes

    PubMed Central

    Wong, Jiun Ru; Shao, Fangwei

    2017-01-01

    DNA/RNA hybrid duplexes are prevalent in many cellular functions and are an attractive target form for electrochemical biosensing and electric nanodevice. However the electronic conductivities of DNA/RNA hybrid duplex remain relatively unexplored and limited further technological applications. Here cyclopropyl-modified deoxyribose- and ribose-adenosines were developed to explore hole transport (HT) in both DNA duplex and DNA/RNA hybrids by probing the transient hole occupancies on adenine tracts. HT yields through both B-form and A-form double helixes displayed similar shallow distance dependence, although the HT yields of DNA/RNA hybrid duplexes were lower than those of DNA duplexes. The lack of oscillatory periods and direction dependence in HT through both helixes implied efficient hole propagation can be achieved via the hole delocalization and coherent HT over adenine tracts, regardless of the structural variations. PMID:28084308

  18. Hole Transport in A-form DNA/RNA Hybrid Duplexes

    NASA Astrophysics Data System (ADS)

    Wong, Jiun Ru; Shao, Fangwei

    2017-01-01

    DNA/RNA hybrid duplexes are prevalent in many cellular functions and are an attractive target form for electrochemical biosensing and electric nanodevice. However the electronic conductivities of DNA/RNA hybrid duplex remain relatively unexplored and limited further technological applications. Here cyclopropyl-modified deoxyribose- and ribose-adenosines were developed to explore hole transport (HT) in both DNA duplex and DNA/RNA hybrids by probing the transient hole occupancies on adenine tracts. HT yields through both B-form and A-form double helixes displayed similar shallow distance dependence, although the HT yields of DNA/RNA hybrid duplexes were lower than those of DNA duplexes. The lack of oscillatory periods and direction dependence in HT through both helixes implied efficient hole propagation can be achieved via the hole delocalization and coherent HT over adenine tracts, regardless of the structural variations.

  19. Unusual Presentation of Duplex Kidneys: Ureteropelvic Junction Obstruction

    PubMed Central

    Başdaş, Cemile; Özaydın, Seyithan; Karaaslan, Birgül; Alim, Elmas Reyhan; Güvenç, Ünal; Sander, Serdar

    2016-01-01

    Aim. Ureteropelvic junction obstruction (UPJO) is rarely associated with a duplex collecting system. We review this unusual anomaly in terms of presentation, diagnostic evaluation, and surgical management. Method. We retrospectively reviewed the medical records of patients diagnosed with a duplex system with UPJO. Result. Sixteen patients (6 girls, 10 boys) with 18 moieties were treated surgically and four patients were treated conservatively. The median age at surgery was two years (range, 2 months to 7 years). The lower pole and upper moiety were affected in 12 and two kidneys, respectively, and both were affected in two patients. The anomaly was right-sided in 12 moieties and left-sided in six. The duplication was incomplete in seven patients and complete in nine. The mean renal pelvis diameter at the time of surgery was 25.6 (range 11–48 mm) mm by USG. The mean renal function of the involved moiety was 28.3% before surgery. Management included pyelopyelostomy or ureteropyelostomy in six moieties, dismembered pyeloplasty in eight moieties, heminephrectomy in four cases, and simultaneous upper heminephrectomy and lower pole ureteropyelostomy in one patient. Conclusion. There is no standard approach for these patients and treatment should be individualized according to physical presentation, detailed anatomy, and severity of obstruction. PMID:27829833

  20. Sex determination in 6 bovid species by duplex PCR.

    PubMed

    Prashant; Gour, Digpal S; Dubey, Prem P; Jain, Anubhav; Gupta, Subhash C; Joshi, Balwinder K; Kumar, Dinesh

    2008-01-01

    Sex determination in domestic animals is of potential value to livestock breeding programs. The aim of this study was to develop a simple and accurate PCR-based sex determination protocol, which can be applicable to 6 major domesticated species of the family Bovidae, viz. Bos frontalis, B. grunniens, B. indicus, Bubalus bubalis, Capra hircus, and Ovis aries. In silico analysis was done to identify conserved DNA sequence in the HMG box region of the sex-determining region of the Y-chromosome (SRY gene) across the bovids. Duplex PCR assay, including the SRY gene and the GAPDH housekeeping gene, was optimized by using genomic DNA extracted from blood samples of known sex. It was possible to identify the sex of animals by amplifying both gender-specific (SRY) and autosomal (GAPDH) genes simultaneously in the duplex reaction, with the male yielding two bands and the female one band. The protocol was subjected to a blind test that showed a 100 percent specificity and accuracy, thus it can be used in sex determination in livestock breeding programs.

  1. Moessbauer measurements of microstructural change in aged duplex stainless steel

    SciTech Connect

    Kirihigashi, A.; Sakamoto, N.; Yamaoka, T.; Nasu, S.

    1995-08-01

    A duplex stainless steel (ASME SA351 CF8M) has usually been manufactured by a continuous casting technique. It consists of a paramagnetic austenite phase and a ferromagnetic ferrite phase. It has been known that the ferrite phase decomposition occurs in this steel after aging between 300 and 450 C. As a result of phase decomposition, a Fe-rich phase and a Cr-rich phase are produced in the ferrite phase. It is difficult to detect the phase decomposition even by not only optical microscopy but also transmission electron microscopy, since the decomposed structure is very fine. However, Moessbauer measurements that can detect the magnetic hyperfine field of magnetic substance may detect the microstructural change. An averaged magnetic hyperfine field increases in the ferrite phase, due to the production of the Fe-rich phase which has high magnetic hyperfine field. Therefore, the authors investigated the phase decomposition of the duplex stainless steel caused by aging, utilization Moessbauer spectroscopy which has capability of detecting this structural change in the atomic level quantitatively. The authors also investigated the potential of backscattering Moessbauer method for NDE technique.

  2. Thermal Aging Phenomena in Cast Duplex Stainless Steels

    SciTech Connect

    Byun, T. S.; Yang, Y.; Overman, N. R.; Busby, J. T.

    2015-11-12

    We used cast stainless steels (CASSs)for the large components of light water reactor (LWR) power plants such as primary coolant piping and pump casing. The thermal embrittlement of CASS components is one of the most serious concerns related to the extended-term operation of nuclear power plants. Many past researches have concluded that the formation of Cr-rich alpha-phase by Spinodal decomposition of delta-ferrite phase is the primary mechanism for the thermal embrittlement. Cracking mechanism in the thermally-embrittled duplex stainless steels consists of the formation of cleavage at ferrite and its propagation via separation of ferrite-austenite interphase. This article intends to provide an introductory overview on the thermal aging phenomena in LWR-relevant conditions. Firstly, the thermal aging effect on toughness is discussed in terms of the cause of embrittlement and influential parameters. Moreover, an approximate analysis of thermal reaction using Arrhenius equation was carried out to scope the aging temperatures for the accelerated aging experiments to simulate the 60 and 80 years of services. Further, an equilibrium precipitation calculation was performed for model CASS alloys using the CALPHAD program, and the results are used to describe the precipitation behaviors in duplex stainless steels. Our results are also to be used to guide an on-going research aiming to provide knowledge-based conclusive prediction for the integrity of the CASS components of LWR power plants during the service life extended up to and beyond 60 years.

  3. Thermal Aging Phenomena in Cast Duplex Stainless Steels

    SciTech Connect

    Byun, T. S.; Yang, Y.; Overman, N. R.; Busby, J. T.

    2016-02-28

    Cast stainless steels (CASSs) have been extensively used for the large components of light water reactor (LWR) power plants such as primary coolant piping and pump casing. The thermal embrittlement of CASS components is one of the most serious concerns related to the extended-term operation of nuclear power plants. Many past researches have concluded that the formation of Cr–rich α'-phase by Spinodal decomposition of δ-ferrite phase is the primary mechanism for the thermal embrittlement. Cracking mechanism in the thermally-embrittled duplex stainless steels consists of the formation of cleavage at ferrite and its propagation via separation of ferrite-austenite interphase. This article intends to provide an introductory overview on the thermal aging phenomena in LWR relevant conditions. Firstly, the thermal aging effect on toughness is discussed in terms of the cause of embrittlement and influential parameters. An approximate analysis of thermal reaction using Arrhenius equation was carried out to scope the aging temperatures for the accelerated aging experiments to simulate the 60 and 80 years of services. Further, equilibrium precipitation calculation was performed for model CASS alloys using the CALPHAD program and the results are used to describe the precipitation behaviors in duplex stainless steels. These results are also to be used to guide an on-going research aiming to provide knowledge-based conclusive prediction for the integrity of the CASS components of LWR power plants during the service life extended up to and beyond 60 years.

  4. Thermal Aging Phenomena in Cast Duplex Stainless Steels

    NASA Astrophysics Data System (ADS)

    Byun, T. S.; Yang, Y.; Overman, N. R.; Busby, J. T.

    2016-02-01

    Cast stainless steels (CASSs) have been extensively used for the large components of light water reactor (LWR) power plants such as primary coolant piping and pump casing. The thermal embrittlement of CASS components is one of the most serious concerns related to the extended-term operation of nuclear power plants. Many past researches have concluded that the formation of Cr-rich α'-phase by Spinodal decomposition of δ-ferrite phase is the primary mechanism for the thermal embrittlement. Cracking mechanism in the thermally-embrittled duplex stainless steels consists of the formation of cleavage at ferrite and its propagation via separation of ferrite-austenite interphase. This article intends to provide an introductory overview on the thermal aging phenomena in LWR-relevant conditions. Firstly, the thermal aging effect on toughness is discussed in terms of the cause of embrittlement and influential parameters. An approximate analysis of thermal reaction using Arrhenius equation was carried out to scope the aging temperatures for the accelerated aging experiments to simulate the 60 and 80 years of services. Further, an equilibrium precipitation calculation was performed for model CASS alloys using the CALPHAD program, and the results are used to describe the precipitation behaviors in duplex stainless steels. These results are also to be used to guide an on-going research aiming to provide knowledge-based conclusive prediction for the integrity of the CASS components of LWR power plants during the service life extended up to and beyond 60 years.

  5. Water-evaporation reduction by duplex films: application to the human tear film.

    PubMed

    Cerretani, Colin F; Ho, Nghia H; Radke, C J

    2013-09-01

    Water-evaporation reduction by duplex-oil films is especially important to understand the physiology of the human tear film. Secreted lipids, called meibum, form a duplex film that coats the aqueous tear film and purportedly reduces tear evaporation. Lipid-layer deficiency is correlated with the occurrence of dry-eye disease; however, in-vitro experiments fail to show water-evaporation reduction by tear-lipid duplex films. We review the available literature on water-evaporation reduction by duplex-oil films and outline the theoretical underpinnings of spreading and evaporation kinetics that govern behavior of these systems. A dissolution-diffusion model unifies the data reported in the literature and identifies dewetting of duplex films into lenses as a key challenge to obtaining significant evaporation reduction. We develop an improved apparatus for measuring evaporation reduction by duplex-oil films including simultaneous assessment of film coverage, stability, and temperature, all under controlled external mass transfer. New data reported in this study fit into the larger body of work conducted on water-evaporation reduction by duplex-oil films. Duplex-oil films of oxidized mineral oil/mucin (MOx/BSM), human meibum (HM), and bovine meibum (BM) reduce water evaporation by a dissolution-diffusion mechanism, as confirmed by agreement between measurement and theory. The water permeability of oxidized-mineral-oil duplex films agrees with those reported in the literature, after correction for the presence of mucin. We find that duplex-oil films of bovine and human meibum at physiologic temperature reduce water evaporation only 6-8% for a 100-nm film thickness pertinent to the human tear film. Comparison to in-vivo human tear-evaporation measurements is inconclusive because evaporation from a clean-water surface is not measured and because the mass-transfer resistance is not characterized.

  6. Mass Drug Administration and beyond: how can we strengthen health systems to deliver complex interventions to eliminate neglected tropical diseases?

    PubMed Central

    2015-01-01

    Achieving the 2020 goals for Neglected Tropical Diseases (NTDs) requires scale-up of Mass Drug Administration (MDA) which will require long-term commitment of national and global financing partners, strengthening national capacity and, at the community level, systems to monitor and evaluate activities and impact. For some settings and diseases, MDA is not appropriate and alternative interventions are required. Operational research is necessary to identify how existing MDA networks can deliver this more complex range of interventions equitably. The final stages of the different global programmes to eliminate NTDs require eliminating foci of transmission which are likely to persist in complex and remote rural settings. Operational research is required to identify how current tools and practices might be adapted to locate and eliminate these hard-to-reach foci. Chronic disabilities caused by NTDs will persist after transmission of pathogens ceases. Development and delivery of sustainable services to reduce the NTD-related disability is an urgent public health priority. LSTM and its partners are world leaders in developing and delivering interventions to control vector-borne NTDs and malaria, particularly in hard-to-reach settings in Africa. Our experience, partnerships and research capacity allows us to serve as a hub for developing, supporting, monitoring and evaluating global programmes to eliminate NTDs.

  7. A comparison of complex sleep behaviors with two short-acting Z-hypnosedative drugs in nonpsychotic patients

    PubMed Central

    Chen, Li-Fen; Lin, Ching-En; Chou, Yu-Ching; Mao, Wei-Chung; Chen, Yi-Chyan; Tzeng, Nian-Sheng

    2013-01-01

    Objective Complex sleep behaviors (CSBs) are classified as “parasomnias” in the International Classifcation of Sleep Disorders, Second Edition (ICSD-2). To realize the potential danger after taking two short-acting Z-hypnosedative drugs, we estimated the incidence of CSBs in nonpsychotic patients in Taiwan. Methods Subjects (N = 1,220) using zolpidem or zopiclone were enrolled from the psychiatric outpatient clinics of a medical center in Taiwan over a 16-month period in 2006–2007. Subjects with zolpidem (N = 1,132) and subjects with zopiclone (N = 88) were analyzed. All subjects completed a questionnaire that included demographic data and complex sleep behaviors after taking hypnotics. Results Among zolpidem and zopiclone users, 3.28% of patients reported incidents of somnambulism or amnesic sleep-related behavior problems. The incidence of CSBs with zolpidem and zopiclone were 3.27%, and 3.41%, respectively, which was signifcantly lower than other studies in Taiwan. Conclusion These results serve as a reminder for clinicians to make inquiries regarding any unusual performance of parasomnic activities when prescribing zolpidem or zopiclone. PMID:23976857

  8. Identifying Inhibitors of the Hsp90-Aha1 Protein Complex, a Potential Target to Drug Cystic Fibrosis, by Alpha Technology.

    PubMed

    Ihrig, Verena; Obermann, Wolfgang M J

    2017-01-01

    Deletion of a single phenylalanine residue at position 508 of the protein CFTR (cystic fibrosis transmembrane conductance regulator), a chloride channel in lung epithelium, is the most common cause for cystic fibrosis. As a consequence, folding of the CFTRΔF508 protein and delivery to the cell surface are compromised, resulting in degradation of the polypeptide. Accordingly, decreased surface presence of CFTRΔF508 causes impaired chloride ion conductivity and is associated with mucus accumulation, a hallmark of cystic fibrosis. Molecular chaperones such as Hsp90 and its co-chaperone partner Aha1 are thought to play a key role in targeting folding-deficient CFTRΔF508 for degradation. Thus, pharmacologic manipulation to inhibit Hsp90-Aha1 chaperone complex formation appears beneficial to inhibit proteolysis of CFTRΔF508 and rescue its residual chloride channel activity. Therefore, we have screened a collection of 14,400 druglike chemical compounds for inhibitors of the Hsp90-Aha1 complex by amplified luminescence proximity homogeneous assay (Alpha). We identified two druglike molecules that showed promising results when we tested their ability to restore chloride channel activity in culture cells expressing the mutant CFTRΔF508 protein. The two molecules were most effective in combination with the corrector VX-809 and may therefore serve as a lead compound that can be further developed into a drug to treat cystic fibrosis patients.

  9. Bone-tissue engineering: complex tunable structural and biological responses to injury, drug delivery, and cell-based therapies.

    PubMed

    Alghazali, Karrer M; Nima, Zeid A; Hamzah, Rabab N; Dhar, Madhu S; Anderson, David E; Biris, Alexandru S

    2015-01-01

    Bone loss and failure of proper bone healing continues to be a significant medical condition in need of solutions that can be implemented successfully both in human and veterinary medicine. This is particularly true when large segmental defects are present, the bone has failed to return to normal form or function, or the healing process is extremely prolonged. Given the inherent complexity of bone tissue - its unique structural, mechanical, and compositional properties, as well as its ability to support various cells - it is difficult to find ideal candidate materials that could be used as the foundation for tissue regeneration from technological platforms. Recently, important developments have been made in the implementation of complex structures built both at the macro- and the nano-level that have been shown to positively impact bone formation and to have the ability to deliver active biological molecules (drugs, growth factors, proteins, cells) for controlled tissue regeneration and the prevention of infection. These materials are diverse, ranging from polymers to ceramics and various composites. This review presents developments in this area with a focus on the role of scaffold structure and chemistry on the biologic processes that influence bone physiology and regeneration.

  10. Stress corrosion cracking of duplex stainless steels in caustic solutions

    NASA Astrophysics Data System (ADS)

    Bhattacharya, Ananya

    Duplex stainless steels (DSS) with roughly equal amount of austenite and ferrite phases are being used in industries such as petrochemical, nuclear, pulp and paper mills, de-salination plants, marine environments, and others. However, many DSS grades have been reported to undergo corrosion and stress corrosion cracking in some aggressive environments such as chlorides and sulfide-containing caustic solutions. Although stress corrosion cracking of duplex stainless steels in chloride solution has been investigated and well documented in the literature but the SCC mechanisms for DSS in caustic solutions were not known. Microstructural changes during fabrication processes affect the overall SCC susceptibility of these steels in caustic solutions. Other environmental factors, like pH of the solution, temperature, and resulting electrochemical potential also influence the SCC susceptibility of duplex stainless steels. In this study, the role of material and environmental parameters on corrosion and stress corrosion cracking of duplex stainless steels in caustic solutions were investigated. Changes in the DSS microstructure by different annealing and aging treatments were characterized in terms of changes in the ratio of austenite and ferrite phases, phase morphology and intermetallic precipitation using optical micrography, SEM, EDS, XRD, nano-indentation and microhardness methods. These samples were then tested for general and localized corrosion susceptibility and SCC to understand the underlying mechanisms of crack initiation and propagation in DSS in the above-mentioned environments. Results showed that the austenite phase in the DSS is more susceptible to crack initiation and propagation in caustic solutions, which is different from that in the low pH chloride environment where the ferrite phase is the more susceptible phase. This study also showed that microstructural changes in duplex stainless steels due to different heat treatments could affect their SCC

  11. Lab-on-a-Membrane Foldable Devices for Duplex Drop-Volume Electrochemical Biosensing Using Quantum Dot Tags.

    PubMed

    Kokkinos, Christos; Angelopoulou, Michailia; Economou, Anastasios; Prodromidis, Mamas; Florou, Ageliki; Haasnoot, Willem; Petrou, Panagiota; Kakabakos, Sotirios

    2016-07-05

    This work describes a new type of integrated lab-on-a-membrane foldable device suitable for on-site duplex electrochemical biosensing using drop-size sample volumes. The devices are fabricated entirely by screen-printing on a nylon membrane and feature two assay zones which are located symmetrically on either side of a three-electrode voltammetric cell with a bismuth citrate-loaded graphite working electrode. After the completion of two spatially separated drop-volume competitive immunoassays on the assay zones using biotinylated antibodies labeled with streptavidin-conjugated Pb- and Cd-based quantum dots (QDs), respectively, the QD labels are dissolved releasing Pb(II) and Cd(II) in the assay zones. Then, the two assay zones are folded over, and they are brought in contact with the voltammetric cell for simultaneous anodic stripping voltammetric (ASV) determination of Pb(II) and Cd(II) at the bismuth nanostructured layer formed on the working electrode by reduction of the bismuth citrate during the preconcentration step. The fabrication of the devices is discussed in detail, and their operational characteristics are exhaustively studied. In order to demonstrate their applicability to the analysis in complex matrices, duplex ASV-QDs-based determination of bovine casein and bovine immunoglobulin G is carried out in milk samples yielding limits of detection of 0.04 μg mL(-1) and 0.02 μg mL(-1), respectively. The potential of the devices to detect milk adulteration is further demonstrated. These new membrane devices enable duplex biosensing with distinct advantages over existing approaches in terms of cost, fabrication, and operational simplicity and rapidity, portability, sample size, disposability, sensitivity, and suitability for field analysis.

  12. Complex drug use patterns and associated HIV transmission risk behaviors in an Internet sample of U.S. men who have sex with men.

    PubMed

    Yu, Gary; Wall, Melanie M; Chiasson, Mary Ann; Hirshfield, Sabina

    2015-02-01

    Although the relationship between drug use and HIV risk among men who have sex with men (MSM) is well described, relatively few studies have employed empirical methods to assess underlying classes of drug use that may better predict the risk of HIV or sexually transmitted infections (STIs) among MSM. The aim of this study was to determine whether latent class analysis (LCA) would identify underlying drug classes reported prior to sex, as well as predict unprotected anal intercourse (UAI) in the last sexual encounter among MSM. From 2004 to 2005, an anonymous online survey was conducted among 8,717 sexually active MSM recruited from gay-affiliated U.S. websites. LCA clustered participants into six distinct drug use classes based on the specific types and number of drugs used: (1) low/no drug use, (2) recreational drug use, (3) poppers with prescription erectile dysfunction (ED) drug use, (4) poppers with both prescription and non-prescription ED drug use, (5) recreational, club, and ED drug use, and (6) high polydrug use. Compared with men in Class 1, men in the highest drug use class were 4.84 times more likely to report UAI in their last sexual encounter and 3.78 times more likely to report an STI in the past year (both ps < .001). Younger MSM aged 18-29 were significantly more likely to report an STI than men aged 50 and above (p < .001). There is a need to better understand the complex relationship between a diverse set of drugs used among MSM and how polydrug use impacts sexual negotiation over time.

  13. Hoogsteen-paired homopurine [RP-PS]-DNA and homopyrimidine RNA strands form a thermally stable parallel duplex.

    PubMed

    Guga, Piotr; Janicka, Magdalena; Maciaszek, Anna; Rebowska, Beata; Nowak, Genowefa

    2007-11-15

    Homopurine deoxyribonucleoside phosphorothioates possessing all internucleotide linkages of R(P) configuration form a duplex with an RNA or 2'-OMe-RNA strand with Hoogsteen complementarity. The duplexes formed with RNA templates are thermally stable at pH 5.3, while those formed with a 2'-OMe-RNA are stable at neutrality. Melting temperature and fluorescence quenching experiments indicate that the strands are parallel. Remarkably, these duplexes are thermally more stable than parallel Hoogsteen duplexes and antiparallel Watson-Crick duplexes formed by unmodified homopurine DNA molecules of the same sequence with corresponding RNA templates.

  14. Preparation and evaluation of a self-nanoemulsifying drug delivery system loaded with Akebia saponin D–phospholipid complex

    PubMed Central

    Shen, Jinyang; Bi, Jianping; Tian, Hongli; Jin, Ye; Wang, Yuan; Yang, Xiaolin; Yang, Zhonglin; Kou, Junping; Li, Fei

    2016-01-01

    Background Akebia saponin D (ASD) exerts various pharmacological activities but with poor oral bioavailability. In this study, a self-nanoemulsifying drug delivery system (SNEDDS) based on the drug–phospholipid complex technique was developed to improve the oral absorption of ASD. Methods ASD–phospholipid complex (APC) was prepared using a solvent-evaporation method and characterized by infrared spectroscopy, differential scanning calorimetry, morphology observation, and solubility test. Oil and cosurfactant were selected according to their ability to dissolve APC, while surfactant was chosen based on its emulsification efficiency in SNEDDS. Pseudoternary phase diagrams were constructed to determine the optimized APC-SNEDDS formulation, which was characterized by droplet size determination, zeta potential determination, and morphology observation. Robustness to dilution and thermodynamic stability of optimized formulation were also evaluated. Subsequently, pharmacokinetic parameters and oral bioavailability of ASD, APC, and APC-SNEDDS were investigated in rats. Results The liposolubility significantly increased 11.4-fold after formation of APC, which was verified by the solubility test in n-octanol. Peceol (Glyceryl monooleate [type 40]), Cremophor® EL (Polyoxyl 35 castor oil), and Transcutol HP (Diethylene glycol monoethyl ether) were selected as oil, surfactant, and cosurfactant, respectively. The optimal formulation was composed of Glyceryl monooleate (type 40), Polyoxyl 35 castor oil, Diethylene glycol monoethyl ether, and APC (1:4.5:4.5:1.74, w/w/w/w), which showed a particle size of 148.0±2.7 nm and a zeta potential of −13.7±0.92 mV after dilution with distilled water at a ratio of 1:100 (w/w) and good colloidal stability. Pharmacokinetic studies showed that APC-SNEDDS exhibited a significantly greater Cmax1 (733.4±203.8 ng/mL) than ASD (437.2±174.2 ng/mL), and a greater Cmax2 (985.8±366.6 ng/mL) than ASD (180.5±75.1 ng/mL) and APC (549.7±113

  15. NMR studies of DNA duplexes singly cross-linked by different synthetic linkers.

    PubMed Central

    Altmann, S; Labhardt, A M; Bur, D; Lehmann, C; Bannwarth, W; Billeter, M; Wüthrich, K; Leupin, W

    1995-01-01

    Molecular modelling studies resulted in the design of a variety of non-nucleotidic covalent linkers to bridge the 3'-end of the (+)-strand and the 5'-end of the (-)-strand in DNA duplexes. Three of these linkers were synthesized and used to prepare singly cross-linked duplexes d(GTGGAATTC)-linker-d(GAATTCCAC). Linker I is an assembly of a propylene-, a phosphate- and a second propylene-group and is thought to mimic the backbone of two nucleotides. Linkers II and III consist of five and six ethyleneglycol units, respectively. The melting temperatures of the cross-linked duplexes are 65 degrees C for I and 73 degrees C for II and III, as compared with 36 degrees C for the corresponding non-linked nonadeoxynucleotide duplex. The three cross-linked duplexes were structurally characterized by nuclear magnetic resonance spectroscopy. The 1H and 31P resonance assignments in the DNA stem were obtained using standard methods. For the resonance assignment of the linker protons, two-dimensional 1H-31P heteronuclear COSY and two-quantum-experiments were used. Distance geometry calculations with NOE-derived distance constraints were performed and the resulting structures were energy-minimized. In duplex I, the nucleotides flanking the propylene-phosphate-propylene-linker do not form a Watson-Crick base pair, whereas in duplexes II and III the entire DNA stem is in a B-type double helix conformation. Images PMID:8532525

  16. Cooperative translocation enhances the unwinding of duplex DNA by SARS coronavirus helicase nsP13.

    PubMed

    Lee, Na-Ra; Kwon, Hyun-Mi; Park, Kkothanahreum; Oh, Sangtaek; Jeong, Yong-Joo; Kim, Dong-Eun

    2010-11-01

    SARS coronavirus encodes non-structural protein 13 (nsP13), a nucleic acid helicase/NTPase belonging to superfamily 1 helicase, which efficiently unwinds both partial-duplex RNA and DNA. In this study, unwinding of DNA substrates that had different duplex lengths and 5'-overhangs was examined under single-turnover reaction conditions in the presence of excess enzyme. The amount of DNA unwound decreased significantly as the length of the duplex increased, indicating a poor in vitro processivity. However, the quantity of duplex DNA unwound increased as the length of the single-stranded 5'-tail increased for the 50-bp duplex. This enhanced processivity was also observed for duplex DNA that had a longer single-stranded gap in between. These results demonstrate that nsP13 requires the presence of a long 5'-overhang to unwind longer DNA duplexes. In addition, enhanced DNA unwinding was observed for gapped DNA substrates that had a 5'-overhang, indicating that the translocated nsP13 molecules pile up and the preceding helicase facilitate DNA unwinding. Together with the propensity of oligomer formation of nsP13 molecules, we propose that the cooperative translocation by the functionally interacting oligomers of the helicase molecules loaded onto the 5'-overhang account for the observed enhanced processivity of DNA unwinding.

  17. Preparation and property of duplex Ni-B-TiO2/Ni nano-composite coatings

    NASA Astrophysics Data System (ADS)

    Wang, Shu-Jen; Wang, Yuxin; Shu, Xin; Tay, Seeleng; Gao, Wei; Shakoor, R. A.; Kahraman, Ramazan

    2015-03-01

    The duplex Nickel-Boron-Titania/Nickel (Ni-B-TiO2/Ni) coatings were deposited on mild steel by using two baths with Ni as the inner layer. TiO2 nanoparticles were incorporated into the Ni-B coatings as the outer layer by using solid particle mixing method. The microstructure, morphology and corrosion resistance of the duplex Ni-B-TiO2/Ni nanocomposite coatings were systemically investigated. The results show that the duplex interface was uniform and the adhesion between two layers was very good. The microhardness of duplex Ni-B-TiO2/Ni coating was much higher than the Ni coating due to the outer layer of Ni-B-TiO2 coating. The corrosion resistance of the duplex Ni-B-TiO2/Ni coating was also significantly improved comparing with single Ni-B coating. The Ni-B-10 g/L TiO2/Ni coating was found to have the best corrosion resistance among these duplex coatings. This type of duplex Ni-B-TiO2/Ni coating, with high hardness and good corrosion resistance properties, should be able to find broad applications under adverse environmental conditions.

  18. Influence of two bulge loops on the stability of RNA duplexes.

    PubMed

    Crowther, Claire V; Jones, Laura E; Morelli, Jessica N; Mastrogiacomo, Eric M; Porterfield, Claire; Kent, Jessica L; Serra, Martin J

    2017-02-01

    Fifty-three RNA duplexes containing two single nucleotide bulge loops were optically melted in 1 M NaCl in order to determine the thermodynamic parameters ΔH°, ΔS°, ΔG°37, and TM for each duplex. Because of the large number of possible combinations and lack of sequence effects observed previously, we limited our initial investigation to adenosine bulges, the most common naturally occurring bulge. For example, the following duplexes were investigated: 5'GGCAXYAGGC/3'CCG YX CCG, 5'GGCAXY GCC/3'CCG YXACGG, and 5'GGC XYAGCC/3'CCGAYX CGG. The identity of XY (where XY are Watson-Crick base pairs) and the total number of base pairs in the terminal and central stems were varied. As observed for duplexes with a single bulge loop, the effect of the two bulge loops on duplex stability is primarily influenced by non-nearest neighbor interactions. In particular, the stability of the stems influences the destabilization of the duplex by the inserted bulge loops. The model proposed to predict the influence of multiple bulge loops on duplex stability suggests that the destabilization of each bulge is related to the stability of the adjacent stems. A database of RNA secondary structures was examined to determine the naturally occurring abundance of duplexes containing multiple bulge loops. Of the 2000 examples found in the database, over 65% of the two bulge loops occur within 3 base pairs of each other. A database of RNA three-dimensional structures was examined to determine the structure of duplexes containing two single nucleotide bulge loops. The structures of the bulge loops are described.

  19. Nucleic acid duplexes incorporating a dissociable covalent base pair

    NASA Technical Reports Server (NTRS)

    Gao, K.; Orgel, L. E.; Bada, J. L. (Principal Investigator)

    1999-01-01

    We have used molecular modeling techniques to design a dissociable covalently bonded base pair that can replace a Watson-Crick base pair in a nucleic acid with minimal distortion of the structure of the double helix. We introduced this base pair into a potential precursor of a nucleic acid double helix by chemical synthesis and have demonstrated efficient nonenzymatic template-directed ligation of the free hydroxyl groups of the base pair with appropriate short oligonucleotides. The nonenzymatic ligation reactions, which are characteristic of base paired nucleic acid structures, are abolished when the covalent base pair is reduced and becomes noncoplanar. This suggests that the covalent base pair linking the two strands in the duplex is compatible with a minimally distorted nucleic acid double-helical structure.

  20. Nucleic Acid Duplexes Incorporating a Dissociable Covalent Base Pair

    NASA Astrophysics Data System (ADS)

    Gao, Kui; Orgel, Leslie E.

    1999-12-01

    We have used molecular modeling techniques to design a dissociable covalently bonded base pair that can replace a Watson-Crick base pair in a nucleic acid with minimal distortion of the structure of the double helix. We introduced this base pair into a potential precursor of a nucleic acid double helix by chemical synthesis and have demonstrated efficient nonenzymatic template-directed ligation of the free hydroxyl groups of the base pair with appropriate short oligonucleotides. The nonenzymatic ligation reactions, which are characteristic of base paired nucleic acid structures, are abolished when the covalent base pair is reduced and becomes noncoplanar. This suggests that the covalent base pair linking the two strands in the duplex is compatible with a minimally distorted nucleic acid double-helical structure.

  1. Efficiency of coaxial stacking depends on the DNA duplex structure.

    PubMed

    Pyshnyi, Dmitrii V; Goldberg, Eugenii L; Ivanova, Eugenia M

    2003-12-01

    Thermodynamic parameters of coaxial stacking at complementary helix-helix interfaces GX*pYG/CZVC (X,Y=A,C,T,G;*-nick) created by contiguous oligonucleotide hybridization were determined. The data obtained were compared to the thermodynamic parameters of coaxial stacking at the interfaces CX*pYC/GZVG. Multiple linear regression analysis has revealed that the free-energy increments of interaction for the contacts GX*pYG/CZVC and CX*pYC/GZVG can be described by a set of uniform Delta G degrees(X*pY/ZV) values. The difference in the observed free-energy of the coaxial stacking between the two sets is defined by the contribution from the factors reflecting structural differences between compared DNA duplexes.

  2. Reduced-stringency DNA reassociation: sequence specific duplex formation.

    PubMed Central

    Burr, H E; Schimke, R T

    1982-01-01

    Reduced-stringency DNA reassociation conditions allow low stability duplexes to be detected in prokaryotic, plant, fish, avian, mammalian, and primate genomes. Highly diverged families of sequences can be detected in avian, mouse, and human unique sequence dNAs. Such a family has been described among twelve species of birds; based on species specific melting profiles and fractionation of sequences belonging to this family, it was concluded that permissive reassociation conditions did not artifactually produce low stability structures (1). We report S1 nuclease and optical melting experiments, and further fractionation of the diverged family to confirm sequence specific DNA reassociation at 50 degrees in 0.5 M phosphate buffer. PMID:6278429

  3. Fault Injection Campaign for a Fault Tolerant Duplex Framework

    NASA Technical Reports Server (NTRS)

    Sacco, Gian Franco; Ferraro, Robert D.; von llmen, Paul; Rennels, Dave A.

    2007-01-01

    Fault tolerance is an efficient approach adopted to avoid or reduce the damage of a system failure. In this work we present the results of a fault injection campaign we conducted on the Duplex Framework (DF). The DF is a software developed by the UCLA group [1, 2] that uses a fault tolerant approach and allows to run two replicas of the same process on two different nodes of a commercial off-the-shelf (COTS) computer cluster. A third process running on a different node, constantly monitors the results computed by the two replicas, and eventually restarts the two replica processes if an inconsistency in their computation is detected. This approach is very cost efficient and can be adopted to control processes on spacecrafts where the fault rate produced by cosmic rays is not very high.

  4. Thermal Aging Phenomena in Cast Duplex Stainless Steels

    DOE PAGES

    Byun, T. S.; Yang, Y.; Overman, N. R.; ...

    2015-11-12

    We used cast stainless steels (CASSs)for the large components of light water reactor (LWR) power plants such as primary coolant piping and pump casing. The thermal embrittlement of CASS components is one of the most serious concerns related to the extended-term operation of nuclear power plants. Many past researches have concluded that the formation of Cr-rich alpha-phase by Spinodal decomposition of delta-ferrite phase is the primary mechanism for the thermal embrittlement. Cracking mechanism in the thermally-embrittled duplex stainless steels consists of the formation of cleavage at ferrite and its propagation via separation of ferrite-austenite interphase. This article intends to providemore » an introductory overview on the thermal aging phenomena in LWR-relevant conditions. Firstly, the thermal aging effect on toughness is discussed in terms of the cause of embrittlement and influential parameters. Moreover, an approximate analysis of thermal reaction using Arrhenius equation was carried out to scope the aging temperatures for the accelerated aging experiments to simulate the 60 and 80 years of services. Further, an equilibrium precipitation calculation was performed for model CASS alloys using the CALPHAD program, and the results are used to describe the precipitation behaviors in duplex stainless steels. Our results are also to be used to guide an on-going research aiming to provide knowledge-based conclusive prediction for the integrity of the CASS components of LWR power plants during the service life extended up to and beyond 60 years.« less

  5. Duplex Doppler ultrasound study of the temporomandibular joint.

    PubMed

    Stagnitti, A; Marini, A; Impara, L; Drudi, F M; Lo Mele, L; Lillo Odoardi, G

    2012-06-01

    Sommario INTRODUZIONE: La fisiologia articolare dell’articolazione temporo-mandibolare (ATM) può essere esaminata sia dal punto di vista clinico che strumentale. La diagnostica per immagini ha da tempo contribuito con la risonanza magnetica (RM) e anche con la radiografia (Rx) e la tomografia computerizzata (TC) all’analisi della morfologia dei capi articolari e della cinetica condilare. L’esame duplex-ecodoppler è una metodica di largo impiego nello studio delle strutture in movimento in particolar modo a livello delle strutture del sistema vascolare. MATERIALI E METODI: È stata utilizzata un’apparecchiatura Toshiba APLIO SSA-770A, con l’uso di tecnica duplex-ecodoppler multi display, che consente la visualizzazione contemporanea dell’immagine ecografica e dei segnali Doppler utilizzando una sonda lineare del tipo phased array con cristalli trasduttori funzionanti ad una frequenza fondamentale di 6 MHz per gli spettri Doppler pulsati e 7.5 MHz per l’imaging ecografico. Sono stati esaminati nel Dipartimento di Scienze Radiologiche, Oncologiche e Anatomo-patologiche dell’Università “Sapienza” di Roma, 30 pazienti del reparto di Ortognatodonzia dell’Istituto di Odontoiatria della stessa Università. RISULTATI: Nei pazienti normali si è ottenuta un’alternanza regolare degli spettri Doppler, mentre nei soggetti con disfunzioni del complesso condilo-meniscale, si è persa la regolarità della sommatoria degli spettri di Fourier, con altezze incostanti in relazione a spostamenti irregolari del complesso condilo-meniscale. CONCLUSIONI: L’esame ecodoppler si è dimostrato, in tutti i pazienti, capace di discriminare quelli normali dai patologici e tra questi ultimi ha permesso di identificare gli aspetti più significativi delle patologie disfunzionali.

  6. Geometry of an outcrop-scale duplex in Devonian flysch, Maine

    USGS Publications Warehouse

    Bradley, D.C.; Bradley, L.M.

    1994-01-01

    We describe an outcrop-scale duplex consisting of 211 exposed repetitions of a single bed. The duplex marks an early Acadian (Middle Devonian) oblique thrust zone in the Lower Devonian flysch of northern Maine. Detailed mapping at a scale of 1:8 has enabled us to measure accurately parameters such as horse length and thickness, ramp angles and displacements; we compare these and derivative values with those of published descriptions of duplexes, and with theoretical models. Shortening estimates based on line balancing are consistently smaller than two methods of area balancing, suggesting that layer-parallel shortening preceded thrusting. ?? 1994.

  7. Spectral, thermal and kinetic studies of charge-transfer complexes formed between the highly effective antibiotic drug metronidazole and two types of acceptors: σ- and π-acceptors.

    PubMed

    Refat, Moamen S; Saad, Hosam A; Adam, Abdel Majid A

    2015-04-15

    Understanding the interaction between drugs and small inorganic or organic molecules is critical in being able to interpret the drug-receptor interactions and acting mechanism of these drugs. A combined solution and solid state study was performed to describe the complexation chemistry of drug metronidazole (MZ) which has a broad-spectrum antibacterial activity with two types of acceptors. The acceptors include, σ-acceptor (i.e., iodine) and π-acceptors (i.e., dichlorodicyanobenzoquinone (DDQ), chloranil (CHL) and picric acid (PA)). The molecular structure, spectroscopic characteristics, the binding modes as well as the thermal stability were deduced from IR, UV-vis, (1)H NMR and thermal studies. The binding ratio of complexation (MZ: acceptor) was determined to be 1:2 for the iodine acceptor and 1:1 for the DDQ, CHL or PA acceptor, according to the CHN elemental analyses and spectrophotometric titrations. It has been found that the complexation with CHL and PA acceptors increases the values of enthalpy and entropy, while the complexation with DDQ and iodine acceptors decreases the values of these parameters compared with the free MZ donor.

  8. Characterization, inclusion mode, phase-solubility and in vitro release studies of inclusion binary complexes with cyclodextrins and meglumine using sulfamerazine as model drug.

    PubMed

    Aloisio, Carolina; Gomes de Oliveira, Anselmo; Longhi, Marcela

    2014-07-01

    In order to investigate the effect on the aqueous solubility and release rate of sulfamerazine (SMR) as model drug, inclusion complexes with β-cyclodextrin (βCD), methyl-β-cyclodextrin (MβCD) and hydroxypropyl-β-cyclodextrin (HPβCD) and a binary system with meglumine (MEG) were developed. The formation of 1:1 inclusion complexes of SMR with the CDs and a SMR:MEG binary system in solution and in solid state was revealed by phase solubility studies (PSS), nuclear magnetic resonance (NMR), Fourier-transform infrared spectroscopy (FT-IR), thermal analysis and X-Ray diffractometry (XRD) studies. The CDs solubilization of SMR could be improved by ionization of the drug molecule through pH adjustments. The higher apparent stability constants of SMR:CDs complexes were obtained in pH 2.00, demonstrating that CDs present more affinity for the unionized drug. The best approach for SMR solubility enhancement results from the combination of MEG and pH adjustment, with a 34-fold increment and a Smax of 54.8 mg/ml. The permeability of the drug was reduced due to the presence of βCD, MβCD, HPβCD and MEG when used as solubilizers. The study then suggests interesting applications of CD or MEG complexes for modulating the release rate of SMR through semipermeable membranes.

  9. Spectral, thermal and kinetic studies of charge-transfer complexes formed between the highly effective antibiotic drug metronidazole and two types of acceptors: σ- and π-acceptors

    NASA Astrophysics Data System (ADS)

    Refat, Moamen S.; Saad, Hosam A.; Adam, Abdel Majid A.

    2015-04-01

    Understanding the interaction between drugs and small inorganic or organic molecules is critical in being able to interpret the drug-receptor interactions and acting mechanism of these drugs. A combined solution and solid state study was performed to describe the complexation chemistry of drug metronidazole (MZ) which has a broad-spectrum antibacterial activity with two types of acceptors. The acceptors include, σ-acceptor (i.e., iodine) and π-acceptors (i.e., dichlorodicyanobenzoquinone (DDQ), chloranil (CHL) and picric acid (PA)). The molecular structure, spectroscopic characteristics, the binding modes as well as the thermal stability were deduced from IR, UV-vis, 1H NMR and thermal studies. The binding ratio of complexation (MZ: acceptor) was determined to be 1:2 for the iodine acceptor and 1:1 for the DDQ, CHL or PA acceptor, according to the CHN elemental analyses and spectrophotometric titrations. It has been found that the complexation with CHL and PA acceptors increases the values of enthalpy and entropy, while the complexation with DDQ and iodine acceptors decreases the values of these parameters compared with the free MZ donor.

  10. Further evidence of complex motor dysfunction in drug naive children with autism using automatic motion analysis of gait.

    PubMed

    Nobile, Maria; Perego, Paolo; Piccinini, Luigi; Mani, Elisa; Rossi, Agnese; Bellina, Monica; Molteni, Massimo

    2011-05-01

    In order to increase the knowledge of locomotor disturbances in children with autism, and of the mechanism underlying them, the objective of this exploratory study was to reliably and quantitatively evaluate linear gait parameters (spatio-temporal and kinematic parameters), upper body kinematic parameters, walk orientation and smoothness using an automatic motion analyser (ELITE systems) in drug naïve children with Autistic Disorder (AD) and healthy controls. The children with AD showed a stiffer gait in which the usual fluidity of walking was lost, trunk postural abnormalities, highly significant difficulties to maintain a straight line and a marked loss of smoothness (increase of jerk index), compared to the healthy controls. As a whole, these data suggest a complex motor dysfunction involving both the cortical and the subcortical area or, maybe, a possible deficit in the integration of sensory-motor information within motor networks (i.e., anomalous connections within the fronto-cerebello-thalamo-frontal network). Although the underlying neural structures involved remain to be better defined, these data may contribute to highlighting the central role of motor impairment in autism and suggest the usefulness of taking into account motor difficulties when developing new diagnostic and rehabilitation programs.

  11. Why Antidiabetic Vanadium Complexes are Not in the Pipeline of "Big Pharma" Drug Research? A Critical Review.

    PubMed

    Scior, Thomas; Guevara-Garcia, Jose Antonio; Do, Quoc-Tuan; Bernard, Philippe; Laufer, Stefan

    2016-01-01

    Public academic research sites, private institutions as well as small companies have made substantial contributions to the ongoing development of antidiabetic vanadium compounds. But why is this endeavor not echoed by the globally operating pharmaceutical companies, also known as "Big Pharma"? Intriguingly, today's clinical practice is in great need to improve or replace insulin treatment against Diabetes Mellitus (DM). Insulin is the mainstay therapeutically and economically. So, why do those companies develop potential antidiabetic drug candidates without vanadium (vanadium- free)? We gathered information about physicochemical and pharmacological properties of known vanadium-containing antidiabetic compounds from the specialized literature, and converted the data into explanations (arguments, the "pros and cons") about the underpinnings of antidiabetic vanadium. Some discoveries were embedded in chronological order while seminal reviews of the last decade about the Medicinal chemistry of vanadium and its history were also listed for further understanding. In particular, the concepts of so-called "noncomplexed or free" vanadium species (i.e. inorganic oxido-coordinated species) and "biogenic speciation" of antidiabetic vanadium complexes were found critical and subsequently documented in more details to answer the question.

  12. Why Antidiabetic Vanadium Complexes are Not in the Pipeline of “Big Pharma” Drug Research? A Critical Review

    PubMed Central

    Scior, Thomas; Guevara-Garcia, Jose Antonio; Do, Quoc-Tuan; Bernard, Philippe; Laufer, Stefan

    2016-01-01

    Public academic research sites, private institutions as well as small companies have made substantial contributions to the ongoing development of antidiabetic vanadium compounds. But why is this endeavor not echoed by the globally operating pharmaceutical companies, also known as “Big Pharma”? Intriguingly, today’s clinical practice is in great need to improve or replace insulin treatment against Diabetes Mellitus (DM). Insulin is the mainstay therapeutically and economically. So, why do those companies develop potential antidiabetic drug candidates without vanadium (vanadium-free)? We gathered information about physicochemical and pharmacological properties of known vanadium-containing antidiabetic compounds from the specialized literature, and converted the data into explanations (arguments, the “pros and cons”) about the underpinnings of antidiabetic vanadium. Some discoveries were embedded in chronological order while seminal reviews of the last decade about the Medicinal chemistry of vanadium and its history were also listed for further understanding. In particular, the concepts of so-called “noncomplexed or free” vanadium species (i.e. inorganic oxido-coordinated species) and “biogenic speciation” of antidiabetic vanadium complexes were found critical and subsequently documented in more details to answer the question. PMID:26997154

  13. Spectrophotometric determination of β-adrenergic antagonists drugs via ion-pair complex formation using MO and EBT

    NASA Astrophysics Data System (ADS)

    El-Didamony, A. M.; Shehata, A. M.

    2014-09-01

    Two simple, rapid and sensitive spectrophotometric methods have been proposed for the assay of bisoprolol fumarate (BSF), propranolol hydrochloride (PRH), and timolol maleate (TIM) either in bulk or in pharmaceutical formulations. The methods are based on the reaction of the selected drugs with methyl orange (MO) and eriochrome black T in acidic buffers, after extracting in dichloromethane and measured quantitatively with maximum absorption at 428 and 518 nm for MO and EBT, respectively. The analytical parameters and their effects on the reported systems are investigated. The extracts are intensely colored and very stable at room temperature. The calibration graphs were linear over the concentration range of 0.8-6.4, 0.4-3.6, 0.8-5.6 μg/mL for BSF, PRH, and TIM, respectively, with MO and 0.8-6.4, 0.4-3.2, and 0.8-8.0 μg/mL for BSF, PRH, and TIM, respectively, with EBT. The stoichiometry of the complexes was found to be 1 : 1 in all cases. The proposed methods were successfully extended to pharmaceutical preparations. Excipients used as additive in commercial formulations did not interfere in the analysis. The proposed methods can be recommended for quality control and routine analysis where time, cost effectiveness and high specificity of analytical technique are of great importance.

  14. Interactions of Yeast Dynein with Dynein Light Chain and Dynactin: GENERAL IMPLICATIONS FOR INTRINSICALLY DISORDERED DUPLEX SCAFFOLDS IN MULTIPROTEIN ASSEMBLIES.

    PubMed

    Jie, Jing; Löhr, Frank; Barbar, Elisar

    2015-09-25

    Intrinsically disordered protein (IDP) duplexes composed of two IDP chains cross-linked by bivalent partner proteins form scaffolds for assembly of multiprotein complexes. The N-terminal domain of dynein intermediate chain (N-IC) is one such IDP that forms a bivalent scaffold with multiple dynein light chains including LC8, a hub protein that promotes duplex formation of diverse IDP partners. N-IC also binds a subunit of the dynein regulator, dynactin. Here we characterize interactions of a yeast ortholog of N-IC (N-Pac11) with yeast LC8 (Dyn2) or with the intermediate chain-binding subunit of yeast dynactin (Nip100). Residue level changes in Pac11 structure are monitored by NMR spectroscopy, and binding energetics are monitored by isothermal titration calorimetry (ITC). N-Pac11 is monomeric and primarily disordered except for a single α-helix (SAH) at the N terminus and a short nascent helix, LH, flanked by the two Dyn2 recognition motifs. Upon binding Dyn2, the only Pac11 residues making direct protein-protein interactions are in and immediately flanking the recognition motifs. Dyn2 binding also orders LH residues of Pac11. Upon binding Nip100, only Pac11 SAH residues make direct protein-protein interactions, but LH residues at a distant sequence position and L1 residues in an adjacent linker are also ordered. The long distance, ligand-dependent ordering of residues reveals new elements of dynamic structure within IDP linker regions.

  15. Features of “All LNA” Duplexes Showing a New Type of Nucleic Acid Geometry

    PubMed Central

    Förster, Charlotte; Eichert, André; Oberthür, Dominik; Betzel, Christian; Geßner, Reinhard; Nitsche, Andreas; Fürste, Jens P.

    2012-01-01

    “Locked nucleic acids” (LNAs) belong to the backbone-modified nucleic acid family. The 2′-O,4′-C-methylene-β-D-ribofuranose nucleotides are used for single or multiple substitutions in RNA molecules and thereby introduce enhanced bio- and thermostability. This renders LNAs powerful tools for diagnostic and therapeutic applications. RNA molecules maintain the overall canonical A-type conformation upon substitution of single or multiple residues/nucleotides by LNA monomers. The structures of “all” LNA homoduplexes, however, exhibit significant differences in their overall geometry, in particular a decreased twist, roll and propeller twist. This results in a widening of the major groove, a decrease in helical winding, and an enlarged helical pitch. Therefore, the LNA duplex structure can no longer be described as a canonical A-type RNA geometry but can rather be brought into proximity to other backbone-modified nucleic acids, like glycol nucleic acids or peptide nucleic acids. LNA-modified nucleic acids provide thus structural and functional features that may be successfully exploited for future application in biotechnology and drug discovery. PMID:22666550

  16. Premelting base pair opening probability and drug binding constant of a daunomycin-poly d(GCAT).poly d(ATGC) complex.

    PubMed Central

    Chen, Y Z; Prohofsky, E W

    1994-01-01

    We calculate room temperature thermal fluctuational base pair opening probability of a daunomycin-poly d(GCAT).poly d(ATGC) complex. This system is constructed at an atomic level of detail based on x-ray analysis of a crystal structure. The base pair opening probabilities are calculated from a modified self-consistent phonon approach of anharmonic lattice dynamics theory. We find that daunomycin binding substantially enhances the thermal stability of one of the base pairs adjacent the drug because of strong hydrogen bonding between the drug and the base. The possible effect of this enhanced stability on the drug inhibition of DNA transcription and replication is discussed. We also calculate the probability of drug dissociation from the helix based on the selfconsistent calculation of the probability of the disruption of drug-base H-bonds and the unstacking probability of the drug. The calculations can be used to determine the equilibrium drug binding constant which is found to be in good agreement with observations on similar daunomycin-DNA systems. PMID:8011914

  17. Effect of initial ion positions on the interactions of monovalent and divalent ions with a DNA duplex as revealed with atomistic molecular dynamics simulations.

    PubMed

    Robbins, Timothy J; Wang, Yongmei

    2013-01-01

    Monovalent (Na(+)) and divalent (Mg(2+)) ion distributions around the Dickerson-Drew dodecamer were studied by atomistic molecular dynamics (MD) simulations with AMBER molecular modeling software. Different initial placements of ions were tried and the resulting effects on the ion distributions around DNA were investigated. For monovalent ions, results were found to be nearly independent of initial cation coordinates. However, Mg(2+) ions demonstrated a strong initial coordinate dependent behavior. While some divalent ions initially placed near the DNA formed essentially permanent direct coordination complexes with electronegative DNA atoms, Mg(2+) ions initially placed further away from the duplex formed a full, nonexchanging, octahedral first solvation shell. These fully solvated cations were still capable of binding with DNA with events lasting up to 20 ns, and in comparison were bound much longer than Na(+) ions. Force field parameters were also investigated with modest and little differences arising from ion (ions94 and ions08) and nucleic acid description (ff99, ff99bsc0, and ff10), respectively. Based on known Mg(2+) ion solvation structure, we conclude that in most cases Mg(2+) ions retain their first solvation shell, making only solvent-mediated contacts with DNA duplex. The proper way to simulate Mg(2+) ions around DNA duplex, therefore, should begin with ions placed in the bulk water.

  18. Matrix trace operators: from spectral moments of molecular graphs and complex networks to perturbations in synthetic reactions, micelle nanoparticles, and drug ADME processes.

    PubMed

    Gonzalez-Diaz, Humberto; Arrasate, Sonia; Juan, Asier Gomez-San; Sotomayor, Nuria; Lete, Esther; Speck-Planche, Alejandro; Ruso, Juan M; Luan, Feng; Cordeiro, Maria Natalia Dias Soeiro

    2014-01-01

    The study of quantitative structure-property relationships (QSPR) is important to study complex networks of chemical reactions in drug synthesis or metabolism or drug-target interaction networks. A difficult but possible goal is the prediction of drug absorption, distribution, metabolism, and excretion (ADME) process with a single QSPR model. For this QSPR modelers need to use flexible structural parameters useful for the description of many different systems at different structural scales (multi-scale parameters). Also they need to use powerful analytical methods able to link in a single multi-scale hypothesis structural parameters of different target systems (multi-target modeling) with different experimental properties of these systems (multi-output models). In this sense, the QSPR study of complex bio-molecular systems may benefit substantially from the combined application of spectral moments of graph representations of complex systems with perturbation theory methods. On one hand, spectral moments are almost universal parameters that can be calculated to many different matrices used to represent the structure of the states of different systems. On the other hand, perturbation methods can be used to add "small" variation terms to parameters of a known state of a given system in order to approach to a solution of another state of the same or similar system with unknown properties. Here we present one state-of-art review about the different applications of spectral moments to describe complex bio-molecular systems. Next, we give some general ideas and formulate plausible linear models for a general-purpose perturbation theory of QSPR problems of complex systems. Last, we develop three new QSPR-Perturbation theory models based on spectral moments for three different problems with multiple in-out boundary conditions that are relevant to biomolecular sciences. The three models developed correctly classify more than pairs 115,600; 48,000; 134,900 cases of the

  19. Two-flux transfer matrix model for predicting the reflectance and transmittance of duplex halftone prints.

    PubMed

    Mazauric, Serge; Hébert, Mathieu; Simonot, Lionel; Fournel, Thierry

    2014-12-01

    We introduce a model allowing convenient calculation of the spectral reflectance and transmittance of duplex prints. It is based on flux transfer matrices and enables retrieving classical Kubelka-Munk formulas, as well as extended formulas for nonsymmetric layers. By making different assumptions on the flux transfers, we obtain two predictive models for the duplex halftone prints: the "duplex Clapper-Yule model," which is an extension of the classical Clapper-Yule model, and the "duplex primary reflectance-transmittance model." The two models can be calibrated from either reflectance or transmittance measurements; only the second model can be calibrated from both measurements, thus giving optimal accuracy for both reflectance and transmittance predictions. The conceptual differences between the two models are deeply analyzed, as well as their advantages and drawbacks in terms of calibration. According to the test carried out in this study with paper printed in inkjet, their predictive performances are good provided appropriate calibration options are selected.

  20. Rapid method to detect duplex formation in sequencing by hybridization methods

    DOEpatents

    Mirzabekov, A.D.; Timofeev, E.N.; Florentiev, V.L.; Kirillov, E.V.

    1999-01-19

    A method for determining the existence of duplexes of oligonucleotide complementary molecules is provided. A plurality of immobilized oligonucleotide molecules, each of a specific length and each having a specific base sequence, is contacted with complementary, single stranded oligonucleotide molecules to form a duplex. Each duplex facilitates intercalation of a fluorescent dye between the base planes of the duplex. The invention also provides for a method for constructing oligonucleotide matrices comprising confining light sensitive fluid to a surface and exposing the light-sensitive fluid to a light pattern. This causes the fluid exposed to the light to coalesce into discrete units and adhere to the surface. This places each of the units in contact with a set of different oligonucleotide molecules so as to allow the molecules to disperse into the units. 13 figs.

  1. Effects of trimethylamine N-oxide and urea on DNA duplex and G-quadruplex

    PubMed Central

    Ueda, Yu-mi; Zouzumi, Yu-ki; Maruyama, Atsushi; Nakano, Shu-ichi; Sugimoto, Naoki; Miyoshi, Daisuke

    2016-01-01

    Abstract We systematically investigated effects of molecular crowding with trimethylamine N-oxide (TMAO) as a zwitterionic and protective osmolyte and urea as a nonionic denaturing osmolyte on conformation and thermodynamics of the canonical DNA duplex and the non-canonical DNA G-quadruplex. It was found that TMAO and urea stabilized and destabilized, respectively, the G-quadruplex. On the other hand, these osmolytes generally destabilize the duplex; however, it was observed that osmolytes having the trimethylamine group stabilized the duplex at the lower concentrations because of a direct binding to a groove of the duplex. These results are useful not only to predict DNA structures and their thermodynamics under physiological environments in living cells, but also design of polymers and materials to regulate structure and stability of DNA sequences. PMID:27933115

  2. View of 501 8th St., a sidegable duplex bungalow with ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View of 501 8th St., a side-gable duplex bungalow with engaged porch and paired and clustered columns. Built as worker housing for Lanett Cotton Mill - 501 Eighth Street (House), 501 Eighth Street, Lanett, Chambers County, AL

  3. Chromatographic behaviour of naproxen-cyclodextrin complexes stationary phase C8 alkyl chain as competitor for the drug release from cyclodextrin cavity.

    PubMed

    Rozou, S; Antoniadou-Vyza, E

    2004-07-02

    Cyclodextrins are known to alter the absorptivity of the guest molecules, therefore, analytical methods that are based on the spectrophotometric data present accuracy problems. In this work, using RP-HPLC methods for naproxen-cyclodextrins quantitation, extensive analytical inaccuracies are detected. Competitive complexation technique is utilised in an attempt to develop an analytical method enabling the determination of naproxen as a free drug. For this reason, stationary phases with silica ligands that can function as competing agents were used, thus contributing to the drug release. The release of the drug from cyclodextrins complexes is achieved by modification of the thermodynamic parameters that determine the stability constant, by changing: the interactions with the mobile phase components (e.g. pH, organic modifier, competitive agents) and the interactions with the stationary phase ligands (C8). After studying the parameters affecting the interaction between the alkyl-chain C8 and naproxen:cyclodextrin complexes, we developed and validated a new specific method for the accurate determination of the drug. Consecutive accumulation of the cyclodextrins molecules on the stationary phase was studied.

  4. Effects of Particle Hydrophobicity, Surface Charge, Media pH Value and Complexation with Human Serum Albumin on Drug Release Behavior of Mitoxantrone-Loaded Pullulan Nanoparticles

    PubMed Central

    Tao, Xiaojun; Jin, Shu; Wu, Dehong; Ling, Kai; Yuan, Liming; Lin, Pingfa; Xie, Yongchao; Yang, Xiaoping

    2015-01-01

    We prepared two types of cholesterol hydrophobically modified pullulan nanoparticles (CHP) and carboxyethyl hydrophobically modified pullulan nanoparticles (CHCP) substituted with various degrees of cholesterol, including 3.11, 6.03, 6.91 and 3.46 per polymer, and named CHP−3.11, CHP−6.03, CHP−6.91 and CHCP−3.46. Dynamic laser light scattering (DLS) showed that the pullulan nanoparticles were 80–120 nm depending on the degree of cholesterol substitution. The mean size of CHCP nanoparticles was about 160 nm, with zeta potential −19.9 mV, larger than CHP because of the carboxyethyl group. A greater degree of cholesterol substitution conferred greater nanoparticle hydrophobicity. Drug-loading efficiency depended on nanoparticle hydrophobicity, that is, nanoparticles with the greatest degree of cholesterol substitution (6.91) showed the most drug encapsulation efficiency (90.2%). The amount of drug loading increased and that of drug release decreased with enhanced nanoparticle hydrophobicity. Nanoparticle surface-negative charge disturbed the amount of drug loading and drug release, for an opposite effect relative to nanoparticle hydrophobicity. The drug release in pullulan nanoparticles was higher pH 4.0 than pH 6.8 media. However, the changed drug release amount was not larger for negative-surface nanoparticles than CHP nanoparticles in the acid release media. Drug release of pullulan nanoparticles was further slowed with human serum albumin complexation and was little affected by nanoparticle hydrophobicity and surface negative charge. PMID:28344259

  5. Non-invasive evaluation of neuroprotective drug candidates for cerebral infarction by PET imaging of mitochondrial complex-I activity

    PubMed Central

    Fukuta, Tatsuya; Asai, Tomohiro; Ishii, Takayuki; Koide, Hiroyuki; Kiyokawa, Chiaki; Hashimoto, Masahiro; Kikuchi, Takashi; Shimizu, Kosuke; Harada, Norihiro; Tsukada, Hideo; Oku, Naoto

    2016-01-01

    The development of a diagnostic technology that can accurately determine the pathological progression of ischemic stroke and evaluate the therapeutic effects of cerebroprotective agents has been desired. We previously developed a novel PET probe, 2-tert-butyl-4-chloro-5-{6-[2-(2-18F-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([18F]BCPP-EF) for detecting activity of mitochondrial complex I (MC-I). This probe was shown to visualize neuronal damage in the living brain of rodent and primate models of neurodegenerative diseases. In the present study, [18F]BCPP-EF was applied to evaluate the therapeutic effects of a neuroprotectant, liposomal FK506 (FK506-liposomes), on cerebral ischemia/reperfusion (I/R) injury in transient middle cerebral artery occlusion rats. The PET imaging using [18F]BCPP-EF showed a prominent reduction in the MC-I activity in the ischemic brain hemisphere. Treatment with FK506-liposomes remarkably increased the uptake of [18F]BCPP-EF in the ischemic side corresponding to the improvement of blood flow disorders and motor function deficits throughout the 7 days after I/R. Additionally, the PET scan could diagnose the extent of the brain damage accurately and showed the neuroprotective effect of FK506-liposomes at Day 7, at which 2, 3, 5-triphenyltetrazolium chloride staining couldn’t visualize them. Our study demonstrated that the PET technology using [18F]BCPP-EF has a potent capacity to evaluate the therapeutic effect of drug candidates in living brain. PMID:27440054

  6. Non-invasive evaluation of neuroprotective drug candidates for cerebral infarction by PET imaging of mitochondrial complex-I activity

    NASA Astrophysics Data System (ADS)

    Fukuta, Tatsuya; Asai, Tomohiro; Ishii, Takayuki; Koide, Hiroyuki; Kiyokawa, Chiaki; Hashimoto, Masahiro; Kikuchi, Takashi; Shimizu, Kosuke; Harada, Norihiro; Tsukada, Hideo; Oku, Naoto

    2016-07-01

    The development of a diagnostic technology that can accurately determine the pathological progression of ischemic stroke and evaluate the therapeutic effects of cerebroprotective agents has been desired. We previously developed a novel PET probe, 2-tert-butyl-4-chloro-5-{6-[2-(2-18F-fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ([18F]BCPP-EF) for detecting activity of mitochondrial complex I (MC-I). This probe was shown to visualize neuronal damage in the living brain of rodent and primate models of neurodegenerative diseases. In the present study, [18F]BCPP-EF was applied to evaluate the therapeutic effects of a neuroprotectant, liposomal FK506 (FK506-liposomes), on cerebral ischemia/reperfusion (I/R) injury in transient middle cerebral artery occlusion rats. The PET imaging using [18F]BCPP-EF showed a prominent reduction in the MC-I activity in the ischemic brain hemisphere. Treatment with FK506-liposomes remarkably increased the uptake of [18F]BCPP-EF in the ischemic side corresponding to the improvement of blood flow disorders and motor function deficits throughout the 7 days after I/R. Additionally, the PET scan could diagnose the extent of the brain damage accurately and showed the neuroprotective effect of FK506-liposomes at Day 7, at which 2, 3, 5-triphenyltetrazolium chloride staining couldn’t visualize them. Our study demonstrated that the PET technology using [18F]BCPP-EF has a potent capacity to evaluate the therapeutic effect of drug candidates in living brain.

  7. Heat Capacity Changes Associated with DNA Duplex Formation: Salt- and Sequence-Dependent Effects†

    PubMed Central

    Mikulecky, Peter J.; Feig, Andrew L.

    2008-01-01

    Duplexes are the most fundamental elements of nucleic acid folding. Although it has become increasingly clear that duplex formation can be associated with a significant change in heat capacity (ΔCp), this parameter is typically overlooked in thermodynamic studies of nucleic acid folding. Analogy to protein folding suggests that base stacking events coupled to duplex formation should give rise to a ΔCp due to the release of waters solvating aromatic surfaces of nucleotide bases. In previous work, we showed that the ΔCp observed by isothermal titration calorimetry (ITC) for RNA duplex formation depended on salt and sequence. In the present work, we apply calorimetric and spectroscopic techniques to a series of designed DNA duplexes to demonstrate that both the salt dependence and sequence dependence of ΔCps observed by ITC reflect perturbations to the same fundamental phenomenon: stacking in the single-stranded state. By measuring the thermodynamics of single strand melting, one can accurately predict the ΔCps observed for duplex formation by ITC at high and low ionic strength. We discuss our results in light of the larger issue of contributions to ΔCp from coupled equilibria and conclude that observed ΔCps can be useful indicators of intermediate states in nucleic acid folding phenomena. PMID:16401089

  8. Thermal stability and energetics of 15-mer DNA duplex interstrand crosslinked by trans-diamminedichloroplatinum(II).

    PubMed

    Hofr, Ctirad; Brabec, Viktor

    2005-03-01

    The effect of the location of the interstrand cross-link formed by trans-diamminedichloroplatinum(II) (transplatin) on the thermal stability and energetics of 15-mer DNA duplex has been investigated. The duplex containing single, site-specific cross-link, thermodynamically equivalent model structures (hairpins) and nonmodified duplexes were characterized by differential scanning calorimetry, temperature-dependent uv absorption, and circular dichroism. The results demonstrate that the formation of the interstrand cross-link of transplatin does not affect pronouncedly thermodynamic stability of DNA: the cross-link induces no marked changes not only in enthalpy, but also in "reduced" (concentration independent) monomolecular transition entropy. These results are consistent with the previous observations that interstrand cross-links of transplatin structurally perturb DNA only to a relatively small extent. On the other hand, constraining the duplex with the interstrand cross-link of transplatin results in a significant increase in thermal stability that is primarily due to entropic effects: the cross-link reduces the molecularity of the oligomer system from bimolecular to monomolecular. Importantly, the position of the interstrand cross-link within the duplex modulates cooperativity of the melting transition of the duplex and consequently its thermal stability.

  9. Thermodynamic Consequences of the Hyperoxidized Guanine Lesion Guanidinohydantoin in Duplex DNA

    PubMed Central

    Yennie, Craig J.; Delaney, Sarah

    2012-01-01

    Guanidinohydantoin (Gh) is a hyperoxidized DNA lesion produced by oxidation of 8-oxo-7,8-dihydroguanine (8-oxoG). Previous work has shown that Gh is potently mutagenic both in vitro and in vivo coding for G → T and G → C transversion mutations. In this work, analysis by circular dichroism shows that the Gh lesion does not significantly alter the global structure of a 15-mer duplex, and that the DNA remains in the B-form. However, we find that Gh causes a large decrease in the thermal stability, decreasing the duplex melting temperature by ~ 17 °C relative to an unmodified duplex control. Using optical melting analysis and differential scanning calorimetry the thermodynamic parameters describing duplex melting were also determined. We find that the Gh lesion causes a dramatic decrease in the enthalpic stability of the duplex. This enthalpic destabilization is somewhat tempered by entropic stabilization yet Gh results in an overall decrease in thermodynamic stability of the duplex relative to a control which lacks DNA damage, with a ΔΔG° of −7 kcal/mol. These results contribute to our understanding of the consequences of hyperoxidation of G and provide insight into how the thermal and thermodynamic destabilization caused by Gh may influence replication and/or repair of the lesion. PMID:22780843

  10. Duplex communicable implanted antenna for magnetic direct feeding method: Functional electrical stimulation

    NASA Astrophysics Data System (ADS)

    Kato, Kentaro; Matsuki, Hidetoshi; Sato, Fumihiro; Satoh, Tadakuni; Handa, Nobuyasu

    2009-04-01

    Functional electrical stimulation (FES) is the therapy used for the rehabilitation of lost movement function by applying electrical stimulation (ES) to paralyzed extremities. To realize ES, we adapted the implanted direct feeding method (DFM). In this method, small implanted stimulators are placed under the skin at a depth of 10-20 mm and stimulus energy and signals for controlling devices are applied to them by a mounted system using magnetic coupling. This method has the merits of having no percutaneous points and high-precision stimulation. However, since the mounted system and implanted elements are separated, it is necessary to add feedback information from inside the body to confirm the system operation for safety therapy or to rehabilitate motor function smoothly. Satisfying both restrictions, we propose the magnetic connective dual resonance (MCDR) antenna, which has two resonance circuits. Adding the LC serial circuit to the LC parallel circuit gives the sending function. In this paper, we report the principle of the MCDR antenna and verify its duplex communication ability through communication experiment. This antenna enables DFM of FES to rehabilitate more complex movements.

  11. Duplex ultrasound in the assessment of peripheral arterial disease

    NASA Astrophysics Data System (ADS)

    Aly, Sayed A. A. F.

    Arteriography plays a central role in the assessment of peripheral arterial disease. Arteriography is associated with the risk of damage to the artery, peripheral embolisation, hazards of intra-arterial injection and exposure to ionising radiation. Arteriography provides an anatomical assessment of arterial stenosis but does not measure the functional results of the stenosis. Modern high resolution ultrasound imaging technology enables non-invasive assessment of vascular diseases and allows functional assessment of blood flow. This investigation is of proven value in studying carotid disease. The aim of the study was to determine the accuracy of duplex ultrasonography (DUS) in assessment of lower limb arterial disease in comparison with arteriography (IA DSA). A technical comparison has been made between the description of arterial lesion as indicated by DUS and IA DSA. In addition, the sensitivity of DUS in assessing multisegmental arterial disease has been determined. The clinical decision has been investigated in a further study in which five surgeons were asked to determine patient management based on IA DSA and DUS data in the same patient group. Concordance between management strategies was assessed. DUS was used as the primary method of investigation in further series of patients. Criteria were established to determine which patients would require angiography. The computer-assisted image analysis was used to study the ultrasound images of arterial stenosis and a method of analysing such images objectively was established. Two studies have been included in this section. These assess the technical accuracy of ultrasound image analysis compared with histological examination of plaque. The reproducibility of the image analysis has also been tested. I have developed a classification for peripheral arterial disease to be used to facilitate the communication between vascular laboratory staff who perform the duplex ultrasonography and surgeons who use this

  12. Influence of drug property and product design on in vitro-in vivo correlation of complex modified-release dosage forms.

    PubMed

    Qiu, Yihong; Li, Xia; Duan, John Z

    2014-02-01

    The present study examines how drug's inherent properties and product design influence the evaluation and applications of in vitro-in vivo correlation (IVIVC) for modified-release (MR) dosage forms consisting of extended-release (ER) and immediate-release (IR) components with bimodal drug release. Three analgesic drugs were used as model compounds, and simulations of in vivo pharmacokinetic profiles were conducted using different release rates of the ER component and various IR percentages. Plasma concentration-time profiles exhibiting a wide range of tmax and maximum observed plasma concentration (Cmax) were obtained from superposition of the simulated IR and ER profiles based on a linear IVIVC. It was found that depending on the drug and dosage form design, direct use of the superposed IR and ER data for IVIVC modeling and prediction may (1) be acceptable within errors, (2) become unreliable and less meaningful because of the confounding effect from the non-negligible IR contribution to Cmax, or (3) be meaningless because of the insensitivity of Cmax to release rate change of the ER component. Therefore, understanding the drug, design and drug release characteristics of the product is essential for assessing the validity, accuracy, and reliability of IVIVC of complex MR products obtained via directly modeling of in vivo data.

  13. Electrochemiluminescent monomers for solid support syntheses of Ru(II)-PNA bioconjugates: multimodal biosensing tools with enhanced duplex stability.

    PubMed

    Joshi, Tanmaya; Barbante, Gregory J; Francis, Paul S; Hogan, Conor F; Bond, Alan M; Gasser, Gilles; Spiccia, Leone

    2012-03-05

    The feasibility of devising a solid support mediated approach to multimodal Ru(II)-peptide nucleic acid (PNA) oligomers is explored. Three Ru(II)-PNA-like monomers, [Ru(bpy)(2)(Cpp-L-PNA-OH)](2+) (M1), [Ru(phen)(2)(Cpp-L-PNA-OH)](2+) (M2), and [Ru(dppz)(2)(Cpp-L-PNA-OH)](2+) (M3) (bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline, dppz = dipyrido[3,2-a:2',3'-c]phenazine, Cpp-L-PNA-OH = [2-(N-9-fluorenylmethoxycarbonyl)aminoethyl]-N-[6-(2-(pyridin-2yl)pyrimidine-4-carboxamido)hexanoyl]-glycine), have been synthesized as building blocks for Ru(II)-PNA oligomers and characterized by IR and (1)H NMR spectroscopy, mass spectrometry, electrochemistry and elemental analysis. As a proof of principle, M1 was incorporated on the solid phase within the PNA sequences H-g-c-a-a-t-a-a-a-a-Lys-NH(2) (PNA1) and H-P-K-K-K-R-K-V-g-c-a-a-t-a-a-a-a-lys-NH(2) (PNA4) to give PNA2 (H-g-c-a-a-t-a-a-a-a-M1-lys-NH(2)) and PNA3 (H-P-K-K-K-R-K-V-g-c-a-a-t-a-a-a-a-M1-lys-NH(2)), respectively. The two Ru(II)-PNA oligomers, PNA2 and PNA3, displayed a metal to ligand charge transfer (MLCT) transition band centered around 445 nm and an emission maximum at about 680 nm following 450 nm excitation in aqueous solutions (10 mM PBS, pH 7.4). The absorption and emission response of the duplexes formed with the cDNA strand (DNA: 5'-T-T-T-T-T-T-T-A-T-T-G-C-T-T-T-3') showed no major variations, suggesting that the electronic properties of the Ru(II) complexes are largely unaffected by hybridization. The thermal stability of the PNA·DNA duplexes, as evaluated from UV melting experiments, is enhanced compared to the corresponding nonmetalated duplexes. The melting temperature (T(m)) was almost 8 °C higher for PNA2·DNA duplex, and 4 °C for PNA3·DNA duplex, with the stabilization attributed to the electrostatic interaction between the cationic residues (Ru(II) unit and positively charged lysine/arginine) and the polyanionic DNA backbone. In presence of tripropylamine (TPA) as co-reactant, PNA2, PNA3, PNA2

  14. Solid and solution NMR studies of the complexation of Ag + with the trans isomer of captopril: Biological activities of this high blood pressure drug along with its Ag + complex

    NASA Astrophysics Data System (ADS)

    Isab, Anvarhusein A.; Wazeer, Mohamed I. M.

    2006-09-01

    Complexation of Ag + with captopril, 1-[(2 S)-3-mercapto-2-methylpropionyl]- L-proline, has been studied by 1H and 13C-NMR spectroscopy. The equilibrium constants for the trans to cis isomers of captopril bound to Ag + were measured by 1H NMR spectroscopy. It is observed that the trans isomer of the drug binds more strongly to Ag + between pH 5 and 8, as shown by the broadening of the trans isomer's resonances in 13C NMR spectra on complexation. A monodentate complexation of the trans captopril with Ag + via the thiol site is proposed based on the solid-state NMR and IR data. A superior antimicrobial activity is exhibited by the Cap-Ag(I) complex compared to captopril ligand itself against Heterotrotropic Plate Counts (HPC), Pseudomonas aeruginosa and Fecal streptococcus bacteria.

  15. Power-Aware Asynchronous Peer-to-Peer Duplex Communication System Based on Multiple-Valued One-Phase Signaling

    NASA Astrophysics Data System (ADS)

    Mizusawa, Kazuyasu; Onizawa, Naoya; Hanyu, Takahiro

    This paper presents a design of an asynchronous peer-to-peer half-duplex/full-duplex-selectable data-transfer system on-chip interconnected. The data-transfer method between channels is based on a 1-phase signaling scheme realized by using multiple-valued current-mode (MVCM) circuits and encoding, which performs high-speed communication. A data transmission is selectable by adding a mode-detection circuit that observes data-transmission modes; full-duplex, half duplex and standby modes. Especially, since current sources are completely cut off during the standby mode, the power dissipation can be greatly reduced. Moreover, both half-duplex and full-duplex communication can be realized by sharing a common circuit except a signal-level conversion circuit. The proposed interface is implemented using 0.18-μm CMOS, and its performance improvement is discussed in comparison with those of the other ordinary asynchronous methods.

  16. Diagnosing erectile dysfunction: the penile dynamic colour duplex ultrasound revisited.

    PubMed

    Aversa, A; Bruzziches, R; Spera, G

    2005-12-01

    A number of disease processes of the penis including Peyronie's disease, priapism, penile fractures and tumors are clearly visualized with ultrasound. Diagnostic evaluation of erectile dysfunction (ED) by penile dynamic colour-duplex Doppler ultrasonography (D-CDDU) is actually considered a second level approach to ED patients because of the fact that intracavernous injections test IV with prostaglandin-E(1) may provide important information about the patients' erectile capacity. However, no direct vascular imaging and a high percentage of false negative diagnoses of vasculogenic ED are its major pitfalls and subsequent treatment decisions remain quite limited. The occurrence of ED and its sentinel relationship to cardiovascular disease has prompted more accurate vascular screening in all patients even in the absence of cardiovascular risk factors. The sonographic evaluation of the intima-media thickness of the carotid arteries may sometimes represent an early manifestation of diffuse atherosclerotic disease and endothelial damage. This latter finding is often the cause of failure to oral agents, i.e. phosphodiesterase inhibitors, because of inability of the dysfunctional endothelium to release nitric oxide. D-CDDU represents an accurate tool to investigate cavernous artery inflow and venous leakage when compared with more invasive diagnostic techniques i.e. selective arteriography and dynamic infusion cavernosometry along with cavernosography.

  17. Phase Separation in Lean Grade Duplex Stainless Steel 2101

    SciTech Connect

    Garfinkel, D.; Poplawsky, Jonathan D.; Guo, Wei; Young, Jr., George A.; Tucker, Julie

    2015-08-19

    The use of duplex stainless steels (DSS) in nuclear power generation systems is limited by thermal instability that leads to embrittlement in the temperature range of 204°C - 538°C. New lean grade alloys, such as 2101, offer the potential to mitigate these effects. Thermal embrittlement was quantified through impact toughness and hardness testing on samples of alloy 2101 after aging at 427°C for various durations (1-10,000 hours). Additionally, atom probe tomography (APT) was utilized in order to observe the kinetics of α-α’ separation and G-phase formation. Mechanical testing and APT data for two other DSS alloys, 2003 and 2205 were used as a reference to 2101. The results show that alloy 2101 exhibits superior performance compared to the standard grade DSS alloy, 2205, but inferior to the lean grade alloy, 2003, in mechanical testing. APT data demonstrates that the degree of α-α’ separation found in alloy 2101 closely resembles that of 2205, and greatly exceeds 2003. Additionally, contrary to what was observed in 2003, 2101 demonstrated G-phase like precipitates after long aging times, though precipitates were not as abundant as was observed in 2205.

  18. Aging of cast duplex stainless steels in LWR systems

    SciTech Connect

    Chopra, O.K.; Chung, H.M.

    1984-10-01

    A program is being conducted to investigate the significance of in-service embrittlement of cast duplex stainless steels under light-water reactor operating conditions. The existing data are evaluated to determine the expected embrittlement of cast components during the operating lifetime of reactors and to define the objectives and scope of the investigation. This presentation describes the status of the program. Data for the metallurgical characterization of the various cast stainless steels used in the investigation are presented. Charpy impact tests on short-term aged material indicate that CF-3 stainless steels are less susceptible to embrittlement than CF-8 or CF-8M stainless steels. Microstructural characterization of cast stainless steels that were obtained from Georg Fischer Co. and aged for up to 70,000 h at 300, 350, and 400/sup 0/C reveals the formation of four different types of precipitates that are not ..cap alpha..'. Embrittlement of the ferrite phase is primarily due to pinning of the dislocations by two of these precipitates, designated as Type M and Type X. The ferrite phase is embrittled after approx. 8 y at 300/sup 0/C and shows cleavage fracture. Examination of the fracture surfaces of the impact-test specimens indicates that the toughness of the long-term aged material is determined by the austenite phase. 8 figures, 3 tables.

  19. Superplastic Forming of Duplex Stainless Steel for Aerospace Part

    NASA Astrophysics Data System (ADS)

    Lee, Ho-Sung; Yoon, Jong-Hoon; Yoo, Joon-Tae; Yi, Young-Moo

    2011-08-01

    In this study, the high temperature forming behavior of duplex stainless steel has been characterized and the outer shell of a combustion chamber was fabricated with pressure difference of hot gas. It consists of two parts which are the outer skin made of stainless steel to sustain the internal pressure and the inner shell made of copper alloy for regenerative cooling channels. Two outer skins partitioned to half with respect to the symmetric axis was prepared by hot gas forming process with a maximum pressure of 7 MPa following to FEM analysis. For inner layer, copper alloy was machined for cooling channels and then placed in the gas pressure welding fixture. It is shown that the optimum condition of gas pressure welding is 7 MPa at 890 °C, for one hour. EDX analysis and scanning electron microscope micrograph confirm the atomic diffusion process is observed at the interface and copper atoms diffuse into steel, while iron and chrome atoms diffuse into copper. The result shows that the manufacturing method with superplastic forming and gas pressure welding of steel and copper alloy has been successful for near net shape manufacturing of scaled combustion chamber of launch vehicle.

  20. Carburizing of Duplex Stainless Steel (DSS) Under Compression Superplastic Deformation

    NASA Astrophysics Data System (ADS)

    Ahamad, Nor Wahida; Jauhari, Iswadi

    2012-12-01

    A new surface carburizing technique which combines superplastic deformation with superplastic carburizing (SPC) is introduced. SPC was conducted on duplex stainless steel under compression mode at a fixed 0.5 height reduction strain rates ranging from 6.25 × 10-5 to 1 × 10-3 s-1 and temperature ranging from 1173 K to 1248 K (900 °C to 975 °C). The results are compared with those from conventional and non-superplastic carburizing. The results show that thick hard carburized layers are formed at a much faster rate compared with the other two processes. A more gradual hardness transition from the surface to the substrate is also obtained. The highest carburized layer thickness and surface hardness are attained under SPC process at 1248 K (975 °C) and 6.25 × 10-5 s-1 with a value of (218.3 ± 0.5) μm and (1581.0 ± 5.0) HV respectively. Other than that, SPC also has the highest scratch resistance.

  1. Eddy current techniques for super duplex stainless steel characterization

    NASA Astrophysics Data System (ADS)

    Camerini, C.; Sacramento, R.; Areiza, M. C.; Rocha, A.; Santos, R.; Rebello, J. M.; Pereira, G.

    2015-08-01

    Super duplex stainless steel (SDSS) is a two-phase material where the microstructure consists of grains of ferrite (δ) and austenite (γ). SDSS exhibit an attractive combination of properties, such as: strength, toughness and stress corrosion cracking resistance. Nevertheless, SDSS attain these properties after a controlled solution heat treatment, leading to a similar volumetric fraction of δ and γ. Any further heat treatment, welding operation for example, can change the balance of the original phases, or may also lead to precipitation of a deleterious phase, such as sigma (σ). For these situations, the material corrosion resistance is severely impaired. In the present study, several SDSS samples with low σ phase content and non-balanced microstructure were intentionally obtained by thermally treating SDSS specimens. Electromagnetic techniques, conventional Eddy Current Testing (ECT) and Saturated Low Frequency Eddy Current (SLOFEC), were employed to characterize the SDSS samples. The results showed that ECT and SLOFEC are reliable techniques to evaluate σ phase presence in SDSS and can provide an estimation of the δ content.

  2. Phase Separation in Lean Grade Duplex Stainless Steel 2101

    DOE PAGES

    Garfinkel, D.; Poplawsky, Jonathan D.; Guo, Wei; ...

    2015-08-19

    The use of duplex stainless steels (DSS) in nuclear power generation systems is limited by thermal instability that leads to embrittlement in the temperature range of 204°C - 538°C. New lean grade alloys, such as 2101, offer the potential to mitigate these effects. Thermal embrittlement was quantified through impact toughness and hardness testing on samples of alloy 2101 after aging at 427°C for various durations (1-10,000 hours). Additionally, atom probe tomography (APT) was utilized in order to observe the kinetics of α-α’ separation and G-phase formation. Mechanical testing and APT data for two other DSS alloys, 2003 and 2205 weremore » used as a reference to 2101. The results show that alloy 2101 exhibits superior performance compared to the standard grade DSS alloy, 2205, but inferior to the lean grade alloy, 2003, in mechanical testing. APT data demonstrates that the degree of α-α’ separation found in alloy 2101 closely resembles that of 2205, and greatly exceeds 2003. Additionally, contrary to what was observed in 2003, 2101 demonstrated G-phase like precipitates after long aging times, though precipitates were not as abundant as was observed in 2205.« less

  3. Cavitation corrosion behavior of cast duplex stainless steel in seawater

    SciTech Connect

    Shalaby, H.M.; Al-Hashem, A.

    1996-10-01

    The cavitation corrosion behavior of a commercial cast duplex stainless steel was studied in seawater using an ultrasonically induced cavitation facility at a frequency of 20 kHz and an amplitude of 25 {micro}m. The work included measurements of the free corrosion potential and mass loss in addition to microscopic examinations. Cavitation caused an active shift in the free corrosion potential. The rate of mass loss was negligible in quiescent seawater, while it significantly increased in the presence of cavitation. The application of cathodic protection reduced the rate of mass loss by 19%. Microscopic examinations revealed that the first signs of cavitation damage were in the form of slip bands and small cavities in the austenite islands and at the ferrite/austenite boundaries. With the progress of cavitation, material loss became mainly at the austenite phase and spread to the ferrite phase at a later stage. Cathodic protection decreased slightly the number of cavities. Cross-sectional examinations revealed the presence of microcracks in the bulk of the material. The microcracks initiated at the surface in the ferrite matrix. Crack propagation was impeded by the austenite islands and branched along parallel slip systems.

  4. Superplastic Forming of Duplex Stainless Steel for Aerospace Part

    SciTech Connect

    Lee, Ho-Sung; Yoon, Jong-Hoon; Yoo, Joon-Tae; Yi, Young-Moo

    2011-08-22

    In this study, the high temperature forming behavior of duplex stainless steel has been characterized and the outer shell of a combustion chamber was fabricated with pressure difference of hot gas. It consists of two parts which are the outer skin made of stainless steel to sustain the internal pressure and the inner shell made of copper alloy for regenerative cooling channels. Two outer skins partitioned to half with respect to the symmetric axis was prepared by hot gas forming process with a maximum pressure of 7 MPa following to FEM analysis. For inner layer, copper alloy was machined for cooling channels and then placed in the gas pressure welding fixture. It is shown that the optimum condition of gas pressure welding is 7 MPa at 890 deg. C, for one hour. EDX analysis and scanning electron microscope micrograph confirm the atomic diffusion process is observed at the interface and copper atoms diffuse into steel, while iron and chrome atoms diffuse into copper. The result shows that the manufacturing method with superplastic forming and gas pressure welding of steel and copper alloy has been successful for near net shape manufacturing of scaled combustion chamber of launch vehicle.

  5. Synthesis, characterization and antimicrobial activity of water-soluble silver(i) complexes of metronidazole drug and selected counter-ions.

    PubMed

    Kalinowska-Lis, Urszula; Felczak, Aleksandra; Chęcińska, Lilianna; Zawadzka, Katarzyna; Patyna, Emilia; Lisowska, Katarzyna; Ochocki, Justyn

    2015-05-07

    A series of water-soluble silver(i) complexes of the type [Ag(MTZ)2X] [MTZ = 1-(2-hydroxyethyl)-2-methyl-5-nitro-1H-imidazole (metronidazole drug); X = NO3(-), ClO4(-), CF3COO(-), BF4(-) and CH3SO3(-)] was synthesised by the reactions of various Ag(i) salts with metronidazole (MTZ). All the complexes were characterized by ESI-MS spectrometry, solution NMR ((1)H and (13)C) and IR spectroscopy, and elemental analysis. Further evidence for the formation and molecular structure of all the complexes was provided by X-ray single-crystal crystallography. The different counter ions affect the crystal packing of the complexes and thus have an impact on the final geometries. The antimicrobial activities of the complexes against two Gram-positive strains: Staphylococcus aureus ATCC 6538, Staphylococcus epidermidis ATCC 12228, three Gram-negative strains: Pseudomonas aeruginosa ATCC 15442, Escherichia coli ATCC 25922, Proteus hauseri ATCC 13315 and yeast Candida albicans ATCC 10231 were evaluated and compared with antibacterial and antifungal properties of appropriate silver salts, metronidazole and silver sulfadiazine drugs. The newly synthesized compounds exhibited significant antibacterial activity against Gram-positive bacteria, better than the referenced silver sulfadiazine. The best active silver(i)-metronidazole complex contains a methanesulphonate counter-ion. Moreover, the complex inhibited the growth of yeast Candida albicans at a concentration 3-fold lower than that required for silver sulfadiazine. In addition, the complexes containing a tetrafluoroborate and a perchlorate as counter-ions were characterized as effective antibacterial agents against the tested Gram-negative bacteria.

  6. Nickel(II) diacetyl monoxime-2-pyridyl hydrazone complex can inhibit Ehrlich solid tumor growth in mice: A potential new antitumor drug.

    PubMed

    Saad, Entsar A; Hassanien, Mohamed M; El-Lban, Faten W

    2017-03-11

    The chief chemotherapeutic drug, cisplatin had common bad effects such as nephrotoxicity, ototoxicity and bone marrow depression. This led us to develop a new potential anticancer drug based on nickel metal ion that may be less toxic. Nickel(II) diacetyl monoxime-2-pyridyl hydrazone complex cytoprotective effect, superoxide dismutase (SOD)-like activity and anticancer activities were studied. In vitro, the complex showed SOD-like activity of 86.62%. It was capable to kill 90.2% of Ehrlich ascites carcinoma (EAC) cells and to protect 92.48% of human RBCs. In vivo, the complex lowered the tumor burden markedly in a concentration-dependent manner. Noticeably, solid tumor growth was suppressed; tumor volume and weight were reduced and mice life span was lengthened. The hematological indices were improved, catalase activity was re-elevated and malondialdehyde (MDA) level was reversed towards normal. Nucleic acids, cholesterol, triglycerides, liver enzymes, urea and creatinine contents were reduced to near normal ranges. Glutathione (GSH), SOD, albumin and total protein levels were increased. In conclusion, our results revealed that the complex has the ability to suppress Ehrlich solid tumor growth in mice with minimal side effects. This may possibly via its redox activity. Surprisingly, nickel complex antitumor activities were more potent than those of cisplatin.

  7. Drug modulation of water-heme interactions in low-spin P450 complexes of CYP2C9d and CYP125A1.

    PubMed

    Conner, Kip P; Cruce, Alex A; Krzyaniak, Matthew D; Schimpf, Alina M; Frank, Daniel J; Ortiz de Montellano, Paul; Atkins, William M; Bowman, Michael K

    2015-02-10

    Azoles and pyridines are commonly incorporated into small molecule inhibitor scaffolds that target cytochromes P450 (CYPs) as a strategy to increase drug binding affinity, impart isoform-dependent selectivity, and improve metabolic stability. Optical absorbance spectra of the CYP-inhibitor complex are widely used to infer whether these inhibitors are ligated directly to the heme iron as catalytically inert, low-spin (type II) complexes. Here, we show that the low-spin complex between a drug-metabolizing CYP2C9 variant and 4-(3-phenylpropyl)-1H-1,2,3-triazole (PPT) retains an axial water ligand despite exhibiting elements of "classic" type II optical behavior. Hydrogens of the axial water ligand are observed by pulsed electron paramagnetic resonance (EPR) spectroscopy for both inhibitor-free and inhibitor-bound species and show that inhibitor binding does not displace the axial water. A (15)N label incorporated into PPT is 0.444 nm from the heme iron, showing that PPT is also in the active site. The reverse type I inhibitor, LP10, of CYP125A1 from Mycobacterium tuberculosis, known from X-ray crystal structures to form a low-spin water-bridged complex, is found by EPR and by visible and near-infrared magnetic circular dichroism spectroscopy to retain the axial water ligand in the complex in solution.

  8. Recovery from rapamycin: drug-insensitive activity of yeast target of rapamycin complex 1 (TORC1) supports residual proliferation that dilutes rapamycin among progeny cells.

    PubMed

    Evans, Stephanie K; Burgess, Karl E V; Gray, Joseph V

    2014-09-19

    The target of rapamycin complex 1 (TORC1) is a key conserved regulator of eukaryotic cell growth. The xenobiotic rapamycin is a potent inhibitor of the yeast complex. Surprisingly, the EGO complex, a nonessential in vivo activator of TORC1, is somehow required for yeast cells to recover efficiently from a period of treatment with rapamycin. Why? Here, we found that rapamycin is only a partial inhibitor of TORC1. We confirmed that saturating amounts of rapamycin do not fully inhibit proliferation of wild-type cells, and we found that the residual proliferation in the presence of the drug is dependent on the EGO complex and on the activity of TORC1. We found that this residual TORC1-dependent proliferation is key to recovery from rapamycin treatment. First, the residual proliferation rate correlates with the ability of cells to recover from treatment. Second, the residual proliferation rate persists long after washout of the drug and until cells recover. Third, the total observable pool of cell-associated rapamycin is extremely stable and decreases only with increasing cell number after washout of the drug. Finally, consideration of the residual proliferation rate alone accurately and quantitatively accounts for the kinetics of recovery of wild-type cells and for the nature and severity of the ego- mutant defect. Overall, our results revealed that rapamycin is a partial inhibitor of yeast TORC1, that persistence of the drug limits recovery, and that rapamycin is not detoxified by yeast but is passively diluted among progeny cells because of residual proliferation.

  9. Spectrophotometric determination of some anti-tussive and anti-spasmodic drugs through ion-pair complex formation with thiocyanate and cobalt(II) or molybdenum(V)

    NASA Astrophysics Data System (ADS)

    El-Shiekh, Ragaa; Zahran, Faten; El-Fetouh Gouda, Ayman Abou

    2007-04-01

    Two rapid, simple and sensitive extractive specrophotometric methods has been developed for the determination of anti-tussive drugs, e.g., dextromethorphan hydrobromide (DEX) and pipazethate hydrochloride (PiCl) and anti-spasmodic drugs, e.g., drotaverine hydrochloride (DvCl) and trimebutine maleate (TM) in bulk and in their pharmaceutical formulations. The proposed methods depend upon the reaction of cobalt(II)-thiocyanate (method A) and molybdenum(V)-thiocyanate ions (method B) with the cited drugs to form stable ion-pair complexes which extractable with an n-butnol-dichloromethane solvent mixture (3.5:6.5) and methylene chloride for methods A and B, respectively. The blue and orange red color complexes are determined either colorimetrically at λmax 625 nm (using method A) and 467 or 470 nm for (DEX and PiCl) or (DvCl and TM), respectively (using method B). The concentration range is 20-400 and 2.5-50 μg mL -1 for methods A and B, respectively. The proposed method was successfully applied for the determination of the studied drugs in pure and in pharmaceutical formulations applying the standard additions technique and the results obtained in good agreement well with those obtained by the official method.

  10. Spectrophotometric determination of some anti-tussive and anti-spasmodic drugs through ion-pair complex formation with thiocyanate and cobalt(II) or molybdenum(V).

    PubMed

    El-Shiekh, Ragaa; Zahran, Faten; El-Fetouh Gouda, Ayman Abou

    2007-04-01

    Two rapid, simple and sensitive extractive specrophotometric methods has been developed for the determination of anti-tussive drugs, e.g., dextromethorphan hydrobromide (DEX) and pipazethate hydrochloride (PiCl) and anti-spasmodic drugs, e.g., drotaverine hydrochloride (DvCl) and trimebutine maleate (TM) in bulk and in their pharmaceutical formulations. The proposed methods depend upon the reaction of cobalt(II)-thiocyanate (method A) and molybdenum(V)-thiocyanate ions (method B) with the cited drugs to form stable ion-pair complexes which extractable with an n-butnol-dichloromethane solvent mixture (3.5:6.5) and methylene chloride for methods A and B, respectively. The blue and orange red color complexes are determined either colorimetrically at lambdamax 625 nm (using method A) and 467 or 470 nm for (DEX and PiCl) or (DvCl and TM), respectively (using method B). The concentration range is 20-400 and 2.5-50 microg mL-1 for methods A and B, respectively. The proposed method was successfully applied for the determination of the studied drugs in pure and in pharmaceutical formulations applying the standard additions technique and the results obtained in good agreement well with those obtained by the official method.

  11. Modeling stopped-flow data for nucleic acid duplex formation reactions: the importance of off-path intermediates.

    PubMed

    Sikora, Jacqueline R; Rauzan, Brittany; Stegemann, Rachel; Deckert, Alice

    2013-08-01

    Evidence for unexpected off-path intermediates to DNA duplex formation is presented. These off-path intermediates are shown to involve unimolecular and, in one case, bimolecular structure in one of the single strands of complementary DNA. Three models are developed to account for the observed single-stranded structures that are formed in parallel with duplex formation. These models are applied to the analysis of stopped-flow data for eight different nonself-complementary duplex formation reactions in order to extract the elementary rate constant for formation of the duplex from the complementary random coil single-stranded DNA. The free energy of activation (at 25 °C) for the denaturation of each duplex is calculated from these data and is shown to have a linear correlation to the overall standard free energy for duplex formation (also at 25 °C). Duplexes that contain mismatches obey a parallel linear free-energy (LFE) relationship with a y-intercept that is greater than that of duplexes without mismatches. Slopes near unity for the LFE relationships indicate that all duplexes go through an early, unstructured transition state.

  12. Thermodynamic profiles and nuclear magnetic resonance studies of oligonucleotide duplexes containing single diastereomeric spiroiminodihydantoin lesions.

    PubMed

    Khutsishvili, Irine; Zhang, Na; Marky, Luis A; Crean, Conor; Patel, Dinshaw J; Geacintov, Nicholas E; Shafirovich, Vladimir

    2013-02-26

    The spiroiminodihydantoins (Sp) are highly mutagenic oxidation products of guanine and 8-oxo-7,8-dihydroguanine in DNA. The Sp lesions have recently been detected in the liver and colon of mice infected with Helicobacter hepaticus that induces inflammation and the development of liver and colon cancers in murine model systems [Mangerich, A., et al. (2012) Proc. Natl. Acad. Sci. U.S.A. 109, E1820-E1829]. The impact of Sp lesions on the thermodynamic characteristics and the effects of the diastereomeric Sp-R and Sp-S lesions on the conformational features of double-stranded 11-mer oligonucleotide duplexes have been studied by a combination of microcalorimetric methods, analysis of DNA melting curves, and two-dimensional nuclear magnetic resonance methods. The nonplanar, propeller-like shapes of the Sp residues strongly diminish the extent of local base stacking interactions that destabilize the DNA duplexes characterized by unfavorable enthalpy contributions. Relative to that of an unmodified duplex, the thermally induced unfolding of the duplexes with centrally positioned Sp-R and Sp-S lesions into single strands is accompanied by a smaller release of cationic counterions (Δn(Na⁺) = 0.6 mol of Na⁺/mol of duplex) and water molecules (Δn(w) = 17 mol of H₂O/mol of duplex). The unfolding parameters are similar for the Sp-R and Sp-S lesions, although their orientations in the duplexes are different. The structural disturbances radiate one base pair beyond the flanking C:G pair, although Watson-Crick hydrogen bonding is maintained at all flanking base pairs. The observed relatively strong destabilization of B-form DNA by the physically small Sp lesions is expected to have a significant impact on the processing of these lesions in biological environments.

  13. Synthesis, crystal structure and spectroscopy of bioactive Cd(II) polymeric complex of the non-steroidal anti-inflammatory drug diclofenac sodium: Antiproliferative and biological activity

    NASA Astrophysics Data System (ADS)

    Tabrizi, Leila; Chiniforoshan, Hossein; McArdle, Patrick

    2015-02-01

    The interaction of Cd(II) with the non-steroidal anti-inflammatory drug diclofenac sodium (Dic) leads to the formation of the complex [Cd2(L)41.5(MeOH)2(H2O)]n(L = Dic), 1, which has been isolated and structurally characterized by X-ray crystallography. Diclofenac sodium and its metal complex 1 have also been evaluated for antiproliferative activity in vitro against the cells of three human cancer cell lines, MCF-7 (breast cancer cell line), T24 (bladder cancer cell line), A-549 (non-small cell lung carcinoma), and a mouse fibroblast L-929 cell line. The results of cytotoxic activity in vitro expressed as IC50 values indicated the diclofenac sodium and cadmium chloride are non active or less active than the metal complex of diclofenac (1). Complex 1 was also found to be a more potent cytotoxic agent against T-24 and MCF-7 cancer cell lines than the prevalent benchmark metallodrug, cisplatin, under the same experimental conditions. The superoxide dismutase activity was measured by Fridovich test which showed that complex 1 shows a low value in comparison with Cu complexes. The binding properties of this complex to biomolecules, bovine or human serum albumin, are presented and evaluated. Antibacterial and growth inhibitory activity is also higher than that of the parent ligand compound.

  14. Synthesis, structural characterization, in vitro antimicrobial and anticancer activity studies of ternary metal complexes containing glycine amino acid and the anti-inflammatory drug lornoxicam

    NASA Astrophysics Data System (ADS)

    Mahmoud, Walaa H.; Mohamed, Gehad G.; El-Dessouky, Maher M. I.

    2015-02-01

    Mixed ligand complexes were synthesized using lornoxicam (LOR) as the primary ligand and glycine amino acid (HGly) as the secondary ligand. They were characterized by FT-IR, UV-Vis, mass, 1H NMR, ESR spectral studies, TG-DTG, X-ray powder diffraction and physical analytical studies. From the molar conductance, magnetic moment and electronic spectral data of the synthesized complexes, general formulae of [M(LOR)2(Gly)]·Xn·yH2O where M = Cr(III) (X = Cl, n = 2, y = 3), Mn(II) (X = Cl, n = 1, y = 1), Co(II) (X = BF4, n = 1, y = 0), Ni(II) (X = Cl, n = 1, y = 0), Cu(II) (X = BF4, n = 1, y = 2) and Zn(II) (X = BF4, n = 1, y = 2) and (M = Fe(II) (X = BF4, n = 1, y = 1) and Fe(III) (X = Cl, n = 2, y = 1) with an octahedral structure were proposed. Thermal analyses show that the complexes lose water molecules of hydration initially and subsequently expel anionic parts and organic ligands in continuous steps. The kinetic parameters namely E, ΔH∗, ΔS∗ and ΔG∗ illustrate the spontaneous association of the metal and ligands in the formation of the complexes. The antimicrobial efficiency of the LOR and HGly ligands and the ternary complexes were examined by in vitro method against various pathogenic bacterial and fungal strains. The metal complexes were found to possess efficient antimicrobial properties compared to lornoxicam and most of these complexes could turn out to be excellent models for the design of effective antibiotic drug substances. Also, the two ligands, in comparison to ternary metal complexes are screened for their anticancer activity against breastic cancer cell line. The results showed that the metal complexes be more active than the parent LOR and glycine free ligands except Cr(III) ternary complex which was found to be inactive.

  15. New mixed ligand zinc(II) complexes based on the antiepileptic drug sodium valproate and bioactive nitrogen-donor ligands. Synthesis, structure and biological properties.

    PubMed

    Darawsheh, Mohanad; Abu Ali, Hijazi; Abuhijleh, A Latif; Rappocciolo, Emilia; Akkawi, Mutaz; Jaber, Suhair; Maloul, Salam; Hussein, Yasmeen

    2014-07-23

    Starting from the precursor [Zinc Valproate complex] (1), new mixed ligand zinc(II) complexes of valproic acid and nitrogen-based ligands, formulating as, [Zn(valp)22,9-dmphen] (2), [Zn2(valp)4(quin)2] (3), [Zn(valp)2(2-ampy)2] (4), and [Zn(valp)2(2-ampic)2] (5) (valp = valproate, 2,9-dmphen = 2,9-dimethyl-1,10-phenanthroline, quin = quinoline, 2-ampy = 2-aminopyridine, 2-ampic = 2-amino-6-picoline) were synthesized and characterized using IR, (1)H NMR, (13)C{(1)H} NMR and UV-Vis spectrometry. The crystal structures of complexes 2, 3 and 4 were determined using single-crystal X-ray diffraction. The complexes were also evaluated for their anti-bacterial activity using in-vitro agar diffusion method against three Gram-positive (Micrococcus luteus, Staphylococcus aureus, and Bacillus subtilis) and three Gram-negative (Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis) species. Complex 2 showed considerable activity against all tested microorganisms and the effect of complexation on the anti-bacterial activity of the parent ligand of 2 was also investigated. The anti-bacterial activity of 2,9-dmphen against Gram-negative bacteria was enhanced upon complexation with zinc valproate. On the other hand, complexes 1 and 3 showed weak inhibition activity against the tested species and complexes 4 and 5 didn't show any activity at all. Two methods were used for testing the inhibition of ferriprotoporphyrinIX bio-mineralization: a semi-quantitative micro-assay and a previously self-developed quantitative in-vitro method. Both were used to study the efficiency of these complexes in inhibiting the formation of the Malaria pigment which considered being the target of many known anti-malarial drugs such as Chloroquine and Amodiaquine. Results showed that the efficiency of complex 2 in preventing the formation of β-Hematin was 80%. The efficiency of Amodiaquine as a standard drug was reported to give 91%.

  16. Excited State Proton Transfer of Natural Flavonoids and Their Chromophores in Duplex and Tetraplex DNAs

    PubMed Central

    2015-01-01

    Fisetin (3,7,3′,4′-tetrahydroxyflavone) and quercetin (3,5,7,3′,4′-pentahydroxyflavone) are the bioactive plant flavonoids that are potentially useful therapeutic drugs for the treatment of a broad spectrum of diseases, including atherosclerosis, cardiovascular disease, obesity, hypertension, and cancer. 3-Hydroxyflavone (3HF) and 7-hydroxyflavone (7HF) are the synthetic chromophores of fisetin and quercetin. We have exploited dual luminescence properties of fisetin and quercetin along with 3-HF and 7HF to examine their efficacy of binding and compare their interactions with DNA, which is one of the macromolecular targets of flavonoids in physiological systems. Following the sequence of the human telomeric DNA 5′-d (CCCTAA-)n/(-TTAGGG)n-5′, two single-stranded DNA oligonucleotides, 5′-d(C3TA2)3C3-3′ and 5′-d(T2AG3)4-3′, and their duplex were used as receptors to study binding by the ligands quercetin, fisetin, and their chromophores. Circular dichroism, differential absorption, UV thermal melting, and size exclusion chromatographic studies indicated the formation of unusual DNA structures (such as C4 and G4 tetraplexes) for both the C- and G-rich single-stranded DNAs. Upon binding to DNA, dramatic changes were observed in the intrinsic fluorescence behavior of the flavonoids. Molecular docking studies were performed to describe the likely binding sites for the ligands. The spectroscopic studies on flavonoid–DNA interactions described herein demonstrate a powerful approach for examining their DNA binding through exploiting the highly sensitive intrinsic fluorescence properties of the flavonoids as their own “reporter” for their interactions with macromolecular targets. PMID:25393681

  17. Utilizing structures of CYP2D6 and BACE1 complexes to reduce risk of drug-drug interactions with a novel series of centrally efficacious BACE1 inhibitors.

    PubMed

    Brodney, Michael A; Beck, Elizabeth M; Butler, Christopher R; Barreiro, Gabriela; Johnson, Eric F; Riddell, David; Parris, Kevin; Nolan, Charles E; Fan, Ying; Atchison, Kevin; Gonzales, Cathleen; Robshaw, Ashley E; Doran, Shawn D; Bundesmann, Mark W; Buzon, Leanne; Dutra, Jason; Henegar, Kevin; LaChapelle, Erik; Hou, Xinjun; Rogers, Bruce N; Pandit, Jayvardhan; Lira, Ricardo; Martinez-Alsina, Luis; Mikochik, Peter; Murray, John C; Ogilvie, Kevin; Price, Loren; Sakya, Subas M; Yu, Aijia; Zhang, Yong; O'Neill, Brian T

    2015-04-09

    In recent years, the first generation of β-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer's disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Herein, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug-drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, we solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogues with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins.

  18. Thermodynamics of HMGB1 interaction with duplex DNA.

    PubMed

    Müller, S; Bianchi, M E; Knapp, S

    2001-08-28

    The high mobility group protein HMGB1 is a small, highly abundant protein that binds to DNA in a non-sequence-specific manner. HMGB1 consists of 2 DNA binding domains, the HMG boxes A and B, followed by a short basic region and a continuous stretch of 30 glutamate or aspartate residues. Isothermal titration calorimetry was used to characterize the binding of HMGB1 to the double-stranded model DNAs poly(dAdT).(dTdA) and poly(dGdC).(dCdG). To elucidate the contribution of the different structural motifs to DNA binding, calorimetric measurements were performed comparing the single boxes A and B, the two boxes plus or minus the basic sequence stretch (AB(bt) and AB), and the full-length HMGB1 protein. Thermodynamically, binding of HMGB1 and all truncated constructs to duplex DNA was characterized by a positive enthalpy change at 15 degrees C. From the slopes of the temperature dependence of the binding enthalpies, heat capacity changes of -0.129 +/- 0.02 and -0.105 +/- 0.05 kcal mol(-1) K(-1) were determined for box A and full-length HMGB1, respectively. Significant differences in the binding characteristics were observed using full-length HMGB1, suggesting an important role for the acid tail in modulating DNA binding. Moreover, full-length HMGB1 binds differently these two DNA templates: binding to poly(dAdT).(dTdA) was cooperative, had a larger apparent binding site size, and proceeded with a much larger unfavorable binding enthalpy than binding to poly(dGdC).(dCdG).

  19. The Usefulness of Duplex Ultrasound for Hemodialysis Access Selection

    PubMed Central

    Choi, Jeong Won; Joh, Jin Hyun; Park, Ho-Chul

    2017-01-01

    Purpose A native vessel is preferable to an artificial graft for dialysis access. Duplex ultrasound (DUS) is noninvasive, cost-effective modality to evaluate the vessels for dialysis. The purpose of this study was to compare the rates of utilization of native vessels after preoperative imaging with DUS and contrast venography (CV). Materials and Methods A retrospective review was performed on patients who received an arteriovenous fistula (AVF) or arteriovenous graft (AVG) between June 2006 and July 2010. Patients were classified into 3 groups. In group 1, CV was used to evaluate the vessel. Both DUS and CV were used in group 2. In group 3, only DUS was used. The frequency of utilization of a native vessel was analyzed in each group. The chi-square test was used for statistical analysis. Results During the study period, 173 patients received an AVF or AVG. Eighty-nine patients were male. The mean age was 60.6±14.6 years. A native vessel was used in 56/81 patients (69.1%) and 74/81 patients (91.4%) in groups 1 and 3, respectively (P<0.001). In group 2, all patients underwent access procedures using native vessels. AVG was initially planned for 2 patients in group 2 after vessel evaluation using CV, but a native vessel was successfully used because DUS identified optimal vessels for AVF. The 1-year primary patency rate was similar in 3 groups. Conclusion Preoperative DUS is safe and easy to use for vessel evaluation, and can be used as a primary imaging modality for creation of access. PMID:28377908

  20. Use of Symmetry in Calibration of Looped Duplex DTS Measurements

    NASA Astrophysics Data System (ADS)

    Van De Giesen, N.; van der Spek, A.

    2014-12-01

    A looped duplex Distributed Temperature Sensing (DTS) deployment uses a bifilar arrangement of two optical fibres in the same cable or conduit. On one end of the cable the ends of the fibres are spliced together. The other ends are connected to a (double ended) DTS system or one end is connected to a (single ended) DTS system. A light pulse shot from one end will eventually emerge from the other end and vice versa. Back scattered Raman-shifted photons will thus be detected twice for each posistion along the cable or conduit but delayed in time by twice the distance from the symmetry point (turn around sub) divided by the speed of light in the fibre.Calibration of a DTS system requires, first and foremost that differential loss; i.e. the difference in optical attenuation between Stokes and anti-Stokes backscattered signals, is compensated for. It will be shown that residual errors due to uncompensated differential loss can only be due to the uneven part of the (non-uniform) differential loss distribution. A bifilar deployment is therefore highly insensitive to uncompensated differential loss because ageing, chemical or mechanical damage to the cable as well as thermal or mechanical strain may vary over the length of the cable but remain symmetrical and therefore even with respect to the turn around sub.By writing the (non-)uniform differential loss as the sum of an even and an uneven part it is possible to derive an equation for the residual error of a DTS temperature measurement expressed as an integral over the uneven part of the differential loss distribution only. Thus it is possible to estimate any residual temperature error under field conditions. Such a capability is especially useful where no access to one end of the cable is possible, such as is the case in borehole applications.

  1. Full-Duplex Digital Communication on a Single Laser Beam

    NASA Technical Reports Server (NTRS)

    Hazzard, D. A.; MacCannell, J. A.; Lee, G.; Selves, E. R.; Moore, D.; Payne, J. A.; Garrett, C. D.; Dahlstrom, N.; Shay, T. M.

    2006-01-01

    A proposed free-space optical communication system would operate in a full-duplex mode, using a single constant-power laser beam for transmission and reception of binary signals at both ends of the free-space optical path. The system was conceived for two-way data communication between a ground station and a spacecraft in a low orbit around the Earth. It has been estimated that in this application, a data rate of 10 kb/s could be achieved at a ground-station-to-spacecraft distance of 320 km, using a laser power of only 100 mW. The basic system concept is also applicable to terrestrial free-space optical communications. The system (see figure) would include a diode laser at one end of the link (originally, the ground station) and a liquid-crystal- based retroreflecting modulator at the other end of the link (originally, the spacecraft). At the laser end, the beam to be transmitted would be made to pass through a quarter-wave plate, which would convert its linear polarization to right circular polarization. For transmission of data from the laser end to the retroreflector end, the laser beam would be modulated with subcarrier phase-shift keying (SC-PSK). The transmitted beam would then pass through an aperture- sharing element (ASE) - basically, a mirror with a hole in it, used to separate the paths of the transmitted and received light beams. The transmitted beam would continue outward through a telescope (which, in the original application, would be equipped with a spacecraft-tracking system) that would launch the transmitted beam along the free-space optical path to the retroreflector end.

  2. Preoperative duplex ultrasound parameters predicting male fertility after successful varicocelectomy

    PubMed Central

    Alshehri, Fahad M.; Akbar, Mahboob H.; Altwairgi, Adel K.; AlThaqufi, Omar J.

    2015-01-01

    Objectives: To assess duplex ultrasound (DUS) parameters, and predicti the outcome of varicocele ligation in male infertility. Methods: This retrospective and follow up study was conducted at Dr. Sulaiman Al Habib Hospital, AlQassim, Saudi Arabia between January 2011 and December 2012. Eighty-two patients were selected, who presented with clinical/subclinical varicocele and male infertility. All these patients had DUS of the scrotum and underwent for low ligation varicocelectomy. These patients were followed for a period of 12-24 months after surgery for the occurrence of paternity. We reviewed pre-operative scrotal DUS of these 82 patients for the testicular size and volume, pampiniform veins caliber and duration of reflux in the dilated veins at rest, and after valsalva maneuver. These DUS parameters were correlated with the postoperative paternity rate. Results: Postoperative paternity was achieved in 18 patients (31.6%) with normal-sized testes, and in 3 patients (12%) with small size testes. The positive paternity rate was higher (38.5%) in patients with clinically detected varicocele, compared with only 16.7% of patients with subclinical varicocele (detected by ultrasound only). In addition, postoperative paternity was significantly higher in patients with bilateral varicocele (70.6%), with shunt-type varicocele (71.4%), and patients with a permanent grade of venous reflux (62.5%). Conclusion: Selection of patients for the successful paternity after varicocele repair depends mainly on DUS parameters, which includes normal size testicles with shunt type of bilateral varicocele and continuous reflux. PMID:26620986

  3. Duplex ultrasound of the superior mesenteric artery in chronic pancreatitis.

    PubMed

    Hornum, M; Larsen, S; Olsen, O; Pedersen, J F

    2006-10-01

    Blood flow in the superior mesenteric artery (SMA) increases after a meal due to a vasoactive effect of the decomposed food. In exocrine pancreatic insufficiency, the digestion of food is compromised. We used duplex ultrasound to test the hypothesis that blood flow in the SMA after a meal increases less in patients with pancreatic insufficiency than in control persons. We studied 16 patients with chronic pancreatitis, eight of them with exocrine insufficiency, and eight healthy volunteers. The resistive index (RI) in the SMA was determined before and after a liquid meal. The RI reflects the downstream circulatory resistance, giving a precise description of mesenteric hyperaemia. Both groups of patients with chronic pancreatitis unexpectedly had lower fasting RI than controls, 0.818 and 0.815 vs 0.851, p = 0.028 and p = 0.0030, respectively. Postprandialy there was significantly less decrease in RI (less increase in flow) in patients with exocrine insufficiency than in controls, 0.055 vs 0.099, p = 0.0047. There was a significant trend for a less pronounced postprandial decrease in RI with more impaired pancreatic function (p = 0.0036). Our study thus demonstrates a reduced postprandial increase in SMA flow in patients with exocrine pancreatic insufficiency, and suggests an increased fasting SMA flow in chronic pancreatitis. Further studies are needed to evaluate the possible role of the test-meal-induced shift in RI in the SMA and of a lower-than-normal fasting RI in the diagnosis and monitoring of chronic pancreatitis.

  4. Pharmaco Penile Duplex Ultrasonography in the Evaluation of Erectile Dysfunction

    PubMed Central

    Ramanjaneyulu, Harshavardhana Kuruba; Susarla, Rammurti; Yarlagadda, Jyotsna; Devraj, Rahul; Palanisamy, Prabakaran

    2017-01-01

    Introduction The National Institute of Health defined ‘erectile dysfunction’ as the persistent inability to achieve and/or to maintain an erection for a satisfactory sexual performance. In last few years, the concept of erectile dysfunction has evolved from that of a disorder referred to as ‘impotence’ which used to be considered predominantly psychogenic to that of ‘Erectile Dysfunction’ (ED), a well understood physiologic result of multiple risk factors, both psychological and organic. The most common cause of organic erectile dysfunction is vasculogenic causes. Doppler evaluation of cavernosal arteries after intracavernosal injection of Papaverine is particularly useful in the evaluation of vasculogenic causes. Aim To define the role of intracavernosal injection of Papaverine in the evaluation of vasculogenic causes of erectile dysfunction that includes arterial insufficiency and veno occlusive nature. Materials and Methods Pharmaco Penile Duplex Ultrasonography (PPDU) was done using a linear broadband phased array transducer (7–12 MHz) on a E-Saote MyLab 60 ultrasound colour Doppler system on 73 patients over a period of three years. Informed consent was taken from all patients. Visual grading score for erection, Cavernosal Artery Diameter (CAD), PSV (Peak Systolic Velocity), EDV (End Diastolic Velocity), RI (Resistive Index), AT (Acceleration Time) and dorsal vein changes were obtained in all patients following intracavernosal injection of Papaverine. Results Visual grading for erectile response was E0 in one patient, E1 in 11 patients, E2 in 9 patients, E3 in 7 patients, E4 in 4 patients and E5 in 41 patients. Eighteen patients were diagnosed as having arterial insufficiency, three patients were diagnosed as having venous insufficiency and two patients showed indeterminate results. Conclusion In our study, Papaverine induced PPDU proved to be highly accurate and excellent method for assessing patients with erectile dysfunction. PMID:28274021

  5. Venous thromboembolic disease after hybrid hip arthroplasty with negative duplex screening.

    PubMed

    Beuhler, K O; D'Lima, D D; Colwell, C W; Otis, S M; Walker, R H

    1999-04-01

    Postoperative duplex ultrasonography screening after total hip arthroplasty has been shown to identify patients who may require treatment or additional monitoring for venous thromboembolic disease. The potential for manifestation of venous thromboembolic disease subsequent to screening remains a concern. The objective of this study was to determine the prevalence of symptomatic venous thromboembolic disease after total hip arthroplasty and after inhospital prophylaxis, inhospital screening with negative results for proximal deep venous thrombosis, and no posthospitalization venous thromboembolic disease prophylaxis. One hundred fifty patients undergoing primary hybrid total hip arthroplasty and using pneumatic compression stockings and aspirin as prophylaxis against venous thromboembolic disease were screened for deep venous thrombosis with duplex ultrasonography on the fourth day after surgery. Duplex ultrasonography screening revealed 17 (11.3%) patients with asymptomatic proximal deep venous thrombosis. In response to duplex ultrasonography screening, these patients with proximal deep venous thrombosis received therapeutic anticoagulation. Of 133 patients with a duplex screen with negative results for proximal deep venous thrombosis, 131 (98.5%) continued to have no symptoms of venous thromboembolic disease and two (1.5%) began to have symptoms for venous thromboembolic disease (one with proximal deep venous thrombosis, one with nonfatal pulmonary embolism) during 12 months of clinical followup after total hip arthroplasty. The overall prevalence of venous thromboembolic disease requiring anticoagulation was 19 of 150 (12.6%) patients. The remaining 131 (87.4%) were not exposed to the risks of postoperative anticoagulation and did not have subsequent symptomatic venous thromboembolic disease.

  6. Localization of duplex thrust-ramps by buckling: analog and numerical modelling

    NASA Astrophysics Data System (ADS)

    Liu, Shumin; Dixon, John M.

    1995-06-01

    Duplex structures in natural fold-thrust belts occur over a wide range of geometric scales. Duplex thrust ramps exhibit a regular spacing linearly related to the thickness of strata involved in the duplex. We suggest that buckling instability in layered systems can produce local stress concentrations which localize thrust ramps with regular spacing. This mechanism is demonstrated through analog (centrifuge) and numerical (finite element) modelling. Centrifuge models containing finely-laminated multilayers composed of plasticine and silicone putty (simulating rocks such as limestone and shale) are compressed from one edge; folds propagate from hinterland to foreland. As shortening continues, the lowest competent unit is thrust into a blind duplex structure by breakthrusting. The duplex develops by serial nucleation of faults from hinterland to foreland; the ramp locations are inherited from the initial buckling instability. Finite-element models based on the analog models and their natural prototypes demonstrate that stress concentrations develop in fore-limbs of anticlines within competent stratigraphie units. Models containing thrust discontinuities (at sites of calculated stress concentration) display additional stress concentrations in the forelimbs of unfaulted folds closer to the foreland. The locus of stress concentration thus propagates towards the foreland, consistent with foreland thrust propagation in nature. The location and regular spacing of ramps are inherited from early (possibly even incipient) buckle folds.

  7. Fluorescence Turn-On Sensing of DNA Duplex Formation by a Tricyclic Cytidine Analogue.

    PubMed

    Burns, Dillon D; Teppang, Kristine L; Lee, Raymond W; Lokensgard, Melissa E; Purse, Byron W

    2017-02-01

    Most fluorescent nucleoside analogues are quenched when base stacked and some maintain their brightness, but there has been little progress toward developing nucleoside analogues that markedly increase their fluorescence upon duplex formation. Here, we report on the design and synthesis of a new tricyclic cytidine analogue, 8-diethylamino-tC (8-DEA-tC), that responds to DNA duplex formation with up to a 20-fold increase in fluorescent quantum yield as compared with the free nucleoside, depending on neighboring bases. This turn-on response to duplex formation is the greatest of any reported nucleoside analogue that can participate in Watson-Crick base pairing. Measurements of the quantum yield of 8-DEA-tC mispaired with adenosine and, separately, opposite an abasic site show that there is almost no fluorescence increase without the formation of correct Watson-Crick hydrogen bonds. Kinetic isotope effects from the use of deuterated buffer show that the duplex protects 8-DEA-tC against quenching by excited state proton transfer. These results, supported by DFT calculations, suggest a rationale for the observed photophysical properties that is dependent on duplex integrity and the electronic structure of the analogue.

  8. Fluorescence Turn-On Sensing of DNA Duplex Formation by a Tricyclic Cytidine Analogue

    PubMed Central

    Burns, Dillon D.; Teppang, Kristine L.; Lee, Raymond W.; Lokensgard, Melissa E.; Purse, Byron W.

    2017-01-01

    Most fluorescent nucleoside analogues are quenched when base stacked and some maintain their brightness, but there has been little progress toward developing nucleoside analogues that markedly increase their fluorescence upon duplex formation. Here, we report on the design and synthesis of a new tricyclic cytidine analogue, 8-diethylamino-tC (8-DEA-tC), that responds to DNA duplex formation with up to a 20-fold increase in fluorescent quantum yield as compared with the free nucleoside, depending on neighboring bases. This turn-on response to duplex formation is the greatest of any reported nucleoside analogue that can participate in Watson–Crick base pairing. Measurements of the quantum yield of 8-DEA-tC mispaired with adenosine and, separately, opposite an abasic site show that there is almost no fluorescence increase without the formation of correct Watson–Crick hydrogen bonds. Kinetic isotope effects from the use of deuterated buffer show that the duplex protects 8-DEA-tC against quenching by excited state proton transfer. These results, supported by DFT calculations, suggest a rationale for the observed photophysical properties that is dependent on duplex integrity and the electronic structure of the analogue. PMID:28080035

  9. Structure of an ‘open’ clamp type II topoisomerase-DNA complex provides a mechanism for DNA capture and transport

    PubMed Central

    Laponogov, Ivan; Veselkov, Dennis A.; Crevel, Isabelle M.-T.; Pan, Xiao-Su; Fisher, L. Mark; Sanderson, Mark R.

    2013-01-01

    Type II topoisomerases regulate DNA supercoiling and chromosome segregation. They act as ATP-operated clamps that capture a DNA duplex and pass it through a transient DNA break in a second DNA segment via the sequential opening and closure of ATPase-, G-DNA- and C-gates. Here, we present the first ‘open clamp’ structures of a 3-gate topoisomerase II-DNA complex, the seminal complex engaged in DNA recognition and capture. A high-resolution structure was solved for a (full-length ParE-ParC55)2 dimer of Streptococcus pneumoniae topoisomerase IV bound to two DNA molecules: a closed DNA gate in a B-A-B form double-helical conformation and a second B-form duplex associated with closed C-gate helices at a novel site neighbouring the catalytically important β-pinwheel DNA-binding domain. The protein N gate is present in an ‘arms-wide-open’ state with the undimerized N-terminal ParE ATPase domains connected to TOPRIM domains via a flexible joint and folded back allowing ready access both for gate and transported DNA segments and cleavage-stabilizing antibacterial drugs. The structure shows the molecular conformations of all three gates at 3.7 Å, the highest resolution achieved for the full complex to date, and illuminates the mechanism of DNA capture and transport by a type II topoisomerase. PMID:23965305

  10. A First Insight into the Genetic Diversity and Drug Susceptibility Pattern of Mycobacterium tuberculosis Complex in Zhejiang, China

    PubMed Central

    Liu, Zhengwei; Chen, Songhua; Wu, Beibei; He, Haibo; Pan, Aizhen

    2016-01-01

    In this study, our aim was to determine the predominant genotypes among the Mycobacterium tuberculosis (MTB) strains circulating in Zhejiang Province. In addition, we also sought to determine the potential associations between MTB genotypes and susceptibility to first-line drugs. Out of these isolates, 673 (71.6%) were classified into the Beijing genotype, while the other 267 (28.4%) were from non-Beijing families. The highest proportion of Beijing genotype was found in Huzhou (80.0%) and the lowest in Lishui (48.3%). Statistical analysis revealed that there was a significant difference in the prevalence of Beijing genotype among different regions (χ2 = 17.57, P = 0.04). In addition, the overall proportions of drug resistance to INH, RIF, SM, and EMB were 13.2% (124/940), 21.8% (75/940), 3.4% (32/940), and 5.9% (55/940) in Zhejiang, respectively. Further comparison revealed that there was no significant difference in drug susceptibility profiles between Beijing and non-Beijing strains (P > 0.05). In conclusion, we describe the genetic diversity and drug susceptibility pattern of MTB in Zhejiang for the first time. Our data demonstrate that Beijing genotype is the predominant lineage in Zhejiang, while the distribution of Beijing-genotype strains shows geographic diversity. In addition, no correlation is observed between Beijing genotype and anti-TB drug resistance. PMID:27995145

  11. Structural and chelation behaviors of new Ru(II), Pt(IV) and Ir(III) gatifloxacin drug complexes: Spectroscopic characterizations

    NASA Astrophysics Data System (ADS)

    Alghamdi, Mohammed T.; Alsibaai, A. A.; El-Shahawi, M. S.; Refat, Moamen S.

    2017-02-01

    The interaction between gatifloxacin drug (GAT) with some transition metals (Ru(III), Pt(IV) and Ir(III)) yield the complexes of formulas [Ru(GAT-NH4)(Cl)3(H2O)2], [Pt(GAT-NH4)2(Cl)4]·3H2O and [Ir(GAT-NH4)2(Cl)2(H2O)2]·Cl·2H2O at pH = 7-8. The composition of the GAT complexes was confirmed by elemental data. The IR frequencies reveal the coordination of the GAT with metal ions and the coordination mode of the sbnd N atom of 3-methylpiperazinyl moiety to metal. XRD pattern show isomorphism among the complexes with similar chelation behavior. Scanning electron microscope (SEM) and transmission electron microscopy (TEM) were used to identify the particle size of GAT complexes. The thermal data reveals that various steps of decomposition of the complexes to form their metal oxide as final product. The electronic spectra and the magnetic susceptibility values reveal that the coordination and geometry of Ru3+, Pt4+ and Ir3+ complexes possess distorted octahedral geometry with six number of coordination. Thermodynamic parameters (E*, ΔS*, ΔH* and ΔG*) were calculated from TG curves dependent on Coats-Redfern and Horowitz-Metzeger non-isothermal methods.

  12. Structure and biological properties of the copper(II) complex with the quinolone antibacterial drug N-propyl-norfloxacin and 2,2'-bipyridine.

    PubMed

    Efthimiadou, Eleni K; Thomadaki, Hellinida; Sanakis, Yiannis; Raptopoulou, Catherine P; Katsaros, Nikos; Scorilas, Andreas; Karaliota, Alexandra; Psomas, George

    2007-01-01

    The neutral mononuclear copper complex with the quinolone antibacterial drug N-propyl-protected norfloxacin, Hpr-norfloxacin, in the presence of the nitrogen donor heterocyclic ligand 2,2'-bipyridine has been prepared and characterized. The crystal structure of (chloro)(2,2'-bipyridine)(pr-norfloxacinato)copper(II), 1, has been determined and refined with X-ray crystallography. X-band electron paramagnetic resonance (=EPR) spectroscopy at liquid helium temperatures from powdered samples indicates the presence of dimeric units in consistency with the crystal structure. In aqueous solutions of 1 the EPR behavior indicates mixture of dimeric and monomeric species. The antimicrobial activity of the complex has been tested on three different microorganisms and the best inhibition (MIC=0.25mugmL(-1)) has been exhibited against Escherichia coli. The study of the interaction of the complex with calf-thymus DNA has been performed with diverse spectroscopic techniques and has shown that complex 1 is bound to calf-thymus DNA by the intercalative mode. Potential anticancer cytostatic and cytotoxic effects of complex 1 on human promyelocytic leukemia HL-60 and human chronic myelogenous leukemia K562 cell lines have been investigated. Complex 1 shows an increased antiproliferative and necrotic effect on both HL-60 and K562 human leukemia cells in comparison to the free pr-norfloxacin.

  13. DNA interaction studies of a copper (II) complex containing an antiviral drug, valacyclovir: the effect of metal center on the mode of binding.

    PubMed

    Shahabadi, Nahid; Fatahi, Parvin

    2012-07-01

    The water-soluble complex, [Cu(Val)(2)(NO(3))(2)]; in which Val = valacyclovir, an antiviral drug, has been synthesized and characterized by elemental analysis, furier transfer-infrared, hydrogen nuclear magnetic resonance (H NMR), and UV-Vis techniques. The binding of this Cu (II) complex to calf thymus DNA was investigated using fluorimetry, spectrophotometry, circular dichroism, and viscosimetry. In fluorimetric studies, the enthalpy and entropy of the reaction between the complex and calf-thymus DNA (CT-DNA) showed that the reaction is endothermic (ΔH = 208.22 kJ mol(-1); ΔS = 851.35 J mol(-1)K(-1)). The complex showed the absorption hyperchromism in its ultra violet-visible (UV-Vis) spectrum with DNA. The calculated binding constant, K(b), obtained from UV-Vis absorption studies was 2 × 10(5) M(-1). Moreover, the complex induced detectable changes in the circular dichroism spectrum of CT-DNA, as well as changes in its viscosity. The results suggest that this copper (II) complex interacts with CT-DNA via a groove-binding mode.

  14. Synthesis, characterization, antibacterial activity, SOD mimic and interaction with DNA of drug based copper(II) complexes

    NASA Astrophysics Data System (ADS)

    Patel, Mohan N.; Dosi, Promise A.; Bhatt, Bhupesh S.; Thakkar, Vasudev R.

    2011-02-01

    Novel metal complexes of the second-generation quinolone antibacterial agent enrofloxacin with copper(II) and neutral bidentate ligands have been prepared and characterized with elemental analysis reflectance, IR and mass spectroscopy. Complexes have been screened for their in-vitro antibacterial activity against two Gram (+ve)Staphylococcus aureus, Bacillus subtilis, and three Gram (-ve)Serratia marcescens, Escherichia coli and Pseudomonas aeruginosa organisms using the double dilution technique. The binding of this complex with CT-DNA has been investigated by absorption titration, salt effect and viscosity measurements. Binding constant is ranging from 1.3 × 10 4-3.7 × 10 4. The cleavage ability of complexes has been assessed by gel electrophoresis using pUC19 DNA. The catalytic activity of the copper(II) complexes towards the superoxide anion (O 2rad -) dismutation was assayed by their ability to inhibit the reduction of nitroblue tetrazolium (NBT).

  15. ESI-MS Investigation of an Equilibrium between a Bimolecular Quadruplex DNA and a Duplex DNA/RNA Hybrid

    NASA Astrophysics Data System (ADS)

    Birrento, Monica L.; Bryan, Tracy M.; Samosorn, Siritron; Beck, Jennifer L.

    2015-07-01

    Electrospray ionization mass spectrometry (ESI-MS) conditions were optimized for simultaneous observation of a bimolecular qDNA and a Watson-Crick base-paired duplex DNA/RNA hybrid. The DNA sequence used was telomeric DNA, and the RNA contained the template for telomerase-mediated telomeric DNA synthesis. Addition of RNA to the quadruplex DNA (qDNA) resulted in formation of the duplex DNA/RNA hybrid. Melting profiles obtained using circular dichroism spectroscopy confirmed that the DNA/RNA hybrid exhibited greater thermal stability than the bimolecular qDNA in solution. Binding of a 13-substituted berberine ( 1) derivative to the bimolecular qDNA stabilized its structure as evidenced by an increase in its stability in the mass spectrometer, and an increase in its circular dichroism (CD) melting temperature of 10°C. The DNA/RNA hybrid did not bind the ligand extensively and its thermal stability was unchanged in the presence of ( 1). The qDNA-ligand complex resisted unfolding in the presence of excess RNA, limiting the formation of the DNA/RNA hybrid. Previously, it has been proposed that DNA secondary structures, such as qDNA, may be involved in the telomerase mechanism. DNA/RNA hybrid structures occur at the active site of telomerase. The results presented in the current work show that if telomeric DNA was folded into a qDNA structure, it is possible for a DNA/RNA hybrid to form as is required during template alignment. The discrimination of ligand ( 1) for binding to the bimolecular qDNA over the DNA/RNA hybrid positions it as a useful compound for probing the role(s), if any, of antiparallel qDNA in the telomerase mechanism.

  16. Rapid method to detect duplex formation in sequencing by hybridization methods

    DOEpatents

    Mirzabekov, Andrei Darievich; Timofeev, Edward Nikolaevich; Florentiev, Vladimer Leonidovich; Kirillov, Eugene Vladislavovich

    1999-01-01

    A method for determining the existence of duplexes of oligonucleotide complementary molecules is provided whereby a plurality of immobilized oligonucleotide molecules, each of a specific length and each having a specific base sequence, is contacted with complementary, single stranded oligonucleotide molecules to form a duplex so as to facilitate intercalation of a fluorescent dye between the base planes of the duplex. The invention also provides for a method for constructing oligonucleotide matrices comprising confining light sensitive fluid to a surface, exposing said light-sensitive fluid to a light pattern so as to cause the fluid exposed to the light to coalesce into discrete units and adhere to the surface; and contacting each of the units with a set of different oligonucleotide molecules so as to allow the molecules to disperse into the units.

  17. Final Report, Volume 3, Guidance Document for the Evaluation of Cast Super Duplex Stainless Steel

    SciTech Connect

    Hariharan, Vasudevan; Lundin, Carl, W.

    2005-09-30

    Volume 3 is comprised of the Development of Qualification Standards for Cast Super Duplex Stainless Steel (A890-5A) which is equivalent to wrought 2507. The objective of this work was to determine the suitability of ASTM A923 Standard Test methods for Detecting Detrimental Intermetallic Phase in Duplex Austenitic-Ferritic Stainless Steels for 25 Cr Cast Super Duplex Stainless Steels (ASTM A890-5A). The various tests which were carried out were ASTM A923 Test Method A, B and C (Sodium Hydroxide Etch Test, Charpy Impact Test and Ferric Chloride Corrosion Test), ferrite measurement using Feritscope®, ASTM E562 Manual Point Count Method and X-Ray Diffraction, hardness measurement using Rockwell B and C and microstructural analysis using SEM and EDS.

  18. Specific DNA duplex formation at an artificial lipid bilayer: towards a new DNA biosensor technology.

    PubMed

    Werz, Emma; Korneev, Sergei; Montilla-Martinez, Malayko; Wagner, Richard; Hemmler, Roland; Walter, Claudius; Eisfeld, Jörg; Gall, Karsten; Rosemeyer, Helmut

    2012-02-01

    A novel technique is described which comprises a base-specific DNA duplex formation at a lipid bilayer-H(2) O-phase boundary layer. Two different probes of oligonucleotides both carrying a double-tailed lipid at the 5'-terminus were incorporated into stable artificial lipid bilayers separating two compartments (cis/trans-channel) of an optically transparent microfluidic sample carrier with perfusion capabilities. Both the cis- and trans-channels are filled with saline buffer. Injection of a cyanine-5-labeled target DNA sequence, which is complementary to only one of the oligonucleotide probes, into the cis-channel, followed by a thorough perfusion, leads to an immobilization of the labeled complementary oligonucleotide on the membrane as detected by single-molecule fluorescence spectroscopy and microscopy. In the case of fluorescent but non-complementary DNA sequences, no immobilized fluorescent oligonucleotide duplex could be detected on the membrane. This clearly verifies a specific duplex formation at the membrane interface.

  19. A macrocyclic bis-acridine shifts the equilibrium from duplexes towards DNA hairpins.

    PubMed Central

    Slama-Schwok, A; Peronnet, F; Hantz-Brachet, E; Taillandier, E; Teulade-Fichou, M P; Vigneron, J P; Best-Belpomme, M; Lehn, J M

    1997-01-01

    Nucleic acids can undergo dynamic conformational changes associated with the regulation of biological processes. A molecule presenting larger affinities for alternative structures relative to a duplex is expected to modify such conformational equilibria. We have previously reported that macrocyclic bis-acridine binds preferentially to single-stranded regions, especially DNA hairpins, due to steric effects. Here, we show, using gel electrophoresis, fluorescence and melting temperature experiments, that the macrocycle bis-acridine shifts an equilibrium from a duplex towards the corresponding hairpins. Competition experiments enlighten the higher affinity of the macrocycle for hairpins compared with double-stranded DNA. The macrocycle bis-acridine destabilizes a synthetic polynucleotide, by the formation of premelted areas. By extrapolation, the macrocycle bis-acridine should be able to disrupt, at least locally, genomic DNA duplexes and to stabilize unpaired areas, especially palindromic ones forming hairpins. Such macrocyclic compounds may have potential applications in the therapy of diseases involving hairpins. PMID:9185566

  20. Positive-intrinsic-negative diode-based duplexer for microcoil nuclear magnetic resonance

    NASA Astrophysics Data System (ADS)

    Seeber, D. A.; Hoftiezer, J. H.; Pennington, C. H.

    2000-07-01

    Microcoil nuclear magnetic resonance (NMR), using receiver coils of diameters of order 100 μm, is increasingly employed to observe very small (˜0.3 nl) samples with high sensitivity. However, many experimental aspects of microcoil NMR differ greatly from conventional NMR. In particular, the duplexer is a device used to switch between the transmit and receive phases of the experiment. The conventional duplexer is a passive device employing crossed diodes, that switch automatically to transmit mode when high rf power is present. In microcoil NMR, however, the transmitter power is necessarily quite low, with voltages that do not greatly exceed characteristic diode voltage drops. Here we present the complete design and construction methods for a duplexer well suited to the special demands of microcoil NMR.

  1. Signal processors in duplex sonography: in vitro comparison between analog and digital methods.

    PubMed

    Zoller, W G; Wierscher, C; Wagner, D R

    1993-01-01

    Using a new flow-test phantom, which respects the acoustic properties of real blood as well as the proximal and distal impedances of body circulation, we assessed the performance of two duplex sonography signal processors on blood-flow measurements. With both the analog and the dynamic signal processor (Fast Fourier Transform), the correlation between duplex sonography and quantitative flow measurements was high (0.96-0.99) for different dynamic conditions (steady or pulsatile blood flow, varying heart rate, blood pressure, and hematocrit) and for different mechanical conditions (silicon tube or animal vessel). The real blood flow was overestimated by duplex sonography; the over-estimation was more pronounced with the analog processor (factor 1.87-4.20) than with the digital processor (factor 1.22-1.64, P < 0.05). Applied to the study of asymmetric stenoses, the digital processor was not superior to the analog processors described in the literature.

  2. Experimental Analysis and Modelling of Fe-Mn-Al-C Duplex Steel Mechanical Behaviour

    SciTech Connect

    Shiekhelsouk, M. N.; Favier, V.; Cherkaoui, M.; Inal, K.; Bouaziz, O.

    2007-04-07

    A new variety of duplex steels with high content of manganese and aluminum has been elaborated in Arcelor Research. These steels contain two phases: austenite and ferrite combining the best features of austenitic and ferritic steels. In this work, four duplex steels with different chemical composition and phase volume fraction are studied. The evolution of internal stresses for the two phases has been determined by X-ray diffraction during an in situ tensile test. These measurements results were used to determine the mechanical behaviour of the duplex steel using a micromechanical approach by scale transition for tensile tests. Though a good agreement between experiments and simulations is found at the macroscopic level, the calculated internal stresses of the austenitic phase do not match experimental results. These discrepancies are attributed to (i) a bad estimation of the austenite yield stress or (ii) the presence of kinematic hardening in the austenitic phase. A new step is then proposed to test these two hypotheses.

  3. Formulation Development and Evaluation of Drug Release Kinetics from Colon-Targeted Ibuprofen Tablets Based on Eudragit RL 100-Chitosan Interpolyelectrolyte Complexes

    PubMed Central

    Ofokansi, Kenneth Chibuzor; Kenechukwu, Franklin Chimaobi

    2013-01-01

    Colon-targeted drug delivery systems (CTDDSs) could be useful for local treatment of inflammatory bowel diseases (IBDs). In this study, various interpolyelectrolyte complexes (IPECs), formed between Eudragit RL100 (EL) and chitosan (CS), by nonstoichiometric method, and tablets based on the IPECs, prepared by wet granulation, were evaluated as potential oral CTDDSs for ibuprofen (IBF). Results obtained showed that the tablets conformed to compendial requirements for acceptance and that CS and EL formed IPECs that showed pH-dependent swelling properties and prolonged the in vitro release of IBF from the tablets in the following descending order: 3 : 2 > 2 : 3 > 1 : 1 ratios of CS and EL. An electrostatic interaction between the carbonyl (–CO–) group of EL and amino (–NH3+) group of CS of the tablets formulated with the IPECs was capable of preventing drug release in the stomach and small intestine and helped in delivering the drug to the colon. Kinetic analysis of drug release profiles showed that the systems predominantly released IBF in a zero-order manner. IPECs based on CS and EL could be exploited successfully for colon-targeted delivery of IBF in the treatment of IBDs. PMID:23986877

  4. Interpolyelectrolyte complexes of Eudragit® EPO with hypromellose acetate succinate and Eudragit® EPO with hypromellose phthalate as potential carriers for oral controlled drug delivery.

    PubMed

    Jeganathan, Balamurugan; Prakya, Vijayalakshmi

    2015-08-01

    The objective of this study was to compare a novel controlled release tablet formulation based on interpolyelectrolyte complex (PEC). Interpolymer interactions between the countercharged polymers like Eudragit® EPO (polycation) and hypromellose acetate succinate (polyanion) and Eudragit® EPO and hypromellose phthalate (polyanion) were investigated with a view to their use in per oral controlled release drug delivery systems. The formation of inter-macromolecular ionic bonds between cationic polymer and anionic polymer was investigated using Fourier transform infrared (FT-IR) spectroscopy and differential scanning calorimetry. The FT-IR spectra of the tested polymeric matrices are characterized by visible changes in the observed IR region indicating the interaction between chains of two oppositely charged copolymers. The performance of the in situ formed PEC as a matrix for controlled release of drugs was evaluated, using acetaminophen as a model drug. The dissolution data of these matrices were fitted to different dissolution models. It was found that drug release followed zero-order kinetics and was controlled by the superposition of the diffusion and erosion. These profiles could be controlled by conveniently modifying the proportion of the polymer ratio, polymer type, and polymer concentration the in the tablets.

  5. Quantitative confocal spectral imaging analysis of mitoxantrone within living K562 cells: intracellular accumulation and distribution of monomers, aggregates, naphtoquinoxaline metabolite, and drug-target complexes.

    PubMed Central

    Feofanov, A; Sharonov, S; Fleury, F; Kudelina, I; Nabiev, I

    1997-01-01

    Confocal spectral imaging (CSI) technique was used for quantitative analysis of the uptake, subcellular localization, and characteristics of localized binding and retention of anticancer agent mitoxantrone (MITOX) within human K562 erythroleukemia cells. The CSI technique enables identification of the state and interactions of the drug within the living cells. Utilizing this unique property of the method, intracellular distributions were examined for monomeric MITOX in polar environment, MITOX bound with hydrophobic cellular structures, naphthoquinoxaline metabolite, and nucleic acid-related complexes of MITOX. The features revealed were compared for the cells treated with 2 microM or 10 microM of MITOX for 1 h and correlated to the known data on antitumor action of the drug. MITOX was found to exhibit high tendency to self-aggregation within intracellular media. The aggregates are concluded to be a determinant of long-term intracellular retention of the drug and a source of persistent intracellular binding of MITOX. Considerable penetration of MITOX in the hydrophobic cytoskeleton structures as well as growing accumulation of MITOX bound to nucleic acids within the nucleus were found to occur in the cells treated with a high concentration of the drug. These effects may be among the factors stimulating and/or accompanying high-dose mitoxantrone-induced programmed cell death or apoptosis. Images FIGURE 1 FIGURE 2 PMID:9414243

  6. Investigating how the attributes of self-associated drug complexes influence the passive transport of molecules through biological membranes.

    PubMed

    Inacio, R; Barlow, D; Kong, X; Keeble, J; Jones, S A

    2016-05-01

    Relatively little is known about how drug self-association influences absorption into the human body. This study presented two hydrophobic membranes with a series of solutions containing different types of tetracaine aggregates with the aim of understanding how the attributes of supramolecular aggregate formation influenced passive membrane transport. The data showed that aqueous solutions of the unprotonated form of tetracaine displayed a significantly higher (p<0.05) passive membrane transport compared to solutions with mixtures of the unprotonated and protonated drug microspecies (e.g. transport through the skin was 0.96±0.31μgcm(-2)min(-1) and 1.59±0.26μgcm(-2)min(-1) respectively). However, despite an enhanced rate of drug transport and a better membrane partitioning the unionised molecules showed a significantly longer (p<0.05) lag time to membrane penetration compared solutions rich in the ionised microspecies. Analytical characterisation of the solutions applied to the apical surface of the membranes in the transport studies showed that larger tetracaine aggregates with smaller surface charge gave rise to the longer lag times. These large aggregates demonstrated more extensive intermolecular bonding and therefore, it was suggest that it was the enhanced propensity of the unionised species to form tightly bound drug aggregates that caused the delay in the membrane penetration.

  7. Investigating how the attributes of self-associated drug complexes influence the passive transport of molecules through biological membranes

    PubMed Central

    Inacio, R.; Barlow, D.; Kong, X.; Keeble, J.; Jones, S.A.

    2016-01-01

    Relatively little is known about how drug self-association influences absorption into the human body. This study presented two hydrophobic membranes with a series of solutions containing different types of tetracaine aggregates with the aim of understanding how the attributes of supramolecular aggregate formation influenced passive membrane transport. The data showed that aqueous solutions of the unprotonated form of tetracaine displayed a significantly higher (p < 0.05) passive membrane transport compared to solutions with mixtures of the unprotonated and protonated drug microspecies (e.g. transport through the skin was 0.96 ± 0.31 μg cm−2 min−1 and 1.59 ± 0.26 μg cm−2 min−1 respectively). However, despite an enhanced rate of drug transport and a better membrane partitioning the unionised molecules showed a significantly longer (p < 0.05) lag time to membrane penetration compared solutions rich in the ionised microspecies. Analytical characterisation of the solutions applied to the apical surface of the membranes in the transport studies showed that larger tetracaine aggregates with smaller surface charge gave rise to the longer lag times. These large aggregates demonstrated more extensive intermolecular bonding and therefore, it was suggest that it was the enhanced propensity of the unionised species to form tightly bound drug aggregates that caused the delay in the membrane penetration. PMID:26965142

  8. Synthesis, characterization and multi-spectroscopic DNA interaction studies of a new platinum complex containing the drug metformin.

    PubMed

    Shahabadi, Nahid; Heidari, Leila

    2014-07-15

    A new platinum(II) complex; [Pt(Met)(DMSO)Cl]Cl in which Met = metformin and DMSO: dimethylsulfoxide, was synthesized and characterized by (1)H NMR, IR, UV-Vis spectra, molar conductivity and computational methods. Binding interaction of this complex with calf thymus (CT) DNA has been investigated by using absorption, emission, circular dichroism, viscosity measurements, differential pulse voltammetry and cleavage studies by agarose gel electrophoresis. UV-Vis absorption studies showed hyperchromism. CD studies showed less perturbation on the base stacking and helicity bands in the CD spectrum of CT-DNA (B→C structural transition). In fluorimeteric studies, the Pt(II) complex can bind with DNA-NR complex and forms a new non-fluorescence adduct. The anodic peak current in the differential pulse voltammogram of the Pt(II) complex decreased gradually with the addition of DNA. Cleavage experiments showed that the Pt(II) complex does not induce any cleavage under the experimental setup. Finally all results indicated that Pt(II) complex interact with DNA via groove binding mode.

  9. Synthesis, characterization and multi-spectroscopic DNA interaction studies of a new platinum complex containing the drug metformin

    NASA Astrophysics Data System (ADS)

    Shahabadi, Nahid; Heidari, Leila

    2014-07-01

    A new platinum(II) complex; [Pt(Met)(DMSO)Cl]Cl in which Met = metformin and DMSO: dimethylsulfoxide, was synthesized and characterized by 1H NMR, IR, UV-Vis spectra, molar conductivity and computational methods. Binding interaction of this complex with calf thymus (CT) DNA has been investigated by using absorption, emission, circular dichroism, viscosity measurements, differential pulse voltammetry and cleavage studies by agarose gel electrophoresis. UV-Vis absorption studies showed hyperchromism. CD studies showed less perturbation on the base stacking and helicity bands in the CD spectrum of CT-DNA (B → C structural transition). In fluorimeteric studies, the Pt(II) complex can bind with DNA-NR complex and forms a new non-fluorescence adduct. The anodic peak current in the differential pulse voltammogram of the Pt(II) complex decreased gradually with the addition of DNA. Cleavage experiments showed that the Pt(II) complex does not induce any cleavage under the experimental setup. Finally all results indicated that Pt(II) complex interact with DNA via groove binding mode.

  10. Assessment of a 96-Well Plate Assay of Quantitative Drug Susceptibility Testing for Mycobacterium Tuberculosis Complex in China

    PubMed Central

    Xia, Hui; Zheng, Yang; Zhao, Bing; van den Hof, Susan; Cobelens, Frank; Zhao, YanLin

    2017-01-01

    Objective To evaluate the performance of the Sensitire MYCOTB MIC Plate (MYCOTB) which could measure the twelve anti-tuberculosis drugs susceptibility on one 96-wells plate. Methods A total of 140 MDR-TB strains and 60 non-MDR strains were sub-cultured and 193 strains were finally tested for drug resistance using MYCOTB and agar proportion method (APM) and another 7 strains failed of subculture. The drugs included ofloxacin (Ofx), moxifloxacin (Mfx), rifampin (RFP), amikacin (Am), rifabutin (Rfb), para-aminosalicylic acid (PAS), ethionamide (Eth), isoniazid (INH), kanamycin (Km), ethambutol (EMB), streptomycin (Sm), and cycloserine(Cs). The categorical agreement, conditional agreement, sensitivity and specificity of MYCOTB were assessed in comparison with APM. For strains with inconsistent results between MYCOTB and APM, the drug resistance related gene fragments were amplified and sequenced: gyrA for Ofx and Mfx; rpoB for RFP and Rfb; embB for EMB; rpsl for Sm; katG and the promoter region of inhA for INH, ethA and the promoter region of inhA for Eth. The sequence results were compared with results of MYCOTB and APM to analyze the consistency between sequence results and MYCOTB or APM. Results The categorical agreement between two methods for each drug ranged from 88.6% to 100%. It was the lowest for INH (88.6%). The sensitivity and specificity of MYCOTB ranged from 71.4% to 100% and 84.3% to 100%, respectively. The sensitivity was lowest for Cs(71.4%), EMB at 10μg/ml (80.0%) and INH at 10.0μg/ml (84.6%). The specificity was lowest for Rfb (84.3%). Overall discordance between the two phenotypic methods was observed for 96 strains, of which 63 (65.6%) were found susceptible with APM and resistant with MYCOTB and the remaining 33(34.4%) strains were resistant by APM and susceptible with MYCOTB. 34/52 (65.4%) sequenced APM susceptible and MYCOTB resistant(APM-S/MYCOTB-R) strains had mutations or insertions in the amplified regions. 20/30 (66.7%) sequenced APM

  11. Using hiCLIP to identify RNA duplexes that interact with a specific RNA-binding protein.

    PubMed

    Sugimoto, Yoichiro; Chakrabarti, Anob M; Luscombe, Nicholas M; Ule, Jernej

    2017-03-01

    The structure of RNA molecules has a critical role in regulating gene expression, largely through influencing their interactions with RNA-binding proteins (RBPs). RNA hybrid and individual-nucleotide resolution UV cross-linking and immunoprecipitation (hiCLIP) is a transcriptome-wide method of monitoring these interactions by identifying RNA duplexes bound by a specific RBP. The hiCLIP protocol consists of the following steps: in vivo cross-linking of RBPs to their bound RNAs; partial RNA digestion and purification of RNA duplexes interacting with the specific RBP using immunoprecipitation; ligation of the two arms of RNA duplexes via a linker; reverse transcription; cDNA library amplification; and finally high-throughput DNA sequencing. Mapping of the sequenced arms to a reference transcriptome identifies the exact locations of duplexes. hiCLIP data can directly identify all types of RNA duplexes bound by RBPs, including those that are challenging to predict computationally, such as intermolecular and long-range intramolecular duplexes. Moreover, the use of an adaptor that links the two arms of the RNA duplex permits hiCLIP to unambiguously identify the duplexes. Here we describe in detail the procedure for a hiCLIP experiment and the subsequent streamlined data analysis with an R package, 'hiclipr' (https://github.com/luslab/hiclipr/). Preparation of the library for high-throughput DNA sequencing takes ∼7 d and the basic bioinformatic pipeline takes 1 d.

  12. A Commentary on "Updating the Duplex Design for Test-Based Accountability in the Twenty-First Century"

    ERIC Educational Resources Information Center

    Brandt, Steffen

    2010-01-01

    This article presents the author's commentary on "Updating the Duplex Design for Test-Based Accountability in the Twenty-First Century," in which Isaac I. Bejar and E. Aurora Graf propose the application of a test design--the duplex design (which was proposed in 1988 by Bock and Mislevy) for application in current accountability assessments.…

  13. Additional base-pair formation in DNA duplexes by a double-headed nucleotide.

    PubMed

    Madsen, Charlotte S; Witzke, Sarah; Kumar, Pawan; Negi, Kushuma; Sharma, Pawan K; Petersen, Michael; Nielsen, Poul

    2012-06-11

    We have designed and synthesised a double-headed nucleotide that presents two nucleobases in the interior of a dsDNA duplex. This nucleotide recognises and forms Watson-Crick base pairs with two complementary adenosines in a Watson-Crick framework. Furthermore, with judicious positioning in complementary strands, the nucleotide recognises itself through the formation of a T:T base pair. Thus, two novel nucleic acid motifs can be defined by using our double-headed nucleotide. Both motifs were characterised by UV melting experiments, CD and NMR spectroscopy and molecular dynamics simulations. Both motifs leave the thermostability of the native dsDNA duplex largely unaltered. Molecular dynamics calculations showed that the double-headed nucleotides are accommodated in the dsDNA by entirely local perturbations and that the modified duplexes retain an overall B-type geometry with the dsDNA unwound by around 25 or 60°, respectively, in each of the modified motifs. Both motifs can be accommodated twice in a dsDNA duplex without incurring any loss of stability and extrapolating from this observation and the results of modelling, it is conceivable that both can be multiplied several times within a dsDNA duplex. These new motifs extend the DNA recognition repertoire and may form the basis for a complete series of double-headed nucleotides based on all 16 base combinations of the four natural nucleobases. In addition, both motifs can be used in the design of nanoscale DNA structures in which a specific duplex twist is required.

  14. Stability of DNA duplexes containing GG, CC, AA, and TT mismatches.

    PubMed

    Tikhomirova, Anna; Beletskaya, Irina V; Chalikian, Tigran V

    2006-09-05

    We employed salt-dependent differential scanning calorimetric measurements to characterize the stability of six oligomeric DNA duplexes (5'-GCCGGAXTGCCGG-3'/5'-CCGGCAYTCCGGC-3') that contain in the central XY position the GC, AT, GG, CC, AA, or TT base pair. The heat-induced helix-to-coil transitions of all the duplexes are associated with positive changes in heat capacity, DeltaC(p), ranging from 0.43 to 0.53 kcal/mol. Positive values of DeltaC(p) result in strong temperature dependences of changes in enthalpy, DeltaH degrees, and entropy, DeltaS degrees , accompanying duplex melting and cause melting free energies, DeltaG degrees, to exhibit characteristically curved shapes. These observations suggest that DeltaC(p) needs to be carefully taken into account when the parameters of duplex stability are extrapolated to temperatures distant from the transition temperature, T(M). Comparison of the calorimetric and van't Hoff enthalpies revealed that none of the duplexes studied in this work exhibits two-state melting. Within the context of the central AXT/TYA triplet, the thermal and thermodynamic stabilities of the duplexes in question change in the following order: GC > AT > GG > AA approximately TT > CC. Our estimates revealed that the thermodynamic impact of the GG, AA, and TT mismatches is confined within the central triplet. In contrast, the thermodynamic impact of the CC mismatch propagates into the adjacent helix domains and may involve 7-9 bp. We discuss implications of our results for understanding the origins of initial recognition of mismatched DNA sites by enzymes of the DNA repair machinery.

  15. Synthetic and spectroscopic characterization of organotin(IV) complexes of biologically active Schiff bases derived from sulpha drugs.

    PubMed

    Gupta, M K; Singh, Har Lal; Varshney, S; Varshney, A K

    2003-01-01

    A number of diorganotin(IV) complexes with Schiffbase have been synthesized and characterized by elemental analysis, conductance measurements, molecular weight determinations, infrared, electronic and multinuclear magnetic resonance ((1)H, (13)C and (119)Sn NMR) spectral data. The molar conductivity data shows non-electrolytic nature of complexes. The bidentate nature of the ligands is inferred from IR and NMR spectral studies. The antimicrobial activities of the ligands and their tin complexes have been screened in vitro against the organism Escherichia coli; Staphylococus aureus, Prouteus mirabilis, Bacillus thurengiensis, Penicillium co.,sogenum, Aspergillus niger and Fusarium oxysporum.

  16. Alternative strategy for adjusting the association specificity of hydrogen-bonded duplexes.

    PubMed

    Zhang, Penghui; Chu, Hongzhu; Li, Xianghui; Feng, Wen; Deng, Pengchi; Yuan, Lihua; Gong, Bing

    2011-01-07

    A strategy for creating new association specificity of hydrogen-bonded duplexes by varying the spacings between neighboring hydrogen bonds is described. Incorporation of naphthalene-based residues has provided oligoamide strands that pair into duplexes sharing the same H-bonding sequences (e.g., DDAA) but differing in the spacings between their intermolecular hydrogen bonds, leading to homo- or heteroduplexes. The ability to manipulate association-specificity as demonstrated by this work may be extended to other multiple hydrogen bonded systems, thereby further enhancing the diversity of multiple hydrogen-bonded association units for constructing supramolecular structures.

  17. A case report of laparoscopic ipsilateral ureteroureterostomy in children with renal duplex

    PubMed Central

    Wong, Yuen Shan; Tam, Yuk Him; Pang, Kristine Kit Yi

    2016-01-01

    We report on two children aged 2 and 6 years, who underwent laparoscopic ipsilateral ureteroureterostomy for their renal duplex anomalies. Both patients had complete duplex and were investigated by ultrasound, micturating cystourethrogram, magnetic resonance urography, and radioisotope scan. One patient had high-grade vesicoureteral reflux to lower moiety complicated with recurrent urinary tract infections, while the other had obstruction to upper moiety due to ectopic ureter. The pathological moieties of both patients were functional. Both patients underwent laparoscopic ipsilateral ureteroureterostomy uneventfully without any intraoperative complications. Postoperative imagings confirmed successful outcomes after surgery. PMID:27014651

  18. Herpes Zoster Duplex Bilateralis in Immuno-Competent Patients: Report of Two Cases.

    PubMed

    Vijay, Atul; Dalela, Gaurav

    2015-12-01

    Herpes Zoster is a common viral disorder, occurs due to reactivation of latent Varicella Zoster Virus (VZV) usually in adults or elderly patients, usually confined to a single dermatome. Herpes zoster duplex is a rare but well established entity which is simultaneous, occurring of herpes zoster at two different non contiguous dermatomes, can be unilateralis or bilateralis. Here we are reporting two cases of herpes zoster duplex bilateralis, in case-1 lesions occurs in two different distant dermatomes while in case-2 it appeared in a single dermatome but both sides were involved. Both the patients were healthy immuno-competent male.

  19. The microstructure and formation of duplex and black plessite in iron meteorites

    NASA Technical Reports Server (NTRS)

    Zhang, J.; Williams, D. B.; Goldstein, J. I.

    1993-01-01

    Two of the most common plessite structures, duplex and black plessite, in the taenite region of the Windmanstatten pattern of two iron meteorites (Grant and Carlton) are characterized using high-resolution electron microscopy and microanalysis techniques. Two types of gamma precipitates, found in the duplex plessite and black plessite regions, respectively, are identified, and their morphologies are described. The formation of the plessite structure is discussed using the information obtained in this study and results of a parallel investigation of decomposed martensitic Fe-Ni laboratory alloys.

  20. Congenital Giant Hydroureteric Cistern in a Duplex System of an Infant

    PubMed Central

    Awolaran, O. T.; Abdur-Rahman, L. O.; Bamigbola, K. T.; Adesiyun, O. M.; Nasir, A. A.

    2013-01-01

    Duplex collecting system is a congenital genitourinary anomaly commonly found incidentally. Our experience with a duplex system associated with giant hydroureter presenting as mobile abdominal swelling that was noticed from birth, constipation, and failure to thrive is described. Ultrasound and IVU did not assist in making the diagnosis, while a barium enema suggested a colonic duplication. Congenital giant hydroureter should be considered as a differential diagnosis in infants with cystic abdominal swelling. A preserved renal moiety attributed to a dilated ureteric cistern was a unique theory in this case. PMID:24171132

  1. A Structural Transition in Duplex DNA Induced by Ethylene Glycol

    PubMed Central

    Brewood, Greg P.; Aliwarga, Theresa; Schurr, J. Michael

    2010-01-01

    The twist energy parameter (ET) that governs the supercoiling free energy, and the linking difference (Δl) are measured for p30 δ DNA in solutions containing 0 to 40 w/v% ethylene glycol (EG). A plot of ET vs. −ln aw, where aw is the water activity, displays the full (reverse) sigmoidal profile of a discrete structural transition. A general theory for the effect of added osmolyte on a cooperative structural transition between two duplex states, 1□ 2, is formulated in terms of parameters applicable to individual base-pairs subunits. The resulting fraction of base-pairs in the 2-state ( f20), is incorporated into expressions for the effective torsion and bending elastic constants, the effective twist energy parameter ( ETeff), and the change in intrinsic twist (δl0). Fitting the expression for ETeff to the measured ET -values yields reasonably unambiguous estimates of ET1and ET2, the midpoint value (ln aw)1/2, and midpoint slope (∂ET/∂ln aw)1/2, but does not yield unambiguous estimates of the equilibrium constant ( K0), the difference in DNA-water preferential interaction coefficient (ΔΓ), or the inverse cooperativity parameter, J. Fitting a non-cooperative model (assumed J=1.0) to the data yields, K0 = 0.067, and ΔΓ = − 30.0 per base-pair (bp). Essentially equivalent fits are provided by models with a wide range of correlated J, ΔΓ, and K0 values. Other results favor ΔΓ in the range − 1.0 to 0, which then requires K0 ≥ 0.914, and a cooperativity parameter, 1/J ≥ 30.0 bp. The measured δl0 and circular dichroism (CD) at 272 nm are found to be compatible with curves predicted using the same f20-values that best-fit the ET -data. At least 7 to 10 % of the base-pairs are inferred to exist in the 2-state in 0.1 M NaCl in the complete absence of added osmolyte. Compared with the 1-state, the 2-state has a ~2.0- to 2.1-fold greater torsion elastic constant, a ~0.70-fold smaller bending elastic constant, a ~0.91-fold smaller ET -value, a ~0

  2. Finding and characterizing the complexes of drug like molecules with quadruplex DNA: combined use of an enhanced hydroxyl radical cleavage protocol and NMR.

    PubMed

    Ranpura, Harikrushan; Bialonska, Dobroslawa; Bolton, Philip H

    2014-01-01

    Structural information on the complexes of drug like molecules with quadruplex DNAs can aid the development of therapeutics and research tools that selectively target specific quadruplex DNAs. Screening can identify candidate molecules that require additional evaluation. An enhanced hydroxyl radical cleavage protocol is demonstrated that can efficiently provide structural information on the complexes of the candidate molecules with quadruplex DNA. NMR methods have been used to offer additional structural information about the complexes as well as validate the results of the hydroxyl radical approach. This multi-step protocol has been demonstrated on complexes of the chair type quadruplex formed by the thrombin binding aptamer, d(GGTTGGTGTGGTTGG). The hydroxyl radical results indicate that NSC 176319, Cain's quinolinium that was found by screening, exhibits selective binding to the two TT loops. The NMR results are consistent with selective disruption of the hydrogen bonding between T4 and T13 as well as unstacking of these residues from the bottom quartet. Thus, the combination of screening, hydroxyl radical footprinting and NMR can find new molecules that selectively bind to quadruplex DNAs as well as provide structural information about their complexes.

  3. Palladium(II) complexes as biologically potent metallo-drugs: Synthesis, spectral characterization, DNA interaction studies and antibacterial activity

    NASA Astrophysics Data System (ADS)

    Prasad, Kollur Shiva; Kumar, Linganna Shiva; Chandan, Shivamallu; Naveen Kumar, R. M.; Revanasiddappa, Hosakere D.

    2013-04-01

    Four novel mononuclear Pd(II) complexes have been synthesized with the biologically active Schiff base ligands (L1-L4) derived from 3-amino-2-methyl-4(3H)-quinazolinone. The structure of the complexes has been proposed by elemental analysis, molar conductance, IR, 1H NMR, mass, UV-Vis spectrometric and thermal studies. The investigation of interaction of the complexes with calf thymus DNA (CT-DNA) has been performed with absorption and fluorescence spectroscopic studies. The nuclease activity was done using pUC19 supercoiled DNA by gel-electrophoresis. All the ligands and their Pd(II) complexes have also been screened for their antibacterial activity by discolor diffusion technique.

  4. [Comparative efficiency of nootropic drugs in complex treatment of patients with remote consequences of closed craniocereberal trauma].

    PubMed

    Hliebova, O S; Tkachenko, O V

    2008-01-01

    Main data of the research were data obtained after a complex treatment of 120 persons with late consequences of closed craniocereberal trauma (CCRCT). The treatment included administration of one of nootropic agents (noophen, aminolon or entropil), magnesium sulfate, group B vitamins. All patients have passed a complex examination: specially developed questionnaire, anamnesis gathering, neurologic status, neuropsychological status with the use of multiple-aspect scales and questionnaires, examination of fundus of eye, rheoencephalography, echoencephalography, brain MRT. Results of a complex examination proved positive effect of the use of nootropic agents, in particular noophen, entropil and aminolon in complex treatment of late consequences of closed craniocereberal trauma. For optimisation of the use of nootropic agents in the treatment of late consequences of closed craniocereberal trauma it is recommended to consider features of influence of nootropic agents on certain clinical aspects of the disease.

  5. Nickel-quinolones interaction. Part 1 - Nickel(II) complexes with the antibacterial drug sparfloxacin: structure and biological properties.

    PubMed

    Skyrianou, Kalliopi C; Efthimiadou, Eleni K; Psycharis, Vassilis; Terzis, Aris; Kessissoglou, Dimitris P; Psomas, George

    2009-12-01

    The mononuclear nickel(II) complexes with the third-generation quinolone antibacterial agent sparfloxacin in the absence or presence of nitrogen donor heterocyclic ligands (1,10-phenanthroline or 2,2'-bipyridine) have been synthesized and characterized. The experimental data suggest that sparfloxacin acts as deprotonated bidentate ligand coordinated to Ni(II) ion through the ketone and carboxylato oxygens. The crystal structure of (1,10-phenanthroline)bis(sparfloxacinato) nickel(II), 2 has been determined by X-ray crystallography. The cyclic voltammograms of the complexes recorded in dmso solution and in 1/2 dmso/buffer (containing 150 mM NaCl and 15 mM trisodium citrate at pH 7.0) solution have shown that in the presence of CT DNA they can bind to CT DNA by the intercalative binding mode. UV study of the interaction of the complexes with calf-thymus DNA (CT DNA) has shown that the complexes can bind to CT DNA and 2 exhibits the highest binding constant to CT DNA. Competitive study with ethidium bromide (EB) has shown that the complexes can displace the DNA-bound EB indicating that they bind to DNA in strong competition with EB for the intercalative binding site. The antimicrobial activity of the complexes has been tested on three different microorganisms and has revealed that the inhibition provided by the complexes is slightly decreased in comparison to free sparfloxacin. The complexes exhibit good binding propensity to human and bovine serum albumin proteins having relatively high binding constant values.

  6. A novel gel based on an ionic complex from a dendronized polymer and ciprofloxacin: Evaluation of its use for controlled topical drug release.

    PubMed

    García, Mónica C; Cuggino, Julio C; Rosset, Clarisa I; Páez, Paulina L; Strumia, Miriam C; Manzo, Ruben H; Alovero, Fabiana L; Alvarez Igarzabal, Cecilia I; Jimenez-Kairuz, Alvaro F

    2016-12-01

    The development and characterization of a novel, gel-type material based on a dendronized polymer (DP) loaded with ciprofloxacin (CIP), and the evaluation of its possible use for controlled drug release, are presented in this work. DP showed biocompatible and non-toxic behaviors in cultured cells, both of which are considered optimal properties for the design of a final material for biomedical applications. These results were encouraging for the use of the polymer loaded with CIP (as a drug model), under gel form, in the development of a new controlled-release system to be evaluated for topical administration. First, DP-CIP ionic complexes were obtained by an acid-base reaction using the high density of carboxylic acid groups of the DP and the amine groups of the CIP. The complexes obtained in the solid state were broadly characterized using FTIR spectroscopy, XRP diffraction, DSC-TG analysis and optical microscopy techniques. Gels based on the DP-CIP complexes were easily prepared and presented excellent mechanical behaviors. In addition, optimal properties for application on mucosal membranes and skin were achieved due to their high biocompatibility and acute skin non-irritation. Slow and sustained release of CIP toward simulated physiological fluids was observed in the assays (in vitro), attributed to ion exchange phenomenon and to the drug reservoir effect. An in vitro bacterial growth inhibition assay showed significant CIP activity, corresponding to 38 and 58% of that exhibited by a CIP hydrochloride solution at similar CIP concentrations, against Staphylococcus aureus and Pseudomonas aeruginosa, respectively. However, CIP delivery was appropriate, both in terms of magnitude and velocity to allow for a bactericidal effect. In conclusion, the final product showed promising behavior, which could be exploited for the treatment of topical and mucosal opportunistic infections in human or veterinary applications.

  7. Functionalized immunostimulating complexes with protein A via lipid vinyl sulfones to deliver cancer drugs to trastuzumab-resistant HER2-overexpressing breast cancer cells

    PubMed Central

    Rodríguez-Serrano, Fernando; Mut-Salud, Nuria; Cruz-Bustos, Teresa; Gomez-Samblas, Mercedes; Carrasco, Esther; Garrido, Jose Manuel; López-Jaramillo, F Javier; Santoyo-Gonzalez, Francisco; Osuna, Antonio

    2016-01-01

    Background Around 20%–30% of breast cancers overexpress the proto-oncogene human epidermal growth receptor 2 (HER2), and they are characterized by being very invasive. Therefore, many current studies are focused on testing new therapies against tumors that overexpress this receptor. In particular, there exists major interest in new strategies to fight breast cancer resistant to trastuzumab (Tmab), a humanized antibody that binds specifically to HER2 interfering with its mitogenic signaling. Our team has previously developed immunostimulating complexes (ISCOMs) as nanocapsules functionalized with lipid vinyl sulfones, which can incorporate protein A and bind to G immunoglobulins that makes them very flexible nanocarriers. Methods and results The aim of this in vitro study was to synthesize and evaluate a drug delivery system based on protein A-functionalized ISCOMs to target HER2-overexpressing cells. We describe the preparation of ISCOMs, the loading with the drugs doxorubicin and paclitaxel, the binding of ISCOMs to alkyl vinyl sulfone-protein A, the coupling of Tmab, and the evaluation in both HER2-overexpressing breast cancer cells (HCC1954) and non-overexpressing cells (MCF-7) by flow cytometry and fluorescence microscopy. Results show that the uptake is dependent on the level of overexpression of HER2, and the analysis of the cell viability reveals that targeted drugs are selective toward HCC1954, whereas MCF-7 cells remain unaffected. Conclusion Protein A-functionalized ISCOMs are versatile carriers that can be coupled to antibodies that act as targeting agents to deliver drugs. When coupling to Tmab and loading with paclitaxel or doxorubicin, they become efficient vehicles for the selective delivery of the drug to Tmab-resistant HER2-overexpressing breast cancer cells. These nanoparticles may pave the way for the development of novel therapies for poor prognosis resistant patients. PMID:27698563

  8. Encapsulation of zinc-rifampicin complex into transferrin-conjugated silver quantum-dots improves its antimycobacterial activity and stability and facilitates drug delivery into macrophages

    PubMed Central

    Pati, Rashmirekha; Sahu, Rojalin; Panda, Jagannath; Sonawane, Avinash

    2016-01-01

    In order to improve the chemotherapy of tuberculosis, there is an urgent need to enhance the efficacy of existing agents and also to develop more efficient drug delivery systems. Here, we synthesized a novel anti-TB drug complex consisting of zinc and rifampicin (Zn-RIF), and encapsulated it into transferrin-conjugated silver quantum-dots (Zn-RIF-Tf-QD) to improve delivery in macrophages. Successful synthesis of Zn-RIF and Zn-RIF-Tf-QD was confirmed by UV/Vis-spectroscopy, TEM, FTIR, photoluminescence, XRD, XPS, and NMR. The sizes of silver QDs and transferrin-conjugated QDs were found to be in the range of 5–20 nm. Activity assays showed that Zn-RIF-Tf-QD exhibited 10-fold higher antibacterial activity against Mycobacterium smegmatis and Mycobacterium bovis-BCG as compared to Zn-RIF, RIF and Zn. Immunofluorescence studies showed that Zn-RIF-Tf-QD-conjugates were actively endocytosed by macrophages and dendritic cells, but not by lung epithelial cells. Treatment with Zn-RIF-Tf-QD efficiently killed mycobacteria residing inside macrophages without exhibiting cytotoxicity and genotoxicity. Moreover, the conjugates remained stable for upto 48 h, were taken up into the late endosomal compartment of macrophages, and released the drug in a sustainable manner. Our data demonstrate that Zn-RIF-Tf-QDs have a great potential as anti-TB drugs. In addition, transferrin-conjugated QDs may constitute an effective drug delivery system for tuberculosis therapy. PMID:27113139

  9. Fluoxetine- and norfluoxetine-mediated complex drug-drug interactions: in vitro to in vivo correlation of effects on CYP2D6, CYP2C19, and CYP3A4.

    PubMed

    Sager, J E; Lutz, J D; Foti, R S; Davis, C; Kunze, K L; Isoherranen, N

    2014-06-01

    Fluoxetine and its circulating metabolite norfluoxetine comprise a complex multiple-inhibitor system that causes reversible or time-dependent inhibition of the cytochrome P450 (CYP) family members CYP2D6, CYP3A4, and CYP2C19 in vitro. Although significant inhibition of all three enzymes in vivo was predicted, the areas under the concentration-time curve (AUCs) for midazolam and lovastatin were unaffected by 2-week dosing of fluoxetine, whereas the AUCs of dextromethorphan and omeprazole were increased by 27- and 7.1-fold, respectively. This observed discrepancy between in vitro risk assessment and in vivo drug-drug interaction (DDI) profile was rationalized by time-varying dynamic pharmacokinetic models that incorporated circulating concentrations of fluoxetine and norfluoxetine enantiomers, mutual inhibitor-inhibitor interactions, and CYP3A4 induction. The dynamic models predicted all DDIs with less than twofold error. This study demonstrates that complex DDIs that involve multiple mechanisms, pathways, and inhibitors with their metabolites can be predicted and rationalized via characterization of all the inhibitory species in vitro.

  10. Polyamine-polycarboxylate metal complexes with different biological effectiveness as nitric oxide scavengers. Clues for drug design.

    PubMed

    Bambagioni, Valentina; Bani, Daniele; Bencini, Andrea; Biver, Tarita; Cantore, Miriam; Chelli, Riccardo; Cinci, Lorenzo; Failli, Paola; Ghezzi, Lisa; Giorgi, Claudia; Nappini, Silvia; Secco, Fernando; Tinè, Maria Rosaria; Valtancoli, Barbara; Venturini, Marcella

    2008-06-12

    The synthesis of the Fe(III), Co(II), Mn(II), and Ru(III) complexes with two polyamine-polycarboxylate ligands, N-(2-hydroxyethyl)ethylenediamine-N, N', N'-triacetic acid (H3L1) and ethylene bisglycol tetraacetic acid (H4L2) is reported. Potentiometric studies showed that these ligands form stable complexes in aqueous solution and no metal release occurs, thus accounting for their low toxicity in cultured RAW 264.7 macrophages. X-ray characterization of the [Co(L1)](-) complex showed that binding sites are available at the metal for NO binding. Efficiency of these compounds to bind NO was studied by UV-vis spectrophotometry. Then their NO-scavenging properties were assayed in a cell-free system under physiological conditions, using S-nitroso-N-acetyl-D,L-penicillamine (SNAP) as NO source. The L1 complexes caused the most effective reduction of free NO, [Mn(L1)](-) being the most efficient. Conversely, in NOS II induced RAW 264.7 macrophages, the Ru(III) and Co(II) complexes with L2 were the most effective compounds. [Ru(L2)](-) also afforded significant protection against lipopolysaccharide-induced endotoxic shock in the mouse in vivo.

  11. Electronic, infrared, mass, 1H NMR spectral studies of the charge-transfer complexes of sulphonamide drugs with π-acceptors in acetonitrile

    NASA Astrophysics Data System (ADS)

    Frag, Eman Y.; Mohamed, Gehad G.

    2010-08-01

    The rapid interaction between sulphonamides (sulphamethoxazole (SMZ), sulphaguanidine (SGD), sulphaquinoxaline sodium (SQX) and sulphadimidine sodium (SDD)) as n-electron donors with the 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and 2,5-dichloro-3,6-dihydroxy-1,4-benzoquinone (chloranilic acid, p-CLA) as π-acceptors resulted in the formation of 1:1 charge-transfer complexes as the final products with the formula [(drug) (acceptor)]. The final products of the reactions have been isolated and characterized using FT-IR, 1H NMR, mass spectroscopy and elemental analyses as well as photometric measurements and thermogravimetric analysis (TG). The stoichiometry and apparent formation constants of the complexes formed were determined by applying the conventional spectrophotometric molar ratio method.

  12. Copper(II) complexes of a nonsteroidal anti-inflammatory drug niflumic acid. Synthesis, crystal structure of tetrakis-mu-(2-[3-(trifluoromethyl) phenyl]aminonicotinato)bis(dimethylsulfoxide)-dicopper(II) complex at 190 K. Anti-inflammatory properties.

    PubMed

    Greenaway, F T; Riviere, E; Girerd, J J; Labouze, X; Morgant, G; Viossat, B; Daran, J C; Roch Arveiller, M; Dung, N H

    1999-07-30

    The synthesis and characterization of three complexes with a potent nonsteroidal anti-inflammatory drug niflumic acid {2-[3-(trifluoromethyl)phenyl]aminonicotinic acid} with formula [Cu(niflumato)2L] (L = H2O, DMSO = dimethylsulfoxide, DMF = N,N-dimethylformamide) were investigated. The crystal and molecular structure of the {Cu(niflumato)2(DMSO)}2 was reported. Crystallographic data are as follows: monoclinic system, space group P2(1)/n, Z = 2, a = 11.1318(8), b = 17.513(2), c = 15.336(1) A, beta = 103.316(8) degrees, V = 2909.4(4) A3. The structure was refined to R = 0.030 and wR = 0.037 for 3702 reflections with I > sigma (I). It consists of centrosymmetric binuclear units with the Cu-Cui (symmetry code i: 1-x, -y, 1-z) distance between two centrosymmetrically related ions of 2.6272(5) A. Each Cu(II) ion in [Cu2(DMSO)2(mu-niflumato)4] is coordinated to an apical dimethylsulfoxide O atom on the one hand and to the equatorial carbonyl and carboxylic O atoms of two crystallographically independent niflumate moieties and their centrosymmetric counterparts on the other hand. In spite of the low-temperature (190 K) crystal measurements, one L-CF3 grouping exhibits some disorder. The biological activities of these complexes were compared to that of niflumic acid. Niflumic acid and its various copper complexes significantly inhibited polymorphonuclear leukocyte (PMNL) oxidative metabolism, as assessed by chemiluminescence and O2- generation measurement. This effect was dose-dependent. All copper complexes exerted a similar inhibiting effect which was always significantly higher than that exerted by the parent drug.

  13. [THE APPLICATION OF ANTIHOMOTOXIC DRUG PREPARATIONS IN THE COMPLEX TREATMENT IN PATIENTS WITH NEUROLOGICAL MANIFESTATIONS OF LUMBAR OSTEOCHONDROSIS].

    PubMed

    Nadkevich, A L; Babinets, L S

    2015-01-01

    The expediency of application homeosyniatry by preparations of Traumel S and Placenta Compositum after the offered chart in relation to a complex with classic acupuncture and in relation to the group of the generally accepted treatment has been proved in complex treatment patients with reflex syndromes of lumbar osteochondrosis. A similar conclusion was done after the statistically reliable (P < 0.05) dynamics of parameters of endogenous intoxication, liperoxydation and antioxydant systems of the protection (by the level of katalase, superoxyddismutase, SH-groups, ceruloplasmine).

  14. Spectroscopic and physical measurements on charge-transfer complexes: Interactions between norfloxacin and ciprofloxacin drugs with picric acid and 3,5-dinitrobenzoic acid acceptors

    NASA Astrophysics Data System (ADS)

    Refat, Moamen S.; Elfalaky, A.; Elesh, Eman

    2011-03-01

    Charge-transfer complexes formed between norfloxacin (nor) or ciprofloxacin (cip) drugs as donors with picric acid (PA) and/or 3,5-dinitrobenzoic acid (DNB) as π-acceptors have been studied spectrophotometrically in methanol solvent at room temperature. The results indicated the formation of CT-complexes with molar ratio1:1 between donor and acceptor at maximum CT-bands. In the terms of formation constant ( KCT), molar extinction coefficient ( ɛCT), standard free energy (Δ Go), oscillator strength ( f), transition dipole moment (μ), resonance energy ( RN) and ionization potential ( ID) were estimated. IR, H NMR, UV-Vis techniques, elemental analyses (CHN) and TG-DTG investigations were used to characterize the structural of charge-transfer complexes. It indicates that the CT interaction was associated with a proton migration from each acceptor to nor or cip donors which followed by appearing intermolecular hydrogen bond. In addition, X-ray investigation was carried out to scrutinize the crystal structure of the resulted CT-complexes.

  15. Multispectroscopic studies on the interaction of a copper(ii) complex of ibuprofen drug with calf thymus DNA.

    PubMed

    Shahabadi, Nahid; Shiri, Farshad

    2017-02-01

    The interaction of copper(II)-ibuprofenato complex with calf thymus DNA (ct-DNA) has been explored following, UV-visible spectrophotometry, fluorescence measurement, dynamic viscosity measurements, and circular dichroism spectroscopy. In spectrophotometric studies of ct-DNA it was found that [Cu(ibp)2]2 can form a complex with double-helical DNA. The association constant of [Cu(ibp)2]2 with DNA from UV-Vis study was found to be 6.19 × 10(4) L mol(-1). The values of Kf from fluorescence measurement clearly underscore the high affinity of [Cu(ibp)2]2 to DNA. The experimental results showed that the conformational changes in DNA helix induced by [Cu(ibp)2]2 are the reason for the fluorescence quenching of the DNA-Hoechst system. In addition, the fluorescence emission spectra of intercalated methylene blue (MB) with increasing concentrations of [Cu(ibp)2]2 represented a significant increase of MB intensity as to release MB from MB-DNA system. The results of circular dichroism (CD) suggested that copper(II)-ibuprofenato complex can change the conformation of DNA. In addition, the results of viscosity measurements suggest that copper(II)-ibuprofenato complex may bind with non-classical intercalative mode. From spectroscopic and hydrodynamic studies, it has been found that [Cu(ibp)2]2 interacts with DNA by partial intercalation mode which contains intercalation and groove properties.

  16. Crystal structures of a therapeutic single chain antibody in complex with two drugs of abuse-Methamphetamine and 3,4-methylenedioxymethamphetamine.

    PubMed

    Celikel, Reha; Peterson, Eric C; Owens, S Michael; Varughese, Kottayil I

    2009-11-01

    Methamphetamine (METH) is a major drug threat in the United States and worldwide. Monoclonal antibody (mAb) therapy for treating METH abuse is showing exciting promise and the understanding of how mAb structure relates to function will be essential for future development of these important therapies. We have determined crystal structures of a high affinity anti-(+)-METH therapeutic single chain antibody fragment (scFv6H4, K(D)= 10 nM) derived from one of our candidate mAb in complex with METH and the (+) stereoisomer of another abused drug, 3,4-methylenedioxymethamphetamine (MDMA), known by the street name "ecstasy." The crystal structures revealed that scFv6H4 binds to METH and MDMA in a deep pocket that almost completely encases the drugs mostly through aromatic interactions. In addition, the cationic nitrogen of METH and MDMA forms a salt bridge with the carboxylate group of a glutamic acid residue and a hydrogen bond with a histidine side chain. Interestingly, there are two water molecules in the binding pocket and one of them is positioned for a C--H...O interaction with the aromatic ring of METH. These first crystal structures of a high affinity therapeutic antibody fragment against METH and MDMA (resolution = 1.9 A, and 2.4 A, respectively) provide a structural basis for designing the next generation of higher affinity antibodies and also for carrying out rational humanization.

  17. Efficient wire-grid duplexer-polarized for CO2 lasers

    NASA Technical Reports Server (NTRS)

    Cheo, P. K.; Bass, C. D.

    1972-01-01

    Chromium wire grid duplexer-polarizer for 10 micrometer carbon dioxide laser communication system is produced by depositing photo-resist film onto silicon substrate, grating by two collimated cadmium helium laser beams, covering of surface with thin chromium layer, and subsequent stripping of uncoated portion to expose etched wires.

  18. Transceiver Design to Maximize the Weighted Sum Secrecy Rate in Full-Duplex SWIPT Systems

    NASA Astrophysics Data System (ADS)

    Wang, Ying; Sun, Ruijin; Wang, Xinshui

    2016-06-01

    This letter considers secrecy simultaneous wireless information and power transfer (SWIPT) in full duplex systems. In such a system, full duplex capable base station (FD-BS) is designed to transmit data to one downlink user and concurrently receive data from one uplink user, while one idle user harvests the radio-frequency (RF) signals energy to extend its lifetime. Moreover, to prevent eavesdropping, artificial noise (AN) is exploited by FD-BS to degrade the channel of the idle user, as well as to provide energy supply to the idle user. To maximize the sum of downlink secrecy rate and uplink secrecy rate, we jointly optimize the information covariance matrix, AN covariance matrix and receiver vector, under the constraints of the sum transmission power of FD-BS and the minimum harvested energy of the idle user. Since the problem is non-convex, the log-exponential reformulation and sequential parametric convex approximation (SPCA) method are used. Extensive simulation results are provided and demonstrate that our proposed full duplex scheme extremely outperforms the half duplex scheme.

  19. Congenital duplex gallbladder and biliary mucocele associated with partial hepatic cholestasis and cholelithiasis in a cat

    PubMed Central

    Woods, Katharine S.; Brisson, Brigitte A.; Defarges, Alice M.N.; Oblak, Michelle L.

    2012-01-01

    A 6-year-old neutered male domestic shorthair cat was presented for acute onset of vomiting. Exploratory laparotomy identified a duplex gallbladder and left cholecystectomy was performed. Histopathology confirmed biliary mucocele and hepatic cholestasis. While rare, biliary mucoceles should be considered as a differential diagnosis for feline extrahepatic bile duct obstruction. PMID:22942442

  20. Influence of Duplex Treatment on Structural and Tribological Properties of Commercially Pure Titanium

    NASA Astrophysics Data System (ADS)

    Çelik, Ilhan

    2017-01-01

    Titanium and its alloys are widely used in many fields, including aerospace and the chemical and biomedical industries. This is due to their mechanical properties, excellent corrosion resistance, and biocompatibility although they do have poor wear resistance. In this study, a duplex layer was successfully formed on the commercially pure titanium surface by duplex treatments (plasma nitriding and physical vapor deposition (PVD)). In the initial treatment, plasma nitriding was performed on the pure titanium samples and in the second treatment, the nitrided samples were coated with CrN by PVD. The friction and wear properties of the duplex-treated samples were investigated for tribological applications. Surface morphology and microstructure of the duplex-treated samples were analyzed by X-ray diffraction (XRD) and scanning electron microscopy (SEM). In addition, the tribological properties were investigated using pin-on-disc tribometer. A compound layer composed of ɛ-Ti2N and δ-TiN phases and a diffusion layer formed under the compound layer were obtained on the surface of pure titanium after the nitriding treatments. CrN coated on the nitrided surface provided an increase in the surface hardness and in the wear resistance.

  1. Sigma phase morphologies in cast and aged super duplex stainless steel

    SciTech Connect

    Martins, Marcelo; Casteletti, Luiz Carlos

    2009-08-15

    Solution annealed and water quenched duplex and super duplex stainless steels are thermodynamically metastable systems at room temperature. These systems do not migrate spontaneously to a thermodynamically stable condition because an energy barrier separates the metastable and stable states. However, any heat input they receive, for example through isothermal treatment or through prolonged exposure to a voltaic arc in the welding process, cause them to reach a condition of stable equilibrium which, for super duplex stainless steels, means precipitation of intermetallic and carbide phases. These phases include the sigma phase, which is easily identified from its morphology, and its influence on the material's impact strength. The purpose of this work was to ascertain how 2-hour isothermal heat treatments at 920 deg. C and 980 deg. C affect the microstructure of ASTM A890/A890M GR 6A super duplex stainless steel. The sigma phase morphologies were found to be influenced by these two aging temperatures, with the material showing a predominantly lacy microstructure when heat treated at 920 deg. C and block-shaped when heat treated at 980 deg. C.

  2. DNA CTG triplet repeats involved in dynamic mutations of neurologically related gene sequences form stable duplexes

    NASA Technical Reports Server (NTRS)

    Smith, G. K.; Jie, J.; Fox, G. E.; Gao, X.

    1995-01-01

    DNA triplet repeats, 5'-d(CTG)n and 5'-d(CAG)n, are present in genes which have been implicated in several neurodegenerative disorders. To investigate possible stable structures formed by these repeating sequences, we have examined d(CTG)n, d(CAG)n and d(CTG).d(CAG)n (n = 2 and 3) using NMR and UV optical spectroscopy. These studies reveal that single stranded (CTG)n (n > 2) forms stable, antiparallel helical duplexes, while the single stranded (CAG)n requires at least three repeating units to form a duplex. NMR and UV melting experiments show that the Tm increases in the order of [(CAG)3]2 < [(CTG)3]2 << (CAG)3.(CTG)3. The (CTG)3 duplex is stable and exhibits similar NMR spectra in solutions containing 0.1-4 M NaCl and at a pH range from 4.6 to 8.8. The (CTG)3 duplex, which contains multiple-T.T mismatches, displays many NMR spectral characteristics similar to those of B-form DNA. However, unique NOE and 1H-31P coupling patterns associated with the repetitive T.T mismatches in the CTG repeats are discerned. These results, in conjunction with recent in vitro studies suggest that longer CTG repeats may form hairpin structures, which can potentially cause interruption in replication, leading to dynamic expansion or deletion of triplet repeats.

  3. DNA CTG triplet repeats involved in dynamic mutations of neurologically related gene sequences form stable duplexes.

    PubMed Central

    Smith, G K; Jie, J; Fox, G E; Gao, X

    1995-01-01

    DNA triplet repeats, 5'-d(CTG)n and 5'-d(CAG)n, are present in genes which have been implicated in several neurodegenerative disorders. To investigate possible stable structures formed by these repeating sequences, we have examined d(CTG)n, d(CAG)n and d(CTG).d(CAG)n (n = 2 and 3) using NMR and UV optical spectroscopy. These studies reveal that single stranded (CTG)n (n > 2) forms stable, antiparallel helical duplexes, while the single stranded (CAG)n requires at least three repeating units to form a duplex. NMR and UV melting experiments show that the Tm increases in the order of [(CAG)3]2 < [(CTG)3]2 << (CAG)3.(CTG)3. The (CTG)3 duplex is stable and exhibits similar NMR spectra in solutions containing 0.1-4 M NaCl and at a pH range from 4.6 to 8.8. The (CTG)3 duplex, which contains multiple-T.T mismatches, displays many NMR spectral characteristics similar to those of B-form DNA. However, unique NOE and 1H-31P coupling patterns associated with the repetitive T.T mismatches in the CTG repeats are discerned. These results, in conjunction with recent in vitro studies suggest that longer CTG repeats may form hairpin structures, which can potentially cause interruption in replication, leading to dynamic expansion or deletion of triplet repeats. PMID:7501450

  4. Real-time duplex PCR for simultaneous HPV 16 and HPV 18 DNA quantitation.

    PubMed

    Jacquin, Elise; Saunier, Maëlle; Mauny, Frédéric; Schwarz, Elisabeth; Mougin, Christiane; Prétet, Jean-Luc

    2013-11-01

    HPV 16 and HPV 18 are responsible for more than 75% of cervical cancers and high HPV 16 loads are associated with both prevalent and incident lesions. The objective of the present study was to develop a method allowing the detection and quantitation of HPV 16 and 18 DNA to improve future strategies for cervical cancer screening. A duplex real-time PCR allowing the simultaneous quantitation of both HPV 16 and HPV 18 was carried out. Mixes of HPV 16 and HPV 18 whole genome plasmids were prepared to test a wide range of viral DNA concentrations. The values obtained for each mix of plasmids with the simplex and the duplex PCR were very close to the theoretical values except when a HPV type represented only 1:1000 genome equivalent or lower than the concurrent type. Cervical samples harboring HPV 16, HPV 18 or both types were tested by comparing the results with simplex and duplex real-time PCR assays. HPV 16 and HPV 18 genome titers were similar with the two assays. In conclusion, the real-time duplex PCR proved to be robust for HPV 16 and HPV 18 DNA quantitation.

  5. Duplex (or quadruplet) CH domain containing human multidomain proteins: an inventory.

    PubMed

    Friedberg, Felix

    2010-04-01

    In this paper, the inventory presented for singlet CH (calponin homology/actin binding) domain containing human multidomain proteins is extended to several duplex and one quadruplet CH containing forms. Invariably, the duplexes are located at the begin of the molecules. The regions connecting the two CH units suggest amino acid conservations which allows the placing of 18 duplex containing molecules into six groups wherein the gene for one member in each group created the others more recently by gene duplication. The ancient multidomain proteins, possibly, were primarily the result of an exon shuffling (transposition) mechanism that also guided the placing of the CH singlet or duplex domain at the amino end of the newly created proteins. A mechanism that creates pseudogenes could conceivably produce genes that encode multi-domain proteins. Intragenomic duplications (slippage) might have facilitated the occurrence of encoding repeats, thus allowing for the creation of multiple identical domains within one molecule. Gene duplication with subsequent modification and small domain gene recombination which formed multidomain proteins are important forces driving evolution.

  6. Development of duplex PCR assay for detection and differentiation of typical and atypical Melissococcus plutonius strains.

    PubMed

    Arai, Rie; Miyoshi-Akiyama, Tohru; Okumura, Kayo; Morinaga, Yuiko; Wu, Meihua; Sugimura, Yuya; Yoshiyama, Mikio; Okura, Masatoshi; Kirikae, Teruo; Takamatsu, Daisuke

    2014-04-01

    Melissococcus plutonius is the causative agent of an important honeybee disease, European foulbrood (EFB). In addition to M. plutonius strains with typical characteristics (typical M. plutonius), we recently reported the presence of atypical M. plutonius, which are phenotypically and genetically distinguished from typical M. plutonius. Because typical and atypical M. plutonius may have different pathogenic mechanisms, differentiation of these two types is very important for diagnosis and more effective control of EFB. In this study, therefore, a duplex PCR assay was developed to detect and differentiate typical and atypical M. plutonius rapidly and easily. On the basis of the results of comparative genomic analyses, we selected Na(+)/H(+) antiporter gene and Fur family transcriptional regulator gene as targets for detection of typical and atypical strains, respectively, by PCR. Under optimized conditions, the duplex PCR system using the designed primers successfully detected and differentiated all typical and atypical M. plutonius strain/isolates tested, while no product was generated from any other bacterial strains/isolates used in this study, including those isolated from healthy honeybee larval guts. Detection limits of the PCR were 50 copies of chromosome/reaction for both types, and it could detect typical and atypical M. plutonius directly from diseased honeybee larvae. Moreover, the duplex PCR diagnosed mixed infections with both M. plutonius types more precisely than standard culture methods. These results indicate that the duplex PCR assay developed in this study is extremely useful for precise diagnosis and epidemiological study of EFB.

  7. Development of Duplex PCR Assay for Detection and Differentiation of Typical and Atypical Melissococcus plutonius strains

    PubMed Central

    ARAI, Rie; MIYOSHI-AKIYAMA, Tohru; OKUMURA, Kayo; MORINAGA, Yuiko; WU, Meihua; SUGIMURA, Yuya; YOSHIYAMA, Mikio; OKURA, Masatoshi; KIRIKAE, Teruo; TAKAMATSU, Daisuke

    2013-01-01

    ABSTRACT Melissococcus plutonius is the causative agent of an important honeybee disease, European foulbrood (EFB). In addition to M. plutonius strains with typical characteristics (typical M. plutonius), we recently reported the presence of atypical M. plutonius, which are phenotypically and genetically distinguished from typical M. plutonius. Because typical and atypical M. plutonius may have different pathogenic mechanisms, differentiation of these two types is very important for diagnosis and more effective control of EFB. In this study, therefore, a duplex PCR assay was developed to detect and differentiate typical and atypical M. plutonius rapidly and easily. On the basis of the results of comparative genomic analyses, we selected Na+/H+ antiporter gene and Fur family transcriptional regulator gene as targets for detection of typical and atypical strains, respectively, by PCR. Under optimized conditions, the duplex PCR system using the designed primers successfully detected and differentiated all typical and atypical M. plutonius strain/isolates tested, while no product was generated from any other bacterial strains/isolates used in this study, including those isolated from healthy honeybee larval guts. Detection limits of the PCR were 50 copies of chromosome/reaction for both types, and it could detect typical and atypical M. plutonius directly from diseased honeybee larvae. Moreover, the duplex PCR diagnosed mixed infections with both M. plutonius types more precisely than standard culture methods. These results indicate that the duplex PCR assay developed in this study is extremely useful for precise diagnosis and epidemiological study of EFB. PMID:24334815

  8. Base pairing and structural insights into the 5-formylcytosine in RNA duplex

    PubMed Central

    Wang, Rui; Luo, Zhipu; He, Kaizhang; Delaney, Michael O.; Chen, Doris; Sheng, Jia

    2016-01-01

    5-Formylcytidine (f5C), a previously discovered natural nucleotide in the mitochondrial tRNA of many species including human, has been recently detected as the oxidative product of 5-methylcytidine (m5C) through 5-hydroxymethylcytidine (hm5C) in total RNA of mammalian cells. The discovery indicated that these cytosine derivatives in RNA might also play important epigenetic roles similar as in DNA, which has been intensively investigated in the past few years. In this paper, we studied the base pairing specificity of f5C in different RNA duplex contexts. We found that the 5-formyl group could increase duplex thermal stability and enhance base pairing specificity. We present three high-resolution crystal structures of an octamer RNA duplex [5′-GUA(f5C)GUAC-3′]2 that have been solved under three crystallization conditions with different buffers and pH values. Our results showed that the 5-formyl group is located in the same plane as the cytosine base and forms an intra-residue hydrogen bond with the amino group in the N4 position. In addition, this modification increases the base stacking between the f5C and the neighboring bases while not causing significant global and local structure perturbations. This work provides insights into the effects of 5-formylcytosine on RNA duplex. PMID:27079978

  9. Duplex PCR for detection of Salmonella and Shigella spp in cockle samples.

    PubMed

    Senachai, Pachara; Chomvarin, Chariya; Wongboot, Warawan; Boonyanugomol, Wongwarut; Tangkanakul, Waraluk

    2013-09-01

    Salmonella and Shigella spp are important causative agents of foodborne diseases. A sensitive, specific and rapid method is essential for detection of these pathogens. In this study, a duplex PCR method was developed for simultaneous detection of Salmonella and Shigella spp in cockle samples and compared with the traditional culture method. Enrichment broths for Salmonella spp recovery were also compared. Sensitivity of the duplex PCR for simultaneous detection of Salmonella and Shigella spp from pure culture was 10(3) CFU/ml (40 CFU/PCR reaction), and that of sterile cockle samples spiked with these two pathogens was 1 CFU/10 g of cockle tissue after 9 hours enrichment [3 hours in buffered peptone water (BPW), followed by 6 hours in Rappaport Vasiliadis (RV) broth or tetrathionate (TT) broth for Salmonella spp and 6 hours enrichment in Shigella broth (SB) for Shigella spp]. There was no significant difference in detection sensitivity between enrichment in RV and TT broths. Salmonella spp detected in cockles in Khon Kaen, Thailand by duplex PCR and culture method was 17% and 13%, respectively but Shigella spp was not detected. The duplex PCR technique developed for simultaneous detection of Salmonella and Shigella spp in cockle samples was highly sensitive, specific and rapid and could serve as a suitable method for food safety assessment.

  10. New insights into Hoogsteen base pairs in DNA duplexes from a structure-based survey

    PubMed Central

    Zhou, Huiqing; Hintze, Bradley J.; Kimsey, Isaac J.; Sathyamoorthy, Bharathwaj; Yang, Shan; Richardson, Jane S.; Al-Hashimi, Hashim M.

    2015-01-01

    Hoogsteen (HG) base pairs (bps) provide an alternative pairing geometry to Watson–Crick (WC) bps and can play unique functional roles in duplex DNA. Here, we use structural features unique to HG bps (syn purine base, HG hydrogen bonds and constricted C1′–C1′ distance across the bp) to search for HG bps in X-ray structures of DNA duplexes in the Protein Data Bank. The survey identifies 106 A•T and 34 G•C HG bps in DNA duplexes, many of which are undocumented in the literature. It also uncovers HG-like bps with syn purines lacking HG hydrogen bonds or constricted C1′–C1′ distances that are analogous to conformations that have been proposed to populate the WC-to-HG transition pathway. The survey reveals HG preferences similar to those observed for transient HG bps in solution by nuclear magnetic resonance, including stronger preferences for A•T versus G•C bps, TA versus GG steps, and also suggests enrichment at terminal ends with a preference for 5′-purine. HG bps induce small local perturbations in neighboring bps and, surprisingly, a small but significant degree of DNA bending (∼14°) directed toward the major groove. The survey provides insights into the preferences and structural consequences of HG bps in duplex DNA. PMID:25813047

  11. Dislocation of the third ventricle due to space-occupying stroke evaluated by transcranial duplex sonography.

    PubMed

    Seidel, G; Gerriets, T; Kaps, M; Missler, U

    1996-10-01

    Transcranial color-coded duplex sonography is a recently introduced method for visualizing (1) the blood flow velocity of the basal cerebral arteries and (2) the brain parenchyma as an acoustic impedance image. Dislocation of the third ventricle due to space-occupying stroke is an important clinical marker. This study evaluated the dislocation of the third ventricle from the brain midline by transcranial duplex sonography in 10 healthy volunteers. The mean dislocation was 0.2 +/- 0.3 mm. Eighteen stroke patients were investigated within 12 hours by both duplex sonography and computed tomography (CT) and the dislocation of the third ventricle was measured. Correlation between the two methods was high (r = 0.87, N = 27). Twelve stroke patients divided into three subgroups according to the extent of the space-occupying effects of the lesion were followed for 3 weeks. The increase and decrease of the dislocation of the third ventricle over the time were monitored. In conclusion, transcranial duplex sonography is a reliable tool to monitor dislocation of the third ventricle due to space-occupying stroke.

  12. Final Report, Volume 1, Metallurgical Evaluation of Cast Duplex Stainless Steels and their Weldments

    SciTech Connect

    Wen, Songqing; Lundin, Carl, W.; Batten, Greg, W.

    2005-09-30

    Duplex stainless steels (DSS) are being specified for chloride containing environments due to their enhanced pitting and stress corrosion cracking resistance. They exhibit improved corrosion performance over the austenitic stainless steels. Duplex stainless steels also offer improved strength properties and are available in various wrought and cast forms. Selected grades of duplex stainless steel castings and their welds, in comparison with their wrought counterparts, were evaluated, regarding corrosion performance and mechanical properties and weldability. Multiple heats of cast duplex stainless steel were evaluated in the as-cast, solution annealed (SA) static cast and SA centrifugal cast conditions, while their wrought counterparts were characterized in the SA condition and in the form of as-rolled plate. Welding, including extensive assessment of autogenous welds and a preliminary study of composite welds (shielded metal arc weld (SMAW)), was performed. The evaluations included critical pitting temperature (CPT) testing, intergranular corrosion (IGC) testing, ASTM A923 (Methods A, B and C), Charpy impact testing, weldability testing (ASTM A494), ferrite measurement and microstructural evaluations. In the study, the corrosion performances of DSS castings were characterized and assessed, including the wrought counterparts for comparison. The evaluation filled the pore of lack of data for cast duplex stainless steels compared to wrought materials. A database of the pitting corrosion and IGC behavior of cast and wrought materials was generated for a greater depth of understanding for the behavior of cast duplex stainless steel. In addition, improved evaluation methods for DSS castings were developed according to ASTM A923, A262, G48 and A494. The study revealed that when properly heat treated according to the specification, (1) DSS castings have equal or better pitting and intergranular corrosion resistance than their wrought counterparts; (2) Welding reduces the

  13. Final Report, Volume 1, Metallurgical Evaluation of Cast Duplex Stainless Steels and their Weldments

    SciTech Connect

    Wen, Songqing; Lundin, Carl, W.; Batten, Greg, W.

    2005-09-30

    Duplex stainless steels (DSS) are being specified for chloride containing environments due to their enhanced pitting and stress corrosion cracking resistance. They exhibit improved corrosion performance over the austenitic stainless steels. Duplex stainless steels also offer improved strength properties and are available in various wrought and cast forms. Selected grades of duplex stainless steel castings and their welds, in comparison with their wrought counterparts, were evaluated, regarding corrosion performance and mechanical properties and weldability. Multiple heats of cast duplex stainless steel were evaluated in the as-cast, solution annealed (SA) static cast and SA centrifugal cast conditions, while their wrought counterparts were characterized in the SA condition and in the form of as-rolled plate. Welding, including extensive assessment of autogenous welds and a preliminary study of composite welds (shielded metal arc weld (SMAW)), was performed. The evaluations included critical pitting temperature (CPT) testing, intergranular corrosion (IGC) testing, ASTM A923 (Methods A, B and C), Charpy impact testing, weldability testing (ASTM A494), ferrite measurement and microstructural evaluations. In the study, the corrosion performances of DSS castings were characterized and assessed, including the wrought counterparts for comparison. The evaluation filled the pore of lack of data for cast duplex stainless steels compared to wrought materials. A database of the pitting corrosion and IGC behavior of cast and wrought materials was generated for a greater depth of understanding for the behavior of cast duplex stainless steel. In addition, improved evaluation methods for DSS castings were developed according to ASTM A923, A262, G48 and A494. The study revealed that when properly heat treated according to the specification, (1) DSS castings have equal or better pitting and intergranular corrosion resistance than their wrought counterparts; (2) Welding reduces the

  14. Structure of the mycobacterial ATP synthase Fo rotor ring in complex with the anti-TB drug bedaquiline.

    PubMed

    Preiss, Laura; Langer, Julian D; Yildiz, Özkan; Eckhardt-Strelau, Luise; Guillemont, Jérôme E G; Koul, Anil; Meier, Thomas

    2015-05-01

    Multidrug-resistant tuberculosis (MDR-TB) is more prevalent today than at any other time in human history. Bedaquiline (BDQ), a novel Mycobacterium-specific adenosine triphosphate (ATP) synthase inhibitor, is the first drug in the last 40 years to be approved for the treatment of MDR-TB. This bactericidal compound targets the membrane-embedded rotor (c-ring) of the mycobacterial ATP synthase, a key metabolic enzyme required for ATP generation. We report the x-ray crystal structures of a mycobacterial c9 ring without and with BDQ bound at 1.55- and 1.7-Å resolution, respectively. The structures and supporting functional assays reveal how BDQ specifically interacts with the rotor ring via numerous interactions and thereby completely covers the c-ring's ion-binding sites. This prevents the rotor ring from acting as an ion shuttle and stalls ATP synthase operation. The structures explain how diarylquinoline chemicals specifically inhibit the mycobacterial ATP synthase and thus enable structure-based drug design of next-generation ATP synthase inhibitors against Mycobacterium tub