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Sample records for drug duplex complex

  1. Infrared Multiphoton Dissociation of Duplex DNA/Drug Complexes in a Quadrupole Ion Trap

    PubMed Central

    Wilson, Jeffrey J.; Brodbelt, Jennifer S.

    2008-01-01

    Non-covalent duplex DNA/drug complexes formed between one of three 14-base pair non-self complementary duplexes with variable GC content and one of eight different DNA-interactive drugs are characterized by infrared multiphoton dissociation (IRMPD), and the resulting spectra are compared to conventional collisional activated dissociation (CAD) mass spectra in a quadrupole ion trap mass spectrometer. IRMPD yielded comparable information to previously reported CAD results in which strand separation pathways dominate for complexes containing the more AT-rich sequences and/or minor groove binding drugs, whereas drug ejection pathways are prominent for complexes containing intercalating drugs and/or duplexes with higher GC base content. The large photoabsorptive cross-section of the phosphate backbone at 10.6 μm promotes highly efficient dissociation within short irradiation times (< 2 ms at 50 W) or using lower laser powers and longer irradiation times (< 15 W at 15 ms), activation times on par with or shorter than standard CAD experiments. This large photoabsorptivity leads to a controllable ion activation method which can be used to produce qualitatively similar spectra to CAD while minimizing uninformative base loss dissociation pathways or instead be tuned to yield a high degree of secondary fragmentation. Additionally, the low mass cut-off associated with conventional CAD plays no role in IRMPD, resulting in richer MS/MS information in the low m/z region. IRMPD is also used for multi-adduct dissociation in order to increase MS/MS sensitivity, and a two stage IRMPD/IRMPD method is demonstrated as a means to give specific DNA sequence information that would be useful when screening drug binding by mixtures of duplexes. PMID:17249688

  2. A novel form of intercalation involving four DNA duplexes in an acridine-4-carboxamide complex of d(CGTACG)2

    PubMed Central

    Adams, Adrienne; Guss, J. Mitchell; Collyer, Charles A.; Denny, William A.; Wakelin, Laurence P. G.

    2000-01-01

    The structures of the complexes formed between 9-amino-[N-(2-dimethyl-amino)butyl]acridine-4-carboxamide and d(CG5BrUACG)2 and d(CGTACG)2 have been solved by X-ray crystallography using MAD phasing methodology and refined to a resolution of 1.6 Å. The complexes crystallised in space group C222. An asymmetric unit in the brominated complex comprises two strands of DNA, one disordered drug molecule, two cobalt (II) ions and 19 water molecules (31 in the native complex). Asymmetric units in the native complex also contain a sodium ion. The structures exhibit novel features not previously observed in crystals of DNA/drug complexes. The DNA helices stack in continuous columns with their central 4 bp adopting a B-like motif. However, despite being a palindromic sequence, the terminal GC base pairs engage in quite different interactions. At one end of the duplex there is a CpG dinucleotide overlap modified by ligand intercalation and terminal cytosine exchange between symmetry-related duplexes. A novel intercalation complex is formed involving four DNA duplexes, four ligand molecules and two pairs of base tetrads. The other end of the DNA is frayed with the terminal guanine lying in the minor groove of the next duplex in the column. The structure is stabilised by guanine N7/cobalt (II) coordination. We discuss our findings with respect to the effects of packing forces on DNA crystal structure, and the potential effects of intercalating agents on biochemical processes involving DNA quadruplexes and strand exchanges. NDB accession numbers: DD0032 (brominated) and DD0033 (native). PMID:11058124

  3. β-Cyclodextrin duplexes that are connected through two disulfide bonds: potent hosts for the complexation of organic molecules.

    PubMed

    Grishina, Anastasia; Stanchev, Stancho; Kumprecht, Lukáš; Buděšínský, Miloš; Pojarová, Michaela; Dušek, Michal; Rumlová, Michaela; Křížová, Ivana; Rulíšek, Lubomír; Kraus, Tomáš

    2012-09-24

    New tubular host molecules, which are composed of two β-cyclodextrin macrocycles that are connected through two disulfide bonds, have been prepared by the air-promoted oxidation of 6(I),6(IV)-dideoxy-6(I),6(IV)-disulfanyl-β-cyclodextrin in aqueous solution. This reaction leads to three products: monomeric intramolecular disulfide and two dimeric species, which are termed as "non-eclipsed" and "eclipsed" cyclodextrin duplexes. Oxidation at a concentration of the starting thiol of 0.1 mM gave the intramolecular disulfide as the major product whereas a concentration in the millimolar range afforded the dimeric species as the dominant products. The tubular structure of the "non-eclipsed" isomer was unequivocally determined by X-ray analysis. The binding affinities of the duplexes to a wide range of compounds, including fluorescent dyes and clinically used drugs Imatinib and Esomeprazol, were studied in water by ITC. For most guest compounds, the experimentally determined K(a) values were in the range 10(7)-10(8) M(-1). These binding affinities are significantly higher than those found in the literature for analogous complexes with native cyclodextrins. In cases of binding of neutral or anionic guest molecules cyclodextrin duplexes outperformed cucurbiturils. A complex between a duplex and Nile blue was used to investigate its ability to penetrate the cytoplasmic membrane of HeLa cells. We found that the complex accumulated in the cell membrane but did not pass into cytosol. Importantly, the complex did not decompose to a significant extent under high dilution in the cellular environment. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Rv1458c: a new diagnostic marker for identification of Mycobacterium tuberculosis complex in a novel duplex PCR assay.

    PubMed

    Shrivastava, Kamal; Garima, Kushal; Narang, Anshika; Bhattacharyya, Kausik; Vishnoi, Ekta; Singh, Roshan Kumar; Chaudhry, Anil; Prasad, Rajendra; Bose, Mridula; Varma-Basil, Mandira

    2017-03-01

    We explored the efficiency of Rv1458c, the gene encoding a putative ABC drug transporter specific for the Mycobacterium tuberculosis complex (MTBC), as a diagnostic marker. A 190 bp region of Rv1458c and a 300 bp region of hsp65 were targeted in a novel duplex PCR assay and the results were compared with those for PCR restriction analysis(PRA) using the restriction enzymes NruI and BamHI. Species identification of a subset of the isolates (n=50) was confirmed by sequencing. Clinical isolates of M. tuberculosis (n=426) obtained from clinically suspected patients of pulmonary tuberculosis and mycobacterial (n=13) and non-mycobacterial (n=8) reference strains were included in the study. The duplex PCR assay correctly identified 320/426 isolates as MTBC and 106/426 isolates as non-tuberculous mycobacteria(NTM). The test was 100 % specific and sensitive when compared with NruI/BamHI PCR restriction analysis and highlighted the use of Rv1458c as a diagnostic marker for MTBC. The duplex PCR assay could be developed for use as a screening test to identify MTBC in clinical specimens in peripheral laboratories with limited resources.

  5. Ultrafast Electron Transfer in Complexes of Doxorubicin with Human Telomeric G-Quadruplexes and GC Duplexes Probed by Femtosecond Fluorescence Spectroscopy.

    PubMed

    Changenet-Barret, Pascale; Gustavsson, Thomas; Markovitsi, Dimitra; Manet, Ilse

    2016-05-04

    Doxorubicin (DOX) is a natural anthracycline widely used in chemotherapy; its combined application as a chemotherapeutic and photodynamic agent has been recently proposed. In this context, understanding the photoinduced properties of DOX complexes with nucleic acids is crucial. Herein, the study of photoinduced electron transfer in DOX-DNA complexes by femtosecond fluorescence spectroscopy is reported. The behaviour of complexes with two model DNA structures, a G-quadruplex (G4) formed by the human telomeric sequence (Tel21) and a d(GC) duplex, is compared. The DOX affinity for these two sequences is similar. Although both 1:1 and 2:1 stoichiometries have been reported for DOX-G4 complexes, only 1:1 complexes form with the duplex. The steady-state absorption indicates a strong binding interaction with the duplex due to drug intercalation between the GC base pairs. In contrast, the interaction of DOX with Tel21 is much weaker and arises from drug binding on the G4 external faces at two independent binding sites. As observed for DOX-d(GC) complexes, fluorescence of the drug in the first binding site of Tel21 exhibits decays within a few picoseconds following a biphasic pattern; this is attributed to the existence of two drug conformations. The fluorescence of the drug in the second binding site of Tel21 shows slower decays within 150 ps. These timescales are consistent with electron transfer from the guanines to the excited drug, as favoured by the lower oxidation potential of the stacked guanines of G4 with respect to those in the duplex. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. 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.

  7. 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.

  8. MHF complex senses branched DNA via binding a pair of crossover DNA duplexes

    PubMed Central

    Zhao, Qi; Saro, Dorina; Sachpatzidis, Aristidis; Singh, Thiyam Ramsing; Schlingman, Daniel; Zheng, Xiao-Feng; Mack, Andrew; Tsai, Miaw-Sheue; Mochrie, Simon; Regan, Lynne; Meetei, Amom Ruhikanta; Sung, Patrick; Xiong, Yong

    2014-01-01

    The conserved MHF1-MHF2 (MHF) complex functions in the activation of the Fanconi anemia (FA) pathway of DNA damage response, in regulating homologous recombination, and in DNA replication fork maintenance. MHF facilitates the processing of multiple types of branched DNAs by the FA DNA translocase FANCM. Here we report the crystal structure of a human MHF-DNA complex that reveals the DNA binding mode of MHF. The structure suggests an MHF preference for branched DNA over double stranded DNA through engaging two duplex arms, which is supported by single molecule studies. Biochemical analyses verify that MHF preferentially engage DNA forks or various four-way junctions independent of the junction-site structure. Genetic experiments provide evidence that the observed DNA-binding interface of MHF is important for cellular resistance to DNA damage. These results provide insights into how the MHF complex recognizes branched DNA and stimulates FANCM activity at such a structure to promote genome maintenance. PMID:24390579

  9. 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. Copyright © 2012 UICC.

  10. 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.

  11. 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.

  12. Sequential and spatial organization of metal complexes inside a peptide duplex.

    PubMed

    Yamada, Yasuyuki; Kubota, Takayuki; Nishio, Motoki; Tanaka, Kentaro

    2014-04-30

    To generate integrated organized molecular properties, multiple molecular components are required to be assembled into the molecular system with sequential and spatial accuracy in accordance with the design of the molecular assembly. Herein, we present a novel programmable synthesis of a cofacially stacked porphyrin array via repetitive construction of a peptide duplex. We designed and synthesized a novel porphyrin having two artificial amino acid moieties at the trans meso-positions. The amino acid moieties can be connected with another porphyrin unit by repetitive doubly coupling reactions to afford the peptide duplex bridged by the porphyrins. In the duplex, the porphyrin units are stacked cofacially, and the efficient electronic communication among the arrayed porphyrin units was characterized by split redox waves in the cyclic voltammograms. We also demonstrated the three different square-planar metal ions, namely Cu(2+), Ni(2+), and Pd(2+), were arranged inside the ladder-type porphyrin array in a programmable fashion.

  13. Structure of an argonaute silencing complex with a seed-containing guide DNA and target RNA duplex

    SciTech Connect

    Wang, Yanli; Juranek, Stefan; Li, Haitao; Sheng, Gang; Tuschl, Thomas; Patel, Dinshaw J.

    2009-01-08

    Here we report on a 3.0 {angstrom} crystal structure of a ternary complex of wild-type Thermus thermophilus argonaute bound to a 5'-phosphorylated 21-nucleotide guide DNA and a 20-nucleotide target RNA containing cleavage-preventing mismatches at the 10-11 step. The seed segment (positions 2 to 8) adopts an A-helical-like Watson-Crick paired duplex, with both ends of the guide strand anchored in the complex. An arginine, inserted between guide-strand bases 10 and 11 in the binary complex, locking it in an inactive conformation, is released on ternary complex formation. The nucleic-acid-binding channel between the PAZ- and PIWI-containing lobes of argonaute widens on formation of a more open ternary complex. The relationship of structure to function was established by determining cleavage activity of ternary complexes containing position-dependent base mismatch, bulge and 2'-O-methyl modifications. Consistent with the geometry of the ternary complex, bulges residing in the seed segments of the target, but not the guide strand, were better accommodated and their complexes were catalytically active.

  14. Duplex ultrasound

    MedlinePlus

    ... duplex ultrasound combines: Traditional ultrasound: This uses sound waves that bounce off blood vessels to create pictures. Doppler ultrasound: This records sound waves reflecting off moving objects, such as blood, to ...

  15. Aminoglycoside complexation with a DNA.RNA hybrid duplex: the thermodynamics of recognition and inhibition of RNA processing enzymes.

    PubMed

    Barbieri, Christopher M; Li, Tsai-Kun; Guo, Susan; Wang, Gang; Shallop, Anthony J; Pan, Weidong; Yang, Gengcheng; Gaffney, Barbara L; Jones, Roger A; Pilch, Daniel S

    2003-05-28

    Spectroscopic and calorimetric techniques were employed to characterize and contrast the binding of the aminoglycoside paromomycin to three octamer nucleic acid duplexes of identical sequence but different strand composition (a DNA.RNA hybrid duplex and the corresponding DNA.DNA and RNA.RNA duplexes). In addition, the impact of paromomycin binding on both RNase H- and RNase A-mediated cleavage of the RNA strand in the DNA.RNA duplex was also determined. Our results reveal the following significant features: (i) Paromomycin binding enhances the thermal stabilities of the RNA.RNA and DNA.RNA duplexes to similar extents, with this thermal enhancement being substantially greater in magnitude than that of the DNA.DNA duplex. (ii) Paromomycin binding to the DNA.RNA hybrid duplex induces CD changes consistent with a shift from an A-like to a more canonical A-conformation. (iii) Paromomycin binding to all three octamer duplexes is linked to the uptake of a similar number of protons, with the magnitude of this number being dependent on pH. (iv) The affinity of paromomycin for the three host duplexes follows the hierarchy, RNA.RNA > DNA.RNA > DNA.DNA. (v) The observed affinity of paromomycin for the RNA.RNA and DNA.RNA duplexes decreases with increasing pH. (vi) The binding of paromomycin to the DNA.RNA hybrid duplex inhibits both RNase H- and RNase A-mediated cleavage of the RNA strand. We discuss the implications of our combined results with regard to the specific targeting of DNA.RNA hybrid duplex domains and potential antiretroviral applications.

  16. 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.

  17. 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.

  18. 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

  19. Energetics, conformation, and recognition of DNA duplexes containing a major adduct of an anticancer azolato-bridged dinuclear Pt(II) complex.

    PubMed

    Mlcouskova, Jarmila; Malina, Jaroslav; Novohradsky, Vojtech; Kasparkova, Jana; Komeda, Seiji; Brabec, Viktor

    2012-10-01

    The design of anticancer metallodrugs is currently focused on platinum complexes which form on DNA major adducts that cannot readily be removed by DNA repair systems. Hence, antitumor azolato-bridged dinuclear Pt(II) complexes, such as [{cis-Pt(NH(3))(2)}(2)(μ-OH)(μ-pyrazolate)](2+) (AMPZ), have been designed and synthesized. These complexes exhibit markedly higher toxic effects in tumor cell lines than mononuclear conventional cisplatin. Biophysical and biochemical aspects of the alterations induced in short DNA duplexes uniquely and site-specifically modified by the major DNA adduct of AMPZ, namely 1,2-GG intrastrand cross-links, were examined. Attention was also paid to conformational distortions induced in DNA by the adducts of AMPZ and cisplatin, associated alterations in the thermodynamic stability of the duplexes, and recognition of these adducts by high-mobility-group (HMG) domain proteins. Chemical probing of DNA conformation, DNA bending studies and translesion synthesis by DNA polymerase across the platinum adduct revealed that the distortion induced in DNA by the major adduct of AMPZ was significantly less pronounced than that induced by similar cross-links from cisplatin. Concomitantly, the cross-link from AMPZ reduced the thermodynamic stability of the modified duplex considerably less. In addition, HMGB1 protein recognizes major DNA adducts of AMPZ markedly less than those of cisplatin. The experimental evidence demonstrates why the major DNA adducts of the new anticancer azolato-bridged dinuclear Pt(II) complexes are poor substrates for DNA repair observed in a previously published report. The relative resistance to DNA repair explains why these platinum complexes show major pharmacological advantages over cisplatin in tumor cells. Copyright © 2012 Elsevier B.V. All rights reserved.

  20. Effects of Monofunctional Adducts of Platinum(II) Complexes on Thermodynamic Stability and Energetics of DNA Duplexes

    PubMed Central

    Bursova, Vendula; Kasparkova, Jana; Hofr, Ctirad; Brabec, Viktor

    2005-01-01

    Effects of adducts of [PtCl(NH3)3]Cl or chlorodiethylenetriamineplatinum(II) on DNA stability were studied with emphasis on thermodynamic origins of that stability. Oligodeoxyribonucleotide duplexes (15-bp) containing the single, site-specific monofunctional adduct at G-residues of the central sequences TGT/ACA or 5′-AGT/5′-ACT were prepared and analyzed by differential scanning calorimetry, temperature-dependent ultraviolet absorption and circular dichroism. The unfolding of the platinated duplexes was accompanied by relatively small unfavorable free energy terms. This destabilization was enthalpic in origin. On the other hand, a relatively large reduction of melting temperature (Tm) was observed as a consequence of the monofunctional adduct in the TGT sequence, whereas Tm due to the adduct in the AGT sequence was reduced only slightly. We also examined the efficiency of the mammalian nucleotide excision repair system to remove from DNA the monofunctional adducts and found that these lesions were not recognized by this repair system. Thus, rather thermodynamic than thermal characterization of DNA adducts of monofunctional platinum compounds is a property implicated in the modulation of downstream effects such as protein recognition and repair. PMID:15574710

  1. 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.

  2. Binding of cationic bis-porphyrins linked with p- or m-xylylenediamine and their zinc(II) complexes to duplex DNA.

    PubMed

    Ishikawa, Yoshinobu; Yamakawa, Naoki; Uno, Tadayuki

    2008-12-15

    Spectroscopic, viscometric, and molecular docking analysis of binding of cationic bis-porphyrins linked with p- or m-xylylenediamine (H(2)pXy and H(2)mXy) and their zinc(II) complexes (ZnpXy and ZnmXy) to duplex DNA are described. H(2)pXy and H(2)mXy bound to calf thymus DNA (CTDNA) stronger than unichromophoric H(2)TMPyP, and showed exciton-type induced circular dichroism spectra of their Soret bands. The H(2)TMPyP-like units of the metal-free bis-porphyrins did not intercalate into CTDNA, and thus the binding mode is outside binding with intramolecular stacking. ZnpXy showed favorable binding to A.T over G.C region, and should lie in the major groove of A.T region.

  3. 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.

  4. 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.

  5. Quantitative analysis of a complex metal carbide formed during furnace cooling of cast duplex stainless steel using EELS and EDS in the TEM.

    PubMed

    Kuimalee, Surasak; Chairuangsri, Torranin; Pearce, John T H; Edmonds, David V; Brown, Andrew P; Brydson, Rik M D

    2010-07-01

    In this work, a method to determine the atomic ratio of Mo and C within complex metal carbides using EELS in the TEM has been developed. The method is based on the determination of k-factors for given experimental conditions from the EEL spectra of Mo(2)C and MoO(3) standards, which had been independently checked by XRD and EPMA. Factors affecting the k(Mo/C) value of the Mo(2)C standard were also investigated and the value was shown to be insensitive to background subtraction window width but sensitive to prolonged irradiation and specimen thicknesses above a critical value. The method and k-factor obtained from the Mo(2)C standard was applied to spectra from a complex metal carbide precipitate formed during furnace cooling of a cast duplex stainless steel. Using EELS and EDS in the TEM, the composition was estimated to be (Cr(1.52)Fe(2.33)Mo(1.25)Ni(0.17)Si(0.46))C, which is close to M(6)C stoichiometry, and the structure was confirmed by electron diffraction. Copyright 2010 Elsevier Ltd. All rights reserved.

  6. Sequence-Selective Formation of Synthetic H-Bonded Duplexes.

    PubMed

    Stross, Alexander E; Iadevaia, Giulia; Núñez-Villanueva, Diego; Hunter, Christopher A

    2017-09-13

    Oligomers equipped with a sequence of phenol and pyridine N-oxide groups form duplexes via H-bonding interactions between these recognition units. Reductive amination chemistry was used to synthesize all possible 3-mer sequences: AAA, AAD, ADA, DAA, ADD, DAD, DDA, and DDD. Pairwise interactions between the oligomers were investigated using NMR titration and dilution experiments in toluene. The measured association constants vary by 3 orders of magnitude (10(2) to 10(5) M(-1)). Antiparallel sequence-complementary oligomers generally form more stable complexes than mismatched duplexes. Mismatched duplexes that have an excess of H-bond donors are stabilized by the interaction of two phenol donors with one pyridine N-oxide acceptor. Oligomers that have a H-bond donor and acceptor on the ends of the chain can fold to form intramolecular H-bonds in the free state. The 1,3-folding equilibrium competes with duplex formation and lowers the stability of duplexes involving these sequences. As a result, some of the mismatch duplexes are more stable than some of the sequence-complementary duplexes. However, the most stable mismatch duplexes contain DDD and compete with the most stable sequence-complementary duplex, AAA·DDD, so in mixtures that contain all eight sequences, sequence-complementary duplexes dominate. Even higher fidelity sequence selectivity can be achieved if alternating donor-acceptor sequences are avoided.

  7. 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

  8. 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.

  9. [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)

  10. 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

  11. 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.

  12. 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.

  13. 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.

  14. Drug Induced Hypersensitivity and the HLA Complex

    PubMed Central

    Alfirevic, Ana; Pirmohamed, Munir

    2011-01-01

    Drug-induced hypersensitivity reactions are of major concern and present a burden for national healthcare systems due to their often severe nature, high rate of hospital admissions and high mortality. They manifest with a wide range of symptoms and signs, and can be initiated by a wide range of structurally diverse chemical compounds. The pathophysiological mechanisms underlying hypersensitivity reactions are not well understood, but it is thought that they are immune mediated. MHC region on Chromosome 6 contains many genes with immune function. Classical MHC molecules are highly polymorphic cell surface glycoproteins whose function is to present peptide antigens to T cells. In addition to conferring protection from some diseases, HLA alleles are also associated with an increased risk of other diseases, including drug-induced hypersensitivity. Pharmacogenetic approach to predict the risk of drug-induced hypersensitivity has been established for several drugs. We will discuss the progress of hypersensitivity pharmacogenetics over the last few years and focus on current efforts of the international community to develop consortia which aim to standardize disease phenotypes and to identify affected individuals through international collaborations. In addition, we will discuss the clinical utility of HLA typing as predictive or diagnostic testing for drug-induced hypersensitivity.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. The application of uniplex, duplex, and multiplex PCR for the absence of specified microorganism testing of pharmaceutical excipients and drug products.

    PubMed

    Ragheb, Suzan M; Yassin, Aymen S; Amin, Magdy A

    2012-01-01

    Notable progress has been made in methods that encourage the use of polymerase chain reaction (PCR) as a rapid and accurate tool in microbiological testing of pharmaceuticals. In this study, the detection of the four main specified microorganisms according to the pharmacopeial recommendations, Salmonella spp, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus, was optimized in different pharmaceutical dosage forms and raw materials. Uniplex PCR was performed for the detection of each microorganism individually targeting the conserved region in each bacterial genome. Further optimizations were done to perform duplex and multiplex PCR assays considering relative concentrations of competitor primers used in the reaction. The uniplex PCR amplicons were successfully sequenced, confirming the conservation of used primers. Other validation parameters such as specificity, sensitivity, and robustness were examined closely. The method provides a high-throughput screening method to test different pharmaceutical preparations for specified microorganisms for the detection of microbiological contamination. Strict regulations govern the production of pharmaceutical products whether they are sterile or nonsterile. Certain official tests are carried out in microbiology testing laboratory in any pharmaceutical production facility to ensure the pharmaceuticals microbiological quality according to the standard pharmacopeial recommendations. Nonsterile products must be free of specified microorganisms that are used as a check for their quality. Topical preparations must be free of Pseudomonas aeruginosa and Staphylococcus aureus, and oral preparations must be free of Salmonella spp and Escherichia coli. Conventional microbiological methods are time-consuming, labor-intensive, and require long incubation times, resulting in delaying the release of the products. In this study, we tested and validated a polymerase chain reaction identification approach to detect indicator

  20. 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.

  1. 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.

  2. 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.

  3. [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.

  4. 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.

  5. Humanized docking system for assembly of targeting drug delivery complexes.

    PubMed

    Backer, Marina V; Gaynutdinov, Timur I; Gorshkova, Inna I; Crouch, Robert J; Hu, Tao; Aloise, Renee; Arab, Mohamed; Przekop, Kristen; Backer, Joseph M

    2003-05-20

    Targeted drug delivery requires 'loading' drugs onto targeting proteins. Traditional technologies for loading drugs rely on chemical conjugation of drugs or drug carriers to targeting proteins. An alternative approach might rely on assembly of targeting complexes using a docking system that includes two components: a 'docking' tag fused to a targeting protein, and a 'payload' module containing an adapter protein for non-covalent binding to the docking tag. We describe here a fully humanized adapter/docking tag system based on non-covalent interaction between two fragments of human pancreatic RNase I. A 15 amino acid long N-terminal fragment of RNase I designed to serve as a docking tag, was fused to the N-terminus of human vascular endothelial growth factor that served as a targeting protein. An 18-125 and an 18-127 amino acid long fragments of RNase I were engineered, expressed and refolded into active conformations to serve as adapter proteins. Interactions between the targeting and adapter proteins were characterized using enzymatic analysis and surface plasmon resonance. Targeting DNA delivery complexes were assembled, characterized by dynamic light scattering, and found to be very effective in receptor-mediated DNA delivery.

  6. 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.

  7. Benefits of Automatic Duplexing Fact Sheet

    EPA Pesticide Factsheets

    This resource provides a how-to duplex guide, informs the reader on the benefits and cost savings from automatic duplexing, and several off the shelf print management software options for your facility.

  8. 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.

  9. 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. Copyright © 2016. Published by Elsevier B.V.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. Solution structure of the luzopeptin-DNA complex

    SciTech Connect

    Zhang, Xiaolu; Patel, D.J. )

    1991-04-23

    The luzopeptin-d(C-A-T-G) complex (1 drug/duplex) has been generated in aqueous solution and its structure characterized by a combined application of two-dimensional NMR experiments and molecular dynamics calculations. Once equivalent of luzopeptin binds to the self-complementary tetranucleotide duplex with the 2-fold symmetry of the antitumor agent and the DNA oligomer retained on complex formation. The authors have assigned the exchangeable and nonexchangeable proton resonances of luzopeptin and the d(C-A-T-G) duplex in the complex and identified the intermolecular proton-proton NOEs that define the alignment of the antitumor agent at its binding site in duplex DNA. The analysis was greatly aided by a large number of intermolecular NOEs involving exchangeable protons on both the luzopeptin and the DNA in the complex. The formation of cis peptide bonds for luzopeptin in the complex results in an increased separation of the long sides of the rectangular cyclic depsipeptide backbone and reorients in the glycine amide proton so that it can form an intermolecular hydrogen bond with the 2-carbonyl of T3 in the complex. This observation explains, in part, the requirement for Watson-Crick A{center dot}T pairs to be sandwiched between the quinolines at the bisintercalation site in the luzopeptin-DNA complex. The NMR studies on the luzopeptin-d(C-A-T-G) complex unequivocally establish that antitumor agents can undergo conformational transitions on complex formation with DNA, and it is the conformation of the drug in the complex that should serve as the starting point for drug design studies. The above structural details on the solution structure of the luzopeptin-DNA complex also explain the sequence selectivity of luzopeptin for bisintercalation at d(C-A){center dot}d(T-G) steps in the d(C-A-T-G) duplex in solution.

  19. 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.

  20. Biodegradable polymer-metal complexes for gene and drug delivery.

    PubMed

    Hosseinkhani, Hossein; Hosseinkhani, Mohsen

    2009-01-01

    The delivery of genes and drugs into cells has increasingly attracted attention for the generation of genetically engineered cells. Successful drug delivery will have enormous academic, clinical, and practical impacts on gene therapy, cell and molecular biology, pharmaceutical and food industries, and bio-production. The major aim of gene therapy is to deliver genetic materials into cells effectively, genetically modifying and repairing cell functions with the possibility of inducing therapeutic healing of disease. The genetic material includes DNA, RNA, antisense, decoy DNA, and ribozymes. The aim is that the appropriate transfection would allow diseased cells to return to a healthy condition. The genetic manipulation is often manifested in the mechanisms of intracellular actions of genes and proteins, and may play an important role in making clear the key genes associated with various diseases. Based on fundamental and scientific knowledge, the delivery technology of genetic material should be applicable to producing various proteins of pharmaceutical value (e.g. cytokines, growth factors, and antibodies) and also to producing seeds resistant to harmful insects and cold weather damage. This implies that the cells might be enhanced to produce valuable pharmaceutical and food products. For each approach, it is important, for successful gene expression, to select an appropriate gene to be delivered as well as to develop the gene delivery technology to enhance transfection efficiency. This review will provide an overview of the enhanced gene expression of plasmid DNA complexed with new non-viral gene delivery vehicles by biodegradable biopolymer-metal complex, introducing our recent research data to emphasize the technical feasibility of biopolymer-metal complexes in gene therapy and biotechnology.

  1. 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

  2. Cell cycle expression of RNA duplex unwindase activity in mammalian cells

    SciTech Connect

    Wagnor, R.W.; Nishikura, K.

    1988-02-01

    An RNA duplex unwindase activity has been found by using an in vitro assay with various types of mammalian, somatic cells, including HeLa, mouse plasmacytoma, and Burkitt lymphoma. The unwindase activity is very low in mouse fibroblast 3T3 cells arrested into quiescence, but increases when the cells are released into renewed growth by serum. In addition, a gel retardation assay proved to be specific and sensitive for detection of RNA duplex-unwindase complexes.

  3. NMR studies of echinomycin bisintercalation complexes with d(A1-C2-G3-T4) and d(T1-C2-G3-A4) duplexes in aqueous solution: sequence-dependent formation of Hoogsteen A1 x T4 and Watson-Crick T1 x A4 base pairs flanking the bisintercalation site

    SciTech Connect

    Gao, X.; Patel, D.J.

    1988-03-08

    The authors report on two-dimensional proton NMR studies of echinomycin complexes with the self-complementary d(A1-C2-G3-Tr) and d(T1-C2-G3-A4) duplexes in aqueous solution. The exchangeable and nonexchangeable antibiotic and nucleic acid protons in the 1 echinomycin per tetranucleotide duplex complexes have been assigned from analyses of scalar coupling and distance connectivities in two-dimensional data sets records in H/sub 2/O and D/sub 2/O solution. An analysis of the intermolecular NOE patterns for both complexes combined with large upfield imino proton and large downfield phosphorus complexation chemical shift changes demonstrates that the two quinoxaline chromophores of echinomycin bisintercalate into the minor groove surrounding the dC-dG step of each tetranucleotide duplex. Further, the quinoxaline rings selectively stack between A1 and C2 bases in the d(ACGT) complex and between T1 and C2 bases in the d(TCGA) complex. The intermolecular NOE patterns and the base and sugar proton chemical shifts for residues C2 and G3 are virtually identical for the d(ACGT) and d(TCGA) complexes. A large set of intermolecular contacts established from nuclear Overhauser effects (NOEs) between antibiotic and nucleic acid protons in the echinomycin-tetranucleotide complexes in solution are consistent with corresponding contacts reported for echinomycin-oligonucleotide complexes in the crystalline state. The authors demonstrate that the G x G base pairs adopt Watson-Crick pairing in both d(ACGT) and d(TCGA) complexes in solution. By contrast, the A1 x T4 base pairs adopt Hoogsteen pairing for the echinomycin-d(A1-C2-G3-Tr) complex while the T1 x A4 base pairs adopt Watson-Crick pairing for the echinomycin-d(T1-C2-G3-A4) complex in aqueous solution. These results emphasize the role of sequence in discriminating between Watson-Crick and Hoogsteen pairs at base pairs flanking the echinomycin bisintercalation site in solution.

  4. Crystal and solution structures of d(CGC[e{sup 6}G]AATTCGCG)-drug complexes reveal conformational polymorphism of O{sup 6}-ethyl-guanine:cytosine base pair

    SciTech Connect

    Sriram, M.; Yang, D.; Gao, Y.G.

    1994-12-31

    O6-ethyl-guanine (e{sup 6}G) is a relatively persistent alkylation lesion caused by the exposure of DNA to carcinogen N-ethyl-N-nitrosurea. We have studied the structural consequences of the e{sup 6}G incorporation in DNA by X-ray crystallography and NMR. We have obtained crystals of the modified DNA dodecamer d(CGC[e{sup 6}G]AATTCGCG) complexed to several minor groove binding drugs including Hoechst 33258, Hoechst 33342, netropsin, and SN6999. The space froup of the crystals from those complexes is P2{sub 1}2{sub 1}2{sub 1}. However, the crystal structure of the SN6999 complex is nor isomorphous to that from the other three complexes. In all four refined crystal structures, the drugs bind in the narrow minor groove at or clase to the central AATT region of the dodecamer B-DNA duplex. THe DNA conformation is influenced by the binding of drugs. The eight independent e{sup 6}G:C base pairs have a conformation ranging from one with three centered hydrogen bonds between the bases to a wobble conformation with two hydrogen bonds. The ethyl group of the eight e{sup 6}G bases is mostly in the proximal orientation to N7. Our 1D and 2D-NMR studies of the same (free) dodecamer reveal that the e{sup 6}G base pairs in the duplex are likely to adopt a wobble conformation in solution. Those results suggest that the e{sup 6}G base pair has a dynamic equilibrium among various conformations, which may present an ambiguous signal to cells. In contrast, the e{sup 6}G:T base pair adopts a Watson-Crick-like conformation. This may be a plausible explanation of why thymine is found preferentially incorporated across the e{sup 6}G during replication.

  5. 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

  6. 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.

  7. 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

  8. Preparation and in vitro release of dual-drug resinate complexes containing codeine and chlorpheniramine.

    PubMed

    Zeng, Huan-Xiang; Wang, Meng; Jia, Fei; Lin, Su-Jing; Cheng, Gang; Pan, Wei-San

    2011-02-01

    To develop the dual-drug resinate complexes containing codeine and chlorpheniramine with a novel batch processing, characterize the dual-drug resinate complexes, and study its drug release behavior in vitro. A procedure of simultaneous dual-drug loading using combination solutions composed of different proportions of codeine phosphate and chlorpheniramine maleate was performed to achieve the specific resinate, and the dual-drug loading content was determined by high-performance liquid chromatography method. The dual-drug resinate complexes were characterized by a scanning electron microscope, and the formation mechanisms were confirmed with X-ray diffraction analyses and differential scanning calorimetric analyses. The release behavior of the two drugs from the dual-drug resinate complexes in vitro was studied in the media simulating in vivo environments (simulated gastric fluid: pH = 1.2 HCl, simulated in vivo ionic strength: 0.15 M NaCl, and simulated intestinal fluid: pH = 6.8 buffer solution containing KH2PO4-NaOH). Scanning electron microscopic analyses proved that the dual-drug resinate complexes had the same appearance and characters as the initiative ion exchange resins (IERs). Via X-ray diffraction and differential scanning calorimetric analyses, it is found that the two drugs in dual-drug resinate complexes were combined with IERs by chemical bond. The drug-resinate complex, like IER, was in amorphous state. More than 90% of codeine phosphate was released in 15 minutes in three different media, whereas little amount of chlorpheniramine maleate was released in all the release time in the medium pH = 1.2 HCl, and the release equilibrium time was about 5 minutes, only 40% was released in the medium 0.15 M NaCl, and the equilibrium time was 40 minutes, and about 90% was released in the medium pH = 6.8 KH2PO4-NaOH. The increased ionic strength generally accelerated the release of the two drugs from the dual-drug resinate complexes. The dual-drug resinate

  9. 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

  10. Pharmacoinformatic approaches to understand complexation of dendrimeric nanoparticles with drugs.

    PubMed

    Jain, Vaibhav; Bharatam, Prasad V

    2014-03-07

    Nanoparticle based drug delivery systems are gaining popularity due to their wide spectrum advantages over traditional drug delivery systems; among them, dendrimeric nano-vectors are the most widely explored carriers for pharmaceutical and biomedical applications. The precise mechanism of encapsulation of drug molecules inside the dendritic matrix, delivery of drugs into specific cells, interactions of nano-formulation with biological targets and proteins, etc. present a substantial challenge to the scientific understanding of the subject. Computational methods complement experimental techniques in the design and optimization of drug delivery systems, thus minimizing the investment in drug design and development. Significant progress in computer simulations could facilitate an understanding of the precise mechanism of encapsulation of bioactive molecules and their delivery. This review summarizes the pharmacoinformatic studies spanning from quantum chemical calculations to coarse-grained simulations, aimed at providing better insight into dendrimer-drug interactions and the physicochemical parameters influencing the binding and release mechanism of drugs.

  11. Duplex gall bladder: bystander or culprit.

    PubMed

    Kumar, Jogender; Yadav, Arushi

    2017-08-30

    Gall bladder (GB) duplication is a rare anatomical malformation, which can be detected by preoperative imaging study. We present a case of duplex gall bladder in a 14-year-old boy who presented with abdominal pain. On ultrasound, he had right nephrolithiasis and duplex gall bladder. Duplex gall bladder was confirmed on MR cholangiopancreatography. There was a dilemma for surgical management of duplex gall bladder; however, he became asymptomatic after conservative treatment. Prophylactic surgery is not recommended for asymptomatic incidentally detected duplex gall bladder. Radiologists and paediatric surgeons should be sensitised about the exact anatomy of this entity. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  12. Self-assembled amorphous drug-polyelectrolyte nanoparticle complex with enhanced dissolution rate and saturation solubility.

    PubMed

    Cheow, Wean Sin; Hadinoto, Kunn

    2012-02-01

    The dissolution rate and solubility of poorly soluble drugs can be enhanced by formulating them into stable amorphous nanoparticle complex (nanoplex). For this purpose, a highly sustainable self-assembly drug-polyelectrolyte complexation process is developed, with ciprofloxacin and dextran sulfate as the drug and polyelectrolyte models, respectively. The nanoplex are prepared by mixing two aqueous salt solutions - one containing the drug and the other containing the oppositely charged polyelectrolyte. The nanoplex suspension is transformed into stable dry-powder form by freeze-drying. The effects of drug concentration, drug-to-polyelectrolyte charge ratio, and salt concentration on the complexation efficiency, yield, drug loading, and nanoplex morphology are examined. The dissolution rates and solubility of the nanoplex are characterized and compared to raw drug crystals. Nearly spherical amorphous nanoplex having fairly uniform sizes in the range of 200-400 nm and 80% drug loading are successfully produced at ≥80% complexation efficiency and yield. The complexation efficiency is governed by the drug concentration and its ratio to the salt concentration. The nanoplex powders exhibit approximately twice higher dissolution rate and solubility than raw drug crystals and remain stable after one-month storage. Overall, amorphous nanoplex represent a promising bioavailability-enhanced formulation of poorly soluble drugs owed to their superior characteristics and ease of preparation. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. 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.

  14. 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

  15. 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.

  16. Drug complexation, in vitro release and cellular entry of dendrimers and hyperbranched polymers.

    PubMed

    Kolhe, Parag; Misra, Ekta; Kannan, Rangaramanujam M; Kannan, Sujatha; Lieh-Lai, Mary

    2003-06-18

    Highly branched, functionalized polymers have potential to act as efficient drug carrier systems. Dendrimers are ideal candidates among model hyperbranched polymers because of their well-defined structure and high density of functional groups. Using ibuprofen as a model drug, we studied the interaction between the drug and Polyamidoamine (PAMAM) dendrimers (generations 3 and 4 with --NH2 functionality) and Perstrop Polyol (generation 5, hyperbranched polyester with --OH functionality). FTIR and NMR studies suggest that ibuprofen predominantly forms a complex with PAMAM dendrimers because of the ionic interaction between the --NH2 end groups and the carboxyl group of ibuprofen. On an average, up to 78 molecules of ibuprofen could be incorporated into one molecule of PAMAM-G4-NH2 with 64 end groups. This complex is stable in deionized water and methanol. The in vitro release of ibuprofen from drug-dendrimer complex is appreciably slower compared to pure ibuprofen. The complexed drug enters A549 cells much more rapidly than pure drug suggesting that dendrimers may be able to carry the complexed drug inside cells efficiently. Hyperbranched Polyol (with 128 --OH end groups) appears to encapsulate approximately 24 drug molecules. Perhaps the lack of strong interactions between the --OH end groups and the drugs prevents complex formation.

  17. Evidence of a sewer vapor transport pathway at the USEPA vapor intrusion research duplex

    DOE PAGES

    McHugh, Thomas; Beckley, Lila; Sullivan, Terry; ...

    2017-04-26

    We report the role of sewer lines as preferential pathways for vapor intrusion is poorly understood. Although the importance of sewer lines for volatile organic compound (VOC) transport has been documented at a small number of sites with vapor intrusion, sewer lines are not routinely sampled during most vapor intrusion investigations. We have used a tracer study and VOC concentration measurements to evaluate the role of the combined sanitary/storm sewer line in VOC transport at the USEPA vapor intrusion research duplex in Indianapolis, Indiana. The results from the tracer study demonstrated gas migration from the sewer main line into themore » duplex. The migration pathway appears to be complex and may include leakage from the sewer lateral at a location below the building foundation. Vapor samples collected from the sewer line demonstrated the presence of tetrachloroethene (PCE) and chloroform in the sewer main in front of the duplex and at multiple sample locations within the sewer line upstream of the duplex. Finally, these test results combined with results from the prior multi-year study of the duplex indicate that the sewer line plays an important role in transport of VOCs from the subsurface source to the immediate vicinity of the duplex building envelope.« less

  18. Equivalence of complex drug products: advances in and challenges for current regulatory frameworks.

    PubMed

    Hussaarts, Leonie; Mühlebach, Stefan; Shah, Vinod P; McNeil, Scott; Borchard, Gerrit; Flühmann, Beat; Weinstein, Vera; Neervannan, Sesha; Griffiths, Elwyn; Jiang, Wenlei; Wolff-Holz, Elena; Crommelin, Daan J A; de Vlieger, Jon S B

    2017-04-26

    Biotechnology and nanotechnology provide a growing number of innovator-driven complex drug products and their copy versions. Biologics exemplify one category of complex drugs, but there are also nonbiological complex drug products, including many nanomedicines, such as iron-carbohydrate complexes, drug-carrying liposomes or emulsions, and glatiramoids. In this white paper, which stems from a 1-day conference at the New York Academy of Sciences, we discuss regulatory frameworks in use worldwide (e.g., the U.S. Food and Drug Administration, the European Medicines Agency, the World Health Organization) to approve these complex drug products and their follow-on versions. One of the key questions remains how to assess equivalence of these complex products. We identify a number of points for which consensus was found among the stakeholders who were present: scientists from innovator and generic/follow-on companies, academia, and regulatory bodies from different parts of the world. A number of topics requiring follow-up were identified: (1) assessment of critical attributes to establish equivalence for follow-on versions, (2) the need to publish scientific findings in the public domain to further progress in the field, (3) the necessity to develop worldwide consensus regarding nomenclature and labeling of these complex products, and (4) regulatory actions when substandard complex drug products are identified. © 2017 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences.

  19. Improvement of drug loading onto ion exchange resin by cyclodextrin inclusion complex.

    PubMed

    Samprasit, Wipada; Rojanarata, Theerasak; Akkaramongkolporn, Prasert; Ngawhirunpat, Tanasait; Sila-on, Warisada; Opanasopit, Praneet

    2013-11-01

    Ion exchange resins have ability to exchange their counter ions for ionized drug in the surrounding medium, yielding "drug resin complex." Cyclodextrin can be applied for enhancement of drug solubility and stability. Cyclodextrin inclusion complex of poorly water-soluble NSAIDs, i.e. meloxicam and piroxicam, was characterized and its novel application for improving drug loading onto an anionic exchange resin, i.e. Dowex® 1×2, was investigated. β-Cyclodextrin (β-CD) and hydroxypropyl β-cyclodextrin (HP-β-CD) were used for the preparation of inclusion complex with drugs in solution state at various pH. The inclusion complex was characterized by phase solubility, continuous variation, spectroscopic and electrochemistry methods. Then, the drug with and without cyclodextrin were equilibrated with resin at 1:1 and 1:2 weight ratio of drug and resin. Solubility of the drugs was found to increase with increasing cyclodextrin concentration and pH. The increased solubility was explained predominantly due to the formation of inclusion complex at low pH and the increased ionization of drug at high pH. According to characterization studies, the inclusion complex was successfully formed with a 1:1 stoichiometry. The presence of cyclodextrin in the loading solution resulted in the improvement of drug loading onto resin. Enhancing drug loading onto ion-exchange resin via the formation of cyclodextrin inclusion complex is usable in the development of ion-exchange based drug delivery systems, which will beneficially reduce the use of harmful acidic or basic and organic chemicals.

  20. [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.

  1. 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.

  2. 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. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  3. DNA Duplexes with Hydrophobic Modifications Inhibit Fusion between HIV-1 and Cell Membranes

    PubMed Central

    Xu, Liang; Cai, Lifeng; Chen, Xueliang; Jiang, Xifeng; Chong, Huihui; Zheng, Baohua; Wang, Kun; He, Junlin; Chen, Wei; Zhang, Tao; Cheng, Maosheng; He, Yuxian

    2013-01-01

    Discovery of new drugs for the treatment of AIDS typically possessing unique structures associated with novel mechanisms of action has been of great importance due to the quick drug-resistant mutations of HIV-1 strains. The work presented in this report describes a novel class of DNA duplex-based HIV-1 fusion inhibitors. Hydrophobic groups were introduced into a DNA duplex skeleton either at one end, at both ends, or in the middle. These modified DNA duplexes inhibited fusion between HIV-1 and human cell membranes at micro- or submicromolar concentrations. Respective inhibitors adopted an aptamer pattern instead of a base-pairing interaction pattern. Structure-activity relationship studies of the respective DNA duplexes showed that the rigid and negatively charged DNA skeletons, in addition to the presence of hydrophobic groups, were crucial to the anti-HIV-1 activity of these compounds. A fluorescent resonance energy transfer (FRET)-based inhibitory assay showed that these duplex inhibitors interacted with the primary pocket in the gp41 N-terminal heptad repeat (NHR) instead of interacting with the lipid bilayers. PMID:23896466

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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

  9. 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…

  10. 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…

  11. Modified naphthalene diimide as a suitable tetraplex DNA ligand: application to cancer diagnosis and anti-cancer drug

    NASA Astrophysics Data System (ADS)

    Takenaka, Shigeori

    2017-07-01

    It is known that naphthalene diimide carrying two substituents binds to DNA duplex with threading intercalation. Naphthalene diimide carrying ferrocene moieties, ferrocenylnaphthalene diimide (FND), formed a stable complex with DNA duplex and an electrochemical gene detection was achieved with current signal generated from FND bound to the DNA duplex between target DNA and DNA probe immobilized electrode. FND couldn't bind to the mismatched and its surrounding region of DNA duplex and thus FND was applied to the precision detection of single nucleotide polymorphisms (SNPs) using the improved discrimination ability between fully matched and mismatched DNA hybrids and multi-electrode chip. Some of FND derivatives bound to telomere DNA tetraplex stronger than to DNA duplex and was applied to cancer diagnosis as a measure of the elongated telomere DNA with telomerase as a suitable maker of cancer. Furthermore, cyclic naphthalene diimides realized the extremely high preference for DNA tetraplex over DNA duplex. Such molecules will open an effective anti-cancer drug based on telomerase specific inhibitor.

  12. 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.

  13. Improvement on dissolution rate of inclusion complex of Rifabutin drug with β-cyclodextrin.

    PubMed

    Shanmuga Priya, Arumugam; Sivakamavalli, Jeyachandran; Vaseeharan, Baskaralingam; Stalin, Thambusamy

    2013-11-01

    The effect of β-cyclodextrin (β-CD) on the improvement of solubility and antimicrobial activity of poorly water soluble drug Rifabutin (RFB) was studied. The solid inclusion complex is prepared under different methods and it is characterized by FT-IR, XRD, DSC and SEM methods. Solubility type, stability constant, stoichiometric ratio were investigated from phase solubility diagram of inclusion complex (RFB with β-CD). The dissolution profiles of the inclusion complexes were carried out and obvious increase in dissolution rate was observed when compared with pure RFB drug. Inclusion complexation process was further confirmed by molecular docking studies using PatchDock server. The in vitro antimicrobial and antibiofilm activity of RFB sensible microorganisms was significantly increased by on inclusion complexation process. This trend of inclusion complexation of poorly water soluble drugs is highly recognized as a successful and useful approach for the application in pharmaceutical field. Copyright © 2013 Elsevier B.V. All rights reserved.

  14. Improvement of the bitter taste of drugs by complexation with cyclodextrins: applications, evaluations and mechanisms.

    PubMed

    Arima, Hidetoshi; Higashi, Taishi; Motoyama, Keiichi

    2012-05-01

    Drugs having bitter tastes cause low patient compliance. Many taste-masking techniques such as physical barrier coatings, chemical modification and sensory masking have been developed. Among chemical modification, the inclusion complexation of drugs with cyclodextrins (CyDs) can provide the effective bitter taste-masking effects without complicated formulation and/or delayed dissolution of drugs. Herein, we describe some quantitative methods to evaluate the taste-masking effects of CyD complexes with drugs in solution and the solid state. In addition, we introduce the recent applications of CyDs to excipients for taste masking against various bitter-taste drugs, as well as discuss the possible mechanisms for the taste-masking effect of CyD complexation.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

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

    PubMed Central

    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. PMID:26544710

  1. Design of a novel curcumin-soybean phosphatidylcholine complex-based targeted drug delivery systems.

    PubMed

    Xie, Jiajiang; Li, Yanxiu; Song, Liang; Pan, Zhou; Ye, Shefang; Hou, Zhenqing

    2017-11-01

    Recently, the global trend in the field of nanomedicine has been toward the design of combination of nature active constituents and phospholipid (PC) to form a therapeutic drug-phospholipid complex. As a particular amphiphilic molecular complex, it can be a unique bridge of traditional dosage-form and novel drug delivery system. In thisarticle, on the basis of drug-phospholipid complex technique and self-assembly technique, we chose a pharmacologically safe and low toxic drug curcumin (CUR) to increase drug-loading ability, achieve controlled/sustained drug release and improve anticancer activity. A novel CUR-soybean phosphatidylcholine (SPC) complex and CUR-SPC complex self-assembled nanoparticles (CUR-SPC NPs) were prepared by a co-solvent method and a nanoprecipitation method. DSPE-PEG-FA was further functionalized on the surface of PEG-CUR-SPC NPs (designed as FA-PEG-CUR-SPC NPs) to specifically increase cellular uptake and targetability. The FA-PEG-CUR-SPC NPs showed a spherical shape, a mean diameter of about 180 nm, an excellent physiological stability and pH-triggered drug release. The drug entrapment efficiency and drug-loading content was up to 92.5 and 16.3%, respectively. In vitro cellular uptake and cytotoxicity studies demonstrated that FA-PEG-CUR-SPC NPs and CUR-SPC NPs presented significantly stronger cellular uptake efficacy and anticancer activity against HeLa cells and Caco-2 cells compared to free CUR, CUR-SPC NPs and PEG-CUR-SPC NPs. More importantly, FA-PEG-CUR-SPC NPs showed the prolonged systemic circulation lifetime and enhanced tumor accumulation compared with free CUR and PEG-CUR-SPC NPs. These results suggest that the FA targeted PEGylated CUR-SPC complex self-assembled NPs might be a promising candidate in cancer therapy.

  2. 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.

  3. 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.

  4. Detection of drug specific circulating immune complexes from in vivo cynomolgus monkey serum samples.

    PubMed

    Pierog, Piotr; Krishna, Murli; Yamniuk, Aaron; Chauhan, Anil; DeSilva, Binodh

    2015-01-01

    Administration of a biotherapeutic can result in the formation of anti-drug antibodies (ADAs). The resulting ADA can potentially form immune complexes (ICs) with the drug leading to altered pharmacokinetic (PK) profiles and/or adverse events. Furthermore the presence of such complexes may interfere with accurate PK assessment, and/or detection of ADA in immunogenicity assays. Here, we present two assays to detect the presence of drug-ADA immune complexes in cynomolgus monkeys. Serum samples were analyzed for IC formation in vivo. 8/8 tested animals were positive for drug specific IC. Depending on the time point tested 4/8 or 7/8 animals tested positive for ADA during drug dosing. All 8 animals were confirmed positive for ADA during the washout phase, indicating drug interference in the bridging assay. Relative amount of IC over time was determined and its correlation with PK and ADA was then assessed. Multivariate data analysis demonstrates good correlation between signals obtained from the anti-drug and FcγRIIIa based capture assays, although due to its biological characteristic FcγRIIIa based assay captured only a subset of drug specific IC. In one animal IC remained in circulation even when the drug levels decreased below detection limit. Results from this study indicate the presence of IC during administration of an immunogenic biotherapeutic. Potential application of these assays includes detection of ADA in an IC during high drug levels. The results on the kinetics of IC formation during ADA response can complement the understanding of PK and ADA profiles. Moreover, the presence of IC indicates possible ADA interference in standard PK assays and potential underestimation of total drug exposure in toxicology studies. In addition this study also highlights the need to understand downstream in vivo consequences of drug-ADA IC as no animals under investigation developed adverse events. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Bypassing fluoroquinolone resistance with quinazolinediones: studies of drug-gyrase-DNA complexes having implications for drug design.

    PubMed

    Drlica, Karl; Mustaev, Arkady; Towle, Tyrell R; Luan, Gan; Kerns, Robert J; Berger, James M

    2014-12-19

    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.

  6. 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.

  7. 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.

  8. 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.

  9. Interpretation of duplex ultrasound dialysis access testing.

    PubMed

    Bandyk, Dennis F

    2013-01-01

    Conditions producing dialysis access dysfunction include failure of access maturation, cannulation injury to the conduit wall, thrombosis, low-volume flow, and aneurysmal degeneration. Duplex ultrasound is an accurate diagnostic technique to assess dialysis access anatomy and function, including the obligatory criteria for maturation, eg, volume flow >800 mL/min, conduit depth 0.6 cm from skin surface, and adequate (>5 mm) conduit diameter for cannulation. Measurement of access volume flow from the brachial artery or access conduit is prognostic for effective dialysis and conduit patency; including the determination of whether access maturation has occurred or when to intervene for a duplex-identified access stenosis. The application of duplex surveillance after autogenous vein or prosthetic bridge dialysis access construction has the potential to improve patency and function in the patient whose life is dependent on effective hemodialysis. © 2013 Elsevier Inc. All rights reserved.

  10. 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

  11. 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

  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. 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

  14. 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.

  15. Genome evolution predicts genetic interactions in protein complexes and reveals cancer drug targets

    PubMed Central

    Lu, Xiaowen; Kensche, Philip R.; Huynen, Martijn A.; Notebaart, Richard A.

    2013-01-01

    Genetic interactions reveal insights into cellular function and can be used to identify drug targets. Here we construct a new model to predict negative genetic interactions in protein complexes by exploiting the evolutionary history of genes in parallel converging pathways in metabolism. We evaluate our model with protein complexes of Saccharomyces cerevisiae and show that the predicted protein pairs more frequently have a negative genetic interaction than random proteins from the same complex. Furthermore, we apply our model to human protein complexes to predict novel cancer drug targets, and identify 20 candidate targets with empirical support and 10 novel targets amenable to further experimental validation. Our study illustrates that negative genetic interactions can be predicted by systematically exploring genome evolution, and that this is useful to identify novel anti-cancer drug targets. PMID:23851603

  16. A Case of Zoster Duplex Bilateralis

    PubMed Central

    Shin, Jung Woong; Kim, Dae-Hyun; Whang, Kyu Uang; Lee, Jongsuk; Park, Younglip; Cho, Moon Kyun; Lee, Sanghoon

    2009-01-01

    The skin lesions of herpes zoster are classically limited to a single dermatome and most cases of multidermatomal herpes zoster have contiguous skin lesions. Simultaneous involvement of two noncontiguous dermatomes is very rare and it has been referred to as zoster duplex unilateralis or bilateralis, depending whether one or both halves of the body are involved. A 67-year-old woman presented with a group of painful vesicles on the right buttock and thigh, and left anterior chest and back. The Tzanck smear and skin biopsy were consistent with a herpetic infection. We report a rare case of zoster duplex bilateralis. PMID:20523839

  17. 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.

  18. 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.

  19. C-1311 (Symadex), a potential anti-cancer drug, intercalates into DNA between A and G moieties. NMR-derived and MD-refined stereostructure of the d(GAGGCCTC)2:C-1311 complex

    NASA Astrophysics Data System (ADS)

    Laskowski, Tomasz; Borzyszkowska, Julia; Grynda, Jakub; Mazerski, Jan

    2017-08-01

    Imidazoacridinone C-1311 (Symadex®) is an antitumor agent which has been recommended for Phase II clinical trials a few years ago. Previously, it was shown experimentally that during the initial stage of its action C-1311 forms stable intercalation complexes with DNA duplexes. Herein, a NMR-derived stereostructure of d(GAGGCCTC)2:C-1311 complex was reported. The ligand was found locating itself between A and G moieties, forming symmetrical DNA:drug 1:2 mol/mol complex. Intercalation site was located upon the DNA-ligand proton/proton dipolar couplings observed in the NOESY spectrum and the performed MD simulations. NMR-derived stereostructure was hence refined by restrained MD using distance restraints obtained from the NOESY data and the result was compared with MD-derived structure of the proposed complex, obtained from the calculations performed with distance restraints applied only for hydrogen bonds in the terminal GC base pairs. The results of both simulations were coherent. Basing on the observed C-1311's intercalation sites and on our previous results concerning the d(CGATCG)2:C-1311 complex, we stated that AG/GA sequences are the preferred binding sites of imidazoacridinone C-1311.

  20. Cisplatin-induced duplex dissociation of complementary and destabilized short GG-containing duplex RNAs.

    PubMed

    Polonyi, Christopher; Alshiekh, Alak; Sarsam, Lamya A; Clausén, Maria; Elmroth, Sofi K C

    2014-08-21

    The ability of the anticancer active drug cisplatin to exert biological activity through interference with nucleic acid function is well documented. Since kinetics play a key role in determining product distributions in these systems, methods for accurate documentation of reactivity serve the purpose to identify preferential metal binding sites. In the present study, the aim has been to further explore a recently communicated approach (C. Polonyi and S. K. C. Elmroth, J. Chem. Soc., Dalton Trans., 2013, 42, 14959-14962) utilizing UV/vis spectroscopy and metal induced duplex RNA melting for monitoring of kinetics. More specifically, the sensitivity of the UV/vis-methodology has been evaluated by investigation of how overall length and changes of base-pairing in the close vicinity of a centrally located GG-site affect the rate of cisplatin binding, using the intracellularly active mono-aquated form of cisplatin (cis-Pt(NH3)2Cl(OH2)(+), ()) as the platination reagent. For this purpose, the reactivity of five different 13- to 17 base-pair duplex RNAs was monitored at 38 °C. A common trend of a ca. 10-fold reduction in reactivity was found to accompany an increase of bulk sodium concentration from CNa+ = 122 mM to 1.0 M. Typical half-lives are exemplified by the interaction of with the fully complementary 15-mer RNA-1 with t1/2 = ca. 0.5 and 4.8 hours, at CNa+ = 122 mM and 1.0 M respectively, and C = 45 μM. Lowering of melting temperature (Tm) was found to promote reactivity regardless of whether the change involved a decrease or increase of the RNA length. For example, at CNa+ = 1.0 M, truncation of the fully complementary and GG-containing 15-mer RNA-1 (Tm = 68.9 °C) to the 13-mer RNA-1-1-S (Tm = 63.9 °C) resulted in an increase of k2,app from ca. 0.9 M(-1) s(-1) to 2.0 M(-1) s(-1). Further, the 17-mer RNA-1-4 (Tm = 42.0 °C) with a central U4 bulge exhibited the highest reactivity of the sequences studied with k2,app = 4.0 M(-1) s(-1). The study shows that the

  1. Three-dimensional shuffling of horses in a strike-slip duplex: an example from the Lambertville sill, New Jersey

    NASA Astrophysics Data System (ADS)

    Laney, Stephen E.; Gates, Alexander E.

    1996-06-01

    Detailed analysis of a dextral strike-slip duplex within the relatively isotropic rocks of the Lambertville sill, New Jersey indicates that horses have experienced vertical, horizontal and oblique movements resulting from extrusional shuffling within a restraining bend. This is the first documentation of the three-dimensional movement of horses within a strike-slip duplex. Deformation within the duplex shows a complex system of early synthetic fractures and reverse faults followed by antithetic fractures which dissect previously continuous slab-shaped horses into diamond-shaped lenses. Most faults are oblique slip. Antithetic fault movements and clockwise rigid rotation of horses dominate the south half of the duplex and synthetic movements and counterclockwise rotations dominate the north half. Slickenline plunges on curved horse-bounding fault surfaces within the duplex range from nearly horizontal to 40° resulting in both lateral movements (middle) to normal movements (tails) on a single horse. Curved slickensides commonly have opposite senses of movement on either side of individual horses indicating relative emergence or submergence. Such a geometry could also result from a group of horses moving in the same oblique direction but at different rates. These complex extrusional-type movements were observed in both cross-sectional and plan views. The net result of the movements is a contraction or flattening of the duplex normal to the bounding faults. The horses shifted to accommodate this flattening as overall displacement was transferred between the bounding faults along curved internal faults.

  2. 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.

  3. Improvement of some pharmaceutical properties of drugs by cyclodextrin complexation. 4. Chlorpromazine hydrochloride.

    PubMed

    Ammar, H O; Ghorab, M; el-Nahhas, S A; Omar, S M; Ghorab, M M

    1995-12-01

    The potentiality of interaction of chlorpromazine hydrochloride (CPZ) with beta-cyclodextrin (beta-CD) was investigated by spectrophotometry, vapour pressure osmometry and DSC thermograms. The results revealed a very strong evidence for molecular interaction between CPZ and beta-CD. The continuous variation method was used to elucidate the stoichiometry of such interaction by spectrophotometric as well as vapour pressure measurements. Both types of data revealed the formation of a 1:1 complex. The stability constant of the complex was determined at different temperatures by the vapour pressure osmometric method. The enthalpy and entropy of interaction were evaluated and the results indicate that the interaction is exothermic. The CPZ/beta-CD complex was prepared, lyophilized and photochemical stability of the drug, its physical mixture with beta-CD as well as the prepared complex was investigated at different pH-values in presence of different buffer systems. The results revealed that the stability of the drug is greatly improved in presence of beta-CD and the great dependency of stability on the pH of the solution is decreased in presence of beta-CD. The partition coefficient of CPZ and its complex with beta-CD was determined. The data reveal a higher p.c. of the complex compared to the parent drug. The effect of beta-CD on the bioavailability of CPZ was investigated by measuring the miotic response intensity in volunteers receiving a single oral dose of the drug, drug/beta-CD physical mixture or complex. The results revealed a distinct improvement of the biological performance of CPZ by beta-CD as evidenced by an increased intensity of drug action and its duration as well as augmenting its bioavailability without affecting the time for maximum effect.

  4. 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.

  5. Modularity in Protein Complex and Drug Interactions Reveals New Polypharmacological Properties

    PubMed Central

    Nacher, Jose C.; Schwartz, Jean-Marc

    2012-01-01

    Recent studies have highlighted the importance of interconnectivity in a large range of molecular and human disease-related systems. Network medicine has emerged as a new paradigm to deal with complex diseases. Connections between protein complexes and key diseases have been suggested for decades. However, it was not until recently that protein complexes were identified and classified in sufficient amounts to carry out a large-scale analysis of the human protein complex system. We here present the first systematic and comprehensive set of relationships between protein complexes and associated drugs and analyzed their topological features. The network structure is characterized by a high modularity, both in the bipartite graph and in its projections, indicating that its topology is highly distinct from a random network and that it contains a rich and heterogeneous internal modular structure. To unravel the relationships between modules of protein complexes, drugs and diseases, we investigated in depth the origins of this modular structure in examples of particular diseases. This analysis unveils new associations between diseases and protein complexes and highlights the potential role of polypharmacological drugs, which target multiple cellular functions to combat complex diseases driven by gain-of-function mutations. PMID:22279562

  6. 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.

  7. Enzymatic Reaction with Unnatural Substrates: DNA Photolyase (Escherichia coli) Recognizes and Reverses Thymine [2+2] Dimers in the DNA Strand of a DNA/PNA Hybrid Duplex

    NASA Astrophysics Data System (ADS)

    Ramaiah, Danaboyina; Kan, Yongzhi; Koch, Troels; Orum, Henrik; Schuster, Gary B.

    1998-10-01

    Peptide nucleic acids (PNA) are mimics with normal bases connected to a pseudopeptide chain that obey Watson--Crick rules to form stable duplexes with itself and natural nucleic acids. This has focused attention on PNA as therapeutic or diagnostic reagents. Duplexes formed with PNA mirror some but not all properties of DNA. One fascinating aspect of PNA biochemistry is their reaction with enzymes. Here we show an enzyme reaction that operates effectively on a PNA/DNA hybrid duplex. A DNA oligonucleotide containing a cis, syn-thymine [2+2] dimer forms a stable duplex with PNA. The hybrid duplex is recognized by photolyase, and irradiation of the complex leads to the repair of the thymine dimer. This finding provides insight into the enzyme mechanism and provides a means for the selective repair of thymine photodimers.

  8. Design of Chitosan and Its Water Soluble Derivatives-Based Drug Carriers with Polyelectrolyte Complexes

    PubMed Central

    Wu, Qing-Xi; Lin, Dong-Qiang; Yao, Shan-Jing

    2014-01-01

    Chitosan, the cationic polysaccharide derived from the natural polysaccharide chitin, has been studied as a biomaterial for more than two decades. As a polycationic polymer with favorable properties, it has been widely used to form polyelectrolyte complexes with polyanions for various applications in drug delivery fields. In recent years, a growing number of studies have been focused on the preparation of polyelectrolyte complexes based on chitosan and its water soluble derivatives. They have been considered well-suited as biomaterials for a number of vital drug carriers with targeted/controlled release profiles, e.g., films, capsules, microcapsules. In this work, an overview highlights not only the favorable properties of chitosan and its water soluble derivatives but also the good performance of the polyelectrolyte complexes produced based on chitosan. Their various types of applications as drug carriers are reviewed in detail. PMID:25532565

  9. 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.

  10. Determination of affinity, stoichiometry and sequence selectivity of minor groove binder complexes with double-stranded oligodeoxynucleotides by electrospray ionization mass spectrometry

    PubMed Central

    Rosu, Frederic; Gabelica, Valérie; Houssier, Claude; De Pauw, Edwin

    2002-01-01

    Electrospray mass spectrometry was evaluated regarding the reliability of the determination of the stoichiometries and equilibrium association constants from single spectra. Complexes between minor groove binders (Hoechst 33258, Hoechst 33342, DAPI, netropsin and berenil) and 12mer oligonucleotide duplexes with a central sequence (A/T)4 flanked by G/C base pairs were chosen as model systems. To validate the electrospray ionization mass spectrometry (ESI-MS) method, comparisons were made with circular dichroism and fluorescence spectroscopy measurements. ESI-MS allowed the detection of minor (2 drug + DNA) species for Hoechst 33258, Hoechst 33342, DAPI and berenil with duplex d(GGGG(A/T)4GGGG)· d(CCCC(A/T)4CCCC), which were undetectable with the other techniques. Assuming that the duplexes and the complexes have the same electrospray response factors, the equilbrium association constants of the 1:1 and 2:1 complexes were determined by ESI-MS, and the values show a good quantitative agreement with fluorescence determined constants for Hoechst 33258 and Hoechst 33342. It is also shown that ESI-MS can quickly give reliable information on the A/T sequence selectivity of a drug: the signal of a complex is directly related to the affinity of the drug for that particular duplex. The potential of ESI-MS as a qualitative and quantitative affinity screening method is emphasized. PMID:12177310

  11. Determination of affinity, stoichiometry and sequence selectivity of minor groove binder complexes with double-stranded oligodeoxynucleotides by electrospray ionization mass spectrometry.

    PubMed

    Rosu, Frederic; Gabelica, Valérie; Houssier, Claude; De Pauw, Edwin

    2002-08-15

    Electrospray mass spectrometry was evaluated regarding the reliability of the determination of the stoichiometries and equilibrium association constants from single spectra. Complexes between minor groove binders (Hoechst 33258, Hoechst 33342, DAPI, netropsin and berenil) and 12mer oligonucleotide duplexes with a central sequence (A/T)4 flanked by G/C base pairs were chosen as model systems. To validate the electrospray ionization mass spectrometry (ESI-MS) method, comparisons were made with circular dichroism and fluorescence spectroscopy measurements. ESI-MS allowed the detection of minor (2 drug + DNA) species for Hoechst 33258, Hoechst 33342, DAPI and berenil with duplex d(GGGG(A/T)4GGGG). d(CCCC(A/T)4CCCC), which were undetectable with the other techniques. Assuming that the duplexes and the complexes have the same electrospray response factors, the equilbrium association constants of the 1:1 and 2:1 complexes were determined by ESI-MS, and the values show a good quantitative agreement with fluorescence determined constants for Hoechst 33258 and Hoechst 33342. It is also shown that ESI-MS can quickly give reliable information on the A/T sequence selectivity of a drug: the signal of a complex is directly related to the affinity of the drug for that particular duplex. The potential of ESI-MS as a qualitative and quantitative affinity screening method is emphasized.

  12. 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

  13. 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.

  14. 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.

  15. Thermodynamic and kinetic analysis of an RNA kissing interaction and its resolution into an extended duplex.

    PubMed

    Salim, Nilshad; Lamichhane, Rajan; Zhao, Rui; Banerjee, Tuhina; Philip, Jane; Rueda, David; Feig, Andrew L

    2012-03-07

    Kissing hairpin interactions form when the loop residues of two hairpins have Watson-Crick complementarity. In a unimolecular context, kissing interactions are important for tertiary folding and pseudoknot formation, whereas in a bimolecular context, they provide a basis for molecular recognition. In some cases, kissing complexes can be a prelude to strand displacement reactions where the two hairpins resolve to form a stable extended intermolecular duplex. The kinetics and thermodynamics of kissing-complex formation and their subsequent strand-displacement reactions are poorly understood. Here, biophysical techniques including isothermal titration calorimetry, surface plasmon resonance, and single-molecule fluorescence have been employed to probe the factors that govern the stability of kissing complexes and their subsequent structural rearrangements. We show that the general understanding of RNA duplex formation can be extended to kissing complexes but that kissing complexes display an unusual level of stability relative to simple duplexes of the same sequence. These interactions form and break many times at room temperature before becoming committed to a slow, irreversible forward transition to the strand-displaced form. Furthermore, using smFRET we show that the primary difference between stable and labile kissing complexes is based almost completely on their off rates. Both stable and labile complexes form at the same rate within error, but less stable species dissociate rapidly, allowing us to understand how these complexes can help generate specificity along a folding pathway or during a gene regulation event. Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  16. Thermodynamic and Kinetic Analysis of an RNA Kissing Interaction and Its Resolution into an Extended Duplex

    PubMed Central

    Salim, Nilshad; Lamichhane, Rajan; Zhao, Rui; Banerjee, Tuhina; Philip, Jane; Rueda, David; Feig, Andrew L.

    2012-01-01

    Kissing hairpin interactions form when the loop residues of two hairpins have Watson-Crick complementarity. In a unimolecular context, kissing interactions are important for tertiary folding and pseudoknot formation, whereas in a bimolecular context, they provide a basis for molecular recognition. In some cases, kissing complexes can be a prelude to strand displacement reactions where the two hairpins resolve to form a stable extended intermolecular duplex. The kinetics and thermodynamics of kissing-complex formation and their subsequent strand-displacement reactions are poorly understood. Here, biophysical techniques including isothermal titration calorimetry, surface plasmon resonance, and single-molecule fluorescence have been employed to probe the factors that govern the stability of kissing complexes and their subsequent structural rearrangements. We show that the general understanding of RNA duplex formation can be extended to kissing complexes but that kissing complexes display an unusual level of stability relative to simple duplexes of the same sequence. These interactions form and break many times at room temperature before becoming committed to a slow, irreversible forward transition to the strand-displaced form. Furthermore, using smFRET we show that the primary difference between stable and labile kissing complexes is based almost completely on their off rates. Both stable and labile complexes form at the same rate within error, but less stable species dissociate rapidly, allowing us to understand how these complexes can help generate specificity along a folding pathway or during a gene regulation event. PMID:22404932

  17. Polymeric complex micelles with double drug-loading strategies for folate-mediated paclitaxel delivery.

    PubMed

    Li, Min; Liu, Yongjun; Feng, Lixia; Liu, Fengxi; Zhang, Li; Zhang, Na

    2015-07-01

    Drug loading is a key procedure in the preparation of drug-loaded nano-carriers. In this study, the paclitaxel (PTX)-loaded polymeric complex micelles (FA-P123-PTX/PTX micelles) with double drug-loading strategies were designed and prepared to improve the drug loading percentage of carriers and its anti-tumor efficiency. PTX was simultaneously conjugated to pluronic P123 (P123) polymer and encapsulated inside the P123 complex micelle. Folate (FA) was linked to the surface of micelles for the active target delivery of micelles to tumor cells. The FA-P123-PTX/PTX micelles showed spherical shaped with high drug loading of 18.08±0.64%. The results of cellular uptake studies suggested that FA could promote the internalization of micelles into the FR positive cells. FA-P123-PTX/PTX micelles showed significant higher anti-tumor activity against FR positive tumor cells compared to Taxol(®) (p<0.05). Moreover, the FA-P123-PTX/PTX micelles exhibited higher anti-tumor efficacy in B16 bearing mice with better safety property compared with Taxol(®). These results suggested that FA-P123-PTX/PTX micelles with double drug-loading strategies showed great potential for targeted delivery of anti-cancer drugs. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Nanosizing of a drug/carrageenan complex to increase solubility and dissolution rate.

    PubMed

    Dai, Wei-Guo; Dong, Liang C; Song, Yan-Qiu

    2007-09-05

    In this study, we present a novel approach of nanosizing a drug/polymeric complex to increase both solubility and dissolution rate of poorly water-soluble compounds. A hydrophilic polymer, lambda-carrageenan, was first complexed with a model poorly water-soluble compound to increase the compound's aqueous solubility. The compound/carrageenan complex was further nanosized by wet-milling to enhance the dissolution rate. By complexing with carrageenan, the compound became amorphous in the complex. Using additional carrageenan as a stabilizer for nanosizing, a nanosuspension of a compound/carrageenan complex with a median particle size of about 0.3 microm was successfully developed. The particle size of the nanosuspension did not increase significantly during the lyophilization process and was stable for at least 39 days at room temperature after lyophilization. This approach of nanosizing a drug/carrageenan complex increased the aqueous solubility of the compound from less than 1 microg/mL to 39 microg/mL. In addition to increasing aqueous solubility, a nanosized compound/carrageenan complex had a faster dissolution rate than the complex, the free compound, and the nanosuspension of the free compound.

  19. 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.

  20. 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.

  1. 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.

  2. [Modeling of protein-ligand interaction complexes as a basic of the rational design of drugs

    PubMed

    Folkers, Gerd

    1995-01-01

    Most of our today"s drugs have been discovered by the lucky coincidences called serendipity. The drugs itself however, have tremendously changed since the ancient times. From the herbal teas as the remedies of our ancestors, we have switched to modern therapeutics, mostly containing only one, very high active compound. Modern analytical methods and the approaches of recent molecular biology have revealed the molecular mechanisms of a lot of this high active drugs. In most of the cases, interaction of the drug molecule with a special protein in the body, located on the surface of the cell releases the biological response. This may lead to the idea, that knowledge of the structure of the protein-ligand complex enables us to design a drug with certain properties on the computer screen. If successful, serendipity could be considerably reduced as well as animal testing. As a matter of fact, it can be shown, that the combination of biophysics, modeling, and biological in vitro methods brings us very close to that goal. However, basic problems, for instance in the handling of complex systems are opposed to the reductionistic approach in the drug research. They prevent the simple application of the lock and key principle in making a drug by fitting a putative drug molecule into the binding site of a receptor. Nevertheless, whenever a biologically active compound has been discovered, be it by pure chance, serendipity, design or ethnological pharmacy, molecular modeling or drug design will be of great help in optimizing the active compounds and enrichment of the whole new class of therapeutics.

  3. 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

  4. 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.

  5. 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

  6. Recent developments in the nanostructured materials functionalized with ruthenium complexes for targeted drug delivery to tumors.

    PubMed

    Thangavel, Prakash; Viswanath, Buddolla; Kim, Sanghyo

    2017-01-01

    In recent years, the field of metal-based drugs has been dominated by other existing precious metal drugs, and many researchers have focused their attention on the synthesis of various ruthenium (Ru) complexes due to their potential medical and pharmaceutical applications. The beneficial properties of Ru, which make it a highly promising therapeutic agent, include its variable oxidation states, low toxicity, high selectivity for diseased cells, ligand exchange properties, and the ability to mimic iron binding to biomolecules. In addition, Ru complexes have favorable adsorption properties, along with excellent photochemical and photophysical properties, which make them promising tools for photodynamic therapy. At present, nanostructured materials functionalized with Ru complexes have become an efficient way to administer Ru-based anticancer drugs for cancer treatment. In this review, the recent developments in the nanostructured materials functionalized with Ru complexes for targeted drug delivery to tumors are discussed. In addition, information on "traditional" (ie, non-nanostructured) Ru-based cancer therapies is included in a precise manner.

  7. 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.

  8. 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

  9. Toward a Better Understanding of the Complexity of Cancer Drug Resistance.

    PubMed

    Gottesman, Michael M; Lavi, Orit; Hall, Matthew D; Gillet, Jean-Pierre

    2016-01-01

    Resistance to anticancer drugs is a complex process that results from alterations in drug targets; development of alternative pathways for growth activation; changes in cellular pharmacology, including increased drug efflux; regulatory changes that alter differentiation pathways or pathways for response to environmental adversity; and/or changes in the local physiology of the cancer, such as blood supply, tissue hydrodynamics, behavior of neighboring cells, and immune system response. All of these specific mechanisms are facilitated by the intrinsic hallmarks of cancer, such as tumor cell heterogeneity, redundancy of growth-promoting pathways, increased mutation rate and/or epigenetic alterations, and the dynamic variation of tumor behavior in time and space. Understanding the relative contribution of each of these factors is further complicated by the lack of adequate in vitro models that mimic clinical cancers. Several strategies to use current knowledge of drug resistance to improve treatment of cancer are suggested.

  10. 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

  11. 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.

  12. Post-transcriptional controls by ribonucleoprotein complexes in the acquisition of drug resistance.

    PubMed

    Kang, Hoin; Kim, Chongtae; Lee, Heejin; Kim, Wook; Lee, Eun Kyung

    2013-08-20

    Acquisition of drug resistance leads to failure of anti-cancer treatments and therapies. Although several successive chemotherapies are available, along with efforts towards clinical applications of new anti-cancer drugs, it is generally realized that there is a long way to go to treat cancers. Resistance to anti-cancer drugs results from various factors, including genetic as well as epigenetic differences in tumors. Determining the molecular and cellular mechanisms responsible for the acquisition of drug resistance may be a helpful approach for the development of new therapeutic strategies to overcome treatment failure. Several studies have shown that the acquisition of drug resistance is tightly regulated by post-transcriptional regulators such as RNA binding proteins (RBPs) and microRNAs (miRNAs), which change the stability and translation of mRNAs encoding factors involved in cell survival, proliferation, epithelial-mesenchymal transition, and drug metabolism. Here, we review our current understanding of ribonucleoprotein complexes, including RBPs and miRNAs, which play critical roles in the acquisition of drug resistance and have potential clinical implications for cancer.

  13. 3D inkjet printing of tablets exploiting bespoke complex geometries for controlled and tuneable drug release.

    PubMed

    Kyobula, Mary; Adedeji, Aremu; Alexander, Morgan R; Saleh, Ehab; Wildman, Ricky; Ashcroft, Ian; Gellert, Paul R; Roberts, Clive J

    2017-09-10

    A hot melt 3D inkjet printing method with the potential to manufacture formulations in complex and adaptable geometries for the controlled loading and release of medicines is presented. This first use of a precisely controlled solvent free inkjet printing to produce drug loaded solid dosage forms is demonstrated using a naturally derived FDA approved material (beeswax) as the drug carrier and fenofibrate as the drug. Tablets with bespoke geometries (honeycomb architecture) were fabricated. The honeycomb architecture was modified by control of the honeycomb cell size, and hence surface area to enable control of drug release profiles without the need to alter the formulation. Analysis of the formed tablets showed the drug to be evenly distributed within the beeswax at the bulk scale with evidence of some localization at the micron scale. An analytical model utilizing a Fickian description of diffusion was developed to allow the prediction of drug release. A comparison of experimental and predicted drug release data revealed that in addition to surface area, other factors such as the cell diameter in the case of the honeycomb geometry and material wettability must be considered in practical dosage form design. This information when combined with the range of achievable geometries could allow the bespoke production of optimized personalised medicines for a variety of delivery vehicles in addition to tablets, such as medical devices for example. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  14. 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.

  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. Duplex-Doppler spectral analysis in the physiopathology of the temporomandibular joint.

    PubMed

    Marini, M; Odoardi, G L; Bolle, G; Tartaglia, P

    1994-01-01

    We introduce a new method of analysis of the normal and abnormal behavior of the TMJ, using a duplex-doppler spectral analysis. The method consists in monitoring the joint movement by means of a study of the Fourier transformed signals, which give information on the velocity distribution of the condylo-meniscal complex during the opening and closing phases of the jaw. Using repeated sampling over short time intervals we get a detailed description of the motion which allows to discriminate the normal and abnormal action of the condylomeniscal complex. We are able to identify various physiopathological conditions, among which opening and/or closing clicks, complex locking conditions and anomalies related to an asymmetrical behavior during the operation cycle. Duplex-doppler spectral analysis is correlated to a clinical examination in order to define various classes of anomalies.

  17. 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

  18. The QDREC web server: determining dose-response characteristics of complex macroparasites in phenotypic drug screens.

    PubMed

    Asarnow, Daniel; Rojo-Arreola, Liliana; Suzuki, Brian M; Caffrey, Conor R; Singh, Rahul

    2015-05-01

    Neglected tropical diseases (NTDs) caused by helminths constitute some of the most common infections of the world's poorest people. The etiological agents are complex and recalcitrant to standard techniques of molecular biology. Drug screening against helminths has often been phenotypic and typically involves manual description of drug effect and efficacy. A key challenge is to develop automated, quantitative approaches to drug screening against helminth diseases. The quantal dose-response calculator (QDREC) constitutes a significant step in this direction. It can be used to automatically determine quantitative dose-response characteristics and half-maximal effective concentration (EC50) values using image-based readouts from phenotypic screens, thereby allowing rigorous comparisons of the efficacies of drug compounds. QDREC has been developed and validated in the context of drug screening for schistosomiasis, one of the most important NTDs. However, it is equally applicable to general phenotypic screening involving helminths and other complex parasites. QDREC is publically available at: http://haddock4.sfsu.edu/qdrec2/. Source code and datasets are at: http://tintin.sfsu.edu/projects/phenotypicAssays.html. rahul@sfsu.edu. Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  19. 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.

  20. 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.

  1. Tannate complexes of antihistaminic drug: sustained release and taste masking approaches.

    PubMed

    Rahman, Ziyaur; Zidan, Ahmed S; Berendt, Robert T; Khan, Mansoor A

    2012-01-17

    The aim of this investigation was to evaluate the complexation potential of brompheniramine maleate (BPM) and tannic acid (TA) for sustained release and taste masking effects. The complexes (1:1-1:7 TA to BPM ratio) were prepared by the solvent evaporation method using methanol, phosphate buffer pH 6.8 or 0.1N HCl as common solvents. The complexes were characterized microscopically by scanning electron microscopy (SEM), chemically by Fourier transform infrared (FTIR) and solid-state NMR (SSNMR), thermally by differential scanning calorimetry (DSC), for crystallinity by powder X-ray powder diffraction (PXRD), for organoleptic evaluation by electronic tongue (e-tongue), and for solubility in 0.1N HCl and phosphate buffer pH 6.8. The dissolution studies were carried out using the USP II method at 50 rpm in 500 ml of dissolution media (0.1N HCl or phosphate buffer pH 6.8). SEM images revealed that the morphology of complexes were completely different from the individual components, and all complexes had the same morphological characteristics, irrespective of the solvent used for their preparation, pH or ratio of BPM and TA. The FTIR spectra showed the presence of chemical interactions between the TA and BPM. DSC, PXRD and SSNMR indicated that the drug lost its crystalline nature by formation of the complex. Complexation has significantly reduced the solubility of BPM and sustained the drug release up to 24h in phosphate buffer pH 6.8 media. The bitter taste of the BPM was completely masked which was indicated by Euclidean distance values which was far from the drug but near to its placebo in the complexes in all ratios studied. The taste masked complexes can be potentially developed as suitable dosage forms for pediatric use. In summary, complexation of BPM and TA effectively sustained the dissolution and masked the bitter taste of drug for the development of suitable dosage forms for pediatric use. Published by Elsevier B.V.

  2. Metal complexes in cancer therapy – an update from drug design perspective

    PubMed Central

    Ndagi, Umar; Mhlongo, Ndumiso; Soliman, Mahmoud E

    2017-01-01

    In the past, metal-based compounds were widely used in the treatment of disease conditions, but the lack of clear distinction between the therapeutic and toxic doses was a major challenge. With the discovery of cisplatin by Barnett Rosenberg in 1960, a milestone in the history of metal-based compounds used in the treatment of cancers was witnessed. This forms the foundation for the modern era of the metal-based anticancer drugs. Platinum drugs, such as cisplatin, carboplatin and oxaliplatin, are the mainstay of the metal-based compounds in the treatment of cancer, but the delay in the therapeutic accomplishment of other metal-based compounds hampered the progress of research in this field. Recently, however, there has been an upsurge of activities relying on the structural information, aimed at improving and developing other forms of metal-based compounds and nonclassical platinum complexes whose mechanism of action is distinct from known drugs such as cisplatin. In line with this, many more metal-based compounds have been synthesized by redesigning the existing chemical structure through ligand substitution or building the entire new compound with enhanced safety and cytotoxic profile. However, because of increased emphasis on the clinical relevance of metal-based complexes, a few of these drugs are currently on clinical trial and many more are awaiting ethical approval to join the trial. In this review, we seek to give an overview of previous reviews on the cytotoxic effect of metal-based complexes while focusing more on newly designed metal-based complexes and their cytotoxic effect on the cancer cell lines, as well as on new approach to metal-based drug design and molecular target in cancer therapy. We are optimistic that the concept of selective targeting remains the hope of the future in developing therapeutics that would selectively target cancer cells and leave healthy cells unharmed. PMID:28424538

  3. 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

  4. Complex disease-associated pharmacogenetics: drug efficacy, drug safety, and confirmation of a pathogenetic hypothesis (Alzheimer's disease).

    PubMed

    Roses, A D; Saunders, A M; Huang, Y; Strum, J; Weisgraber, K H; Mahley, R W

    2007-02-01

    Safety and efficacy pharmacogenetics can be applied successfully to the drug discovery and development pipeline at multiple phases. We review drug-target screening using high throughput SNP associations with complex diseases testing more than 1,800 candidate targets with approximately 7,000 SNPs. Alzheimer's disease data are provided as an example. The supplementation of target-selected screening with genome-wide SNP association, to also define susceptibility genes and relevant disease pathways for human diseases, is discussed. Applications for determining predictive genetic or genomic profiles, or derived biomarkers, for drug efficacy and safety during clinical development are exemplified by several successful experiments at different phases of development. A Phase I-IIA study of side effects using an oral drug for the treatment of breast cancer is used as an example of early pipeline pharmacogenetics to predict side effects and allow optimization of dosing. References are provided for several other recently published genetic association studies of adverse events during drug development. We illustrate the early identification of gene variant candidates related to efficacy in a Phase IIA obesity drug trial to generate hypotheses for testing in subsequent development. How these genetic data generated in Phase IIA are subsequently incorporated as hypotheses into later Phase clinical protocols is discussed. A Phase IIB clinical trial for Alzheimer's disease is described that exemplifies the major pipeline decision between program attrition and further clinical development. In this case, there was no significant improvement in 511 intention-to-treat patients but, applying a confirmed prognostic biomarker (APOE4) to segment the clinical trial population, all three doses of rosiglitazone demonstrated improvement in patients who did not carry the APOE4 allele. The data for the APOE4 carriers demonstrated no significant improvement but suggested that there may be a need

  5. Duplex Stirling gas fired heating only heat pump

    NASA Astrophysics Data System (ADS)

    Beale, W.

    1982-03-01

    In phase I the Duplex Stirling Gas fired Heat Pump was analyzed with the aid of the Sunpower third order simulation and optimization code and found to show heating COP of 1.7 at the rating point of 8 C (17 F) with a heat delivery of 10 kW. Also it was found that a direct heat exchange between working fluid and source and sink air was consistent with high COP in the heat pump, thus eliminating the need for an intermediate heat transfer fluid and its associated pumps and controls. Further, it was demonstrated in the simulation that the heat engine power output could be matched to the heat pump load over the range of source temperatures without need of complex control systems. Cost estimates, along with COP figures from the analysis indicated a payback time of 2 to 4 years in completion with existing combustion heating systems in northern climates.

  6. 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.

  7. 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.

  8. Reversed-phase ion-pair liquid chromatography method for purification of duplex DNA with single base pair resolution

    PubMed Central

    Wysoczynski, Christina L.; Roemer, Sarah C.; Dostal, Vishantie; Barkley, Robert M.; Churchill, Mair E. A.; Malarkey, Christopher S.

    2013-01-01

    Obtaining quantities of highly pure duplex DNA is a bottleneck in the biophysical analysis of protein–DNA complexes. In traditional DNA purification methods, the individual cognate DNA strands are purified separately before annealing to form DNA duplexes. This approach works well for palindromic sequences, in which top and bottom strands are identical and duplex formation is typically complete. However, in cases where the DNA is non-palindromic, excess of single-stranded DNA must be removed through additional purification steps to prevent it from interfering in further experiments. Here we describe and apply a novel reversed-phase ion-pair liquid chromatography purification method for double-stranded DNA ranging in lengths from 17 to 51 bp. Both palindromic and non-palindromic DNA can be readily purified. This method has the unique ability to separate blunt double-stranded DNA from pre-attenuated (n-1, n-2, etc) synthesis products, and from DNA duplexes with single base pair overhangs. Additionally, palindromic DNA sequences with only minor differences in the central spacer sequence of the DNA can be separated, and the purified DNA is suitable for co-crystallization of protein–DNA complexes. Thus, double-stranded ion-pair liquid chromatography is a useful approach for duplex DNA purification for many applications. PMID:24013567

  9. Parallel thermodynamic analysis of duplexes on oligodeoxyribonucleotide microchips.

    SciTech Connect

    Fotin, A. V.; Drobyshev, A. L.; Proudnikov, D. Y.; Perov, A. N.; Mirzabekov, A. D.; Center for Mechanistic Biology and Biotechnology; Engelhardt Inst. of Molecular Biology

    1998-03-15

    A microchip method has been developed for massive and parallel thermodynamic analyses of DNA duplexes. Fluorescently labeled oligonucleotides were hybridized with oligonucleotides immobilized in the 100 x 100 x 20 mum gel pads of the microchips. The equilibrium melting curves for all microchip duplexes were measured in real time in parallel for all microchip duplexes. Thermodynamic data for perfect and mismatched duplexes that were obtained using the microchip method directly correlated with data obtained in solution. Fluorescent labels or longer linkers between the gel and the oligonucleotides appeared to have no significant effect on duplex stability. Extending the immobilized oligonucleotides with a four-base mixture from the 3'-end or one or two universal bases (5-nitroindole) from the 3'- and/or 5'- end increased the stabilities of their duplexes. These extensions were applied to increase the stabilities of the duplexes formed with short oligonucleotides in microchips, to significantly lessen the differences in melting curves of the AT- and GC-rich duplexes, and to improve discrimination of perfect duplexes from those containing poorly recognized terminal mismatches. This study explored a way to increase the efficiency of sequencing by hybridization on oligonucleotide microchips.

  10. Improvement of aqueous solubility of fenretinide and other hydrophobic anti-tumor drugs by complexation with amphiphilic dextrins.

    PubMed

    Orienti, I; Zuccari, G; Carosio, R; Montaldo, P G

    2009-10-01

    This study relates to the preparation of a series of amphiphilic dextrins and their evaluation as complexing agents for anti-tumor hydrophobic drugs such as fenretinide, paclitaxel, etoposide, and camptothecin. The amphiphilic dextrins were obtained by conjugation of low molecular weight dextrin (average molecular weight 1670, average polymerization degree 9.33 glucose monomer) with hydrocarbon chains at substitution degree of about 0.1 mole hydrocarbon chain per mole of glucose monomer, as confirmed by 1H-NMR spectra. The conjugates were highly soluble in water and dissolved with formation of nano-aggregates endowed with hydrophobic inner cores able to host hydrophobic drugs by complexation. Complexation raised hydrophobic drugs aqueous solubility; the best results were obtained with fenretinide. Solid complexes with fenretinide were prepared by using three different approaches: the kneading method, the co-solubilisation method, and the co-precipitation method. Kneading method provided the complexes endowed with the best functional properties. Thermogravimetric analysis on solid samples suggested a notable thermal stability up to 300 degrees C for both the conjugated dextrins and the solid complexes. In differential scanning calorimetry profiles no significant differences were observed among amphiphilic dextrins and complexed drug, indicating that the guest molecule exists in an amorphous state in the solid matrices. Particle size analysis confirmed the dimensional suitability of the complexes for parenteral administration. Moreover, sustained drug release, in vitro, has been observed from all the complexes analyzed. Regarding the biological effects, the cytotoxicity of complexed fenretinide towards HTLA-230 neuroblastoma cell line was always higher than the free drug, suggesting that complexation increased drug bioavailability. These findings, taken together, indicated that these biodegradable, self-assembling dextrin conjugates may be regarded as new potential

  11. 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.

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

    PubMed Central

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

    2009-01-01

    A social epidemiologic perspective considers factors at multiple levels of influence (e.g., social networks, neighborhoods, 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. PMID:18930649

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. Development of a Novel Polymeric Nanocomposite Complex for Drugs with Low Bioavailability.

    PubMed

    Sithole, Mduduzi N; Choonara, Yahya E; du Toit, Lisa C; Kumar, Pradeep; Marimuthu, Thashree; Kondiah, Pierre P D; Pillay, Viness

    2017-07-17

    Semi-synthetic biopolymer complex (SSBC) nanoparticles were investigated as a potential oral drug delivery system to enhance the bioavailability of a poorly water-soluble model drug acyclovir (ACV). The SSBCs were prepared from cross-linking of hydroxyl groups on hyaluronic acid (HA) with poly(acrylic acid) (PAA) resulting in ether linkages. Thereafter, conjugation of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) onto HA-PAA was accomplished using a 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)/N-hydroxysuccinimide (NHS)-promoted coupling reaction. Nanoparticle powders were prepared by spray drying of drug-loaded SSBC emulsions in a laboratory nano spray dryer. The prepared SSBC was characterized by Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), (1)H nuclear magnetic resonance (NMR) imaging, and X-ray diffraction (XRD) spectroscopy. The average particle size was found to be 257.92 nm. An entrapment efficiency of 85% was achieved as ACV has enhanced affinity for the hydrophobic inner core of the complex. It was shown that SSBC improved the solubility of ACV by 30% and the ex vivo permeation by 10% compared to the conventional ACV formulation, consequentially enhancing its bioavailability. Overall, this study resulted in the successful preparation of a hybrid chemically conjugated SSBC which has great potential for enhanced oral absorption of ACV with possible tuneable ACV permeability and solubility, producing an "intelligent" nanoenabled drug delivery system.

  18. 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.

  19. A Histone Deacetylase Complex Mediates Biofilm Dispersal and Drug Resistance in Candida albicans

    PubMed Central

    Fox, Emily P.; Hartooni, Nairi; Mitchell, Kaitlin F.; Hnisz, Denes; Andes, David R.; Kuchler, Karl; Johnson, Alexander D.

    2014-01-01

    ABSTRACT Biofilms are resilient, surface-associated communities of cells with specialized properties (e.g., resistance to drugs and mechanical forces) that are distinct from those of suspension (planktonic) cultures. Biofilm formation by the opportunistic human fungal pathogen Candida albicans is medically relevant because C. albicans infections are highly correlated with implanted medical devices, which provide efficient substrates for biofilm formation; moreover, biofilms are inherently resistant to antifungal drugs. Biofilms are also important for C. albicans to colonize diverse niches of the human host. Here, we describe four core members of a conserved histone deacetylase complex in C. albicans (Set3, Hos2, Snt1, and Sif2) and explore the effects of their mutation on biofilm formation. We find that these histone deacetylase complex members are needed for proper biofilm formation, including dispersal of cells from biofilms and multifactorial drug resistance. Our results underscore the importance of the physical properties of biofilms in contributing to drug resistance and dispersal and lay a foundation for new strategies to target biofilm dispersal as a potential antifungal intervention. PMID:24917598

  20. 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

  1. Structural Insights into the Quadruplex-Duplex 3' Interface Formed from a Telomeric Repeat: A Potential Molecular Target.

    PubMed

    Russo Krauss, Irene; Ramaswamy, Sneha; Neidle, Stephen; Haider, Shozeb; Parkinson, Gary N

    2016-02-03

    We report here on an X-ray crystallographic and molecular modeling investigation into the complex 3' interface formed between putative parallel stranded G-quadruplexes and a duplex DNA sequence constructed from the human telomeric repeat sequence TTAGGG. Our crystallographic approach provides a detailed snapshot of a telomeric 3' quadruplex-duplex junction: a junction that appears to have the potential to form a unique molecular target for small molecule binding and interference with telomere-related functions. This unique target is particularly relevant as current high-affinity compounds that bind putative G-quadruplex forming sequences only rarely have a high degree of selectivity for a particular quadruplex. Here DNA junctions were assembled using different putative quadruplex-forming scaffolds linked at the 3' end to a telomeric duplex sequence and annealed to a complementary strand. We successfully generated a series of G-quadruplex-duplex containing crystals, both alone and in the presence of ligands. The structures demonstrate the formation of a parallel folded G-quadruplex and a B-form duplex DNA stacked coaxially. Most strikingly, structural data reveals the consistent formation of a TAT triad platform between the two motifs. This triad allows for a continuous stack of bases to link the quadruplex motif with the duplex region. For these crystal structures formed in the absence of ligands, the TAT triad interface occludes ligand binding at the 3' quadruplex-duplex interface, in agreement with in silico docking predictions. However, with the rearrangement of a single nucleotide, a stable pocket can be produced, thus providing an opportunity for the binding of selective molecules at the interface.

  2. Urea Mimics Nucleobases by Preserving the Helical Integrity of B-DNA Duplexes via Hydrogen Bonding and Stacking Interactions.

    PubMed

    Suresh, Gorle; Padhi, Siladitya; Patil, Indrajit; Priyakumar, U Deva

    2016-10-11

    Urea lesions are formed in DNA because of free radical damage of the thymine base, and their occurrence in DNA blocks DNA polymerases, which has deleterious consequences. Recently, it has been shown that urea is capable of forming hydrogen bonding and stacking interactions with nucleobases, which are responsible for the unfolding of RNA in aqueous urea. Base pairing and stacking are inherent properties of nucleobases; because urea is able to form both, this study attempts to investigate if urea can mimic nucleobases in the context of nucleic acid structures by examining the effect of introducing urea lesions complementary to the four different nucleobases on the overall helical integrity of B-DNA duplexes and their thermodynamic stabilities using molecular dynamics (MD) simulations. The MD simulations resulted in stable duplexes without significant changes in the global B-DNA conformation. The urea lesions occupy intrahelical positions by forming hydrogen bonds with nitrogenous nucleobases, in agreement with experimental results. Furthermore, these urea lesions form hydrogen bonding and stacking interactions with other nucleobases of the same and partner strands, analogous to nucleobases in typical B-DNA duplexes. Direct hydrogen bond interactions are observed for the urea-purine pairs within DNA duplexes, whereas two different modes of pairing, namely, direct hydrogen bonds and water-mediated hydrogen bonds, are observed for the urea-pyrimidine pairs. The latter explains the complexities involved in interpreting the experimental nuclear magnetic resonance data reported previously. Binding free energy calculations were further performed to confirm the thermodynamic stability of the urea-incorporated DNA duplexes with respect to pure duplexes. This study suggests that urea mimics nucleobases by pairing opposite all four nucleobases and maintains the overall structure of the B-DNA duplexes.

  3. [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

  4. 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

  5. Mitomycin C-soybean phosphatidylcholine complex-loaded self-assembled PEG-lipid-PLA hybrid nanoparticles for targeted drug delivery and dual-controlled drug release.

    PubMed

    Li, Yang; Wu, Hongjie; Yang, Xiangrui; Jia, Mengmeng; Li, Yanxiu; Huang, Yu; Lin, Jinyan; Wu, Shichao; Hou, Zhenqing

    2014-08-04

    Most present drug-phospholipid delivery systems were based on a water-insoluble drug-phospholipid complex but rarely water-soluble drug-phospholipid complex. Mitomycin C (MMC) is a water-soluble anticancer drug extensively used in first-line chemotherapy but is limited by its poor aqueous stability in vitro, rapid elimination from the body, and lack of target specificity. In this article, we report the MMC-soybean phosphatidylcholine complex-loaded PEG-lipid-PLA hybrid nanoparticles (NPs) with Folate (FA) functionalization (FA-PEG-PE-PLA NPs@MMC-SPC) for targeted drug delivery and dual-controlled drug release. FA-PEG-PE-PLA NPs@MMC-SPC comprise a hydrophobic core (PLA) loaded with MMC-SPC, an amphiphilic lipid interface layer (PE), a hydrophilic shell (PEG), and a targeting ligand (FA) on the surface, with a spherical shape, a nanoscaled particle size, and high drug encapsulation efficiency of almost 95%. The advantage of the new drug delivery systems is the early phase controlled drug release by the drug-phospholipid complex and the late-phase controlled drug release by the pH-sensitive polymer-lipid hybrid NPs. In vitro cytotoxicity and hemolysis assays demonstrated that the drug carriers were cytocompatible and hemocompatible. The pharmacokinetics study in rats showed that FA-PEG-PE-PLA NPs@MMC-SPC significantly prolonged the blood circulation time compared to that of the free MMC. More importantly, FA-PEG-PE-PLA NPs@MMC-SPC presented the enhanced cell uptake/cytotoxicity in vitro and superior tumor accumulation/therapeutic efficacy in vivo while reducing the systemic toxicity. A significant accumulation of MMC in the nuclei as the site of MMC action achieved in FA-PEG-PE-PLA NPs@MMC-SPC made them ideal for MMC drug delivery. This study may provide an effective strategy for the design and development of the water-soluble drug-phospholipid complex-based targeted drug delivery and sustained/controlled drug release.

  6. 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.

  7. 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.

  8. Preserving the supersaturation generation capability of amorphous drug-polysaccharide nanoparticle complex after freeze drying.

    PubMed

    Kiew, Tie Yi; Cheow, Wean Sin; Hadinoto, Kunn

    2015-04-30

    While the supersaturation generation capability of amorphous nanopharmaceuticals (NPs) in their aqueous suspension form has been well established, their supersaturation generation is adversely affected after drying. Herein we investigated the effects of freeze drying on the supersaturation generation capability of a new class of amorphous NPs referred to as drug nanoplex prepared and stabilized by electrostatic complexation of drug molecules with polysaccharides (dextran sulfate). Using ciprofloxacin as the model drug, two types of freeze-drying adjuvants were investigated, i.e., (1) highly water-soluble excipient (trehalose, mannitol), whose role was to prevent irreversible NPs aggregations upon drying, and (2) crystallization inhibitor (hydroxypropylmethylcellulose (HPMC)), whose role was to suppress crystallization of the dissolved drug and the remaining solid phase. The results showed that dual-adjuvant formulations (i.e. trehalose-HPMC and mannitol-HPMC) were required to preserve the supersaturation generation capability of the drug nanoplex suspension after drying. Freeze drying with only one adjuvant type, or incorporating HPMC as physical mixtures with the freeze-dried nanoplex, were ineffective in preserving the supersaturation. The dual-adjuvant formulations produced prolonged supersaturation levels over 240min at ≈6-8× of the saturation solubility with comparable area under the curve (AUC) in the concentration versus time plot as that exhibited by the suspension form. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. 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.

  10. Sigmatization of duplex forgings: A case history

    SciTech Connect

    Crolet, J.L.; Corbineau, S.; Perrollet, C.P.

    1997-08-01

    An S31803 (22-05 alloy) duplex stainless steel flow-cross in service fin the H{sub 2}S-containing Saint-Faust gas field near Lacq was almost broken in two by a corrosion crack resulting from improper heat treatment. Sensitization had occurred much more rapidly than expected from the kinetics of sigma phase formation generally considered in the literature. None of the inspection techniques routinely employed in the oil and gas industry would have been capable of detecting this manufacturing defect. More stringent quality acceptance criteria are therefore necessary.

  11. Streamlined duplex live-dead microplate assay for cultured cells.

    PubMed

    Pfeffer, Bruce A; Fliesler, Steven J

    2017-08-01

    A duplex fluorescence assay to assess the viability of cells cultured in multi-well plates is described, which can be carried out in the original culture plate using a plate reader, without exchanges of culture or assay medium, or transfer of cells or cell supernatant. The method uses freshly prepared reagents and does not rely on a proprietary, commercially supplied kit. Following experimental treatment, calcein acetoxymethyl ester (CaAM) is added to each well of cultured cells; after 30 min, the fluorescence intensity (emission λmax ∼ 530 nm) is measured. The signal is due to formation of calcein, which is produced from CaAM by action of esterase activity found in intact live cells. Since live cells may express plasma membrane multidrug transport proteins, especially of the ABC transporter family, the CaAM incubation is carried out in the presence of an inhibitor of this efflux process, thereby improving the dynamic range of the assay. Next, SYTOX(®) Orange (SO) is added to the culture wells, and, after a 30-min incubation, fluorescence intensity (emission λmax ∼ 590 nm) is measured again. SO is excluded from cells that have an intact plasma membrane, but penetrates dead/dying cells and can diffuse into the nucleus, where it binds to and forms a fluorescent complex with DNA. The CaAM already added to the wells causes no interference with the latter fluorescent signal. At the conclusion of the duplex assay, both live and dead cells remain in the culture wells and can be documented by digital imaging to demonstrate correlation of cellular morphology with the assay output. Two examples of the application of this method are provided, using cytotoxic compounds having different mechanisms of action. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. 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

  13. 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.

  14. 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

  15. 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…

  16. MAIN VIEW OF DUPLEX FROM THE NORTH SIDE OF THE ...

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

    MAIN VIEW OF DUPLEX FROM THE NORTH SIDE OF THE STREET SHOWING DUAL DRIVEWAYS WITH CENTRAL PLANTING STRIP - Camp H.M. Smith and Navy Public Works Center Manana Title VII (Capehart) Housing, M-Shaped Four-Bedroom Duplex Type 5, Birch Circle, Cedar Drive, Pearl City, Honolulu County, HI

  17. 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

  18. Structural Properties of G,T-Parallel Duplexes

    PubMed Central

    Aviñó, Anna; Cubero, Elena; Gargallo, Raimundo; González, Carlos; Orozco, Modesto; Eritja, Ramon

    2010-01-01

    The structure of G,T-parallel-stranded duplexes of DNA carrying similar amounts of adenine and guanine residues is studied by means of molecular dynamics (MD) simulations and UV- and CD spectroscopies. In addition the impact of the substitution of adenine by 8-aminoadenine and guanine by 8-aminoguanine is analyzed. The presence of 8-aminoadenine and 8-aminoguanine stabilizes the parallel duplex structure. Binding of these oligonucleotides to their target polypyrimidine sequences to form the corresponding G,T-parallel triplex was not observed. Instead, when unmodified parallel-stranded duplexes were mixed with their polypyrimidine target, an interstrand Watson-Crick duplex was formed. As predicted by theoretical calculations parallel-stranded duplexes carrying 8-aminopurines did not bind to their target. The preference for the parallel-duplex over the Watson-Crick antiparallel duplex is attributed to the strong stabilization of the parallel duplex produced by the 8-aminopurines. Theoretical studies show that the isomorphism of the triads is crucial for the stability of the parallel triplex. PMID:20798879

  19. 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.

  20. Regulation of nuclear reactors by duplexed control rods; Linearized analysis

    SciTech Connect

    Haidar, N.H.S. ); Diab, H.B. )

    1991-10-01

    In this paper the dynamic behavior of a duplex control rod for a nuclear reactor is analyzed by linearized modeling. A simulation-aided design for this duplex, which has performance and safety characteristics that are improved over those of conventional single control rods with the same stability margins, is reported.

  1. Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters

    SciTech Connect

    Shen, Chen-Hsiang; Wang, Yuan-Fang; Kovalevsky, Andrey Y.; Harrison, Robert W.; Weber, Irene T.

    2010-10-22

    The structural and kinetic effects of amprenavir (APV), a clinical HIV protease (PR) inhibitor, were analyzed with wild-type enzyme and mutants with single substitutions of V32I, I50V, I54V, I54M, I84V and L90M that are common in drug resistance. Crystal structures of the APV complexes at resolutions of 1.02-1.85 {angstrom} reveal the structural changes due to the mutations. Substitution of the larger side chains in PR{sub V32I}, PR{sub I54M} and PR{sub L90M} resulted in the formation of new hydrophobic contacts with flap residues, residues 79 and 80, and Asp25, respectively. Mutation to smaller side chains eliminated hydrophobic interactions in the PR{sub I50V} and PR{sub I54V} structures. The PR{sub I84V}-APV complex had lost hydrophobic contacts with APV, the PR{sub V32I}-APV complex showed increased hydrophobic contacts within the hydrophobic cluster and the PR{sub I50V} complex had weaker polar and hydrophobic interactions with APV. The observed structural changes in PR{sub I84V}-APV, PR{sub V32I}-APV and PR{sub I50V}-APV were related to their reduced inhibition by APV of six-, 10- and 30-fold, respectively, relative to wild-type PR. The APV complexes were compared with the corresponding saquinavir complexes. The PR dimers had distinct rearrangements of the flaps and 80's loops that adapt to the different P1{prime} groups of the inhibitors, while maintaining contacts within the hydrophobic cluster. These small changes in the loops and weak internal interactions produce the different patterns of resistant mutations for the two drugs.

  2. 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.

  3. 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

  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. Nickel-free duplex stainless steels

    SciTech Connect

    Wang, J.; Uggowitzer, P.J.; Magdowski, R.; Speidel, M.O.

    1998-12-04

    It is well known that nitrogen-alloying in steel produces a variety of exceptional properties such as high strength, high ductility and, eventually, resistance to stress corrosion cracking. High-nitrogen steels (HNS), therefore, have recently been developed to enhance the strength and corrosion resistance of stainless steels. However, due to a low solubility of nitrogen in a liquid steel under atmospheric pressure, the production of such high-nitrogen alloys needs high-pressure facilities that cause an extra cost. A possible route of developing high-nitrogen alloys under atmospheric pressure is to choose a duplex microstructure, where the amount of austenite and ferrite phase is nearly equal. A much lower nitrogen content is needed to maintain a 50% austenite phase compared with the necessary addition of nitrogen to reach a 100% austenitic microstructure. In addition, duplex stainless steels (DSS) with 40--60% ferrite can significantly improve the SCC-resistance. The objective of this work was to develop a new group of nickel-free, high strength and corrosion resistant DSS. Nickel was completely replaced by nitrogen in order to enhance SCC resistance and reduce the alloying element cost. The microstructure, mechanical properties, corrosion resistance and cost analysis of new alloys are investigated in comparison with some commercial stainless steels.

  7. 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.

  8. 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.

  9. Essential drugs policy in three rural counties in China: what does a complexity lens add?

    PubMed

    Xiao, Yue; Zhao, Kun; Bishai, David M; Peters, David H

    2013-09-01

    In 2009 the government of China identified an essential drugs policy as one of five priority areas for health system reform. Since then, a national essential drugs policy has been defined, along with plans to implement it. As a large scale social intervention, the policy will have a significant impact on various local health actors. This paper uses the lens of complex adaptive systems to examine how the policy has been implemented in three rural Chinese counties. Using material gathered from interviews with key actors in county health bureaus and township health centers, we illustrate how a single policy can lead to multiple unanticipated outcomes. The complexity lens applied to the material gathered in interviews helps to identify relevant actors, their different relationships and policy responses and a new framework to better understand heterogeneous pathways and outcomes. Decision-makers and policy implementers are advised to embrace the complex and dynamic realities of policy implementation. This involves developing mechanisms to monitor different behaviors of key actors as well as the intended outcomes and unintended consequences of the policy. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. 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

  11. 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.

  12. Improving cyclodextrin complexation of a new antihepatitis drug with glacial acetic acid.

    PubMed

    Johnson, Jennifer L H; He, Yan; Jain, Akash; Yalkowsky, Samuel H

    2006-02-24

    The purpose of this study was to develop and evaluate a solid nonaqueous oral dosage form for a new hepatitis C drug, PG301029, which is insoluble and unstable in water. Hydroxypropyl-beta-cyclodextrin (HPbetaCD) and PG301029 were dissolved in glacial acetic acid. The acetic acid was removed by rotoevaporation such that the drug exists primarily in the complexed form. The stability of formulated PG301029 was determined upon dry storage and after reconstitution in simulated intestinal fluid (SIF), simulated gastric fluid (SGF), and water. Formulated PG301029 was found to be stable upon storage and can be reconstituted with water to a concentration 200 times that of the intrinsic solubility. Once reconstituted, the powder dissolves rapidly and PG301029 remains stable for 21 hours in SGF, SIF, and water. The unique use of acetic acid and HPbetaCD results in a solid dosage form of PG301029 that is both soluble and stable in water.

  13. 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.

  14. 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

  15. (Pentamethylcyclopentadienato)rhodium complexes for delivery of the curcumin anticancer drug [Rhodium pentamethylcyclopentadienato complexes for delivery of the curcumin anti-cancer drug

    DOE PAGES

    Markham, Jack; Liang, Jun; Levina, Aviva; ...

    2017-01-23

    [RhIII(*Cp)Cl(X,Y)]n+ complexes {X, Y = Cl, PTA, n = 0 (2); X, Y = en, n = 1 (3, Cl– salt; 4, PF6– salt); X, Y = acac, n = 0 (5); X, Y = cur, n = 0 (6), where *Cp = pentamethylcyclopentadienato, curH = curcumin; PTA = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane; en = 1,2-ethanediamine; acac = acetylacetonato = 2,4-pentanedionato(1–)} were synthesized from [Rh(*Cp)(µ-Cl)Cl]2 (1). While 2–5 were inactive against human epithelial A549 lung-cancer cells in assays of cytotoxicity, and antimetastatic and proapoptotic behaviors, 6 had a cytotoxic activity similar to that of curH over 72 h, but at 24 h inmore » real-time cell migration assays, it was less active, showing slow release of curH. All complexes underwent ligand-exchange reactions with biomolecules and cells within the timeframes of the assays (X-ray absorption spectroscopy). Intracellular elemental distributions (X-ray fluorescence microscopy) showed that 6 effectively delivered curH to cells, where it was released. Other elemental distributions and caspase activities were consistent with preapoptotic activities. As such, 6 is a promising delivery agent for bioactive ligands, such as curH. However, pure curcumin itself showed a previously unrecognized ability to promote migration of A549 cells at subtoxic concentrations in the presence of endothelial growth factor, which may be a concern for its widespread use as a nutritional supplement and as a potential drug. As a result, this aspect warrants further research.« less

  16. 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.

  17. A new type of polymeric heavy metal complexing precipitant used as fishery disinfectant and antiparasitic drug

    NASA Astrophysics Data System (ADS)

    Liu, Y. C.; Zhang, A. N.; Wang, X. B.; Xu, J.; Zeng, X. H.; Wang, H. M.

    2017-08-01

    This paper presents a technique to produce a new kind of fishery drug that is water emulsion suspending agent containing polymeric calcium-iron-dithiocarbamate with heavy metal complexing precipitate ability, good disinfection and auxiliary insecticidal efficacy. The product has good dispersion, high efficiency and low toxicity, as well as no pollution and no harmful residues. It not only can be used in the pond waters and ornamental waters, but also can meet the high requirements of the aquaculture waters. There is non-pollutant emission in the production, which is a green environment-friendly technique without three waste discharges. This technology belongs to the ecological and environmental protection.

  18. Roles of Multifunctional COP9 Signalosome Complex in Cell Fate and Implications for Drug Discovery.

    PubMed

    Li, Ping; Xie, Longxiang; Gu, Yinzhong; Li, Jiang; Xie, Jianping

    2017-06-01

    The eight subunits containing COP9 signalosome (CSN) complex, is highly conserved among eukaryotes. CSN, identified as a negative regulator of photomorphogenesis, has also been demonstrated to be important in proteolysis, cellular signal transduction and cell cycle regulation in various eukaryotic organisms. This review mainly summarizes the roles of CSN in cell cycle regulation, signal transduction and apoptosis, and its potential as diagnostic biomarkers, drug targets for cancer and infectious diseases. J. Cell. Physiol. 232: 1246-1253, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  19. 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.

  20. 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.

  1. 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.

  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. Lubrication for high load duplex bearings

    SciTech Connect

    Steinhoff, R.G.

    1997-08-01

    Three ES and H-compatible lubricants (Environment, Safety and Health) for high load duplex bearing applications were evaluated and compared against 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. Bearings with Supercritical CO{sub 2} deposition of PTFE extracted from Vydax AR/IPA, bearings with titanium carbide coated balls, and bearings with diamond-like carbon races and retainers were evaluated. Bearings with Supercritical CO{sub 2} deposition of PTFE from Vydax AR/IPA performed as well as bearings with Freon deposition of PTFE from Freon-based Vydax.

  4. 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.

  5. 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

  6. 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.

  7. The evolving role of drug-coated balloons for the treatment of complex femoropopliteal lesions.

    PubMed

    Korosoglou, Grigorios; Lichtenberg, Michael; Celik, Sultan; Andrassy, Joachim; Brodmann, Marianne; Andrassy, Martin

    2017-10-02

    Conventional therapies for transcatheter treatment of patients with infrainguinal obstructive disease remain compromised by high restenosis rates. Drug-coated balloons (DCB) offer a novel therapeutic alternative targeting the source of neo-intimal hyperplasia, without the need for a permanent endovascular scaffold and their inherent limitations. A systematic research of the medical databases (Pubmed) has been conducted for this up-to-date review. Keywords, such as "drug-coated balloons (DCB), "drug-eluting balloon (DEB), "in-stent-restenosis" (ISR), "de novo stenosis", "plain old angioplasty" (POBA), "atherectomy", "debulking", "superficial femoral artery" (SFA), "popliteal artery" (PA), "above/below the knee" and "peripheral artery disease" (PAD) have been used. Furthermore, data from reviews, original contributions, randomized controlled studies, observational studies, registries and single center experiences have been considered. Overall, an increasing level of evidence supports the use of DCB for the treatment of long, complex, heavily calcified femoropopliteal non-occlusive and occlusive lesions, including failure after BM stent implantation due to ISR. However, more studies will be necessary to investigate the long term effects of DCB-treatment in these real world lesions.

  8. Recent development of chitosan-based polyelectrolyte complexes with natural polysaccharides for drug delivery.

    PubMed

    Luo, Yangchao; Wang, Qin

    2014-03-01

    Chitosan, as a unique positively charged polysaccharide, has been one of the most popular biopolymers for development of drug delivery systems for various applications, due to its promising properties, including high biocompatibility, excellent biodegradability, low toxicity, as well as abundant availability and low production cost. Since last decade, increasing attention has been attracted by delivery systems fabricated from natural biopolymer-based polyelectrolyte complexes (PEC), formed by electrostatic interactions between two oppositely charged biopolymers. In order to tailor specific applications of chitosan-based PEC drug delivery systems, various forms have been developed in recent years, including nanoparticles, microparticles, beads, tablets, gels, as well as films and membranes. The present review focuses on the recent advances in drug delivery applications of chitosan-based PEC with other natural polysaccharides, including alginate, hyaluronic acid, pectin, carrageenan, xanthan gum, gellan gum, gum arabic, and carboxymethyl cellulose, etc. The fabrication techniques, characterizations, as well as in vitro and in vivo evaluations of each PEC delivery system are discussed in detail. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. 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

  10. 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.

  11. 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

  12. The effects of drug complexation on the stability and conformation of human serum albumin: protein unfolding.

    PubMed

    Ahmed-Ouameur, A; Diamantoglou, S; Sedaghat-Herati, M R; Nafisi, Sh; Carpentier, R; Tajmir-Riahi, H A

    2006-01-01

    We report different analytical methods used to study the effects of 3\\'-azido-3\\'-deoxythymidine, aspirin, taxol, cisplatin, atrazine, 2,4-dichlorophenoxyacetic, biogenic polyamines, chlorophyll, chlorophyllin, poly(ethylene glycol), vanadyl cation, vanadate anion, cobalt-hexamine cation, and As2O3, on the stability and secondary structure of human serum albumin (HSA) in aqueous solution, using capillary electrophoresis, Fourier transform infrared, ultraviolet visible, and circular dichroism (CD) spectroscopic methods. The concentrations of HSA used were 4% to 2% or 0.6 to 0.3 mM, while different ligand concentrations were 1 microM to 1 mM. Structural data showed drugs are mostly located along the polypeptide chains with both specific and nonspecific interactions. The stability of drug-protein complexes were in the order K(VO(2+)) 1.2 x 10(8) M(-1) > K(AZT) 1.9 x 10(6) M(-)1 > K(PEG) 4.1 x 10(5) M(-1) > K(atrazine) 3.5 x 10(4) M(-1) > K(chlorophyll) 2.9 x 10(4) M(-1) > K2,4-D 2.5 x 10(4) M-1 > K(spermine) 1.7 x 10(4) M(-1) > K(taxol) 1.43 x 10(4) M(-1) > K(Co(3+)) > 1.1 x 10(4) M(-1) > K(aspirin) 1.04 x 10(4)i(-1) > K(chlorophyllin) 7.0 x 10(3) M(-1) > K(VO(3)(-)) 6.0 x 103 M(-1) > K(spermidine) 5.4 x 10(3) M(-1) > K(putrescine) 3.9 x 10(3) M(-1) > K(As(2)O(3)) 2.2 x 10(3) M(-1)> K(cisplatin) 1.2 x 10(2) M(-1). The protein conformation was altered (infrared and CD results) with major reduction of alpha-helix from 60 to 55% (free HSA) to 49 to 40% and increase of beta-structure from 22 to 15% (free HSA) to 33 to 23% in the drug-protein complexes. The alterations of protein secondary structure are attributed to a partial unfolding of HSA on drug complexation.

  13. 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

  14. Duplex scanning on admission prevents unnecessary carotid endarterectomies.

    PubMed

    Dalainas, I; Nano, G; Casana, R; Bianchi, P; Stegher, S; Malacrida, G; Tealdi, D G

    2006-06-01

    This retrospective single Institution study, aims to evaluate the performance of duplex scanning on admission of patients with carotid artery disease to avoid unnecessary carotid endarterectomies. From 1 January 1997 until 31 Decem-ber 2004, 1 504 patients were admitted to our Institution to undergo carotid endarterectomy. A duplex scan on admission was performed in all of them. A total of 1 369 from these patients (91%) underwent surgery, while 135 (9%) were dismissed because there was no indication for surgical treatment. They were put in conservative treatment and periodic duplex control appointments. In 9% of the patients, unnecessary carotid endarterectomy was avoided.

  15. 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.

  16. Differences in the longevity of topo IIalpha and topo IIbeta drug-stabilized cleavable complexes and the relationship to drug sensitivity.

    PubMed

    Errington, Fiona; Willmore, Elaine; Leontiou, Chrysoula; Tilby, Michael J; Austin, Caroline A

    2004-02-01

    DNA topoisomerase II (topo II) is an important cellular target for chemotherapeutic agents. Human cells have two isoforms of topo II (alpha and beta), and both are inhibited by the chemotherapeutic agents etoposide, amsacrine (mAMSA) and mitoxantrone. It is known that the cytotoxic importance of topo IIalpha or topo IIbeta drug-induced complexes differs depending on which drug is present. This study was designed to (a) assess isoform-specific formation and reversal of topo IIalpha and beta cleavable complexes, and (b) determine whether the cytotoxic importance of either isoform was related to differences in the longevity of the complexes. Mouse embryonic fibroblasts (MEFs) were used to study the cellular response to the topo II poisons etoposide, mitoxantrone and mAMSA. The longevity of topo IIalpha and beta complexes was determined using the TARDIS assay. This immunofluorescence assay can differentiate between the topo II isoforms and thus allowed us to investigate the persistence and importance of topo IIalpha and beta complexes for the first time. In MEFs treated with etoposide, 50% of topo IIalpha complexes dissociated within 40 min whereas dissociation of topo IIbeta complexes took only 20 min. Disappearance of complexes was a slower process for mitoxantrone-treated cells. The time taken to reduce topo IIalpha and topo IIbeta cleavable complexes by 50% was 10 and 6 h, respectively. In contrast, mAMSA-stabilized topo IIalpha and topo IIbeta cleavable complexes were equally stable (dissociation within 15 min for both isoforms). These stability data were confirmed using an in vitro assay. We previously demonstrated that topo IIalpha is the major target for etoposide and mitoxantrone but that both topo IIalpha and topo IIbeta are important for mAMSA cytotoxicity. The longevity of the topo IIalpha and beta cleavable complexes shown here is therefore an important factor in determining the cytotoxic sensitivity of either isoform to these drugs.

  17. 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.

  18. Crystallization and initial crystallographic analysis of covalent DNA-cleavage complexes of Staphyloccocus aureus DNA gyrase with QPT-1, moxifloxacin and etoposide.

    PubMed

    Srikannathasan, Velupillai; Wohlkonig, Alexandre; Shillings, Anthony; Singh, Onkar; Chan, Pan F; Huang, Jianzhong; Gwynn, Michael N; Fosberry, Andrew P; Homes, Paul; Hibbs, Martin; Theobald, Andrew J; Spitzfaden, Claus; Bax, Benjamin D

    2015-10-01

    Fluoroquinolone drugs such as moxifloxacin kill bacteria by stabilizing the normally transient double-stranded DNA breaks created by bacterial type IIA topoisomerases. Previous crystal structures of Staphylococcus aureus DNA gyrase with asymmetric DNAs have had static disorder (with the DNA duplex observed in two orientations related by the pseudo-twofold axis of the complex). Here, 20-base-pair DNA homoduplexes were used to obtain crystals of covalent DNA-cleavage complexes of S. aureus DNA gyrase. Crystals with QPT-1, moxifloxacin or etoposide diffracted to between 2.45 and 3.15 Å resolution. A G/T mismatch introduced at the ends of the DNA duplexes facilitated the crystallization of slightly asymmetric complexes of the inherently flexible DNA-cleavage complexes.

  19. 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.

  20. A DNA-binding protein from Ustilago maydis prefers duplex DNA without chain interruptions.

    PubMed Central

    Rusche, J R; Holloman, W K

    1983-01-01

    Using a nitrocellulose filter binding assay, we have partially purified a protein from mitotic cells of Ustilago maydis that binds preferentially to covalently closed circular duplex DNA. DNA containing single- or double-strand breaks is bound poorly by the protein. Once formed, the DNA-protein complex is stable, resisting dissociation in high salt. However, when a DNA strand is broken, the complex appears to dissociate. The protein binds equally well to form I DNA of phi X174 or the plasmid pBR322, but has a higher affinity for a hybrid plasmid containing a cloned region of Drosophila melanogaster satellite DNA. Images PMID:6304499

  1. 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.

  2. 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.

  3. Kinetics and mechanism of reactions of the drug tiopronin with platinum(IV) complexes.

    PubMed

    Huo, Shuying; Shi, Hongmei; Liu, Dongzhi; Shen, Shigang; Zhang, Jiong; Song, Changying; Shi, Tiesheng

    2013-08-01

    Tiopronin, a synthetic thiol-containing drug being used in treatments of cystinuria and certain types of rare arthritis, is also a hepatoprotective and a detoxifying agent. Many analytical methods have been developed based on its redox chemistry with metal ions/complexes, but the kinetic and mechanistic aspects are poorly understood. In this work, the oxidation of tiopronin by cisplatin prodrug and a model compound, cis-[Pt(NH3)2Cl4] and trans-[PtCl2(CN)4](2-), was investigated. The oxidation kinetics was followed by a stopped-flow spectrophotometer over a wide pH range under the pseudo first-order conditions of [Tiopronin]≫[Pt(IV)]. Time-resolved spectra were also recorded for both Pt(IV) complexes, enabling to establish an overall second-order rate law: -d[Pt(IV)]/dt=k'[Tiopronin][Pt(IV)], where k' pertains to observed second-order rate constants. Under the kinetic conditions, tiopronin was oxidized to form the tiopronin-disulfide exclusively as identified by mass spectrometry. A reaction mechanism was proposed, involving parallel reductions of the Pt(IV) complexes by the three protolytic tiopronin species as rate-determining steps. The rate constants for the rate-determining steps were derived. The fully deprotonated tiopronin is about 4×10(4) more reactive than its corresponding thiol form for both Pt(IV) complexes; the huge reactivity difference orchestrates closely with the fact that the nucleophilicity of thiolate is much higher than the corresponding thiol. Hence, the attack of the sulfur atom in thiol/thiolate of tiopronin on the axially-coordinated chloride in the Pt(IV) complexes is nucleophilic in nature in the rate-determining steps, resulting in a bridge formation and a subsequent bridged electron-transfer. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. 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.

  5. 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

  6. 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

  7. 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.

  8. [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.

  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. 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

  11. 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

  12. 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

  13. 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.

  14. 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.

  15. Allele-Selective Inhibition of Mutant Atrophin-1 Expression by Duplex and Single-Stranded RNAs

    PubMed Central

    2015-01-01

    Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive neurodegenerative disorder that currently has no curative treatments. DRPLA is caused by an expansion of a CAG trinucleotide repeat region within the protein-encoding sequence of the atrophin-1 (ATN-1) gene. Inhibition of mutant ATN-1 protein expression is one strategy for treating DRPLA, and allele-selective gene silencing agents that block mutant expression over wild-type expression would be lead compounds for therapeutic development. Here we develop an assay for distinguishing mutant from wild-type ATN-1 protein by gel electrophoresis. We use this assay to evaluate duplex RNAs and single-stranded silencing RNAs (ss-siRNAs) for allele-selective inhibition of ATN-1 protein expression. We observed potent and allele-selective inhibition by RNA duplexes that contain mismatched bases relative to the CAG target and have the potential to form miRNA-like complexes. ss-siRNAs that contained mismatches were as selective as mismatch-containing duplexes. We also report allele-selective inhibition by duplex RNAs containing unlocked nucleic acids or abasic substitutions, although selectivities are not as high. Five compounds that showed >8-fold allele selectivity for mutant ATN-1 were also selective for inhibiting the expression of two other trinucleotide repeat disease genes, ataxin-3 (ATXN-3) and huntingtin (HTT). These data demonstrate that the expanded trinucleotide repeat within ATN-1 mRNA is a potential target for compounds designed to achieve allele-selective inhibition of ATN-1 protein, and one agent may allow the targeting of multiple disease genes. PMID:24981774

  16. 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

  17. 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

  18. Magnetic resonance urography in duplex kidney with ectopic ureteral insertion

    PubMed Central

    Thambidorai, Conjeevaram Rajendrarao; Anuar, Zulfiqar

    2011-01-01

    This is a report on the use of magnetic resonance urography (MRU) in a 6-year-old girl who presented with urinary incontinence. She had a left duplex kidney with poorly functioning upper moiety and ectopic insertion of the dilated upper pole ureter. MRU has been shown to be superior to conventional imaging techniques in delineating poorly functioning moieties of duplex kidneys and ectopic ureters. PMID:21897576

  19. 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

  20. Thermodynamics of RNA duplexes modified with unlocked nucleic acid nucleotides

    PubMed Central

    Pasternak, Anna; Wengel, Jesper

    2010-01-01

    Thermodynamics provides insights into the influence of modified nucleotide residues on stability of nucleic acids and is crucial for designing duplexes with given properties. In this article, we introduce detailed thermodynamic analysis of RNA duplexes modified with unlocked nucleic acid (UNA) nucleotide residues. We investigate UNA single substitutions as well as model mismatch and dangling end effects. UNA residues placed in a central position makes RNA duplex structure less favourable by 4.0–6.6 kcal/mol. Slight destabilization, by ∼0.5–1.5 kcal/mol, is observed for 5′- or 3′-terminal UNA residues. Furthermore, thermodynamic effects caused by UNA residues are extremely additive with ΔG°37 conformity up to 98%. Direct mismatches involving UNA residues decrease the thermodynamic stability less than unmodified mismatches in RNA duplexes. Additionally, the presence of UNA residues adjacent to unpaired RNA residues reduces mismatch discrimination. Thermodynamic analysis of UNA 5′- and 3′-dangling ends revealed that stacking interactions of UNA residues are always less favourable than that of RNA residues. Finally, circular dichroism spectra imply no changes in overall A-form structure of UNA–RNA/RNA duplexes relative to the unmodified RNA duplexes. PMID:20562222

  1. Isoniazid metal complex reactivity and insights for a novel anti-tuberculosis drug design.

    PubMed

    Sousa, Eduardo Henrique Silva; Basso, Luiz Augusto; Santos, Diógenes S; Diógenes, Izaura Cirino Nogueira; Longhinotti, Elisane; Lopes, Luiz Gonzaga de França; Moreira, Icaro de Sousa

    2012-02-01

    For over a decade, tuberculosis (TB) has been the leading cause of death among infectious diseases. Since the 1950s, isoniazid has been used as a front-line drug in the treatment of TB; however, resistant TB strains have limited its use. The major route of isoniazid resistance relies on KatG enzyme disruption, which does not promote an electron transfer reaction. Here, we investigated the reactivity of isoniazid metal complexes as prototypes for novel self-activating metallodrugs against TB with the aim to overcome resistance. Reactivity studies were conducted with hydrogen peroxide, hexacyanoferrate(III), and aquopentacyanoferrate(III). The latter species showed a preference for the inner-sphere electron transfer reaction pathway. Additionally, electron transfer reaction performed with either free isoniazid or (isoniazid)pentacyanoferrate(II) complex resulted in similar oxidized isoniazid derivatives as observed when the KatG enzyme was used. However, upon metal coordination, a significant enhancement in the formation of isonicotinic acid was observed compared with that of isonicotinamide. These results suggest that the pathway of a carbonyl-centered radical might be favored upon coordination to the Fe(II) owing to the π-back-bonding effect promoted by this metal center; therefore, the isoniazid metal complex could serve as a potential metallodrug. Enzymatic inhibition assays conducted with InhA showed that the cyanoferrate moiety is not the major player involved in this inhibition but the presence of isoniazid is required in this process. Other isoniazid metal complexes, [Ru(CN)(5)(izd)](3-) and [Ru(NH(3))(5)(izd)](2+) (where izd is isoniazid), were also unable to inhibit InhA, supporting our proposed self-activating mechanism of action. We propose that isoniazid reactivity can be rationally modulated by metal coordination chemistry, leading to the development of novel anti-TB metallodrugs.

  2. 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

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. Complexation of ibuprofen with water soluble p-sulfonatocalix [4]arene: A potential candidate for drug delivery applicatio.

    PubMed

    Khokhar, Tahira S; Memon, Shahabuddin; Panhwar, Qadeer K; Memon, Fakhar N; Memon, Ayaz A; Samejo, Muhammad Qasim; Muneer, Saba; Tulu, Metin

    2017-05-01

    Complexation of ibuprofen with water soluble p-sulfonatocalix[4]arene (3) was evaluated. Both molecules exhibit a host and guest type complexation. pH, complex stoichiometry and binding constant were determined by UV-Vis and FT-IR spectroscopy. The maximum complexation of 3 with ibuprofen occurs at pH 2. Stability constant values (9.897) show that there is favorable complex formed due to vital role of p-sulfonatocalix[4]arene, while the thermodynamic parameters, i.e. δG, ΔH and δS have been found as -24.09 KJ/mol, 0.012 KJ/mol and 0.12 KJ/mol. K, respectively. The results show that 3 has efficiency to carry the drug at particular conditions and can be used for drug delivery as a carrier.

  11. 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.

  12. 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.

  13. [Appendix vermiformis duplex--a rare surprise].

    PubMed

    Sobhian, Babak; Mostegel, Margit; Kunc, Claudia; Karner, Josef

    2005-07-01

    Duplication of the vermiform appendix is extremely rare. It is found in only 1/25.000 patients (0.004%) operated on for acute appendicitis. A 60-year-old male patient was hospitalized for a peridiverticular sigmoid abscess without signs of a free abdominal perforation and an abscess cavity in the small pelvis. A Hartmann's resection and an appendectomy (the vermiform appendix was part of the abscess wall) were performed. The pathology report described an external appendicitis. After 3 months, the intestine was successfully reanastomosed. During mobilisation of the coecum, a second retrocoecal vermiform appendix was surprisingly found. Because of signs of a chronic appendicitis a second resection was performed. Although the diagnosis of an appendix duplex is a rarity, surgeons should be aware of the possibility, especially when clinical signs and symptoms point to appendicitis, although at laparotomy the appendix looks normal. A routine exploration for a second appendix is definitely not indicated because of the rarity and the increased complication rate.

  14. Wavelength-tunable duplex integrated light source

    NASA Astrophysics Data System (ADS)

    Okamoto, Hiroshi; Yasaka, Hiroshi; Oe, Kunishige

    1996-04-01

    A monolithically integrated opto-electronic device is proposed as a fast wavelength-switching light source. This tunable duplex integrated light source comprises two wavelength-tunable distributed Bragg reflector (DBR) laser diodes (LDs), two MQW-electro-absorption optical switches, a Y-shaped waveguide coupler, a MQW-electro-absorption modulator, and two thermal drift compensators (TDCs). The wavelength-switching time of the optical switches was estimated to be 60 ps including a 50-ps rise time for the electrical-pulse generator. The wavelength of a 10-Gbit/s NRZ-modulated optical signal can be switched without bit loss. The function of the TDCs is to keep the device-chip temperature constant. Thermal-transient- induced wavelength drift with a millisecond-order time constant, which has been reported for DBR-LDs, and thermal crosstalk between the tuning regions of the integrated LDs, which causes wavelength fluctuation, are effectively suppressed by thermal-drift-compensation operation using the TDCs.

  15. 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.

  16. An improved relaxed complex scheme for receptor flexibility in computer-aided drug design

    NASA Astrophysics Data System (ADS)

    Amaro, Rommie E.; Baron, Riccardo; McCammon, J. Andrew

    2008-09-01

    The interactions among associating (macro)molecules are dynamic, which adds to the complexity of molecular recognition. While ligand flexibility is well accounted for in computational drug design, the effective inclusion of receptor flexibility remains an important challenge. The relaxed complex scheme (RCS) is a promising computational methodology that combines the advantages of docking algorithms with dynamic structural information provided by molecular dynamics (MD) simulations, therefore explicitly accounting for the flexibility of both the receptor and the docked ligands. Here, we briefly review the RCS and discuss new extensions and improvements of this methodology in the context of ligand binding to two example targets: kinetoplastid RNA editing ligase 1 and the W191G cavity mutant of cytochrome c peroxidase. The RCS improvements include its extension to virtual screening, more rigorous characterization of local and global binding effects, and methods to improve its computational efficiency by reducing the receptor ensemble to a representative set of configurations. The choice of receptor ensemble, its influence on the predictive power of RCS, and the current limitations for an accurate treatment of the solvent contributions are also briefly discussed. Finally, we outline potential methodological improvements that we anticipate will assist future development.

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. Multi-target drugs to address multiple checkpoints in complex inflammatory pathologies: evolutionary cues for novel "first-in-class" anti-inflammatory drug candidates: a reviewer's perspective.

    PubMed

    Mathew, Geetha; Unnikrishnan, M K

    2015-10-01

    Inflammation is a complex, metabolically expensive process involving multiple signaling pathways and regulatory mechanisms which have evolved over evolutionary timescale. Addressing multiple targets of inflammation holistically, in moderation, is probably a more evolutionarily viable strategy, as compared to current therapy which addresses drug targets in isolation. Polypharmacology, addressing multiple targets, is commonly used in complex ailments, suggesting the superior safety and efficacy profile of multi-target (MT) drugs. Phenotypic drug discovery, which generated successful MT and first-in-class drugs in the past, is now re-emerging. A multi-pronged approach, which modulates the evolutionarily conserved, robust and pervasive cellular mechanisms of tissue repair, with AMPK at the helm, regulating the complex metabolic/immune/redox pathways underlying inflammation, is perhaps a more viable strategy than addressing single targets in isolation. Molecules that modulate multiple molecular mechanisms of inflammation in moderation (modulating TH cells toward the anti-inflammatory phenotype, activating AMPK, stimulating Nrf2 and inhibiting NFκB) might serve as a model for a novel Darwinian "first-in-class" therapeutic category that holistically addresses immune, redox and metabolic processes associated with inflammatory repair. Such a multimodal biological activity is supported by the fact that several non-calorific pleiotropic natural products with anti-inflammatory action have been incorporated into diet (chiefly guided by the adaptive development of olfacto-gustatory preferences over evolutionary timescales) rendering such molecules, endowed with evolutionarily privileged molecular scaffolds, naturally oriented toward multiple targets.

  2. Efficacy of duplex ultrasound surveillance after infrainguinal vein bypass may be enhanced by identification of characteristics predictive of graft stenosis development.

    PubMed

    Tinder, Chelsey N; Chavanpun, Joe P; Bandyk, Dennis F; Armstrong, Paul A; Back, Martin R; Johnson, Brad L; Shames, Murray L

    2008-09-01

    Controversy regarding the efficacy of duplex ultrasound surveillance after infrainguinal vein bypass led to an analysis of patient and bypass graft characteristics predictive for development of graft stenosis and a decision of secondary intervention. Retrospective analysis of a contemporary, consecutive series of 353 clinically successful infrainguinal vein bypasses performed in 329 patients for critical (n = 284; 80%) or noncritical (n = 69; 20%) limb ischemia enrolled in a surveillance program to identify and repair duplex-detected graft stenosis. Variables correlated with graft stenosis and bypass repair included: procedure indication, conduit type (saphenous vs nonsaphenous vein; reversed vs nonreversed orientation), prior bypass graft failure, postoperative ankle-brachial index (ABI) < 0.85, and interpretation of the first duplex surveillance study as "normal" or "abnormal" based on peak systolic velocity (PSV) and velocity ratio (Vr) criteria. Overall, 126 (36%) of the 353 infrainguinal bypasses had 174 secondary interventions (endovascular, 100; surgery, 74) based on duplex surveillance; resulting in 3-year Kaplan-Meier primary (46%), assisted-primary (80%), and secondary (81%) patency rates. Characteristics predictive of duplex-detected stenosis leading to intervention (PSV: 443 +/- 94 cm/s; Vr: 8.6 +/- 9) were: "abnormal" initial duplex testing indicating moderate (PSV: 180-300 cm/s, Vr: 2-3.5) stenosis (P < .0001), non-single segment saphenous vein conduit (P < .01), warfarin drug therapy (P < .01), and redo bypass grafting (P < .001). Procedure indication, postoperative ABI level, statin drug therapy, and vein conduit orientation were not predictive of graft revision. The natural history of 141 (40%) bypasses with an abnormal first duplex scan differed from "normal" grafts by more frequent (51% vs 24%, P < .001) and earlier (7 months vs 11 months) graft revision for severe stenosis and a lower 3-year assisted primary patency (68% vs 87%; P < .001). In 52

  3. 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.

  4. 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

  5. Simultaneous detection of bovine and porcine DNA in pharmaceutical gelatin capsules by duplex PCR assay for Halal authentication.

    PubMed

    Nikzad, Jafar; Shahhosseini, Soraya; Tabarzad, Maryam; Nafissi-Varcheh, Nastaran; Torshabi, Maryam

    2017-02-14

    In the pharmaceutical industry, hard- and soft-shelled capsules are typically made from gelatin, commonly derived from bovine and porcine sources. To ensure that pharmaceutical products comply with halal regulations in Muslim countries (no porcine products allowed), development of a valid, reliable, quick, and most importantly, cost-effective tests are of utmost importance. We developed a species-specific duplex polymerase chain reaction (PCR) assay targeting 149 bp porcine and 271 bp bovine mitochondrial DNA (mtDNA) to simultaneously detect both porcine and bovine DNA (in one reaction at the same time) in gelatin. Some additional simplex PCR tests (targeting 126 bp bovine and 212 bp porcine mtDNA) and real-time PCR using a commercially available kit (for identification of porcine DNA) were used to verify the selectivity and sensitivity of our duplex PCR. After optimization of DNA extraction and PCR methods, hard/soft pharmaceutical gelatin capsules (containing drug) were tested for the presence of porcine and/or bovine DNA. Duplex PCR detected the presence of as little as 0.1% porcine DNA, which was more accurate than the commercially available kit. Of all gelatin capsules tested (n = 24), 50% contained porcine DNA (pure porcine gelatin alone or in combination with bovine gelatin). Duplex PCR presents an easy-to-follow, quick, low-cost and reliable method to simultaneously detect porcine and bovine DNAs (>100 bp) in minute amounts in highly processed gelatin-containing pharmaceutical products (with a 0.1% sensitivity for porcine DNA) which may be used for halal authentication. Simultaneous detection of porcine and bovine DNA in gelatin capsules by duplex PCR.

  6. Sequence-specific intercalating agents: intercalation at specific sequences on duplex DNA via major groove recognition by oligonucleotide-intercalator conjugates.

    PubMed Central

    Sun, J S; François, J C; Montenay-Garestier, T; Saison-Behmoaras, T; Roig, V; Thuong, N T; Hélène, C

    1989-01-01

    An acridine derivative was covalently linked to the 5' end of a homopyrimidine oligonucleotide. Specific binding to a homopurine-homopyrimidine sequence of duplex DNA was demonstrated by spectroscopic studies (absorption and fluorescence) and by "footprinting" experiments with a copper phenanthroline chelate used as an artificial nuclease. A hypochromism and a red shift of the acridine absorption were observed. Triple-helix formation was also accompanied by a hypochromism in the ultraviolet range. The fluorescence of the acridine ring was quenched by a stacking interaction with a G.C base pair adjacent to the homopurine-homopyrimidine target sequence. The intercalating agent strongly stabilized the complex formed by the oligopyrimidine with its target duplex sequence. Cytosine methylation further increased the stability of the complexes. Footprinting studies revealed that the oligopyrimidine binds in a parallel orientation with respect to the homopurine-containing strand of the duplex. The intercalated acridine extended by 2 base pairs the region of the duplex protected by the oligopyrimidine against degradation by the nuclease activity of the copper phenanthroline chelate. Random intercalation of the acridine ring was lost due to the repulsive effect of the negatively charged oligonucleotide tail. Intercalation occurred only at those double-stranded sequences where the homopyrimidine oligonucleotide recognized the major groove of duplex DNA. Images PMID:2594761

  7. 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.

  8. 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.

  9. 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. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Recapitulation of complex transport and action of drugs at the tumor microenvironment using tumor-microenvironment-on-chip.

    PubMed

    Han, Bumsoo; Qu, Chunjing; Park, Kinam; Konieczny, Stephen F; Korc, Murray

    2016-09-28

    Targeted delivery aims to selectively distribute drugs to targeted tumor tissues but not to healthy tissues. This can address many clinical challenges by maximizing the efficacy but minimizing the toxicity of anti-cancer drugs. However, a complex tumor microenvironment poses various barriers hindering the transport of drugs and drug delivery systems. New tumor models that allow for the systematic study of these complex environments are highly desired to provide reliable test beds to develop drug delivery systems for targeted delivery. Recently, research efforts have yielded new in vitro tumor models, the so called tumor-microenvironment-on-chip, that recapitulate certain characteristics of the tumor microenvironment. These new models show benefits over other conventional tumor models, and have the potential to accelerate drug discovery and enable precision medicine. However, further research is warranted to overcome their limitations and to properly interpret the data obtained from these models. In this article, key features of the in vivo tumor microenvironment that are relevant to drug transport processes for targeted delivery were discussed, and the current status and challenges for developing in vitro transport model systems were reviewed. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  11. 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. Copyright © 2012 Elsevier B.V. All rights reserved.

  12. 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

  13. Synthesis and Biological Evaluation of Novel Folic Acid Receptor-Targeted, β-Cyclodextrin-Based Drug Complexes for Cancer Treatment

    PubMed Central

    Yin, Juan-Juan; Sharma, Sonali; Shumyak, Stepan P.; Wang, Zhi-Xin; Zhou, Zhi-Wei; Zhang, Yangde; Guo, Peixuan; Li, Chen-Zhong; Kanwar, Jagat R.; Yang, Tianxin; Mohapatra, Shyam S.; Liu, Wanqing; Duan, Wei; Wang, Jian-Cheng; Li, Qi; Zhang, Xueji; Tan, Jun; Jia, Lee; Liang, Jun; Wei, Ming Q.; Li, Xiaotian; Zhou, Shu-Feng

    2013-01-01

    Drug targeting is an active area of research and nano-scaled drug delivery systems hold tremendous potential for the treatment of neoplasms. In this study, a novel cyclodextrin (CD)-based nanoparticle drug delivery system has been assembled and characterized for the therapy of folate receptor-positive [FR(+)] cancer. Water-soluble folic acid (FA)-conjugated CD carriers (FACDs) were successfully synthesized and their structures were confirmed by 1D/2D nuclear magnetic resonance (NMR), matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF-MS), high performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FTIR), and circular dichroism. Drug complexes of adamatane (Ada) and cytotoxic doxorubicin (Dox) with FACD were readily obtained by mixed solvent precipitation. The average size of FACD-Ada-Dox was 1.5–2.5 nm. The host-guest association constant Ka was 1,639 M−1 as determined by induced circular dichroism and the hydrophilicity of the FACDs was greatly enhanced compared to unmodified CD. Cellular uptake and FR binding competitive experiments demonstrated an efficient and preferentially targeted delivery of Dox into FR-positive tumor cells and a sustained drug release profile was seen in vitro. The delivery of Dox into FR(+) cancer cells via endocytosis was observed by confocal microscopy and drug uptake of the targeted nanoparticles was 8-fold greater than that of non-targeted drug complexes. Our docking results suggest that FA, FACD and FACD-Ada-Dox could bind human hedgehog interacting protein that contains a FR domain. Mouse cardiomyocytes as well as fibroblast treated with FACD-Ada-Dox had significantly lower levels of reactive oxygen species, with increased content of glutathione and glutathione peroxidase activity, indicating a reduced potential for Dox-induced cardiotoxicity. These results indicate that the targeted drug complex possesses high drug association and sustained drug release properties

  14. Duplex Ultrasonography in Assessing Restenosis of Renal Artery Stents

    SciTech Connect

    Bakker, Jeannette; Beutler, Jaap J.; Elgersma, Otto E.H.; Lange, Eduard E. de; Kort, Gerard A.P. de; Beek, Frederik J. A.

    1999-11-15

    Purpose: To determine the accuracy and optimal threshold values of duplex ultrasonography (US) in assessing restenosis of renal artery stents. Methods: Twenty-four consecutive patients with 33 renal arteries that had previously been treated with placement of a Palmaz stent underwent duplex US prior to intraarterial digital subtraction angiography (DSA), which was the reference standard. Diagnostic accuracy of in-stent peak systolic velocity (PSV) and reno-aortic ratio (RAR = PSV renal stent/PSV aorta) in detecting > 50% in-stent restenosis were evaluated by the receiver operating characteristic curve. Sensitivity and specificity were determined using the optimal threshold values, and using published threshold values: RAR > 3.5 and in-stent PSV > 180 cm/sec. Results: Six examinations were technically inadequate. Nine stents had residual or restenosis > 50% at DSA. The two duplex parameters were equally accurate since areas under the curves were similar (0.943). With optimal threshold values of 226 cm/sec for PSV and 2.7 for RAR, sensitivities and specificities were 100% and 90%, and 100% and 84%, respectively. Using the published duplex criteria resulted in sensitivities and specificities of 100% and 74% for PSV, and 50% and 89% for RAR. Conclusion: Duplex US is a sensitive modality for detecting in-stent restenosis if laboratory-specific threshold values are used.

  15. Quantifying the Temperature Dependence of Glycine Betaine RNA Duplex Destabilization

    PubMed Central

    Schwinefus, Jeffrey J.; Menssen, Ryan J.; Kohler, James M.; Schmidt, Elliot C.; Thomas, Alexandra L.

    2013-01-01

    Glycine betaine stabilizes folded protein structure due to its unfavorable thermodynamic interactions with amide oxygen and aliphatic carbon surface area exposed during protein unfolding. However, glycine betaine can attenuate nucleic acid secondary structure stability, although its mechanism of destabilization is not currently understood. In this work we quantify glycine betaine interactions with the surface area exposed during thermal denaturation of nine RNA dodecamer duplexes with guanine-cytosine (GC) contents of 17–100%. Hyperchromicity values indicate increasing glycine betaine molality attenuates stacking. Glycine betaine destabilizes higher GC content RNA duplexes to a greater extent than low GC content duplexes due to greater accumulation at the surface area exposed during unfolding. The accumulation is very sensitive to temperature and displays characteristic entropy-enthalpy compensation. Since the entropic contribution to the m-value (used to quantify GB interaction with the RNA solvent accessible surface area exposed during denaturation) is more dependent on temperature than the enthalpic contribution, higher GC content duplexes with their larger transition temperatures are destabilized to a greater extent than low GC content duplexes. The concentration of glycine betaine at the RNA surface area exposed during unfolding relative to bulk was quantified using the solute partitioning model. Temperature correction predicts a glycine betaine concentration at 25 °C to be nearly independent of GC content, indicating that glycine betaine destabilizes all sequences equally at this temperature. PMID:24219229

  16. Doppler ultrasonography of the central retinal artery by duplex scanning.

    PubMed

    Steigerwalt, R D; Cesarone, M R; Laurora, G; Belcaro, G V; De Sanctis, M T; Incandela, L; Christopoulos, V

    1996-01-01

    To present duplex scanning of the central retinal artery, which the authors have termed duplex scanner imaging, as an alternative to color Doppler imaging in the evaluation of retinal blood flow velocity, and to show the difference in measurements obtained with the two different techniques. The high-resolution ATL-Ultramark 4 duplex scanner (Advanced Technology Laboratories, Bothell, WA) with the variable focus access probe was used to measure blood flow velocity of the central retinal artery in the eyes of 48 healthy volunteers. Using this technique the peak systolic flow velocity (+/- standard deviation [SD]) of the central retinal artery was 36.6 +/- 10.8 cm/sec, and the end diastolic flow velocity was 12.6 +/- 3.7 cm/sec. The flow velocity measurements of the central retinal artery obtained with this technique were much higher than those obtained by other authors using color Doppler imaging (9.6 cm/sec for the peak systolic flow velocity, and 4.7 cm/sec for the end diastolic flow velocity). The authors propose duplex scanner imaging as an alternative to color Doppler imaging for evaluating retinal blood flow velocity. The duplex scanner also can be used to measure the flow velocity of orbital vessels.

  17. 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.

  18. 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.

  19. 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.

  20. Genomics, complexity and drug discovery: insights from Boolean network models of cellular regulation.

    PubMed

    Huang, S

    2001-08-01

    The completion of the first draft of the human genome sequence has revived the old notion that there is no one-to-one mapping between genotype and phenotype. It is now becoming clear that to elucidate the fundamental principles that govern how genomic information translates into organismal complexity, we must overcome the current habit of ad hoc explanations and instead embrace novel, formal concepts that will involve computer modelling. Most modelling approaches aim at recreating a living system via computer simulation, by including as much details as possible. In contrast, the Boolean network model reviewed here represents an abstraction and a coarse-graining, such that it can serve as a simple, efficient tool for the extraction of the very basic design principles of molecular regulatory networks, without having to deal with all the biochemical details. We demonstrate here that such a discrete network model can help to examine how genome-wide molecular interactions generate the coherent, rule-like behaviour of a cell - the first level of integration in the multi-scale complexity of the living organism. Hereby the various cell fates, such as differentiation, proliferation and apoptosis, are treated as attractor states of the network. This modelling language allows us to integrate qualitative gene and protein interaction data to explain a series of hitherto non-intuitive cell behaviours. As the human genome project starts to reveal the limits of the current simplistic 'one gene - one function - one target' paradigm, the development of conceptual tools to increase our understanding of how the intricate interplay of genes gives rise to a global 'biological observable' will open a new perspective for post-genomic drug target discovery.

  1. 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

  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. 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.

  4. 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.

  5. The relative flexibility of B-DNA and A-RNA duplexes: database analysis

    PubMed Central

    Pérez, Alberto; Noy, Agnes; Lankas, Filip; Luque, F. Javier; Orozco, Modesto

    2004-01-01

    An extensive analysis of structural databases is carried out to investigate the relative flexibility of B-DNA and A-RNA duplexes in crystal form. Our results show that the general anisotropic concept of flexibility is not very useful to compare the deformability of B-DNA and A-RNA duplexes, since the flexibility patterns of B-DNA and A-RNA are quite different. In other words, ‘flexibility’ is a dangerous word for describing macromolecules, unless it is clearly defined. A few soft essential movements explain most of the natural flexibility of A-RNA, whereas many are necessary for B-DNA. Essential movements occurring in naked B-DNAs are identical to those necessary to deform DNA in DNA–protein complexes, which suggest that evolution has designed DNA–protein complexes so that B-DNA is deformed according to its natural tendency. DNA is generally more flexible, but for some distortions A-RNA is easier to deform. Local stiffness constants obtained for naked B-DNAs and DNA complexes are very close, demonstrating that global distortions in DNA necessary for binding to proteins are the result of the addition of small concerted deformations at the base-pair level. Finally, it is worth noting that in general the picture of the relative deformability of A-RNA and DNA derived from database analysis agrees very well with that derived from state of the art molecular dynamics (MD) simulations. PMID:15562006

  6. Unstable Hoogsteen base pairs adjacent to echinomycin binding sites within a DNA duplex

    SciTech Connect

    Gilbert, D.E.; van der Marel, G.A.; van Boom, J.H.; Feigon, J. )

    1989-05-01

    The bisintercalation complex present between the DNA octamer (d(ACGTACGT)){sub 2} and the cyclic octadepsipeptide antibiotic echinomycin has been studied by one- and two-dimensional proton NMR, and the results obtained have been compared with the crystal structures of related DNA-echinomycin complexes. Two echinomycins are found to bind cooperatively to each DNA duplex at the CpG steps, with the two quinoxaline rings of each echinomycin bisintercalating between the C{center dot}G and A{center dot}T base pairs. At low temperatures, the A{center dot}T base pairs on either side of the intercalation site adopt the Hoogsteen conformation, as observed in the crystal structures. However, as the temperature is raised, the Hoogsteen base pairs in the interior of the duplex are destabilized and are observed to be exchanging between the Hoogsteen base pair and either an open or a Watson-Crick base-paired state. The terminal A{center dot}T base pairs, which are not as constrained by the helix as the internal base pairs, remain stably Hoogsteen base-paired up to at least 45{degree}C. The implications of these results for the biological role of Hoogsteen base pairs in echinomycin-DNA complexes in vivo are discussed.

  7. 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

  8. 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.

  9. Characterization of Danaparoid Complex Extractive Drug by an Orthogonal Analytical Approach.

    PubMed

    Gardini, Cristina; Urso, Elena; Guerrini, Marco; van Herpen, René; de Wit, Pauline; Naggi, Annamaria

    2017-07-05

    Danaparoid sodium salt, is the active component of ORGARAN, an anticoagulant and antithrombotic drug constituted of three glycosaminoglycans (GAGs) obtained from porcine intestinal mucosa extracts. Heparan sulfate is the major component, dermatan sulfate and chondroitin sulfate being the minor ones. Currently dermatan sulfate and chondroitin sulfate are quantified by UV detection of their unsaturated disaccharides obtained by enzymatic depolymerization. Due to the complexity of danaparoid biopolymers and the presence of shared components, an orthogonal approach has been applied using more advanced tools and methods. To integrate the analytical profile, 2D heteronuclear single quantum coherence (HSQC) NMR spectroscopy was applied and found effective to identify and quantify GAG component signals as well as those of some process signatures of danaparoid active pharmaceutical ingredient (API) batches. Analyses of components of both API samples and size separated fractions proceeded through the determination and distribution of the molecular weight (Mw) by high performance size exclusion chromatographic triple detector array (HP-SEC-TDA), chain mapping by LC/MS, and mono- (¹H and (13)C) and bi-dimensional (HSQC) NMR spectroscopy. Finally, large scale chromatographic isolation and depolymerization of each GAG followed by LC/MS and 2D-NMR analysis, allowed the sequences to be defined and components to be evaluated of each GAG including oxidized residues of hexosamines and uronic acids at the reducing ends.

  10. Self-assembly of drug-polymer complexes: a spontaneous nanoencapsulation process monitored by atomic force microscopy.

    PubMed

    Oliva, Mireia; Díez-Pérez, Ismael; Gorostiza, Pau; Lastra, Cecilia F; Oliva, Ignasi; Caramella, Carla; Mariño, Eduardo L

    2003-01-01

    Since hydrophilic matrices were proposed for controlled drug delivery, many polymeric excipients have been studied to make drug release fit the desired profiles. It has been pointed out that lambda-carrageenan, a sulfated polymer from algae, can suitably control the release rate of basic drugs from hydrophilic matrices. Furthermore, the relevance of hydrophobic interactions in drug-polymer aqueous systems has already been demonstrated, although no references to morphological features as well as to the kinetics of the interaction complexes formation have been published to date. In this work, we propose a method to monitor the topographical evolution of the interaction between lambda-carrageenan and dexchlorpheniramine maleate, in order to determine how the release profiles can be so easily controlled. For this purpose, solutions of both polymer and drug were prepared at very low concentration. Solutions were mixed and small volumes were taken every hour for over a period of 24 h and subsequently analyzed. The characterization technique used, atomic force microscopy, provides a high resolution, allowing plotting of three-dimensional images of the sample morphology within the nanometric scale. The results demonstrate that lambda-carrageenan is able to nanoencapsulate spontaneously dexchlorpheniramine maleate molecules, which offers the possibility of controlling the release rate of the drug with no need of complex technological processes. Moreover, this work demonstrates the suitability of atomic force microscopy for the specific case of the on-time monitoring of interaction processes that occur in pharmaceutical systems. Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association

  11. 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.

  12. Fluoroquinolone-Gyrase-DNA Complexes

    PubMed Central

    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

    2014-01-01

    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-Cys466 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-Gly81 and GyrB-Glu466 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. PMID:24497635

  13. 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.

  14. 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.

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. Subsistence of inclusion complex via assembly of a drug into cyclic oligosaccharide: Its formation, mechanism, behaviour and importance

    NASA Astrophysics Data System (ADS)

    Kundu, Mitali; Roy, Mahendra Nath

    2017-08-01

    The aim of this present work is to make soluble DEPM in aqueous medium through the formation inclusion complex into the hydrophobic hollow space of β-cyclodextrin (β-Cyd) which will provide a novel approach for designing drug delivery system in aqueous medium. The study of supramolecular complexation of DEPM with β-Cyd has been designed in both solution and solid state. In solution phase the evidences of the presence of non-covalent interactions in inclusion complex with 1:1 stoichiometry behaviour are obtained by investigating the UV-spectroscopy. The resultant solid of DEPM and β-Cyd is established by 1H NMR, FTIR, powder XRD and SEM techniques. So, β-Cyd has the ability to encapsulate DEPM into their core without formation any covalent bonds and also increases the bioavailability of the water insoluble DEPM drug.

  2. 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.

  3. 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.

  4. Exploration of inclusion complexes of probenecid with α and β-cyclodextrins: Enhancing the utility of the drug

    NASA Astrophysics Data System (ADS)

    Roy, Aditi; Saha, Subhadeep; Roy, Mahendra Nath

    2017-09-01

    Herein, we report the formation of inclusion complexes between a poor water soluble drug, namely, probenecid and α/β-cyclodextrins. Solubility of probenecid has been enhanced by formation of inclusion complexes with the two cyclodextrins. The stoichiometries of the inclusion complexes were determined by Job's method using UV-visible spectroscopy. Surface tension and conductance study prove the inclusion phenomenon, while stereo-chemical nature of the inclusion complexes has been explained by 2D ROSEY NMR spectroscopy. FT-IR spectra and HRMS study also support the inclusion process. Association constants for both the inclusion complexes have been calculated using Benesi-Hildebrand method, while the thermodynamic parameters have been estimated with the help of van't Hoff equation. The association constant value was found to be higher in case of β-cyclodextrin than that of α-cyclodextrin which was explained on the basis of their molecular structures.

  5. 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.

  6. 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

  7. 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.

  8. A dabigatran etexilate phospholipid complex nanoemulsion system for further oral bioavailability by reducing drug-leakage in the gastrointestinal tract.

    PubMed

    Ge, Liang; He, Xinyi; Zhang, Yajie; Zhang, Yuan; Chai, Fujuan; Jiang, Liqun; Webster, Thomas J; Zheng, Chunli

    2017-08-27

    Dabigatran etexilate (DE) is insoluble at neutral pH values but soluble at low pH values due to protonation, which is the major cause for the poor bioavailability of commercial DE products. Here, we first developed a DE nanoemulsion system and improved dissolution in simulated intestinal fluids by encapsulating DE into an oil phase, but 35.8% of the drug still leaked out. Further, we prepared a DE-phospholipid complex (DE-PC) to enhance lipophilicity and solubility of DE. The resulting DE-PC nanoemulsions significantly (P<0.05) reduced drug leakage and subsequent precipitation. As a result, the relative bioavailability of DE-PC nanoemulsions increased to 147.3% and 606.6% compared to DE nanoemulsions and commercial DE products, respectively. Thus, the presently developed drug-phospholipid complex nanoemulsion system is a promising drug delivery system for improving the oral bioavailability of pH-dependent soluble drugs. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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

  14. 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

  15. 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

  16. Sequence-dependent dynamics of duplex DNA: the applicability of a dinucleotide model.

    PubMed Central

    Okonogi, T M; Alley, S C; Reese, A W; Hopkins, P B; Robinson, B H

    2002-01-01

    The short-time (submicrosecond) bending dynamics of duplex DNA were measured to determine the effect of sequence on dynamics. All measurements were obtained from a single site on duplex DNA, using a single, site-specific modified base containing a rigidly tethered, electron paramagnetic resonance active spin probe. The observed dynamics are interpreted in terms of single-step sequence-dependent bending force constants, determined from the mean squared amplitude of bending relative to the end-to-end vector using the modified weakly bending rod model. The bending dynamics at a single site are a function of the sequence of the nucleotides constituting the duplex DNA. We developed and examined several dinucleotide-based models for flexibility. The models indicate that the dominant feature of the dynamics is best explained in terms of purine- and pyrimidine-type steps, although distinction is made among all 10 unique steps: It was found that purine-purine steps (which are the same as pyrimidine-pyrimidine steps) were near average in flexibility, but the pyrimidine-purine steps (5' to 3') were nearly twice as flexible, whereas purine-pyrimidine steps were more than half as flexible as average DNA. Therefore, the range of stepwise flexibility is approximately fourfold and is characterized by both the type of base pair step (pyrimidine/purine combination) and the identity of the bases within the pair (G, A, T, or C). All of the four models considered here underscore the complexity of the dependence of dynamics on DNA sequence with certain sequences not satisfactorily explainable in terms of any dinucleotide model. These findings provide a quantitative basis for interpreting the dynamics and kinetics of DNA-sequence-dependent biological processes, including protein recognition and chromatin packaging. PMID:12496111

  17. 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

  18. Medication beliefs, treatment complexity, and non-adherence to different drug classes in patients with type 2 diabetes.

    PubMed

    de Vries, Sieta T; Keers, Joost C; Visser, Rosalie; de Zeeuw, Dick; Haaijer-Ruskamp, Flora M; Voorham, Jaco; Denig, Petra

    2014-02-01

    To assess the relationship of patients' medication beliefs and treatment complexity with unintentional and intentional non-adherence for three therapeutic groups commonly used by patients with type 2 diabetes. Survey data about adherence (Medication Adherence Report Scale) and beliefs about medicines (Beliefs about Medicines Questionnaire) were combined with prescription data from the Groningen Initiative to ANalyse Type 2 diabetes Treatment (GIANTT) database. Patients were classified as being adherent, mainly unintentional non-adherent, or partly intentional non-adherent per therapeutic group (glucose-, blood pressure-, and lipid-lowering drugs). Treatment complexity was measured using the Medication Regimen Complexity Index, which includes the dosage form, dosing frequency and additional directions of taking the drug. Analyses were performed using Kruskal-Wallis and Mann-Whitney U-tests. Of 257 contacted patients, 133 (52%) returned the questionnaire. The patients had a mean age of 66years and 50% were females. Necessity beliefs were not significantly different between the adherers, mainly unintentional non-adherers, and partly intentional non-adherers (differences smaller than 5 points on a scale from 5 to 25). For blood pressure-lowering drugs, patients reporting intentional non-adherence had higher concern beliefs than adherers (8 point difference, P=0.01). Treatment complexity scores were lower for adherers but similar for mainly unintentional and partly intentional non-adherers to glucose- and blood pressure-lowering drugs. Treatment complexity was related to non-adherence in general. Beliefs about necessity were not strongly associated with non-adherence, while patients' concern beliefs may be associated with intentional non-adherence. However, the role of these determinants differs per therapeutic group. Copyright © 2013 Elsevier Inc. All rights reserved.

  19. Ternary metal complexes of guaifenesin drug: Synthesis, spectroscopic characterization and in vitro anticancer activity of the metal complexes.

    PubMed

    Mahmoud, W H; Mahmoud, N F; Mohamed, G G; El-Sonbati, A Z; El-Bindary, A A

    2015-01-01

    The coordination behavior of a series of transition metal ions named Cr(III), Fe(III), Mn(II), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) with a mono negative tridentate guaifenesin ligand (GFS) (OOO donation sites) and 1,10-phenanthroline (Phen) is reported. The metal complexes are characterized based on elemental analyses, IR, (1)H NMR, solid reflectance, magnetic moment, molar conductance, UV-vis spectral studies, mass spectroscopy, ESR, XRD and thermal analysis (TG and DTG). The ternary metal complexes were found to have the formulae of [M(GFS)(Phen)Cl]Cl·nH2O (M=Cr(III) (n=1) and Fe(III) (n=0)), [M(GFS)(Phen)Cl]·nH2O (M=Mn(II) (n=0), Zn(II) (n=0) and Cu(II) (n=3)) and [M(GFS)(Phen)(H2O)]Cl·nH2O (M=Co(II) (n=0), Ni(II) (n=0) and Cd(II) (n=4)). All the chelates are found to have octahedral geometrical structures. The ligand and its ternary chelates are subjected to thermal analyses (TG and DTG). The GFS ligand, in comparison to its ternary metal complexes also was screened for their antibacterial activity on gram positive bacteria (Bacillus subtilis and Staphylococcus aureus), gram negative bacteria (Escherichia coli and Neisseria gonorrhoeae) and for in vitro antifungal activity against (Candida albicans). The activity data show that the metal complexes have antibacterial and antifungal activity more than the parent GFS ligand. The complexes were also screened for its in vitro anticancer activity against the Breast cell line (MFC7) and the results obtained show that they exhibit a considerable anticancer activity. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. 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.

  1. Design of chitospheres loaded with pristine polymer particles for extended drug delivery via polyelectrolyte complexation and particulate leaching.

    PubMed

    Ramburrun, Poornima; Choonara, Yahya E; Kumar, Pradeep; du Toit, Lisa C; Pillay, Viness

    2015-02-01

    The aim of this study was to investigate the drug release from swellable chitospheres laden with pristine polymethylmethacrylate (PMMA) nanoparticles. Chitosan matrices were prepared by sodium tripolyphosphate crosslinking from a chitosan suspension containing the model BCS class II drug, indomethacin. PMMA particles were added to the chitospheres as the modulator for drug release. Swelling and erosion studies in conjunction with textural profiling provided an understanding of the dominant and underlying drug release mechanisms of the ionically crosslinked chitospheres loaded with the pristine PMMA particles. A series of drug release studies performed in PBS pH 7.4 showed that the pristine particle-loaded chitospheres released indomethacin over 144 h in a first-order manner with 50% drug release occurring over 48 h. The study also revealed that in situ porogen leaching for pore creation and polyelectrolyte complex formation were the main mechanisms of release from the chitospheres. The results of this study may be utilized for the development of neuro-implants for controlled delivery of bioactives to the brain where scaffolds of superior mechanical strength and reduced swelling properties are required. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. 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.

  3. 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

  4. A most spectrum-efficient duplexing system: CDD

    NASA Astrophysics Data System (ADS)

    Lee, William C. Y.

    2001-10-01

    The game to play in wireless communications when it comes to increasing spectrum efficiency is to eliminate interference. Currently, all cellular systems use FDD (Frequency Division Duplexing) in an attempt to eliminate the interference from the adjacent cells. Through the use of many technologies only one type of interference remains and that is the adjacent base-tohome mobile interference. TDD (Time Division Duplexing) has not been used for mobile cellular systems, not only because of the adjacent base-to-home mobile interference, but also because of the additional adjacent base-to-home base interference, and adjacent mobile-to-home mobile interference. Therefore, TDD can only be used for small, confined area systems. CDD (Code Division Duplexing) can eliminate all three kinds of interference; the adjacent base-to-home mobile, the adjacent baseto-home base, and the adjacent mobile- to- home in cellular systems. Eliminating each of these interferences makes CDD the most spectrum efficient duplexing system. This talk will elaborate on a set of smart codes, which will make an efficient CDD system a reality.

  5. 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

  6. Micromechanics of base pair unzipping in the DNA duplex.

    PubMed

    Volkov, Sergey N; Paramonova, Ekaterina V; Yakubovich, Alexander V; Solov'yov, Andrey V

    2012-01-25

    All-atom molecular dynamics (MD) simulations of DNA duplex unzipping in a water environment were performed. The investigated DNA double helix consists of a Drew-Dickerson dodecamer sequence and a hairpin (AAG) attached to the end of the double-helix chain. The considered system is used to examine the process of DNA strand separation under the action of an external force. This process occurs in vivo and now is being intensively investigated in experiments with single molecules. The DNA dodecamer duplex is consequently unzipped pair by pair by means of the steered MD. The unzipping trajectories turn out to be similar for the duplex parts with G·C content and rather distinct for the parts with A·T content. It is shown that during the unzipping each pair experiences two types of motion: relatively quick rotation together with all the duplex and slower motion in the frame of the unzipping fork. In the course of opening, the complementary pair passes through several distinct states: (i) the closed state in the double helix, (ii) the metastable preopened state in the unzipping fork and (iii) the unbound state. The performed simulations show that water molecules participate in the stabilization of the metastable states of the preopened base pairs in the DNA unzipping fork.

  7. Catalytically-active complex of HIV-1 integrase with a viral DNA substrate binds anti-integrase drugs.

    PubMed

    Alian, Akram; Griner, Sarah L; Chiang, Vicki; Tsiang, Manuel; Jones, Gregg; Birkus, Gabriel; Geleziunas, Romas; Leavitt, Andrew D; Stroud, Robert M

    2009-05-19

    HIV-1 integration into the host cell genome is a multistep process catalyzed by the virally-encoded integrase (IN) protein. In view of the difficulty of obtaining a stable DNA-bound IN at high concentration as required for structure determination, we selected IN-DNA complexes that form disulfide linkages between 5'-thiolated DNA and several single mutations to cysteine around the catalytic site of IN. Mild reducing conditions allowed for selection of the most thermodynamically-stable disulfide-linked species. The most stable complexes induce tetramer formation of IN, as happens during the physiological integration reaction, and are able to catalyze the strand transfer step of retroviral integration. One of these complexes also binds strand-transfer inhibitors of HIV antiviral drugs, making it uniquely valuable among the mutants of this set for understanding portions of the integration reaction. This novel complex may help define substrate interactions and delineate the mechanism of action of known integration inhibitors.

  8. 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.

  9. Evoked potentials to auditory movement sensation in duplex perception.

    PubMed

    Laufer, Ilan; Pratt, Hillel

    2003-07-01

    The purpose of this study was to examine the processing of auditory movement sensation accompanying duplex perception in binaural hearing. Stimuli were formant transitions (presented to the front, left or right of the subject) and base (presented to the front), that fused to result in vowel-consonant-vowel (V-C-V) sequences /aga/ and /ada/. An illusion of auditory movement (duplex sensation) accompanied the fusion of these V-C-V sequences when the spatial locations of the formant transitions and base were different. Ten right-handed, adult, native Hebrew speakers discriminated each fused stimulus, and the brain potentials associated with performance of the task were recorded from 21 electrodes. The processing of auditory movement was studied by a factorial design (ANOVA) and statistical non-parametric mapping (SnPM) of low resolution electromagnetic tomography (LORETA) images of the net-fusion response. Brain regions implicated in auditory movement processing were expected to be associated with the lateralized formant location, which gave rise to duplex perception. In addition, the time-course of significant activation in brain areas that differentiated between fusion conditions was determined. The posterior parietal, anterior cingulate and premotor cortices were found to be implicated in duplex processing. Auditory cortex involvement was also evident, and together with the latter two brain regions was affected by right-ear advantage. Duplex perception resulting from fusion of spatially separate sounds forming an auditory object results in activation of a network of brain regions reflecting enhanced allocation of attention and the effect of language processing.

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

    PubMed

    Avachat, Amelia M; Patel, Vijay G

    2015-07-01

    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.

  11. 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

  12. 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.

  13. 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.

  14. 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.

  15. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex.

    PubMed

    Hess, Evan J; Moody, Kirsten A; Geffrey, Alexandra L; Pollack, Sarah F; Skirvin, Lauren A; Bruno, Patricia L; Paolini, Jan L; Thiele, Elizabeth A

    2016-10-01

    Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder with highly variable expression. The most common neurologic manifestation of TSC is epilepsy, which affects approximately 85% of patients, 63% of whom develop treatment-resistant epilepsy. Herein, we evaluate the efficacy, safety, and tolerability of cannabidiol (CBD), a nonpsychoactive compound derived from the marijuana plant, as an adjunct to current antiepileptic drugs in patients with refractory seizures in the setting of TSC. Eighteen of the 56 patients who have enrolled in our current expanded-access study of cannabidiol for patients with treatment-resistant epilepsy carry a diagnosis of TSC. After an initial baseline period of 1 month, patients began treatment with CBD. The initial dose of 5 mg/kg/day was increased by 5 mg/kg/day every week up to a maximum dose of 50 mg/kg/day, if tolerated. Weekly seizure frequencies, percent change in seizure frequencies, and responder rates were calculated during the 2nd, 3rd, 6th, 9th, and 12th month of treatment with CBD. The median weekly seizure frequency during the baseline period was 22.0 (interquartile range [IQR] 14.8-57.4), which decreased to 13.3 (IQR 5.1-22.1) after 3 months of treatment with cannabidiol. The median percent change in total weekly seizure frequency was -48.8% (IQR -69.1% to -11.1%) after 3 months of treatment. The 50% responder rates over the course of the study were 50%, 50%, 38.9%, 50%, and 50% after 2, 3, 6, 9, and 12 months of treatment with CBD, respectively. In patients taking clobazam concurrently with CBD (n = 12), the responder rate after 3 months of treatment was 58.3%, compared to 33.3% in patients not taking clobazam (n = 6). Twelve (66.7%) of 18 patients in this study experienced at least one adverse event thought possibly related to CBD; the most common adverse events were drowsiness (n = 8, 44.4%), ataxia (n = 5, 27.8%), and diarrhea (n = 4, 22.2%). Although double-blind, placebo

  16. 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

  17. 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.

  18. 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

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. Complexities in drug trials: enrichment, biomarkers and surrogates. Interview with Robert Temple.

    PubMed

    Temple, Robert

    2008-04-01

    Dr Robert Temple is Director of the Office of Medical Policy of FDA's Center for Drug Evaluation and Research and is also Acting Director of the Office of Drug Evaluation I (ODE-I). He has served in this capacity since the office's establishment in 1995. Dr Temple received his medical degree from the New York University School of Medicine in 1967. In 1972, he joined CDER as a review Medical Officer in the Division of Metabolic and Endocrine Drug Products. He later moved into the position of Director of the Division of Cardio-Renal Drug Products. In his current position, Dr Temple oversees ODE-1, which is responsible for the regulation of cardio-renal, neuropharmacologic and psychopharmacologic drug products. He also oversees The Office of Medical Policy, which is responsible for regulation of promotion through the Division of Drug Marketing, Advertising and Communication and for assessing quality of clinical trials. Dr Temple has a long-standing interest in the design and conduct of clinical trials and has written extensively on this subject, especially on choice of control group in clinical trials, evaluation of active control trials, trials to evaluate dose-response and trials using 'enrichment' designs.

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

    PubMed

    Basha, Syed Hussain; Talluri, Deepthi; Raminni, Nalini Prasad

    2013-04-15

    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. 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. 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 role in its binding activity

  7. 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

  8. 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. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. 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.

  10. Metal complexes of the third-generation quinolone antimicrobial drug sparfloxacin: Structure and biological evaluation.

    PubMed

    Efthimiadou, Eleni K; Karaliota, Alexandra; Psomas, George

    2010-04-01

    Five metal complexes of the third-generation quinolone antimicrobial agent sparfloxacin with Fe(3+), VO(2+), Mn(2+), Ni(2+) and UO(2)(2+) have been prepared and characterized with physicochemical and spectroscopic techniques. In these complexes, sparfloxacin acts as a bidentate deprotonated ligand bound to the metal through the ketone oxygen and a carboxylate oxygen. The complexes are six-coordinate with distorted octahedral geometry. For VO(sparfloxacinato)(2)(H(2)O) the axial position, trans to the vanadyl oxygen, is occupied by a ketone oxygen atom. Molecular mechanics calculations have been performed in order to propose a model for the structure of each complex. The antimicrobial activity of the complexes has been tested against three microorganisms showing that they exhibit lower activity than free sparfloxacin. UV spectroscopic titration with calf-thymus DNA (CT DNA) has shown that the complexes can bind to CT DNA and the binding constants to CT DNA have been calculated. The cyclic voltammograms of the complexes in the presence of CT DNA have shown that they bind to CT DNA probably by the intercalative binding mode. Fluorescence competitive studies with ethidium bromide (EB) have revealed the ability of the complexes to displace the DNA-bound EB. The complexes exhibit good binding propensity to human and bovine serum albumin proteins having relatively high binding constant values. Copyright 2009 Elsevier Inc. All rights reserved.

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

    PubMed

    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

    2016-07-01

    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.

  12. 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

  13. 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

  14. 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.

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

    NASA Astrophysics Data System (ADS)

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

    2012-10-01

    The water-soluble Pt (II) complex, [PtCl (DMSO)(N4N7-ribavirin)]· H2O (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, Kb, was 7.2 × 105 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.

  16. 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.

  17. 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

  18. 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.

  19. 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

  20. The α7 nicotinic acetylcholine receptor complex: one, two or multiple drug targets?

    PubMed

    Thomsen, Morten S; Mikkelsen, Jens D

    2012-05-01

    The α7 nicotinic acetylcholine receptor (nAChR) is a promising drug target for a number of diseases ranging from schizophrenia and Alzheimer's disease to chronic pain and inflammatory diseases. Focusing on the central nervous system, we describe how endogenous and experimental compounds and proteins regulate expression and function of the α7 nAChR. Drug development efforts have hitherto focused on direct manipulation of the α7 nAChR, but it is still not clear, whether agonism/antagonism or allosteric modulation is preferable as a potential drug therapy. In addition, the action of such compounds in vivo is highly dependent on α7 nAChR-interacting proteins, such as RIC-3 and lynx1, which modulate expression and function of the receptor. These regulatory proteins are often not expressed in in vitro models used to study α7 nAChR function, and it is not known to what extent they are involved in diseases such as schizophrenia and Alzheimer's disease. Furthermore, α7 nAChR agonists and allosteric modulators differentially alter expression and functionality of the α7 nAChR with repeated administration, which suggests that there may be fundamentally different outcomes of long-term administration with these different types of compounds. Finally, we describe the special case of Aβ1-42 binding to the α7 nAChR, which may pose a unique challenge to drug development of α7 nAChR-specific ligands for Alzheimer's disease. Hopefully, a greater knowledge of the many factors influencing α7 nAChR function as well as an increasing pipeline of specific drug candidates, enabling a more subtle manipulation of α7 nAChR function, may facilitate α7 nAChR drug development efforts.

  1. 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.

  2. 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

  3. 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.

  4. 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

  5. Gas-fired duplex free-piston Stirling refrigerator

    NASA Astrophysics Data System (ADS)

    Urieli, L.

    1984-03-01

    The duplex free-piston Stirling refrigerator is a potentially high efficiency, high reliability device which is ideally suited to the home appliance field, in particular as a gas-fired refrigerator. It has significant advantages over other equivalent devices including freedom from halogenated hydrocarbons, extremely low temperatures available at a high efficiency, integrated water heating, and simple burner system control. The design and development of a portable working demonstration gas-fired duplex Stirling refrigeration unit is described. A unique combination of computer aided development and experimental development was used, enabling a continued interaction between the theoretical analysis and practical testing and evaluation. A universal test rig was developed in order to separately test and evaluate major subunits, enabling a smooth system integration phase.

  6. Smectic phase in suspensions of gapped DNA duplexes

    SciTech Connect

    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

    2016-11-15

    Smectic ordering in aqueous solutions of monodisperse stiff double-stranded DNA fragments is known not to occur, in spite of 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. These results demonstrate that DNA as a building block offers an exquisitely tunable means to engineer a potentially rich assortment of lyotropic liquid crystals.

  7. 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

  8. 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.

  9. Conserved guanine-guanine stacking in tetraplex and duplex DNA.

    PubMed

    Kypr, J; Fialová, M; Chládková, J; Tůmová, M; Vorlícková, M

    2001-12-01

    Using a series of suitably chosen oligonucleotides, we demonstrate that the DNA duplex of d(CCCCGGGG) provides an almost identical CD spectrum as the parallel-stranded tetraplex of d(GGGG). The CD spectra are very sensitive to base stacking in DNA so that the above observation indicates that guanine-guanine stacking is essentially the same within the duplex of d(CCCCGGGG) and the tetraplex of d(GGGG). A very similar CD spectrum is also provided by the A-form of d(CCCCGGGG) induced by trifluoroethanol. These results reveal that guanine-guanine stacking is a structural invariant conserved in various nucleic acid conformers. The structural invariance is likely to cohere with evolution of the genetic molecules and be important for fundamental functions, e.g. initiation of transcription.

  10. Duplex stainless steels for the pulp and paper industry

    SciTech Connect

    Alfonsson, E.; Olsson, J.

    1999-07-01

    The metallurgy and corrosion resistance of duplex stainless steel, particularly with regards to applications in the pulp and paper industry, are described. Practical experiences from pressure vessel installations in cooking plants and bleach plants as well as from non-pressurized items in different parts along the fiber line, are given. The paper also reviews corrosion test results presented previously and compares these with recent test data and the practical experiences. Though most of the installations have been successful, some cases of corrosion attacks on duplex stainless steel have been reported, although these are very limited in number: one digester, one calorifier, two pulp storage towers, and two bleach plant filter washers, of a total of more than 700 identified installations.

  11. 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.

  12. 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.

  13. Recursive DNA Assembly Using Protected Oligonucleotide Duplex Assisted Cloning (PODAC).

    PubMed

    Van Hove, Bob; Guidi, Chiara; De Wannemaeker, Lien; Maertens, Jo; De Mey, Marjan

    2017-06-16

    A problem rarely tackled by current DNA assembly methods is the issue of cloning additional parts into an already assembled construct. Costly PCR workflows are often hindered by repeated sequences, and restriction based strategies impose design constraints for each enzyme used. Here we present Protected Oligonucleotide Duplex Assisted Cloning (PODAC), a novel technique that makes use of an oligonucleotide duplex for iterative Golden Gate cloning using only one restriction enzyme. Methylated bases confer protection from digestion during the assembly reaction and are removed during replication in vivo, unveiling a new cloning site in the process. We used this method to efficiently and accurately assemble a biosynthetic pathway and demonstrated its robustness toward sequence repeats by constructing artificial CRISPR arrays. As PODAC is readily amenable to standardization, it would make a useful addition to the synthetic biology toolkit.

  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. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. Effect of Radiofrequency Radiation on DNA Duplex Stability and Replication.

    DTIC Science & Technology

    1983-08-01

    CHART NATIONAL BUREAU OF STANDARDS-1963-A Report USAFSAM-TR. 83-20 *--EFFECT OF RADIOFREQUENCY RADIATION ON DNA K’*DUPLEX STABILITY AND REPLICATION ...photons affect the stability and/or replication of mammalian DNA . Two of the approaches involved experiments with female CD-l mice, including...analyses of RF effects on sister chromatid exchanges (SCE) in bone marrow as one index of DNA stability and RF effects on replication of the animals’ marrow

  2. End-to-end attraction of duplex DNA

    PubMed Central

    Maffeo, Christopher; Luan, Binquan; Aksimentiev, Aleksei

    2012-01-01

    Recent experiments [Nakata, M. et al., End-to-end stacking and liquid crystal condensation of 6 to 20 basepair DNA duplexes. Science 2007; 318:1276–1279] have demonstrated spontaneous end-to-end association of short duplex DNA fragments into long rod-like structures. By means of extensive all-atom molecular dynamic simulations, we characterized end-to-end interactions of duplex DNA, quantitatively describing the forces, free energy and kinetics of the end-to-end association process. We found short DNA duplexes to spontaneously aggregate end-to-end when axially aligned in a small volume of monovalent electrolyte. It was observed that electrostatic repulsion of 5′-phosphoryl groups promoted the formation of aggregates in a conformation similar to the B-form DNA double helix. Application of an external force revealed that rupture of the end-to-end assembly occurs by the shearing of the terminal base pairs. The standard binding free energy and the kinetic rates of end-to-end association and dissociation processes were estimated using two complementary methods: umbrella sampling simulations of two DNA fragments and direct observation of the aggregation process in a system containing 458 DNA fragments. We found the end-to-end force to be short range, attractive, hydrophobic and only weakly dependent on the ion concentration. The relation between the stacking free energy and end-to-end attraction is discussed as well as possible roles of the end-to-end interaction in biological and nanotechnological systems. PMID:22241779

  3. 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

  4. 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.

  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. 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

  7. Mechanisms of Resistance to Hsp90 Inhibitor Drugs: A Complex Mosaic Emerges

    PubMed Central

    Piper, Peter W.; Millson, Stefan H.

    2011-01-01

    The molecular chaperone Hsp90 holds great promise as a cancer drug target, despite some of the initial clinical trials of Hsp90 inhibitor drugs having not lived up to expectation. Effective use of these drugs will benefit greatly from a much more detailed understanding of the factors that contribute to resistance, whether intrinsic or acquired. We review how cell culture studies have revealed a number of different mechanisms whereby cells can be rendered less susceptible to the effects of Hsp90 inhibitor treatment. A major influence is Hsp90 inhibition causing strong induction of the heat shock response, a stress response that increases cellular levels of prosurvival chaperones such as Hsp27 and Hsp70. Another problem seems to be that these inhibitors do not always access the Hsp90 proteins of the mitochondrion, forms of Hsp90 that—in cancer cells—are operating to suppress apoptosis. It should be possible to overcome these drawbacks through the appropriate drug redesign or with the combinatorial use of an Hsp90 inhibitor with a drug that targets either heat shock factor or the chaperone Hsp70. Still though, cells will often differ in the key antiapoptotic versus proapoptotic activities that are dependent on Hsp90, in the key steps in their apoptotic pathways responsive to Hsp90 inhibition or Hsp70 level, as well as the extents to which their survival is dependent on oncogenic tyrosine kinases that are clients of Hsp90. A systems approach will therefore often be required in order to establish the most prominent effects of Hsp90 inhibition in each type of cancer cell. PMID:27721330

  8. 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.

  9. 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.

  10. 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.

  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. 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.

  13. Docetaxel/2-Hydroxypropyl β -Cyclodextrin Inclusion Complex Increases Docetaxel Solubility and Release from a Nanochannel Drug Delivery System.

    PubMed

    Ferrati, Silvia; Nicolov, Eugenia; Bansal, Shyam; Hosali, Sharath; Landis, Melissa; Grattoni, Alessandro

    2015-01-01

    Breast cancer remains the second leading cause of cancer deaths for women in the U.S. The need for new and alternative strategies to treat this cancer is imperative. Here we show the optimization of our nanochannel delivery system (nDS) for constant and sustained delivery of docetaxel (DTX) for thetreatment of triple negative breast cancer. DTX is a highly hydrophobic drug, making it difficult to reach the therapeutic levels when released in aqueous solutions from our implantable delivery system. To overcome this challenge and test the release of DTX from nDS, we prepared DTX/2-hydroxypropyl β-cyclodextrin (DTX/HPCD) inclusion complexes in different molar ratios. The 1:10 DTX/HPCD complex achieved 5 times higher solubility than the 1:2 complex and 3 times higher in vitrorelease of DTX than with free DTX. When released in SCID/Beige mice from nanochannel system, the DTX/HPCD complex showed reduced tumor growth, comparable to the standard bolus injections of DTX, indicating that the structural stability and biological activity of DTX were retained in the complex, after its diffusion through the nanochannel system.

  14. Bacteriophage T4Dam DNA-(adenine-N(6))-methyltransferase. Comparison of pre-steady state and single turnover methylation of 40-mer duplexes containing two (un)modified target sites.

    PubMed

    Malygin, Ernst G; Sclavi, Bianca; Zinoviev, Victor V; Evdokimov, Alexey A; Hattman, Stanley; Buckle, Malcolm

    2004-11-26

    We analyzed pre-steady state and single turnover kinetics of bacteriophage T4Dam DNA-(adenine-N(6))-methyltransferase-mediated methyl group transfer from S-adenosyl-l-methionine (AdoMet) to 40-mer duplexes containing native recognition sites (5'-GATC/5'-GATC) or some modified variant(s). The results extend a model from studies with single-site 20-mer duplexes. Under pre-steady state conditions, monomeric T4Dam methyltransferase-AdoMet complexes were capable of rapid methylation of adenine residues in 40-mer duplexes containing two sites. During processive movement of T4Dam to the next site, the rate-limiting step was the exchange of the product S-adenosyl-l-homocysteine (AdoHcy) for AdoMet without T4Dam dissociating from the duplex. Consequently, instead of a single exponential rate dependence, complex methylation curves were obtained with at least two pre-steady state steps. With 40-mer duplexes containing a single target site, the kinetics were simpler, fitting a single exponential followed by a linear steady state phase. Single turnover methylation of 40-mer duplexes also proceeded in two stages. First, two dimeric T4Dam-AdoMet molecules bound, and each catalyzed a two-step methylation. Instead of processive movement of T4Dam, a conformational adaptation occurred. We propose that following methyl transfer to one strand, dimeric (T4Dam-AdoMet)-(T4Dam-AdoHcy) was capable of rapidly reorienting itself and catalyzing methyl transfer to the target adenine on the complementary, unmethylated strand. This second stage methyl transfer occurred at a rate about 25-fold slower than in the first step; it was rate-limited by Dam-AdoHcy dissociation or its clearance from the methylated complementary strand. Under single turnover conditions, there was complete methylation of all target adenine residues with each of the two-site 40-mer duplexes.

  15. 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.

  16. Cisplatin adducts on a GGG sequence within a DNA duplex studied by NMR spectroscopy and molecular dynamics simulations.

    PubMed

    Téletchéa, Stéphane; Skauge, Tormod; Sletten, Einar; Kozelka, Jirí

    2009-11-16

    The antitumor drug cisplatin(cis-[PtCl2(NH3)2]) reacts with cellular DNA to form GG intrastrand adducts between adjacent guanines as predominant lesions. GGG sites have been shown to be hotspots of platination. To study the structural perturbation induced by binding of cisplatin to two adjacent guanines of a GGG trinucleotide,we examined here the decanucleotide duplex d[(G1C2C3G*4 G*5 G6T7-C8G9C10).d(G11C12G13A14C15C16C17G18-G19C20)] (dsCG*G*G) intrastrand cross-linked at the G* guanines by cis-{Pt(NH3)2}2+ using NMR spectroscopy and molecular dynamics (MD) simulations.The NMR spectra of dsCG*G*G were found to be similar to those of previously characterized DNA duplexes cross-linked by cisplatin at apyG*G*X site (py=pyrimidine; X=C,T, A). This similarity of NMR spectra indicates that the base at the 3'-side of the G*G*-Pt cross-link does not affect the structure to a large extent. An unprecedented reversible isomerization between the duplex dsCG*G*G (bearing a G*4 G*5 -Pt chelate) and duplex dsGG*G*T (bearing a G*5 G*6 -Pt chelate)was observed, which yielded a 40:60 equilibrium between the two intrastrand GG-Pt cross-links. No formation of interstrand cross-links was observed.NMR spectroscopic data of dsCG*G*G indicated that the deoxyribose of the 5'-G* adopts an N-type conformation, and the cytidines C3, C15,and C16 have average phase angles intermediate between S and N. The NMR spectroscopic chemical shifts of dsGG*G*T showed some fundamental differences to those of pyG*G*-platinum adducts but were in agreement with the NMR spectra reported previously for the DNA duplexes crosslinked at an AG*G*C sequence by cisplatin or oxaliplatin. The presence of apurine instead of a pyrimidine at the 5'-side of the G*G* cross-link seems therefore to affect the structure of the XG* step significantly.

  17. A combination of complexation and self-nanoemulsifying drug delivery system for enhancing oral bioavailability and anticancer efficacy of curcumin.

    PubMed

    Shukla, Mahendra; Jaiswal, Swati; Sharma, Abhisheak; Srivastava, Pradeep Kumar; Arya, Abhishek; Dwivedi, Anil Kumar; Lal, Jawahar

    2017-05-01

    Curcumin, the golden spice from Indian saffron, has shown chemoprotective action against many types of cancer including breast cancer. However, poor oral bioavailability is the major hurdle in its clinical application. In the recent years, self-nanoemulsifying drug delivery system (SNEDDS) has emerged as a promising tool to improve the oral absorption and enhancing the bioavailability of poorly water-soluble drugs. In this context, complexation with lipid carriers like phospholipid has also shown the tremendous potential to improve the solubility and therapeutic efficacy of certain drugs with poor oral bioavailability. In the present investigation, a systematic combination of both the approaches is utilized to prepare the phospholipid complex of curcumin and facilitate its incorporation into SNEDDS. The combined use of both the approaches has been explored for the first time to enhance the oral bioavailability and in turn increase the anticancer activity of curcumin. As evident from the pharmacokinetic studies and in situ single pass intestinal perfusion studies in Sprague-Dawley rats, the optimized SNEDDS of curcumin-phospholipid complex has shown enhanced oral absorption and bioavailability of curcumin. The cytotoxicity study in metastatic breast carcinoma cell line has shown the enhancement of cytotoxic action by 38.7%. The primary tumor growth reduction by 58.9% as compared with the control group in 4T1 tumor-bearing BALB/c mice further supported the theory of enhancement of anticancer activity of curcumin in SNEDDS. The developed formulation can be a potential and safe carrier for the oral delivery of curcumin.

  18. Apparent circular dichroism signature of stirring-oriented DNA and drug-DNA complexes.

    PubMed

    Zsila, Ferenc

    2015-01-01

    It is shown that in water with no added salts calf-thymus DNA and its drug-loaded forms exhibit peculiar, completely reversible circular dichroism (CD) spectroscopic changes upon mechanical rotatory stirring. Due to the stirring-induced spatial alignment of the helices, the CD spectra are overwhelmed by the much more intense linear dichroism contribution. This apparent chiroptical response can be generated and detected without using any sophisticated attachment. It is a technically simple complement to existing methods suitable to obtain additional structural information which can not be derived from isotropic spectra. Drug-DNA interactions generating no or very weak CD spectroscopic changes under isotropic conditions become easily detectable upon stirring the sample solution. Stirring-induced changes of the CD profile also enable to clarify the DNA binding mode of various compounds (e.g., imatinib, thioflavin T) which would remain ambiguous considering isotropic spectral data only. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. 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

  6. 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).

  7. 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.

  8. Mechanism of enhanced oral absorption of morin by phospholipid complex based self-nanoemulsifying drug delivery system.

    PubMed

    Zhang, Jinjie; Li, Jianbo; Ju, Yuan; Fu, Yao; Gong, Tao; Zhang, Zhirong

    2015-02-02

    Phospholipid complex (PLC) based self-nanoemulsifying drug delivery system (PLC-SNEDDS) has been developed for efficient delivery of drugs with poor solubility and low permeability. In the present study, a BCS class IV drug and a P-glycoprotein (P-gp) substrate, morin, was selected as the model drug to elucidate the oral absorption mechanism of PLC-SNEDDS. PLC-SNEDDS was superior to PLC in protecting morin from degradation by intestinal enzymes in vitro. In situ perfusion study showed increased intestinal permeability by PLC was duodenum-specific. In contrast, PLC-SNEDDS increased morin permeability in all intestinal segments and induced a change in the main absorption site of morin from colon to ileum. Moreover, ileum conducted the lymphatic transport of PLC-SNEDDS, which was proven by microscopic intestinal visualization of Nile red labeled PLC-SNEDDS and lymph fluids in vivo. Low cytotoxicity and increased Caco-2 cell uptake suggested a safe and efficient delivery of PLC-SNEDDS. The increased membrane fluidity and disrupted actin filaments were closely associated with the increased cell uptake of PLC-SNEDDS. PLC-SNEDDS could be internalized into enterocytes as an intact form in a cholesterol-dependent manner via clathrin-mediated endocytosis and macropinocytosis. The enhanced oral absorption of morin was attributed to the P-gp inhibition by Cremophor RH and the intact internalization of M-PLC-SNEDDS into Caco-2 cells bypassing P-gp recognition. Our findings thus provide new insights into the development of novel nanoemulsions for poorly absorbed drugs.

  9. 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.

  10. A novel therapeutic drug (copper nicotinic acid complex) for non-alcoholic fatty liver.

    PubMed

    Salama, Ragaa H M; Nassar, Ahmed Y A; Nafady, Allam A M; Mohamed, Hesham H T

    2007-05-01

    Fatty liver is the accumulation of fat in liver cells, which leads to disruption of the normal liver structure and function. A non-alcoholic fatty liver rat model received copper (Cu) (I)-nicotinate complex [CuCl(HNA)2] for 4 weeks. Clinical signs and histopathological examinations showed obvious improvements in rats that received Cu complex who were continuously on an (HCFF) diet than those returned to standard diet with Cu complex. The improvement was matched in total lipids in sera and hepatic tissue, with disappearance of fat droplets from liver sections. Furthermore, the gain in body weight and the corresponding decrease in liver weight, decreased liver transaminases and alkaline phosphatase were prominent. The oxidative stress markers such as nitric oxide, lipid peroxides, glutathione and superoxide dismutase were obviously changed to healthy normal levels. The Cu complex may serve as a novel chemical restoring agent in fatty degenerated liver cells and for renewal of their structure and functions. However, clinical trials are required for more evaluation of the Cu complex in humans.

  11. 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.

  12. 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.

  13. 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.

  14. Binding of small molecules at interface of protein-protein complex - A newer approach to rational drug design.

    PubMed

    Gurung, A B; Bhattacharjee, A; Ajmal Ali, M; Al-Hemaid, F; Lee, Joongku

    2017-02-01

    Protein-protein interaction is a vital process which drives many important physiological processes in the cell and has also been implicated in several diseases. Though the protein-protein interaction network is quite complex but understanding its interacting partners using both in silico as well as molecular biology techniques can provide better insights for targeting such interactions. Targeting protein-protein interaction with small molecules is a challenging task because of druggability issues. Nevertheless, several studies on the kinetics as well as thermodynamic properties of protein-protein interactions have immensely contributed toward better understanding of the affinity of these complexes. But, more recent studies on hot spots and interface residues have opened up new avenues in the drug discovery process. This approach has been used in the design of hot spot based modulators targeting protein-protein interaction with the objective of normalizing such interactions.

  15. Loading antifungal drugs onto silica particles grafted with cyclodextrins by means of inclusion complex formation at the solid surface.

    PubMed

    Hbaieb, Souhaira; Kalfat, Rafik; Chevalier, Yves

    2012-12-15

    Immobilization of antifungal drugs to solid particles has been addressed in order to limit the skin penetration to the skin surface during topical administration. Antifungal drug griseofulvin has been immobilized at the surface of silica particles by formation of its inclusion complex with β-cyclodextrins grafted to silica. A simple and fast process for loading griseofulvin into the hydrophobic cavity of cyclodextrins at the surface of the solid particles in aqueous suspension has been designed. It allowed the formation of the griseofulvin:cyclodextrin inclusion complex of 1:1 stoichiometry to completion. Grafting β-cyclodextrins to silica surface has been performed in a two-step procedure. The coupling agent 3-amino-propylmethyldiethoxysilane was reacted onto fumed silica particles as a first step. The second step was the reaction of grafted primary amino groups with tosylated β-cyclodextrin that led to β-cyclodextrin grafted silica. Loading griseofulvin onto grafted silica particles have been investigated by IR spectroscopy and by tracking possible crystals of griseofulvin in aqueous suspension by optical and scanning electron microscopy and X-ray diffraction. Successful formation of the inclusion complex at the surface of grafted silica suggested a strong adsorption of griseofulvin by means of heterogeneous nucleation of crystals, followed by inclusion complexation taking place between the partners being in close proximity at the surface of silica particles. The high adsorption capacity of CD-grafted silica for griseofulvin compared to bare silica and amino-grafted silica supports this interpretation. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. 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

  17. 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.

  18. [Potentials for the use of complex drugs in the treatment of patients with chronic abacterial prostatitis].

    PubMed

    Neĭmark, A I; Neĭmark, B A; Nozdrachev, N A

    2014-01-01

    Efficiency and safety of complex preparation prostadoz was evaluated in 25 patients with chronic abacterial prostatitis. It is proved that the use of prostadoz has a positive effect on the main subjective and objective signs of the disease: improves urination, reduces the severity of pain, moderately reduces the prostate volume, improves sexual-ejaculatory performance and improves quality of life.

  19. Catalytically-active complex of HIV-1 integrase with a viral DNA substrate binds anti-integrase drugs

    PubMed Central

    Alian, Akram; Griner, Sarah L.; Chiang, Vicki; Tsiang, Manuel; Jones, Gregg; Birkus, Gabriel; Geleziunas, Romas; Leavitt, Andrew D.; Stroud, Robert M.

    2009-01-01

    HIV-1 integration into the host cell genome is a multistep process catalyzed by the virally-encoded integrase (IN) protein. In view of the difficulty of obtaining a stable DNA-bound IN at high concentration as required for structure determination, we selected IN–DNA complexes that form disulfide linkages between 5′-thiolated DNA and several single mutations to cysteine around the catalytic site of IN. Mild reducing conditions allowed for selection of the most thermodynamically-stable disulfide-linked species. The most stable complexes induce tetramer formation of IN, as happens during the physiological integration reaction, and are able to catalyze the strand transfer step of retroviral integration. One of these complexes also binds strand-transfer inhibitors of HIV antiviral drugs, making it uniquely valuable among the mutants of this set for understanding portions of the integration reaction. This novel complex may help define substrate interactions and delineate the mechanism of action of known integration inhibitors. PMID:19416821

  20. 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.

  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. 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.

  3. Hydrosoluble 50% N-acetylation-thiolated chitosan complex with cobalt as a pH-responsive renal fibrosis targeting drugs.

    PubMed

    Li, Min; Tan, Lishan; Tang, Liangfeng; Li, Aiqing; Hu, Jianqiang

    2016-07-01

    About 50% N-acetylation-thiolated chitosan possessing good water solubility was modified from commercial low-molecular-weight chitosan. Chitosan performed obvious target toward renal tubular epithelial cells, and bivalent cobalt ions improved the renal fibrosis inflammation significantly. There were many complexation sites on chitosan after being modified with sulfydryl. So sulfydryl played a role of connecting bridge between chitosan and cobalt ions. Then, this N-acetylation-thiolated chitosan cobalt (NTCC) nanocomplex was designed. The nanocomplex showed excellent stability under normal physiological conditions, and cobalt would be released from the biomaterials in acidic environment. As it was affected by inflammation, the pH in renal fibrosis lesion region was acidic. So there was a specific drug release process happening in lesion region. And drug release efficiency was determined by acidity, which demonstrated that lower the acidity, the faster and more the cobalt ion release. When this nanocomplex was intraperitoneally injected into ureter-obstructed mice, obvious attenuation of fibrotic progression was shown. It was demonstrated that NTCC exhibited special renal-targeting capacity and could be chosen as drug for treating renal fibrosis.

  4. Comparison of generation 3 polyamidoamine dendrimer and generation 4 polypropylenimine dendrimer on drug loading, complex structure, release behavior, and cytotoxicity

    PubMed Central

    Shao, Naimin; Su, Yunzhang; Hu, Jingjing; Zhang, Jiahai; Zhang, Hongfeng; Cheng, Yiyun

    2011-01-01

    Background Polyamidoamine (PAMAM) and polypropylenimine (PPI) dendrimers are the commercially available and most widely used dendrimers in pharmaceutical sciences and biomedical engineering. In the present study, the loading and release behaviors of generation 3 PAMAM and generation 4 PPI dendrimers with the same amount of surface amine groups (32 per dendrimer) were compared using phenylbutazone as a model drug. Methods The dendrimer-phenylbutazone complexes were characterized by 1H nuclear magnetic resonance and nuclear Overhauser effect techniques, and the cytotoxicity of each dendrimer was evaluated. Results Aqueous solubility results suggest that the generation 3 PAMAM dendrimer has a much higher loading ability towards phenylbutazone in comparison with the generation 4 PPI dendrimer at high phenylbutazone-dendrimer feeding ratios. Drug release was much slower from the generation 3 PAMAM matrix than from the generation 4 PPI dendrimer. In addition, the generation 3 PAMAM dendrimer is at least 50-fold less toxic than generation 4 PPI dendrimer on MCF-7 and A549 cell lines. Conclusion Although the nuclear Overhauser effect nuclear magnetic resonance results reveal that the generation 4 PPI dendrimer with a more hydrophobic interior encapsulates more phenylbutazone, the PPI dendrimer-phenylbutazone inclusion is not stable in aqueous solution, which poses a great challenge during drug development. PMID:22267921

  5. 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.

  6. Carbon dioxide inhalation, stress and anxiogenic drugs reduce the function of GABAA receptor complex in the rat brain.

    PubMed

    Concas, A; Sanna, E; Cuccheddu, T; Mascia, M P; Santoro, G; Maciocco, E; Biggio, G

    1993-07-01

    1. The effect of different stressful stimuli on the function of the GABAA-ionophore receptor complex was evaluated by measuring the binding of 35S-TBPS to the chloride channel associated recognition sites. 2. Foot-shock stress enhanced 35S-TBPS binding in membrane preparation from rat cerebral cortex. The effect of foot-shock on 35S-TBPS binding was mimicked by the anxiogenic and proconvulsant beta-carboline FG 7142 and antagonized by anxiolytic benzodiazepines and by the novel anxiolytic and anticonvulsant beta-carboline, abecarnil. 3. A brief exposure of rats to CO2 inhalation produced, like foot-shock and FG 7142, a marked increase of 35S-TBPS binding in the cerebral cortex, cerebellum and hippocampus. The effect of CO2 inhalation was maximal 10 min after treatment and return to control value in 2 hours. Previous administration of anxiolytic drugs (alprazolam and abecarnil) completely prevented the CO2 inhalation-induced increase of 35S-TBPS binding. 4. All together these data strongly suggest that carbon dioxide inhalation, like stress and anxiogenic drugs, decreases the function of the GABAA receptor complex.

  7. A Hybrid Methacrylate-Sodium Carboxymethylcellulose Interpolyelectrolyte Complex: Rheometry and in Silico Disposition for Controlled Drug Release

    PubMed Central

    Ngwuluka, Ndidi Chinyelu; Choonara, Yahya Essop; Kumar, Pradeep; Modi, Girish; du Toit, Lisa Claire; Pillay, Viness

    2013-01-01

    The rheological behavioral changes that occurred during the synthesis of an interpolyelectrolyte complex (IPEC) of methacrylate copolymer and sodium carboxymethylcellulose were assessed. These changes were compared with the rheological behavior of the individual polymers employing basic viscosity, yield stress, stress sweep, frequency sweep, temperature ramp as well as creep and recovery testing. The rheological studies demonstrated that the end-product of the complexation of low viscous methacrylate copolymer and entangled solution of sodium carboxymethylcellulose generated a polymer, which exhibited a solid-like behavior with a three-dimensional network. Additionally, the rheological profile of the sodium carboxymethylcellulose and methacrylate copolymer with respect to the effect of various concentrations of acetic acid on the synthesis of the IPEC was elucidated using molecular mechanics energy relationships (MMER) by exploring the spatial disposition of carboxymethylcellulose and methacrylate copolymer with respect to each other and acetic acid. The computational results corroborated well with the experimental in vitro drug release data. Results have shown that the IPEC may be suitable polymeric material for achieving controlled zero-order drug delivery. PMID:28788332

  8. Complementary and partially complementary DNA duplexes tethered to a functionalized substrate: a molecular dynamics approach to biosensing.

    PubMed

    Monti, Susanna; Cacelli, Ivo; Ferretti, Alessandro; Prampolini, Giacomo; Barone, Vincenzo

    2011-07-21

    Molecular dynamics simulations (90 ns) of different DNA complexes attached to a functionalized substrate in solution were performed in order to clarify the behavior of mismatched DNA sequences captured by a tethered DNA probe (biochip). Examination of the trajectories revealed that the substrate influence and a series of cooperative events, including recognition, reorientation and reorganization of the bases, could induce the formation of stable duplexes having non-canonical arrangements. Major adjustment of the structures was observed when the mutated base was located in the end region of the chain close to the surface. This journal is © the Owner Societies 2011

  9. 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.

  10. Visualization of drug-nucleic acid interactions at atomic resolution. VII. Structure of an ethidium/dinucleoside monophosphate crystalline complex, ethidium: uridylyl(3'-5')adenosine

    SciTech Connect

    Jain, S.C.; Sobell, H.M.

    1984-01-01

    Ethidium forms a crystalline complex with the dinucleoside monophosphate, uridylyl (3'-5') adenosine (UpA). The complex crystallizes in the monoclinic space group P2/sub 1/ with unit cell dimensions, a = 13.704 A, b = 31.674 A, c = 15.131 A, ..beta.. = 113.8/sup 0/. This light atom structure has been solved to atomic resolution and refined by full matrix least squares to a residual of 0.12, using 3034 observed reflections. The asymmetric unit consists of two ethidium molecules, two UpA molecules and 19 solvent molecules, a total of 145 non-hydrogen atoms. The two UPa molecules are hydrogen-bonded together by Watson-Crick base pairing. Base-pairs in this duplex are separated by 6.7 A; this reflects intercalative binding by one of the ethidium molecules. The other ethidium molecule stacks on either side of the intercalated base-paired dinucleoside monophosphate, being related by a unit cell translation along the a axis. The conformation of the sugar-phosphate backbone accompanying intercalation has been accurately determined in this analysis, and contains the mixed sugar-puckering pattern: C3' endo (3'-5') C2' endo. This same structural feature has been observed in the ethidium-iodoUpA and ethidium-iodoCpG complexes, and exists in two additional structures containing ethidium-CpG. Taken together, these studies confirm the authors earlier sugar-puckering assignments and demonstrate that iodine covalently bound to the C5 position on uridine or cytosine does not alter the basic sugar-phosphate geometry or the mode of ethidium intercalation in these model studies. The authors have proposed this stereochemistry to explain the intercalation of ethidium into both DNA and into double-helical RNA. 15 references, 10 figures, 2 tables.

  11. 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.

  12. 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.

  13. Cost-utility analysis of competing treatment strategies for drug-resistant epilepsy in children with Tuberous Sclerosis Complex.

    PubMed

    Fallah, Aria; Weil, Alexander G; Wang, Shelly; Lewis, Evan; Baca, Christine B; Mathern, Gary W

    2016-10-01

    The management of drug-resistant epilepsy in children with Tuberous Sclerosis Complex (TSC) is challenging because of the multitude of treatment options, wide range of associated costs, and uncertainty of seizure outcomes. The most cost-effective approach for children whose epilepsy has failed to improve with first-line medical therapy is uncertain. A review of MEDLINE from 1990 to 2015 was conducted. A cost-utility analysis, from a third-party payer perspective, was performed for children with drug-resistant epilepsy that had failed to improve with 2 antiseizure drugs (ASDs) and that was amenable to resective epilepsy surgery, across a time-horizon of 5years. Four strategies were included: (1) resective epilepsy surgery, (2) vagus nerve stimulator (VNS) implantation, (3) ketogenic diet, and (4) addition of a third ASD (specifically, carbamazepine). The incremental cost per quality-adjusted life year (QALY) gained was analyzed. Given a willingness-to-pay (WTP) of $100,000 per QALY, the addition of a third ASD ($6600 for a gain of 4.14 QALYs) was the most cost-effective treatment strategy. In a secondary analysis, if the child whose epilepsy had failed to improve with 3 ASDs, ketogenic diet, addition of a fourth ASD, and resective epilepsy surgery were incrementally cost-effective treatment strategies. Vagus nerve stimulator implantation was more expensive yet less effective than alternative strategies and should not be prioritized. The addition of a third ASD is a universally cost-effective treatment option in the management of children with drug-resistant epilepsy that has failed to improve with 2 ASDs. For children whose epilepsy has failed to improve with 3 ASDs, the most cost-effective treatment depends on the health-care resources available reflected by the WTP. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Distribution of Spoligotyping Defined Genotypic Lineages among Drug-Resistant Mycobacterium tuberculosis Complex Clinical Isolates in Ankara, Turkey

    PubMed Central

    Kisa, Ozgul; Tarhan, Gulnur; Gunal, Selami; Albay, Ali; Durmaz, Riza; Saribas, Zeynep; Zozio, Thierry; Alp, Alpaslan; Ceyhan, Ismail; Tombak, Ahmet; Rastogi, Nalin

    2012-01-01

    specifity for Turkey), Beijing and LAM were predominant lineages observed in almost 80% of the drug-Resistant M. tuberculosis complex clinical isolates in Ankara, Turkey. PMID:22279583

  15. 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

  16. 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

  17. Effect of guest drug character encapsulated in the cavity and intermolecular spaces of γ-cyclodextrins on the dissolution property of ternary γ-cyclodextrin complex.

    PubMed

    Liu, Nan; Higashi, Kenjirou; Ueda, Keisuke; Moribe, Kunikazu

    2017-04-24

    Various ternary Guest 2/(Guest 1/γ-cyclodextrin (CD)) complexes were prepared using a cogrinding and subsequent heating method, wherein Guest 1 was incorporated in the cavity of γ-CD and Guest 2 was incorporated into the intermolecular spaces between γ-CD columns. Dissolution fluxes of Guest 1 and Guest 2 from all ternary complexes were almost identical. The dissolution flux of flurbiprofen (Guest 1) from the ternary complexes depended on the solubility of Guest 2 drugs (naproxencomplexes with ketoprofen and ethenzamide as Guest 2 drugs was further enhanced compared with that from the flurbiprofen/γ-CD inclusion complex. The ternary complex of the acidic drug ketoprofen as Guest 1 and the neutral drug hydrocortisone as Guest 2 showed an increased dissolution flux, which was dependent on the increase in pH of the dissolution medium. The pH-dependent dissolution should reflect the solubility of ketoprofen/γ-CD inclusion complex in each dissolution medium. These results indicated that the dissolution flux of the ternary γ-CD complexes could be controlled by selecting the appropriate Guest 1 and Guest 2 species. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. 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.

  19. Identification of sigma and chi phases in duplex stainless steels

    SciTech Connect

    Llorca-Isern, Núria; López-Luque, Héctor; López-Jiménez, Isabel; Biezma, Maria Victoria

    2016-02-15

    The aim of this work is to find out the most suitable method for detecting and analyzing accurately the formation conditions of secondary phases, particularly Sigma-phase (σ-phase) and Chi-phase (χ-phase) in duplex stainless steels (UNS S32205 and UNS S32750). The microstructure was characterized after a solution annealing at 1080 °C followed by an isothermal heating at 830 °C for different time ranges, ranging from 1 min to 9 h, in order to enlighten the controversial point concerning the mechanism of χ-phase nucleation in relation with the σ-phase. Etched samples were observed using optical microscopy (MO), and scanning electron microscopy (FESEM) with a backscattered electron detector (BSE) was used on unetched samples. Compositional microanalysis (EDS) was carried out for identifying the different phases present in the steels. Sigma phase was easily observed using different etching procedures, whereas χ-phase was only clearly detected with FESEM–BSE on unetched samples. The compositional analyses showed that the molybdenum content in χ-phase almost doubles the content of this element in σ-phase, and as a result the kinetics of nucleation and growth were also found to be remarkably faster when the alloy content in the steel is higher. In addition, chromium nitrides and carbides were also observed to precipitate as a result of the heat treatments and, in the case of the chromium nitrides, they act as a favorable site for the nucleation of σ-phase and χ-phase. - Highlights: • Microscopy was used on heat treated duplex steels for microstructure identification. • FESEM–BSE observation on unetched samples provided the best contrast between phases. • Analyses of carbides, nitrides, chi and sigma phases were possible by EDS and WDS. • Chromium nitrides act as favorable site for the nucleation of chi and sigma phases. • Secondary phases nucleation kinetics are faster in superduplex than in duplex steels.

  20. 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.

  1. Human MUS81-EME2 can cleave a variety of DNA structures including intact Holliday junction and nicked duplex.

    PubMed

    Amangyeld, Tamir; Shin, Yong-Keol; Lee, Miju; Kwon, Buki; Seo, Yeon-Soo

    2014-05-01

    MUS81 shares a high-degree homology with the catalytic XPF subunit of the XPF-ERCC1 endonuclease complex. It is catalytically active only when complexed with the regulatory subunits Mms4 or Eme1 in budding and fission yeasts, respectively, and EME1 or EME2 in humans. Although Mus81 complexes are implicated in the resolution of recombination intermediates in vivo, recombinant yeast Mus81-Mms4 and human MUS81-EME1 isolated from Escherichia coli fail to cleave intact Holliday junctions (HJs) in vitro. In this study, we show that human recombinant MUS81-EME2 isolated from E. coli cleaves HJs relatively efficiently, compared to MUS81-EME1. Furthermore, MUS81-EME2 catalyzed cleavage of nicked and gapped duplex deoxyribonucleic acids (DNAs), generating double-strand breaks. The presence of a 5' phosphate terminus at nicks and gaps rendered DNA significantly less susceptible to the cleavage by MUS81-EME2 than its absence, raising the possibility that this activity could play a role in channeling damaged DNA duplexes that are not readily repaired into the recombinational repair pathways. Significant differences in substrate specificity observed with unmodified forms of MUS81-EME1 and MUS81-EME2 suggest that they play related but non-overlapping roles in DNA transactions. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  2. Identifying Novel Drug Targets for the Treatment of Tuberous Sclerosis Complex Using High Throughput Technologies. Addendum

    DTIC Science & Technology

    2007-07-01

    55kD B subunit is referred to by the symbol Vha55 (CG17369, FBgn0005671) CG30035, CG7797 CG4688 CG12688 CG30396 Gustatory receptor 58a is...Complex (TSC), the problematic cells that initiate and constitute tumors have lost TSC1 or TSC2 function. A promising approach to develop an effective...requirement for TSC1/2 or specifically kill or arrest cells that have lost TSC function. Unfortunately, very little is known about the proteins in this

  3. 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.

  4. 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.

  5. 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.

  6. 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).

  7. Application of steered molecular dynamics (SMD) to study DNA drug complexes and probing helical propensity of amino acids

    NASA Astrophysics Data System (ADS)

    Orzechowski, Marek; Cieplak, Piotr

    2005-05-01

    We present the preliminary results of two computer experiments involving the application of an external force to molecular systems. In the first experiment we simulated the process of pulling out a simple intercalator, the 9-aminoacridine molecule, from its complex with a short DNA oligonucleotide in aqueous solution. Removing a drug from the DNA is assumed to be an opposite process to the complex formation. The force and energy profiles suggest that formation of the DNA-9-aminoacridine complex is preferred when the acridine approaches the DNA from the minor groove rather than the major groove side. For a given mode of pulling the intercalation process is also shown to be nucleotide sequence dependent. In another computer experiment we performed a series of molecular dynamics simulations for stretching short, containing 15 amino acids, helical polypeptides in aqueous solution using an external force. The purpose of these simulations is to check whether this type of approach is sensitive enough to probe the sequence dependent helical propensity of short polypeptides.

  8. Interactions between iron(III)-hydroxide polymaltose complex and commonly used drugs / simulations and in vitro studies.

    PubMed

    Burckhardt-Herold, Susanna; Klotz, Jürgen; Funk, Felix; Büchi, Ruth; Petrig-Schaffland, Jeannine; Geisser, Peter

    2007-01-01

    Under physiological conditions, ferric ions are essentially insoluble because of the formation of polynuclear hydroxo-bridged complexes. Ferrous ions are more soluble but may produce hydroxyl radicals on reaction with hydrogen peroxide. Chelation of ferric and ferrous ions with organic ligands may prevent these undesirable reactions. Alternatively, iron(III)-hydroxide/oxide can be stabilized and solubilized by tight interactions with carbohydrates. The data presented in this work show that, because of its physicochemical properties, the iron(III)-hydroxide polymaltose complex (IPC, Maltofer) does not interact with the active ingredients of commonly used drugs such as acetylsalicylic acid (CAS 50-78-2), tetracycline hydrochloride (CAS 64-75-5), calcium hydrogen-phosphate (CAS 7757-93-9), methyl-L-dopa sesquihydrate (CAS 41372-08-1), and magnesium-L-aspartate hydrochloride (CAS 28184-71-6). In contrast, as confirmed by calculations using thermodynamic parameters, FeCl3 x 6H2O (CAS 10025-77-1) can form different types of complexes with these substances. Moreover, the data show that under aerobic conditions high concentrations of ascorbic acid (CAS 50-81-7) can lead to mobilization of iron from IPC and, thus, support the observation that orange juice slightly increases the uptake of iron from IPC.

  9. Synthesis and structure of duplex DNA containing the genotoxic nucleobase lesion N7-methylguanine

    SciTech Connect

    Lee, S.; Bowman, B.R.; Ueno, Y.; Wang, S.; Verdine, G.L.

    2008-11-03

    The predominant product of aberrant DNA methylation is the genotoxic lesion N7-methyl-2{prime}-deoxyguanosine (m{sup 7}dG). M{sup 7}dG is recognized and excised by lesion-specific DNA glycosylases, namely A