Готові списки джерел за темами / DNA-ligand interactions

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Добірка наукової літератури з теми "DNA-ligand interactions"

Автор: Grafiati
Опубліковано: 4 червня 2021
Оновлено: 20 лютого 2023

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Статті в журналах з теми "DNA-ligand interactions"

1

Piosik, Jacek, Kacper Wasielewski, Anna Woziwodzka, Wojciech Śledź, and Anna Gwizdek-Wiśniewska. "De-intercalation of ethidium bromide and propidium iodine from DNA in the presence of caffeine." Open Life Sciences 5, no. 1 (February 1, 2010): 59–66. http://dx.doi.org/10.2478/s11535-009-0077-2.

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AbstractCaffeine (CAF) is capable of interacting directly with several genotoxic aromatic ligands by stacking aggregation. Formation of such hetero-complexes may diminish pharmacological activity of these ligands, which is often related to its direct interaction with DNA. To check these interactions we performed three independent series of spectroscopic titrations for each ligand (ethidium bromide, EB, and propidium iodine, PI) according to the following setup: DNA with ligand, ligand with CAF and DNA-ligand mixture with CAF. We analyzed DNA-ligand and ligand-CAF mixtures numerically using well known models: McGhee-von Hippel model for ligand-DNA interactions and thermodynamic-statistical model of mixed association of caffeine with aromatic ligands developed by Zdunek et al. (2000). Based on these models we calculated association constants and concentrations of mixture components using a novel method developed here. Results are in good agreement with parameters calculated in separate experiments and demonstrate de-intercalation of EB and PI molecules from DNA caused by CAF.
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2

Hopfinger, A. J., Mario G. Cardozo, and Y. Kawakami. "Molecular modelling of ligand–DNA intercalation interactions." J. Chem. Soc., Faraday Trans. 91, no. 16 (1995): 2515–24. http://dx.doi.org/10.1039/ft9959102515.

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3

Piehler, Jacob, Andreas Brecht, Günter Gauglitz, Marion Zerlin, Corinna Maul, Ralf Thiericke, and Susanne Grabley. "Label-Free Monitoring of DNA–Ligand Interactions." Analytical Biochemistry 249, no. 1 (June 1997): 94–102. http://dx.doi.org/10.1006/abio.1997.2160.

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4

van Royen, Martin E., Sónia M. Cunha, Maartje C. Brink, Karin A. Mattern, Alex L. Nigg, Hendrikus J. Dubbink, Pernette J. Verschure, Jan Trapman, and Adriaan B. Houtsmuller. "Compartmentalization of androgen receptor protein–protein interactions in living cells." Journal of Cell Biology 177, no. 1 (April 9, 2007): 63–72. http://dx.doi.org/10.1083/jcb.200609178.

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Steroid receptors regulate gene expression in a ligand-dependent manner by binding specific DNA sequences. Ligand binding also changes the conformation of the ligand binding domain (LBD), allowing interaction with coregulators via LxxLL motifs. Androgen receptors (ARs) preferentially interact with coregulators containing LxxLL-related FxxLF motifs. The AR is regulated at an extra level by interaction of an FQNLF motif in the N-terminal domain with the C-terminal LBD (N/C interaction). Although it is generally recognized that AR coregulator and N/C interactions are essential for transcription regulation, their spatiotemporal organization is largely unknown. We performed simultaneous fluorescence resonance energy transfer and fluorescence redistribution after photobleaching measurements in living cells expressing ARs double tagged with yellow and cyan fluorescent proteins. We provide evidence that AR N/C interactions occur predominantly when ARs are mobile, possibly to prevent unfavorable or untimely cofactor interactions. N/C interactions are largely lost when AR transiently binds to DNA, predominantly in foci partly overlapping transcription sites. AR coregulator interactions occur preferentially when ARs are bound to DNA.
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5

Adasme, Melissa F., Katja L. Linnemann, Sarah Naomi Bolz, Florian Kaiser, Sebastian Salentin, V. Joachim Haupt, and Michael Schroeder. "PLIP 2021: expanding the scope of the protein–ligand interaction profiler to DNA and RNA." Nucleic Acids Research 49, W1 (May 5, 2021): W530—W534. http://dx.doi.org/10.1093/nar/gkab294.

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Abstract With the growth of protein structure data, the analysis of molecular interactions between ligands and their target molecules is gaining importance. PLIP, the protein–ligand interaction profiler, detects and visualises these interactions and provides data in formats suitable for further processing. PLIP has proven very successful in applications ranging from the characterisation of docking experiments to the assessment of novel ligand–protein complexes. Besides ligand–protein interactions, interactions with DNA and RNA play a vital role in many applications, such as drugs targeting DNA or RNA-binding proteins. To date, over 7% of all 3D structures in the Protein Data Bank include DNA or RNA. Therefore, we extended PLIP to encompass these important molecules. We demonstrate the power of this extension with examples of a cancer drug binding to a DNA target, and an RNA–protein complex central to a neurological disease. PLIP is available online at https://plip-tool.biotec.tu-dresden.de and as open source code. So far, the engine has served over a million queries and the source code has been downloaded several thousand times.
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Murade, Chandrashekhar U., and George T. Shubeita. "A fluorescent reporter on electrostatic DNA-ligand interactions." Biomedical Optics Express 13, no. 1 (December 7, 2021): 159. http://dx.doi.org/10.1364/boe.439791.

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Cremers, Glenn A. O., Bas J. H. M. Rosier, Ab Meijs, Nicholas B. Tito, Sander M. J. van Duijnhoven, Hans van Eenennaam, Lorenzo Albertazzi, and Tom F. A. de Greef. "Determinants of Ligand-Functionalized DNA Nanostructure–Cell Interactions." Journal of the American Chemical Society 143, no. 27 (June 28, 2021): 10131–42. http://dx.doi.org/10.1021/jacs.1c02298.

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Peterman, Erwin J. G., and Peter Gross. "Biophysics of DNA–ligand interactions resolved by force." Physics of Life Reviews 7, no. 3 (September 2010): 344–45. http://dx.doi.org/10.1016/j.plrev.2010.06.005.

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Murat, Pierre, Yashveer Singh, and Eric Defrancq. "Methods for investigating G-quadruplex DNA/ligand interactions." Chemical Society Reviews 40, no. 11 (2011): 5293. http://dx.doi.org/10.1039/c1cs15117g.

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Shi, Xuesong, and Robert B. Macgregor. "Volume and hydration changes of DNA–ligand interactions." Biophysical Chemistry 125, no. 2-3 (February 2007): 471–82. http://dx.doi.org/10.1016/j.bpc.2006.10.011.

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Дисертації з теми "DNA-ligand interactions"

1

Rackham, Benjamin. "Single molecule studies of ligand-DNA interactions using atomic force microscopy." Thesis, University of East Anglia, 2014. https://ueaeprints.uea.ac.uk/48783/.

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This thesis describes the results of experiments into the intra and inter-molecular binding of various ligands with dsDNA via the mechanism of intercalation, principally using the technique of atomic force microscopy (AFM). Since the description of the first AFM in the mid 1980’s, AFM has emerged as a sensitive and versatile analytical tool, capable both of detecting and manipulating artefacts at picometer resolutions. In these studies, AFM imaging, supported by circular dichroism, reveals unusual conformational changes in DNA that occur as a result of the binding of ligands that incorporate the acridine chromophore. These changes are distinct from those observed following the binding of other intercalators such as doxorubicin and echinomycin. Direct measurement of the length of linear DNA strands bound to acridine based ligands reveals a shortening of the DNA at very low ligand concentrations. This observation suggests that the structural changes that occur in DNA following the intercalation of the acridine chromophore are more wide ranging than previously thought and support molecular modeling studies that have proposed that the intercalated DNA duplex exhibits characteristics of both B and A form DNA. Variations in the conformational changes that occur in DNA as a result of intercalation may have implications for the application of new intercalating ligands as chemotherapeutic agents. In addition, single molecule force spectroscopy has been used to examine the capacity of bisintercalators to bind to DNA in an inter-molecular fashion. By stretching individual strands of dsDNA, acridine dimers are shown to bind to separate strands of DNA. Intermolecular binding of this kind remains an unexplored cytotoxic mechanism that may yet find an application in vivo. This observation is supported by a novel assay that utilises the controlled aggregation of gold nanoparticles. These nanoparticles, functionalised with DNA, are shown to aggregate on addition of a bisintercalator. The aggregation is fully reversible with the addition of sodium dodecylsulphate. These force spectroscopy experiments have also uncovered a previously unobserved, intermolecular binding mode of the peptide antibiotics echinomycin and TANDEM. In certain circumstances, these ligands are revealed to bind exclusively to the termini of separate DNA strands in a sequence dependent fashion. This finding may have implications for the employment of these ligands in the nanosciences, as a tool for joining short pieces of DNA or improving the efficiency of the enzymatic, blunt-end ligation of DNA.
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2

Zietlow, Christopher Mark. "SPIN-LABELED DNA CATIONIC LIGAND INTERACTIONS ASSOCIATED WITH NON-VIRAL GENE THERAPY." University of Cincinnati / OhioLINK, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=ucin997112806.

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3

Rangan, Anupama. "Structural studies of nucleic acids dynamics of RNA pseudoknots and G-quadruplex DNA-ligand interactions /." Access restricted to users with UT Austin EID, 2001. http://wwwlib.umi.com/cr/utexas/fullcit?p3077362.

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4

Schechner-Resom, Martina Gabriele. "Ligand binding and molecular flexibility : Studies on DNA gyrase B." Université Louis Pasteur (Strasbourg) (1971-2008), 2005. http://www.theses.fr/2005STR1A001.

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L’ADN gyrase est une enzyme vitale pour la bactérie grâce à sa capacité de manipuler les molécules d’ADN dans la cellule vivante. Cette capacité fait de l’ADN gyrase une cible idéale pour des composés anti-infectieux. Dans ce travail, l’ADN gyrase a été étudié par des méthodes de modélisatoin moléculaire. Une approche de conception de ligands basée sur la structure a été entreprise sur le sous-domaine N-terminal de 24 kDa de l’ADN gyrase B (domaine GHKL). La flexibilité de deux boucles du site actif du domaine GHKL a été étudiée par des simulations de dynamiques moléculaires en présence de différents ligands. Dans une dernière partie, une analyse des modes normaux du dimère du domaine N-terminal de 43 kDa a été entreprise
DNA gyrase is a vital bacterial enzyme necessary for the handling of the large DNA molecules in the living cell. Therefore DNA gyrase is an ideal target enzyme for anti-infectious compounds. In this work DNA gyrase has been studied by molecular modelling methods. A computational structure-based ligand design approach has been carried out on the N-terminal 24 kDa subdomain of DNA gyrase B (GHKL domain). To further examine the flexibility of two active site loops, molecular dynamics simulations have been carried out on the GHKL domain in different ligand binding conditions. In a final part, normal mode analysis has been carried out on the dimer of the 43 kDa domain of DNA gyrase B
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5

Greguric, Antun, University of Western Sydney, of Science Technology and Environment College, and of Science Food and Horticulture School. "The DNA binding interactions of Ru(II) polypyridyl complexes." THESIS_CSTE_SFH_Greguric_A.xml, 2002. http://handle.uws.edu.au:8081/1959.7/620.

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This thesis reports on the synthesis, characterisation, enantiomeric resolution, 1H NMR structural study and physical evaluation of a series of certain bidentate ligand metal complexes, where ‘L-L’ denotes the ancillary bidentate ligand and ‘intercalator’ indicates the intercalating bidentate ligand. The L-L series varies in size and shape. Results of many tests and projects conducted are explained in detail.
Master of Science (Hons)
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6

McFail-Isom, Lori. "Effects of ligand binding, coordinate error and ion binding on nucleic acid structure and conformation." Diss., Georgia Institute of Technology, 1998. http://hdl.handle.net/1853/30735.

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Greguric, Antun. "The DNA binding interactions of Ru(II) polypyridyl complexes." Thesis, View thesis View thesis, 2002. http://handle.uws.edu.au:8081/1959.7/620.

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Анотація:
This thesis reports on the synthesis, characterisation, enantiomeric resolution, 1H NMR structural study and physical evaluation of a series of certain bidentate ligand metal complexes, where ‘L-L’ denotes the ancillary bidentate ligand and ‘intercalator’ indicates the intercalating bidentate ligand. The L-L series varies in size and shape. Results of many tests and projects conducted are explained in detail.
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8

Siu, Kit-man Phyllis. "Luminescent cyclometalated platinum(II) complexes : protein binding studies and biological applications /." View the Table of Contents & Abstract, 2005. http://sunzi.lib.hku.hk/hkuto/record/B30575357.

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9

Wang, Yan. "Effects of glucocorticoid receptor binding on base excision repair at deoxyuridine in the glucocorticoid response element." Online access for everyone, 2006. http://www.dissertations.wsu.edu/Thesis/Summer2006/y%5Fwang%5F072106.pdf.

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Rhoad, Jonathan Sidney. "DNA-binding carbohydrates for coordination to a photoactive dirhodium complex and molecular dynamics studies of methyl furanosides evaluation of available force fields /." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1101315894.

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Thesis (Ph. D.)--Ohio State University, 2004.
Title from first page of PDF file. Document formatted into pages; contains xviii, 160 p.; also includes graphics Includes bibliographical references (p. 117-120). Available online via OhioLINK's ETD Center
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Книги з теми "DNA-ligand interactions"

1

Guschlbauer, Wilhelm, and Wolfram Saenger, eds. DNA—Ligand Interactions. Boston, MA: Springer US, 1987. http://dx.doi.org/10.1007/978-1-4684-5383-6.

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2

NATO ASI/FEBS Course on DNA-Ligand Interactions: From Drugs to Proteins (1986 Abbey of Fontevraud). DNA-ligand interactions: From drugs to proteins. New York: Plenum Press, 1987.

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3

Neidle, Stephen. DNA structure and recognition. Oxford, Eng: IRL Press at Oxford University Press, 1994.

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4

Martin, Patrick N. Design, synthesis, kinetics and biological evaluation of acridine baseed DNA intercalators. Dublin: University College Dublin, 1996.

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5

D, Hadjiliadis Nick, and Sletten Einar, eds. Metal complexes: DNA interactions. Chichester: John Wiley & Sons, 2009.

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6

Ismail, Matthew Arif. DNA-ligand interactions: A biophysical study of 9-hydroxyellipticine, Hoechst 33258 and a meso-substituted porphyrin derivative binding to DNA. [s.l.]: typescript, 1998.

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7

Aldrich-Wright, Janice. Metallointercalators: Synthesis and Techniques to Probe Their Interactions with Biomolecules. Vienna: Springer-Verlag/Wien, 2011.

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8

Pollwein, Peter. Spezifische Bindungsstellen von SV40 T-Antigen im zellulären Mausgenom. Konstanz: Hartung-Gorre, 1987.

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9

Wang, Ying. Nanomechanics of DNA-ligand interaction investigated with magnetic tweezers. Bielefeld: Universitätsbibliothek Bielefeld, 2017.

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10

Bibudhendra, Sarkar, and International Symposium on "Metals and Genetics" (1st : 1994 : Toronto, Ont.), eds. Genetic response to metals. New York: M. Dekker, 1995.

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Частини книг з теми "DNA-ligand interactions"

1

Kennard, Olga. "DNA Structure: Current Results from Single Crystal X-Ray Diffraction Studies." In DNA—Ligand Interactions, 1–21. Boston, MA: Springer US, 1987. http://dx.doi.org/10.1007/978-1-4684-5383-6_1.

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2

Hippel, Peter H., and Otto G. Berg. "On the Nature and Specificity of DNA-Protein Interactions in the Regulation of Gene Expression." In DNA—Ligand Interactions, 159–71. Boston, MA: Springer US, 1987. http://dx.doi.org/10.1007/978-1-4684-5383-6_10.

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3

Lehming, Norbert, Juergen Sartorius, Brigitte von Wilcken-Bergmann, and Benno Mueller-Hill. "Searching for the Code of Ideal Protein-DNA-Recognition." In DNA—Ligand Interactions, 173–82. Boston, MA: Springer US, 1987. http://dx.doi.org/10.1007/978-1-4684-5383-6_11.

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4

Sigler, P. B., A. Joachimiak, R. W. Schevitz, C. L. Lawson, R. G. Zhang, Z. Otwinowski, and R. Marmostein. "trp Repressor, A Crystallographic Study of Allostery in Genetic Regulation." In DNA—Ligand Interactions, 183–84. Boston, MA: Springer US, 1987. http://dx.doi.org/10.1007/978-1-4684-5383-6_12.

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5

Steitz, T. A., L. Beese, B. Engelman, P. Freemont, J. Friedman, M. Sanderson, S. Schultz, G. Shields, and J. Warwicker. "Structural Studies of Three DNA Binding Proteins: Catabolite Gene Activator Protein, Resolvase, and the Klenow Fragment of DNA Polymerase I." In DNA—Ligand Interactions, 185–89. Boston, MA: Springer US, 1987. http://dx.doi.org/10.1007/978-1-4684-5383-6_13.

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Boelens, R., R. M. Scheek, R. M. J. N. Lamerichs, J. de Vlieg, J. H. van Boom, and R. Kaptein. "A Two-Dimensional NMR Study of the Complex of lac Repressor Headpiece with a 14 Base Pair lac Operator Fragment." In DNA—Ligand Interactions, 191–215. Boston, MA: Springer US, 1987. http://dx.doi.org/10.1007/978-1-4684-5383-6_14.

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Radman, Miroslav. "DNA Methylation and Mismatch Repair: Molecular Specificities." In DNA—Ligand Interactions, 217–24. Boston, MA: Springer US, 1987. http://dx.doi.org/10.1007/978-1-4684-5383-6_15.

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Maass, Guenter. "Recognition of DNA Sequences by Restriction Endonucleases." In DNA—Ligand Interactions, 225–37. Boston, MA: Springer US, 1987. http://dx.doi.org/10.1007/978-1-4684-5383-6_16.

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Bennett, S. Paul, and Stephen E. Halford. "Mechanism and Specificity of two Restriction Enzymes, CauI and CauII, that Recognize Asymmetrical DNA Sequences." In DNA—Ligand Interactions, 239–50. Boston, MA: Springer US, 1987. http://dx.doi.org/10.1007/978-1-4684-5383-6_17.

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Rosenberg, John M., Judith A. McClarin, Christin A. Frederick, Bi-Cheng Wang, John Grable, Herbert W. Boyer, and Patricia Greene. "Structure of the DNA-EcoRI Endonuclease Recognition Complex." In DNA—Ligand Interactions, 251–56. Boston, MA: Springer US, 1987. http://dx.doi.org/10.1007/978-1-4684-5383-6_18.

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Тези доповідей конференцій з теми "DNA-ligand interactions"

1

Murade, Chandrashekhar U., and George T. Shubeita. "Detecting DNA-Ligand Electrostatic Interactions With a FRET-Based Probe." In 3D Image Acquisition and Display: Technology, Perception and Applications. Washington, D.C.: Optica Publishing Group, 2022. http://dx.doi.org/10.1364/3d.2022.jw5d.5.

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DNA-ligand interactions are dominated by electrostatics as DNA is a highly charged molecule at physiological conditions. Here, we present a FRET-based sensor which can optically report on these interactions between DNA and charged ligands.
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Matsushita, Y., T. Murakawa, K. Shimamura, M. Oishi, T. Ohyama, and N. Kurita. "Specific interactions between DNA and regulatory protein controlled by ligand-binding: Ab initio molecular simulation." In THE IRAGO CONFERENCE 2014. AIP Publishing LLC, 2015. http://dx.doi.org/10.1063/1.4913556.

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3

Brewer, Bryson M., Yandong Gao, Rebecca M. Sappington, and Deyu Li. "Microfluidic Molecular Trap: Probing Extracellular Signaling by Selectively Blocking Exchange of Specific Molecules in Cell-Cell Interactions." In ASME 2013 International Mechanical Engineering Congress and Exposition. American Society of Mechanical Engineers, 2013. http://dx.doi.org/10.1115/imece2013-64489.

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Communication among cell populations is achieved via a wide variety of soluble, extracellular signaling molecules [1]. In order to investigate the role of specific molecules in a cellular process, researchers often utilize in vitro cell culture techniques in which the molecule under question has been removed from the signaling pathway. Traditionally, this has been accomplished by eliminating the gene in the cell that is responsible for coding the targeted ligand/receptor by using modern DNA technology such as gene knockout; however, this process is expensive, time-consuming, and labor intensive. Previously, we have demonstrated a microfluidic platform that uses a semi-permeable barrier with embedded receptor-coated nanoparticles to selectively remove a specific molecule or ligand from the extracellular signaling pathway in a cell co-culture environment [2]. This initial proof-of-principle was conducted using biotinylated nanoparticles and fluorescently tagged avidin molecules, as the avidin/biotin complex is the strongest known non-covalent interaction between a protein and a ligand (Dissociation constant kd = 10−15 M). Also, the trap was only effective for short time periods (<15 min) because the high concentration of fluorescently tagged avidin molecules required for visualization quickly saturated the barrier. However, nearly all biologically relevant ligand-receptor interactions have lower binding affinities than the avidin-biotin complex, with dissociation constants that are larger by several orders of magnitude. In addition, many in vitro cell culture experiments are conducted over multiple hours or days. Thus, a practically useful molecular trap device must be able to operate in a lower binding affinity regime while also lasting for extended time periods. Here we present results in which a biotinylated-particle barrier was used to successfully block lower concentrations of fluorescently tagged avidin for multiple days, showcasing the applicability of the device for long term experiments. In addition, we introduce a modified molecular trap in which the protein A/goat IgG complex was used to demonstrate the effectiveness of the platform for lower binding affinity protein-ligand interactions. These results indicate the potential usefulness of the microfluidic molecular trap platform for probing extracellular signaling pathways.
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Rilak Simović, Ana, Dejan Lazić, Milica Međedović, Dušan Ćoćić, and Biljana Petrović. "SYNTHESIS AND BIOLOGICAL ACTIVITY OF THE NEW PINCER TYPE RUTHENIUM(III) COMPLEX." In 1st INTERNATIONAL Conference on Chemo and BioInformatics. Institute for Information Technologies, University of Kragujevac, 2021. http://dx.doi.org/10.46793/iccbi21.316rs.

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We synthesized and characterized the ruthenium(III) pincer-type complex [RuCl3(H2Lt-Bu] (H2Lt- Bu = 2,6-bis(5-tert-butyl-1H-pyrazol-3-yl)pyridine, 1) by elemental analysis, IR and UV-Vis spectroscopy, and mass spectrometry (MS) method ESI Q-TOF. For comparison reason, we also studied ruthenium(III) terpyridine complexes of the general formula [Ru(N-N-N)Cl3] where N-N-N = 4′-chloro- terpyridine (Cl-tpy; 2) or 4′-chlorophenyl-terpyridine (Cl-Ph-tpy; 3). Kinetic study of the substitution reactions of 1–3 with biomolecules showed that the rate constants depend on the properties of the spectator ligand and the nature of the entering nucleophile. To gain further insight into the reactivity of ruthenium complexes with potential biological targets, we examined the interactions of 1 – 3 with DNA and HSA. The DNA/HSA binding study showed that in comparison to complex 1 (bis– pyrazolylpyridine), the other two (2 and 3) terpyridine complexes had a slightly better binding affinity to calf thymus DNA (CT DNA), while in the case of human serum albumin (HSA), complex 1 exhibited the most strong quenching ability.
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Tersch, C., C. Witte, F. Lisdat, and J. Glöckler. "5.1.3 DNA electrodes for detection of sequence specific nucleic acid-ligand interaction." In 14th International Meeting on Chemical Sensors - IMCS 2012. AMA Service GmbH, Von-Münchhausen-Str. 49, 31515 Wunstorf, Germany, 2012. http://dx.doi.org/10.5162/imcs2012/5.1.3.

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Selamat, Norhidayah, Lee Yook Heng, Nurul Izzaty Hassan, and Nurul Huda Abd Karim. "Synthesis and characterization of 6,6’-bis(2-hydroxyphenyl)-2,2’-bipyridine ligand and its interaction with ct-DNA." In THE 2015 UKM FST POSTGRADUATE COLLOQUIUM: Proceedings of the Universiti Kebangsaan Malaysia, Faculty of Science and Technology 2015 Postgraduate Colloquium. AIP Publishing LLC, 2015. http://dx.doi.org/10.1063/1.4931296.

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Bussel, J. "FOR MODULATION AS A MEANS OF ELEVATING THE PLATELET COUNT IN ITP." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644761.

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ITP is an autoantibody-mediated disease which would logically be treated by decreasing the level of autoantibody. However, the most exciting developments in understanding the pathophysiology of the thrombocytopenia and its treatment involve a better understanding of the MPS FcR system and ways in which it can be modulated. This work has focussed on phagocytic paralysis or FcR blockade (FcRBl): the slowing of destruction of antibody-coated platelets despite the persistent presence of antibody on the surface of the platelet.Several areas have been explored in learning about the MPS system. Investigation by Kurlander among others have revealed that at least 2 FcR's exist on mononuclear phagocytes: one with high and one with low affinity for monomeric IgG. Study of the high affinity FcR expressed by circulating monocytes, by Schreiber among others, has explored the effect of Danazol to decrease the expression of this FcR. The clinical relevance of this receptor is uncertain however because it is saturated in vitro by physiologic concentrations of IgG. Unkeless defined the properties of the low affinity "immune complex" FcR, expressed on macrophages and neutrophils, via monoclonal antibody 3G8 (see below) which blocks ligand binding to this FcR. The exact roles of these two, and possibly more, FcR's are being explored. Another still unsolved controversy involves whether the interaction Fc portions of antibodies coating particles with FcR's is mediated by a conformational change of the Fc portion or by a multipoint attachment of several Fc parts.Studies by Mollison in the 60's demonstrated that the MPS had a limited capacity for removal of antibody-coated (red) cells. Shulman pursued MPS modulation by exploring the inhibition of thrombocytopenia caused by infusion of ITP plasma into normals. Kelton demonstrated that "compensated" ITP may be caused by a decreased clearance of antibody-coated cells and that the rate of clearance of antibody-coated cells may be correlated with rate of clearance of antibody-coated cells may be correlated with the intrinsic levels of IgG. Stossel investigated FcRBl as a mechanism of effect of corticosteroids and related it clinically. Subsequently intravenous gammaglobulin (IVGG) was introducedas a treatment of ITP and Fehr et al first demonstrated FcRBl as the mechanism of effect of IVGG. Exploration of the mechanism of the FcRBl caused by IVGGled Salama and Mueller-Eckhardt to demonstrate the therapeutic effect of I anti-D, which apparentlycoats RBC with antibody and causes their destruction atthe coats RBC with antibody and causes their destruction at the expense of antibody-coated platelets. A similar degree of FcRBl has been shown for aldometrelated to the development of antibody on RBC.Our studies, including Drs. Clarkson, Kimberly, Nachman, and Unkeless, have focussed on the role of the low affinity or "Immune complex" FcR by using monoclonal antibody 3G8 in vivo. An infusion of 1 mg/kg of 3G8 in chimpanzees caused a reproducible FcRBl demonstrable by a slowing of the destruction of antibody-coated RBC for > 10 days (JEM, 1986). Less effect of 3G8 to inhibit CIC removal was seen using DNA-anti-DNA as the immune complex. In view of the wel1-documented effects of IVGG infusion to create FcRBl, we infused 3G8 into 6 adults with refractory ITP (NEJM, 1986). Specifically these patients were refractory to all forms of conventional therapy including splenectomy, steroids, vinca alkaloid infusion, immunosuppressives and danazol . 3 of the 6 patients had peak platelet responses to >80,000/ul. The other 3 had short-lived platelet increases from 10 to 30,000/ul. These responses confirmed the effect of FcRBl, specifically of the low affinity FcR, to underlie a dramatic platelet increase in therapy of ITP. Surprisingly 3 of the patients had apparent longterm effects of this therapy demonstrable in 2 cases as a maintenance of the platelet count >20,0C0/ul without any further therapy and in 1 case as a clearly enhanced responsiveness to other therapies following 3G8 infusion. Since Natural Killer activity was (transiently) ablated by 3G8 infusion, we speculate that an alternation of regulation of (auto) antibody production by NK cells may be responsible for this effect and that FcR interactions include regulatory roles in addition to their primary function of removal of CIC.
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