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Interaction of Pyrrolobenzodiazepine conjugates with DNA
No full textPyrrolobenzodiazepines (PBD) are a group of naturally occurring antitumor antibiotics that consist of a tricyclic system containing anthranilate, diazepine and pyrrolidine ring. The compounds bind preferentially to 5’-Pu-G-Pu-3’ sequences in the minor groove of double stranded DNA by covalently linking the diazepine ring with the 2-amino group of guanine. The PBD binding sites can be extended by conjugating the C8 position of the anthranilate ring with heterocyclic moieties such as pyrrole, imidazole and thiazole. Alternatively, benzofused rings such as benzothiophene, benzofuran and indole can be used for conjugate formation; some natural compounds containing these benzofused heterocycles have been found to show anticancer activities.We have examined the sequence selectivity of PBD-conjugates using DNase I footprinting with substrates that contain every tetranucleotide (MS1 and MS2) and every symmetrical hexanucleotide (HexA and HexB). Conjugates with pyrrole, imidazole and thiazole were found to bind adjacent to AT-rich sequences; their binding preferences towards AT-rich sequences were confirmed with synthetic DNA fragments in which the compounds bound at ATATAT with a guanine at either the 5’- or 3’-end. Conjugation with benzothiophene and benzofuran benzofused rings produced similar binding profiles, though indole conjugates did not appear to bind. The benzofusedconjugates bound at lower concentrations than the polyamide conjugates. These binding sites indicate that the conjugated component plays a vital role in determining the sequence selectivity, while the PBD unit forms the covalent linkage with guanine. PBD-conjugates were also studied by fluorescence melting to evaluate their effect on melting profiles of different oligonucleotide duplexes; the compounds produced biphasic melting curves with large increases in melting temperature.We also describe a simple ligation assay for determining the sequence selectivity of PBD-dimers. The assay involves chemically joining two DNA duplexes by a PBD-dimer when a binding site is generated by overhanging single-stranded ‘sticky ends’. Oligonucleotides containing GATC or GTAC or GAATC overhangs were used to demonstrate that SJG-136 has strongest affinity for GATC; it also produces cross-links with GTAC, but not with GAATC.The final chapter uses DNase I footprinting to examine the sequence specificity of two pyrrole/imidazole hairpin polyamides that were expected to bind to the sequences (A/T)GG(A/T)G(A/T) and (A/T)GG(A/T)C(A/T). We confirm the expected selectivity, but demonstrate that they can also form strong interactions with some secondary sites
Sequence-selective binding of C8-conjugated pyrrolobenzodiazepines (PBDs) to DNA
Get PDFDNA footprinting and melting experiments have been used to examine the sequence-specific binding of C8-conjugates of pyrrolobenzodiazepines (PBDs) and benzofused rings including benzothiophene and benzofuran, which are attached using pyrrole- or imidazole-containing linkers. The conjugates modulate the covalent attachment points of the PBDs, so that they bind best to guanines flanked by A/T-rich sequences on either the 5′- or 3′-side. The linker affects the binding, and pyrrole produces larger changes than imidazole. Melting studies with 14-mer oligonucleotide duplexes confirm covalent attachment of the conjugates, which show a different selectivity to anthramycin and reveal that more than one ligand molecule can bind to each duplex
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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