1,720,967 research outputs found
Insights into inhibition of heme-dependent dioxygenases
Get PDFTryptophan 2,3-dioxygenase (TDO), along with indoleamine 2,3-dioxygenase (IDO)
and indoleamine 2,3-dioxygenase-2 (IDO2) are the three enzymes that catalyse
oxidation of L-tryptophan (L-Trp) in the first step of the kynurenine pathway.
Despite the fact that all three catalyse the same reaction, they were detected and
characterized in different chronological periods; TDO, IDO and IDO2 were
discovered in 1936, 1967 and 2007 respectively. Years of studies showed that
abnormal regulation of L-Trp, in the first step of kynurenine pathway, is related with
several disorders, including cancer. Regardless of their distinct dissimilarities, TDO,
IDO and IDO2 were all detected in various cancers, supporting tumour escape and
survival. The early identification of IDO immunomodulatory action (1990s) led to
intense research for the development of IDO inhibitors, but not TDO. Despite this
effort, the most pharmacologically suitable IDO inhibitor, 1-methyltryptophan (1-
MT), appears to be ineffective as monotherapeutic drug. Discovery of IDO2 showed
that 1-MT action is not fully understood, raising questions about the biological
significance of IDO2.
The ultimate goal of the current study was to address the problems outlined
above. Because TDO and IDO are two druggable molecular targets, the discovery of
a new class of effective inhibitors was pursued. Plate screening of ~2800 potential
inhibitor compounds obtained from National Cancer Institute (NCI), USA, indicated
seven promising compounds that inhibit both TDO and IDO in either nanomolar or
low micromolar range. Interestingly, of these seven inhibitors, six have been
identified to have cytotoxic action against several types of tumour cell lines (NCI
data). NSC 26326, known as ß-lapachone, is a natural occurring quinone and the
strongest inhibitor of all seven. This NCI compound inhibits both TDO and IDO with
inhibition constants of ~30-70 nM and 97 ± 14 nM respectively. Like NSC 26326,
NSC 36398 is another natural occurring product and the only compound that showed
selectivity against TDO with inhibition constant of 16.3 ± 3.8 μM. Among the seven
compounds that displayed promise as inhibitors of TDO and IDO was mitomycin C.
Mitomycin C, which is an approved oncology drug and a known inhibitor of IDO (Kᵢ = 24.2 ± 1.2 μM), is also inhibitor of TDO with inhibition constant of 2.86 ± 0.03
μM. Another major goal of the current work was the discovery of isatin derivatives
as inhibitors of TDO and IDO. Using the tryptophan-like structure of isatin as
starting point, a number of structural modifications were carried out (structureactivity
relationship (SAR)) succeeding the optimization of their inhibition activity.
This new family of TDO and IDO inhibitors demonstrated inhibition potencies in the
low micromolar range with 5,7-dicholoisatin to reach the nanomolar range (in the
case of TDO). Halogenation of isatin and its derivatives was found to increase
noticeably the inhibition potencies of these molecules by 12fold and 6fold for TDO
and IDO respectively while breakdown of isatin’s pyrrolidine ring had a disastrous
result on the inhibition of both enzymes. Combinations of 1-MT with either the
newly-identified NCI inhibitors or the isatin derivatives were also examined. The in
vitro combinations of 1-MT with either the NCI inhibitors or the isatin derivatives
revealed an additive effect without though excluding the possibility of synergistic
effect in vivo.
The specificity of TDO, IDO and IDO2 against the two stereoisomers of 1-
MT was also investigated, with interesting results. While IDO is inhibited only by
the L-isoform of 1-MT (Kᵢ= 18.0 ± 3.4 μM), IDO2 is inhibited by both 1-Me-L-Trp
and 1-Me-D-Trp with inhibition constants of 306 ± 17 μM and 3419 ± 259 μM
respectively. Biochemical characterization of human IDO2 was another goal of the
current thesis, which completed successfully. Kinetic, redox and inhibition study of
human IDO2 indicated significant differences in comparison with human IDO
something which suggests the potential implication of IDO2 in an identified
biological pathway (other than tryptophan catabolism function).The findings
presented herein help to solve the mystery of 1-MT action, at least in vitro, give
answers in regards to IDO2 function, and provide a number of new, promising
inhibitors for TDO and IDO
The N-terminus of MIF Controls the Flexibility of Specific β-sheet Residues Resulting in Dynamic Regulation of CD74 Activation
Get PDFMacrophage migration inhibitory factor (MIF) is a pleiotropic protein with catalytic, CD74, CXCR2, CXCR4, and nuclease activities that contribute to the pathology of various inflammatory disorders, cardiovascular diseases, and cancer. The majority of MIF-triggered pathological conditions are associated with the activation of CD74, MIF’s cell surface receptor. The mechanistic details of MIF-induced activation of CD74 were mostly unknown until recently where it was shown that intramolecular dynamic signals transmitted from an allosteric center regulate the CD74activation site on MIF’s surface. Via backbone dynamic signals, the same center also controls the enzymatic pocket of MIF and more specifically the catalytically active residue Pro1, which serves as the sole target for the discovery and development of CD74 antagonists. Through these findings, the need to explore the dynamic communication between the enzymatic and CD74 activation sites became apparent. By utilizing molecular dynamics(MD) simulations, nuclear magnetic resonance (NMR) and circular dichroism (CD) experiments, we investigated how changes of the N-terminal flexibility influence the surface of MIF. Our findings support that dynamic signals transmitted from the enzymatic site reach the surface of MIF, affecting CD74 activation. For the first time, such data were able to provide dynamic profiles that explain the differences between MIF variants serving as CD74 agonists or antagonists
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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