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    Biochemical and toxicological evaluation of agent-cofactor reactivity as a mechanism of action for osteolathyrism

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    In vitro reactivity for each of four osteolathyrogens with a model compound for the lysyl oxidase (LO) cofactor was evaluated and coupled with mixture toxicity testing to evaluate agent-cofactor reactivity as a potential mechanism of action for osteolathyrism. Reactivity of the model cofactor (mLTQ: 4-butylamino-5-methyl-o-quinone), with each of two ureides, semicarbazide (SC) and thiosemicarbazide (TSC), and each of two aminonitriles, aminoacetonitrile (AAN) and beta-aminopropionitrile (betaAPN), was assessed using UV-vis spectrophotometry; both in the absence and presence of Cu(II)-bipyridine (bipy) complex. Two sets of mixture toxicity experiments were conducted using a frog embryo assay that assessed the incidence of osteolathyrism in the notochord of tadpoles after 96-h exposure. The resulting concentration-response curves for each set were evaluated (chi(2) goodness-of-fit test) against theoretical curves for two combined effects models: dose-addition and independence, to determine the combined effect of each osteolathyrogen combination. The agents SC, TSC and AAN each showed rapid, irreversible reactivity with mLTQ, both in the absence and presence of Cu(II)-bipy complex, as indicated by bleaching of the mLTQ peak (504 nm) and formation of an adduct at 350 nm. betaAPN showed no apparent reactivity in the absence of prolonged incubation with mLTQ, whether Cu(II)-bipy complex was present or not. After prolonged incubation (24-144 h) a new peak formed at 350 nm, suggesting that betaAPN reacts weakly with the cofactor, but in a manner different from the other agents examined. The toxicity tests indicated a dose-additive combined effect for the SC:TSC, AAN:SC and AAN:SC:TSC mixtures (0.1 < P < 0.9; with slope and EC50 additivity quotient values between 0.93-1.14), suggesting these agents induce osteolathyrism via a common mechanism. The betaAPN:SC and betaAPN: SC:TSC mixtures. showed a greater-than dose-additive combined effect (P < 0.001; slope and EC50 additivity quotient values from 0.74 to 0.89), suggesting a different or additional mechanism of osteolathyrism for βAPN. Taken together the results indicate that SC, TSC and AAN induce osteolathyrism primarily, if not completely, by binding to the LO cofactor, thereby inhibiting proper connective tissue fiber cross-linking. While βAPN also has the potential to react with the cofactor, the nature of the reactivity observed suggests that βAPN-cofactor binding is, at best, a secondary mechanism for induction of osteolathyrism in vivo

    Going Beyond Counting First Authors in Author Co-citation Analysis

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    The 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

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    “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

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    We 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

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    We 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

    Evaluation of dose-response curve analysis in delineating shared or different molecular sites of action for osteolathyrogens

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    Single-chemical and mixture concentration-response curves generated using a frog embryo model were examined for value in assessing whether chemicals exert toxic effects at the same or at different molecular sites of action. Toxicity tests were conducted on a series of osteolathyrogens, i.e. chemicals that inhibit cross-linking of developing connective tissue fibers. Induction of osteolathyrism, which manifests as lesions in the notochord of exposed tadpoles, has several possible molecular sites of action, including agent-cofactor reactivity during the enzyme-mediated cross-linking process. UV-VIS spectrophotometry of osteolathyrogen-cofactor reactivity (i.e. in vitro analysis) was coupled with the 96-h frog embryo mixture toxicity assay (i.e. in vivo toxicity) to compare molecular sites of action for several osteolathyrogens with the combined osteolathyritic effects of the agents. Single-chemical concentration-response curves were used to calculate theoretical curves for the dose-addition model of combined effect. Slope and EC50 values for both theoretical and experimental mixture curves were then generated to statistically examine the hypothesis that agents with shared sites of action have dose-response curve (DRC) slopes that are similar when given alone and in combination, and slope and EC50 values that, when administered together, are consistent with those calculated for dose-addition. For combinations of cofactor-binding agents (semicarbazide, thiosemicarbazide, aminoacetonitrile), slope values were generally similar with additivity quotients near 1.0 (1.0 = dose-additive) and combined osteolathyritic effects that were consistent with dose-addition. None of these were true for combinations that included agents that did not show rapid cofactor binding (beta-aminopropionitrile, methyleneaminoacetonitrile). The results suggest that DRC analysis could be a useful tool for delineating common or different molecular sites of toxic action and that the approaches used warrant further study for evaluating the mechanistic basis for combined effects of toxicants

    Author Index

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    koamabayili/VECTRON-author-checklist: VECTRON author checklist

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    We 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
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