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Endokrine Störungen verursacht durch Umweltchemikalien : Wirkungen auf Schlüsselenzyme des Steroidhormon-Metabolismus von Menschen und Tieren
No full textMany environmental chemicals are suspected of disturbing the human and animal endocrine system. These so-called endocrine disruptors can operate in many ways. The interaction of endocrine disruptive effects that eventually endanger human health is still unclear. However, one of the basic mecha-nisms of endocrine disruption is the inhibition of key enzymes in the hormone metabolism. In this study, we focused on the inhibitory potency of suspected endocrine disrupting compounds on aromatase (P450arom) and 5alpha-reductase (5alpha-Re) activities in human tissue and human cancer cells. Both enzymes are essential for the human sex steroid hormone metabolism. We were able to demonstrate that the organotin compounds tributyltin (TBT) and triphenyltin (TPT) are potent unspecific inhibitors of P450arom and 5alpha-Re activity. Prochloraz and fenarimol inhibited P450arom activity at low concentrations (IC5010 µM). While the human tissue assay proved to be more practical and sensitive as a screening tool for putative endocrine disruptors, the cell assay reflected partly the situation in vivo. In another experimental series, we investigated the inhibitory effect of TPT on P450arom, 5alpha-Re, 3beta-HSD type 2, 17beta-HSD type 1 and type 3 alone and in combination with the strong antioxidant dithioerythrithol (DTE). TPT inhibited unspecifically all enzymes that were tested. The experiments also showed that DTE is able to compensate the adverse effects of TPT, and that the effectiveness of the compensatory activity of DTE differs among the enzymes investigated. The suppressed 5alpha-Re activity could not be reactivated with DTE. Conceivably, cysteine residues that are responsible for the tertiary and quarternary structure of the enzyme are critical targets for TPT. A human sampling study was undertaken with the COMPRENDO partner in Gdansk. 60 Polish and 15 German blood samples were investigated for chemical residues and sex hormone concentrations. In addition, 15 placenta samples from Poland and Germany, respectively, were tested for chemical residues, P450arom activities and CYP19 mRNA contents. The chemical analysis was performed by the COMPRENDO partners in Milan (p,p´DDE), Orleans (TBT and TPT) and Ioannina (diuron, fenarimol, linuron und vinclozolin). The results showed that individual sex hormone concentrations in blood were not correlated with chemical body burden. The detected differences in sex hormone concentrations, specific aromatase activity and relative CYP19 mRNA content of Polish and German donors were presumably the result of other factors than the ones determined in this study. Another task of the EU-project was the investigation of the effects of chemical exposure of the aquatic model organisms Pimephales promelas, Rutilus rutilus and Xenopus laevis. We investigated the specific P450arom and 5alpha-Re activities in brain and gonads of the animals. During the qualitative investigation of the androgen metabolism in Xenopus laevis brain, 5alpha-reductase activity was discovered for the first time. In contrast to the inhibitory potency of TPT discovered in our enzyme assays, TPT exposure of aquatic model organisms had no observed effect on enzyme activity in the organs investigated, except for P450arom activities in female gonads of Pimephales promelas at 320 ng TPT/L. In this group, mean P450arom activities were elevated, possibly as a result of an overshooting upregulation due to the inhibition of P450arom by TPT. The exposure of Rutilus rutilus and Xenopus laevis to the effector substances methyltestosterone and letrozole resulted in slightly different mean enzyme activities compared to the control group. In conclusion, many of the tested pesticides are able to inhibit P450arom and 5alpha-Re, and thus might be of clinical relevance. However, results are not always coherent, and possible risks for human and wildlife health are therefore difficult to predict. Risk assessment will require large studies with an additional number of short and long term in vitro and in vivo assays. Any extrapolation to humans should be very meticulously performed.Viele Umweltchemikalien stehen im Verdacht, das endokrine System von Menschen und Tieren zu schädigen. Diese sogenannten endokrinen Disruptoren können auf verschiedene Weise wirken. Das Zusammenspiel der verschiedenen endokrinen Wirkungen, welches letztendlich zu einer Beeinträchtigung der Gesundheit führt, ist bis jetzt noch unklar. Einer der wesentlichen Faktoren für endokrine Schädigung ist jedoch die Inhibition von Schlüsselenzymen im Hormonmetabolismus, die in der vorliegenden Arbeit untersucht wird. In erster Linie wurde die inhibitorischen Wirkung potentieller endokriner Disruptoren auf die Aktivität von Aromatase (P450arom) und 5alpha-Reduktase (5alpha-Re) in menschlichen Geweben und humanen Krebszellen untersucht. Diese beiden Enzyme sind für den humanen Sexualsteroid-hormon-Metabolismus unerlässlich. Die Organozinnverbindungen Tributylzinn (TBT) und Triphenylzinn (TPT) wurden als starke unspezifische Inhibitoren der P450arom und 5alpha-Re identifiziert. Prochloraz und Fenarimol hemmten die P450arom- Aktivität bereits bei niedrigen Konzentrationen (IC5010 µM). Als Screening-Test für endokrine Disruptoren erwies sich der Gewebe-Enzymtest als überaus geeignet, da er empfindlich reagiert und einfach zu handhaben ist. Dagegen spiegelt der Krebszell-Enzymtest zu einem gewissen Teil die Situation in vivo wider. In einer weiteren Studie wurde die inhibitorische Wirkung von TPT auf die Enzyme P450arom, 5alpha-Re, 3beta-HSD Typ 2, 17beta-HSD Typ 1 und Typ 3 allein und in Kombination mit dem starken Antioxidanz Dithioerythritol (DTE) untersucht. TPT hemmte unspezifisch alle getesteten Enzyme in ihrer Aktivität. Die Untersuchungen zeigten außerdem, dass DTE den schädigenden Effekt von TPT kompensieren kann und dass dieser schützende Effekt unterschiedlich stark bei den getesteten Enzymen ist. Die TPT-supprimierte 5alpha-Re-Aktivität konnte durch den Einsatz von DTE nur teilweise wiederhergestellt werden. Die Ergebnisse führen zu der Vermutung, dass Cysteinreste, die durch die Ausbildung von Disulfidbrücken entscheidend für die Tertiär- und Quartärstruktur des Enzyms sind, einen kritischen Angriffspunkt für TPT darstellen. Im Rahmen des EU-Projekts COMPRENDO wurde ein Human-Biomonitoring mit unseren Partnern in Danzig durchgeführt. Blutproben von 60 Probanden in Polen und 15 Probanden in Deutschland wurden auf Chemikalien-rückstände und Konzentrationen von Sexualhormonen getestet. Außerdem wurden je 15 Plazentaproben aus Polen und Deutschland auf Chemikalienrückstände, spezifische P450arom-Aktivität und CYP19 mRNA-Gehalt untersucht. Die Chemikalienanalyse wurde von COMPRENDO-Partnern in Mailand (p,p´DDE), Orleans (TBT und TPT) und Ioannina (Diuron, Fenarimol, Linuron und Vinclozolin) durchgeführt. Im Ergebnis zeigt sich, dass individuelle Sexualhormon-Konzentrationen im Blut mit den jeweiligen Chemikalienrückständen nicht korrelierten. Für die Unterschiede der Sexualhormon-Konzentrationen, der spezifischen P450arom-Aktivität und des relativen CYP19-Gehalts, die zwischen den beiden Gruppen in Polen und Deutschland gemessen wurden, sind daher andere Faktoren verantwortlich als die hier gemessenen. Eine weitere gemeinsam mit EU-Partnern durchgeführte Studie sollte Aufschluss über die Wirkung einer Chemikalienexposition auf die aquatischen Modellorganismen Xenopus laevis, Rutilus rutilus und Pimephales promelas geben. Es wurden die spezifischen Enzymaktivitäten in den Gehirnen und Gonaden der Tiere untersucht. Bei der qualitativen Untersuchung des Androgenmetabolismus im Gehirn von Xenopus laevis wurde zum ersten mal 5beta-Reduktase-Aktivität nachgewiesen. Im Unterschied zur starken inhibitorischen Wirkung von TPT in unseren Enzymtests fanden wir keine veränderten P450arom- oder 5alpha-Re-Aktivitäten in den untersuchten Organen, außer in den Ovarien von Pimephales promelas, die einer Konzentration von 320 ng TPT/L ausgesetzt waren. In dieser Gruppe war die mittlere P450arom-Aktivität erhöht, wahrscheinlich durch eine überschießende Hochregulierung, die durch die Inhibition durch TPT ausgelöst wurde. Die Substanzen Methyltestosteron und Letrozol führten im Vergleich zur Kontrollsubstanz Ethanol zu veränderten Enzymaktivitäten bei Rutilus rutilus und Xenopus laevis. Mehrere der getesteten Chemikalien inhibieren die P450arom- und/oder die 5alpha-Re-Aktivität und können daher von klinischer Relevanz sein. Allerdings sind die Ergebnisse der verschiedenen Experimente nicht immer einheitlich, daher lassen sich Schlussfolgerungen möglicher Gefahren für den Menschen und Tiere nur schwer ziehen. Für eine bessere Risikoabschätzung werden Studien mit verschiedenen in vitro und in vivo Kurz- und Langzeit-Testsysteme benötigt. Jede Extrapolation auf den Menschen sollte jedoch immer mit größter Sorgfalt erfolgen
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
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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