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Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase
Keller, Tracy L,Zocco, Davide,Sundrud, Mark S,Hendrick, Margaret,Edenius, Maja,Yum, Jinah,Kim, Yeon-Jin,Lee, Hak-Kyo,Cortese, Joseph F,Wirth, Dyann F,Dignam, John David,Rao, Anjana,Yeo, Chang-Yeol,Maz Nature Publishing Group, a division of Macmillan P 2012 Nature chemical biology Vol.8 No.3
Febrifugine, the bioactive constituent of one of the 50 fundamental herbs of traditional Chinese medicine, has been characterized for its therapeutic activity, though its molecular target has remained unknown. Febrifugine derivatives have been used to treat malaria, cancer, fibrosis and inflammatory disease. We recently demonstrated that halofuginone (HF), a widely studied derivative of febrifugine, inhibits the development of T<SUB>H</SUB>17-driven autoimmunity in a mouse model of multiple sclerosis by activating the amino acid response (AAR) pathway. Here we show that HF binds glutamyl-prolyl-tRNA synthetase (EPRS), inhibiting prolyl-tRNA synthetase activity; this inhibition is reversed by the addition of exogenous proline or EPRS. We further show that inhibition of EPRS underlies the broad bioactivities of this family of natural product derivatives. This work both explains the molecular mechanism of a promising family of therapeutics and highlights the AAR pathway as an important drug target for promoting inflammatory resolution.
ZUR WISSENSCHAFTSGESCHICHTE EINER EVOLUTIONAREN THEORIE DES SPRACHLICHEN WANDELS
Keller, Von Rudi 東亞大學校 獨逸學硏究所 1992 獨逸學硏究 Vol.- No.8
Der Titel der Sektion, in der dieser Text (in nur wenig anderer Form) als Vortag gehalten wurde, heiβt "Wissenschaftsgeschichte der Sprachgeschikchtsschreibung". Da die Geschichte einer Theorie des sprachlichen Wandels nur indirekt mit der Wissenschaftsgeschichte der Sprachgeschichtsschreibung zu tun hat, will ich einige Bemerkungen vorausschicken zum Verha¨ltnis von Sprachgeschichtsschreibung und Theorie des sprachlichen Wandels. Im wesentlichen teile ich die Acsicht Herrmann Pauls, daβ "ohne Erledigung der prinzipiellen Fragen, ohne Festestellung der allgemeinen Bedingungen des geschichtlichen Werdens"(Paun 1920 : 4) Sprachgeschichtsschreibung gar nicht mo¨glich w¨are. Der Sprachgeschichte - so heiβt es im ersten Satz seines Buches- "muss…eine Wissenschaft zur Seite stehen, welche sich mit den allgemeinen Lebensbedingungen des geschichtlich sich entwickelnden Objektes bescha¨ftigt."(Paul 1920 : 1) Eine solche Wissenschaft nennt er-weil er "das Wort Philosophie lieber vermeiden"(Paul 1920 : 2) will-Prinzipienwissenschaft. In neuerer Zeit finden wir etwa bei Friedrich August von Hayek eine analoge Ansicht : "Die Existenz von Strukturen, mit denen sich die Theorie komplexer Pha¨nomene bescha¨ftig, kann nur versta¨ndlich gemacht werden durch eine Kosmologie, wie es der Physiker nennen wurde, das ist eine Theorie ihrer Evolution."(Hayek 1969 : 154)
Interpretation und Sprachkritik
Keller, Rudi 東亞大學校 獨逸學硏究所 1987 獨逸學硏究 Vol.- No.3
Interpretation und Sprachkritik sind verwandte Tatigkeiten. Sprachkritik ist Interpretation durch Analyse in aulklarerischer Absicht. Sprachkritik will hellhorig machen. Hellhorigkeit ist ein Teil der Mundigkeit. Wir sind tagtaglich einer Flut persuativer sprachlicher Bemuhungen von Mitmenschen ausgesetzt, die etwas von uns wollen: unsere Stimme, unsere Seele, unser Geld, unsere Zuneigung, usw, Um diesem-meist ungebetenen-Ansturm von Verlockungen, oder auch Drohungen aus der Feder oder dem Mund viefach professioneller Kommunikatoren gewachsen zusein, bedarf es sprachlicher Wachsamkeit.
Readout of Higher-Level Processing in the Discharge of Superior Colliculus Neurons
KELLER, EDWARD L.,LEE, KYOUNG-MIN,MCPEEK, ROBERT M. Wiley (Blackwell Publishing) 2005 Annals of the New York Academy of Sciences Vol.1039 No.1
<P>The discharge of neurons in the deeper layers of the superior colliculus (SC) was studied while monkeys performed two visual discrimination tasks that required different amounts of cognitive processing. In a search paradigm the animal's task was to saccade to the location of an odd-colored stimulus located in an array of distractors of uniform color (pop-out visual search). The visual stimuli remained on the screen as the discrimination process distinguished target from distractors. In a choice response task the color of a central cue signaled which stimulus from a previously presented array of colored stimuli was to be the target of a saccade. The stimulus array was turned off well before the central cue was presented. Most neurons showed activity aligned on both the visual input and the motor response in single-target tasks. Many of these same neurons showed additional discharge that was correlated with the required higher-level decision processes in both of these more natural visual tasks. In the case of pop-out search the SC has been shown to be functionally involved in the decision processes. The cue-aligned activity in SC in the choice response task is surprising because no transient visual stimulus appeared in the response field of the neuron.</P>
Motivation in Cyber Learning Environments
Keller,John M Korean Society for Educational Technology 1999 International Journal of Educational Technology Vol.1 No.1
Although the novelty and potential capability of cyber learning environments attract us, We need to address motivational problem as indicated by low completion rates. This article describes, first, issues associated with motivating students to learn in cyber learning environments. Second, the ARCS model is overviewed as a basis for systematic motivational design. Third, a simplified motivational design is described to help practitioners design attractive cyber learning environment. Finally, two recent developments are introduced: one is 'motivationally-adaptive CAI', the other is 'use of motivational messages in distance education'.