Pfade der Grammatikalisierung : ein systematischer Überblick

In der Forschung zu Grammatikalisierungsphänomenen wurden die Untersuchungsergebnisse häufig in Form grafischer Schemata dargestellt. Die einschlägige Forschungsliteratur spricht daher von 'grammaticalization paths', 'chains' und 'channels'. Wir möchten in dieser Arbeit erstens einen Überblick darüber bieten, welche Grammatikalisierungspfade – und zu welchen traditionellen grammatischen Domänen – bisher vorgeschlagen wurden. Zweitens möchten wir mittels der Zusammmenstellung der Pfade in einem Gesamtbild veranschaulichen, wie ein Grammatik-Modell aussehen könnte, dem die Grammatikalisierungstheorie zugrunde liegt. Ein solcher Überblick ist aus mehreren Gründen problematisch: Zum einen liegen für einige Grammatikalisierungsentwicklungen verschiedene Vorschläge vor, von denen wir jeweils die auswählten, für die ausreichend Belegmaterial angeführt wurde. Ein anderes Problem stellt die Heterogenität der grafischen Schemata dar, für die wir versucht haben, ein einheitliches Format zu erarbeiten, um sie in unser Gesamtmodell zu integrieren. In gleicher Weise wurden die Vorschläge einbezogen, die nicht in grafischer Gestalt vorlagen. Ein grundlegendes Kriterium für die Auswahl aus der vielfältigen Literatur war, daß die Bewegung eines sprachlichen Elements entlang seines historisch belegten Pfades betrachtet wurde. Im ersten Teil der Arbeit wird die Gesamtgrafik in Bezug auf die von Himmelmann 1992 skizzierte Grammatikalisierungtheorie in einzelnen Aspekten erläutert. Der zweite Teil dient der Einordnung der historisch belegten Entwicklungen in das Gesamtschema, wobei zwei Pfade gesondert behandelt werden. Zum Abschluß möchten wir kurz auf die Möglichkeiten und die Mängel des Modells eingehen

Efficiency of protein synthesis inhibition depends on tRNA and codon compositions

Regulation and maintenance of protein synthesis are vital to all organisms and are thus key targets of attack and defense at the cellular level. Here, we mathematically analyze protein synthesis for its sensitivity to the inhibition of elongation factor EF-Tu and/or ribosomes in dependence of the system's tRNA and codon compositions. We find that protein synthesis reacts ultrasensitively to a decrease in the elongation factor's concentration for systems with an imbalance between codon usages and tRNA concentrations. For well-balanced tRNA/codon compositions, protein synthesis is impeded more effectively by the inhibition of ribosomes instead of EF-Tu. Our predictions are supported by re-evaluated experimental data as well as by independent computer simulations. Not only does the described ultrasensitivity render EF-Tu a distinguished target of protein synthesis inhibiting antibiotics. It may also enable persister cell formation mediated by toxin-antitoxin systems. The strong impact of the tRNA/codon composition provides a basis for tissue-specificities of disorders caused by mutations of human mitochondrial EF-Tu as well as for the potential use of EF-Tu targeting drugs for tissue-specific treatments

Deducing the kinetics of protein synthesis in vivo from the transition rates measured in vitro

The molecular machinery of life relies on complex multistep processes that involve numerous individual transitions, such as molecular association and dissociation steps, chemical reactions, and mechanical movements. The corresponding transition rates can be typically measured in vitro but not in vivo. Here, we develop a general method to deduce the in-vivo rates from their in-vitro values. The method has two basic components. First, we introduce the kinetic distance, a new concept by which we can quantitatively compare the kinetics of a multistep process in different environments. The kinetic distance depends logarithmically on the transition rates and can be interpreted in terms of the underlying free energy barriers. Second, we minimize the kinetic distance between the in-vitro and the in-vivo process, imposing the constraint that the deduced rates reproduce a known global property such as the overall in-vivo speed. In order to demonstrate the predictive power of our method, we apply it to protein synthesis by ribosomes, a key process of gene expression. We describe the latter process by a codon-specific Markov model with three reaction pathways, corresponding to the initial binding of cognate, near-cognate, and non-cognate tRNA, for which we determine all individual transition rates in vitro. We then predict the in-vivo rates by the constrained minimization procedure and validate these rates by three independent sets of in-vivo data, obtained for codon-dependent translation speeds, codon-specific translation dynamics, and missense error frequencies. In all cases, we find good agreement between theory and experiment without adjusting any fit parameter. The deduced in-vivo rates lead to smaller error frequencies than the known in-vitro rates, primarily by an improved initial selection of tRNA. The method introduced here is relatively simple from a computational point of view and can be applied to any biomolecular process, for which we have detailed information about the in-vitro kinetics

Neural correlates of anticipation risk reflect risk preferences

Individual risk preferences have a large influence on decisions, such as financial investments, career and health choices, or gambling. Decision making under risk has been studied both behaviorally and on a neural level. It remains unclear, however, how risk attitudes are encoded and integrated with choice. Here, we investigate how risk preferences are reflected in neural regions known to process risk. We collected functional magnetic resonance images of 56 human subjects during a gambling task (Preuschoff et al., 2006). Subjects were grouped into risk averters and risk seekers according to the risk preferences they revealed in a separate lottery task. We found that during the anticipation of high-risk gambles, risk averters show stronger responses in ventral striatum and anterior insula compared to risk seekers. In addition, risk prediction error signals in anterior insula, inferior frontal gyrus, and anterior cingulate indicate that risk averters do not dissociate properly between gambles that are more or less risky than expected. We suggest this may result in a general overestimation of prospective risk and lead to risk avoidance behavior. This is the first study to show that behavioral risk preferences are reflected in the passive evaluation of risky situations. The results have implications on public policies in the financial and health domain