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Englmeier K.,Schmalkalden University of Applied Sciences | Murtagh F.,University of Derby
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2016

Information Discovery (ID) is predominantly addressed by approaches from Artificial Intelligence (AI). Automatic ID scans large amounts of data and identifies as many potential candidates for discovery as possible. Mass discovery may in fact serve the needs of many information consumers. However, that does not mean that it addresses a broad range of user interests, too. Economies of scale urge the development of automatic tools to address user needs only from a certain critical mass. Hence, many user needs remain unaddressed. This is where HCI comes into play and provides fundamentals for pattern languages that empower information consumers to stage their own information discovery. With this paper we want to draw attention to an approach that is developed around the paradigm of human-centered interaction design. We present an Open Discovery Language that can completely be controlled by information consumers. © Springer International Publishing Switzerland 2016.

Kusch J.,Friedrich - Schiller University of Jena | Thon S.,Friedrich - Schiller University of Jena | Schulz E.,Schmalkalden University of Applied Sciences | Biskup C.,Friedrich - Schiller University of Jena | And 4 more authors.
Nature Chemical Biology | Year: 2012

Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels are tetrameric membrane proteins that generate electrical rhythmicity in specialized neurons and cardiomyocytes. The channels are primarily activated by voltage but are receptors as well, binding the intracellular ligand cyclic AMP. The molecular mechanism of channel activation is still unknown. Here we analyze the complex activation mechanism of homotetrameric HCN2 channels by confocal patch-clamp fluorometry and kinetically quantify all ligand binding steps and closed-open isomerizations of the intermediate states. For the binding affinity of the second, third and fourth ligand, our results suggest pronounced cooperativity in the sequence positive, negative and positive, respectively. This complex interaction of the subunits leads to a preferential stabilization of states with zero, two or four ligands and suggests a dimeric organization of the activation process: within the dimers the cooperativity is positive, whereas it is negative between the dimers. © 2012 Nature America, Inc. All rights reserved.

Benndorf K.,Friedrich - Schiller University of Jena | Kusch J.,Friedrich - Schiller University of Jena | Schulz E.,Schmalkalden University of Applied Sciences
PLoS Computational Biology | Year: 2012

Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels are voltage-gated tetrameric cation channels that generate electrical rhythmicity in neurons and cardiomyocytes. Activation can be enhanced by the binding of adenosine-3′,5′-cyclic monophosphate (cAMP) to an intracellular cyclic nucleotide binding domain. Based on previously determined rate constants for a complex Markovian model describing the gating of homotetrameric HCN2 channels, we analyzed probability fluxes within this model, including unidirectional probability fluxes and the probability flux along transition paths. The time-dependent probability fluxes quantify the contributions of all 13 transitions of the model to channel activation. The binding of the first, third and fourth ligand evoked robust channel opening whereas the binding of the second ligand obstructed channel opening similar to the empty channel. Analysis of the net probability fluxes in terms of the transition path theory revealed pronounced hysteresis for channel activation and deactivation. These results provide quantitative insight into the complex interaction of the four structurally equal subunits, leading to non-equality in their function. © 2012 Benndorf et al.

Kusch J.,Universitatsklinikum Jena | Zimmer T.,Universitatsklinikum Jena | Holschuh J.,Universitatsklinikum Jena | Biskup C.,Universitatsklinikum Jena | And 3 more authors.
Biophysical Journal | Year: 2010

Cyclic nucleotide-gated (CNG) channels mediate sensory signal transduction in retinal and olfactory cells. The channels are activated by the binding of cyclic nucleotides to a cyclic nucleotide-binding domain (CNBD) in the C-terminus that is located at the intracellular side. The molecular events translating the ligand binding to the pore opening are still unknown. We investigated the role of the S4-S5 linker in the activation process by quantifying its interaction with other intracellular regions. To this end, we constructed chimeric channels in which the N-terminus, the S4-S5 linker, the C-linker, and the CNBD of the retinal CNGA1 subunit were systematically replaced by the respective regions of the olfactory CNGA2 subunit. Macroscopic concentration-response relations were analyzed, yielding the apparent affinity to cGMP and the Hill coefficient. The degree of functional coupling of intracellular regions in the activation gating was determined by thermodynamic double-mutant cycle analysis. We observed that all four intracellular regions, including the relatively short S4-S5 linker, are involved in controlling the apparent affinity of the channel to cGMP and, moreover, in determining the degree of cooperativity between the subunits, as derived from the Hill coefficient. The interaction energies reveal an interaction of the S4-S5 linker with both the N-terminus and the C-linker, but no interaction with the CNBD. © 2010 by the Biophysical Society.

Nache V.,Friedrich - Schiller University of Jena | Eick T.,Friedrich - Schiller University of Jena | Schulz E.,Schmalkalden University of Applied Sciences | Schmauder R.,Friedrich - Schiller University of Jena | Benndorf K.,Friedrich - Schiller University of Jena
Nature Communications | Year: 2013

Tetrameric cyclic nucleotide-gated (CNG) channels mediate receptor potentials in olfaction and vision. The channels are activated by the binding of cyclic nucleotides to a binding domain embedded in the C terminus of each subunit. Here using a fluorescent cGMP derivative (fcGMP), we show for homotetrameric CNGA2 channels that ligand unbinding is ∼50 times faster at saturating than at subsaturating fcGMP. Analysis with complex Markovian models reveals two pathways for ligand unbinding; the partially liganded open channel unbinds its ligands from closed states only, whereas the fully liganded channel reaches a different open state from which it unbinds all four ligands rapidly. Consequently, the transition pathways for ligand binding and activation of a fully liganded CNGA2 channel differ from that of ligand unbinding and deactivation, resulting in pronounced hysteresis of the gating mechanism. This concentration-dependent gating mechanism allows the channels to respond to changes in the cyclic nucleotide concentration with different kinetics. © 2013 Macmillan Publishers Limited. All rights reserved.

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