Flud: a hybrid crowd-algorithm approach for visualizing biological networks

Modern experiments in many disciplines generate large quantities of network (graph) data. Researchers require aesthetic layouts of these networks that clearly convey the domain knowledge and meaning. However, the problem remains challenging due to multiple conflicting aesthetic criteria and complex domain-specific constraints. In this paper, we present a strategy for generating visualizations that can help network biologists understand the protein interactions that underlie processes that take place in the cell. Specifically, we have developed Flud, an online game with a purpose (GWAP) that allows humans with no expertise to design biologically meaningful graph layouts with the help of algorithmically generated suggestions. Further, we propose a novel hybrid approach for graph layout wherein crowdworkers and a simulated annealing algorithm build on each other's progress. To showcase the effectiveness of Flud, we recruited crowd workers on Amazon Mechanical Turk to lay out complex networks that represent signaling pathways. Our results show that the proposed hybrid approach outperforms state-of-the-art techniques for graphs with a large number of feedback loops. We also found that the algorithmically generated suggestions guided the players when they are stuck and helped them improve their score. Finally, we discuss broader implications for mixed-initiative interactions in human computation games.Comment: This manuscript is currently under revie

The essential role of the N-terminal domain of the orange carotenoid protein in cyanobacterial photoprotection: importance of a positive charge for phycobilisome binding

Most cyanobacteria, under high light conditions, decrease the amount of energy arriving at the reaction centers by increasing thermal energy dissipation at the level of the phycobilisome, the extramembranous antenna. This mechanism is induced by photoactivation of the Orange Carotenoid Protein (OCP). To identify how the activated OCP interacts with phycobilisomes (PBs), several OCP mutants were constructed, and the influence of mutations on photoactivity, stability, and binding to PBs was characterized. The disruption of the salt bridge between Arg155 and Glu244, which stabilizes the interaction between the N- and C-terminal domains, increased the rate of photoactivity and the stability of the photoactivated OCP, suggesting that the activated OCP has an open structure with decreased interdomain interaction. Changing Glu244 to leucine had no effect on OCP binding to PBs. By contrast, substitution of Arg155 with a neutral or a negatively charged amino acid largely decreased OCP binding to the PBs, whereas substitution with a lysine slightly perturbed the interaction. These results strongly suggest that the surface of the N-terminal domain, containing the Arg155, interacts with the PB and that the positive charge of Arg155 plays a key role in photoprotection

Development of potentiometric ion sensors based on insertion materials as sensitive element

We have demonstrated the feasibility of developing stable Li+ potentiometric sensors, using a composite plastic technology as electrode support. Both triphylite LiFePO4- and FePO4-based sensors display good Li+ sensing properties (reversibility, stability, linearity in the serum Li+ concentration range). Besides, the reversible insertion of various cations (Na+, K+, Mg2+) into the FePO4 host structure was unraveled, providing the necessary information to clearly demonstrate that, within these materials, the sensing mechanism is nested in the ability of the structure to undergo cation insertion/deinsertion reactions. This process was shown to be governed by the Nernst's law. To our knowledge, besides the LiMn2O4/MnO2 spinel-type system, the LiFePO4/FePO4 constitutes the second example of a sensor based on this mechanism. © 2003 Elsevier Science B.V. All rights reserved

Picosecond Kinetics of Light Harvesting and Photoprotective Quenching in Wild-Type and Mutant Phycobilisomes Isolated from the Cyanobacterium Synechocystis PCC 6803

In high light conditions, cyanobacteria dissipate excess absorbed energy as heat in the light-harvesting phycobilisomes (PBs) to protect the photosynthetic system against photodamage. This process requires the binding of the red active form of the Orange Carotenoid Protein (OCPr), which can effectively quench the excited state of one of the allophycocyanin bilins. Recently, an in vitro reconstitution system was developed using isolated OCP and isolated PBs from Synechocystis PCC 6803. Here we have used spectrally resolved picosecond fluorescence to study wild-type and two mutated PBs. The results demonstrate that the quenching for all types of PBs takes place on an allophycocyanin bilin emitting at 660 nm (APCQ660) with a molecular quenching rate that is faster than (1 ps)-1. Moreover, it is concluded that both the mechanism and the site of quenching are the same in vitro and in vivo. Thus, utilization of the in vitro system should make it possible in the future to elucidate whether the quenching is caused by charge transfer between APCQ660 and OCP or by excitation energy transfer from APCQ660 to the S1 state of the carotenoid—a distinction that is very hard, if not impossible, to make in vivo

Resolving the contribution of the uncoupled phycobilisomes to cyanobacterial pulse-amplitude modulated (PAM) fluorometry signals.

International audiencePulse-amplitude modulated (PAM) fluorometry is extensively used to characterize photosynthetic organisms on the slow time-scale (1-1000 s). The saturation pulse method allows determination of the quantum yields of maximal (F(M)) and minimal fluorescence (F(0)), parameters related to the activity of the photosynthetic apparatus. Also, when the sample undergoes a certain light treatment during the measurement, the fluorescence quantum yields of the unquenched and the quenched states can be determined. In the case of cyanobacteria, however, the recorded fluorescence does not exclusively stem from the chlorophyll a in photosystem II (PSII). The phycobilins, the pigments of the cyanobacterial light-harvesting complexes, the phycobilisomes (PB), also contribute to the PAM signal, and therefore, F(0) and F(M) are no longer related to PSII only. We present a functional model that takes into account the presence of several fluorescent species whose concentrations can be resolved provided their fluorescence quantum yields are known. Data analysis of PAM measurements on in vivo cells of our model organism Synechocystis PCC6803 is discussed. Three different components are found necessary to fit the data: uncoupled PB (PB(free)), PB-PSII complexes, and free PSI. The free PSII contribution was negligible. The PB(free) contribution substantially increased in the mutants that lack the core terminal emitter subunits allophycocyanin D or allophycocyanin F. A positive correlation was found between the amount of PB(free) and the rate constants describing the binding of the activated orange carotenoid protein to PB, responsible for non-photochemical quenching

Novel Donepezil-Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer's Disease

Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid-β (Aβ) aggregation. Some of these hybrids also prevented Aβ-induced cell toxicity. Significantly, drug-like properties were predicted, including for blood-brain permeability. Compound 9 emerged as a promising multi-target lead compound (AChE inhibition (IC50 1.6 μM); Aβ aggregation inhibition 60.7%). Overall, this family of hybrids is worthy of further exploration, due to the wide biological activity of sulfonamides