Conduction in the Heart Wall: Helicoidal Fibers Minimize Diffusion Bias.

The mammalian heart must function as an efficient pump while simultaneously conducting electrical signals to drive the contraction process. In the ventricles, electrical activation begins at the insertion points of the Purkinje network in the endocardium. How does the diffusion component of the subsequent excitation wave propagate from the endocardium in a healthy heart wall without creating directional biases? We show that this is a consequence of the particular geometric organization of myocytes in the heart wall. Using a generalized helicoid to model fiber orientation, we treat the myocardium as a curved space via Riemannian geometry, and then use stochastic calculus to model local signal diffusion. Our analysis shows that the helicoidal arrangement of myocytes minimizes the directional biases that could lead to aberrant propagation, thereby explaining how electrophysiological principles are consistent with local measurements of cardiac fiber geometry. We discuss our results in the context of the need to balance electrical and mechanical requirements for heart function.

Boutiques: a flexible framework to integrate command-line applications in computing platforms.

We present Boutiques, a system to automatically publish, integrate, and execute command-line applications across computational platforms. Boutiques applications are installed through software containers described in a rich and flexible JSON language. A set of core tools facilitates the construction, validation, import, execution, and publishing of applications. Boutiques is currently supported by several distinct virtual research platforms, and it has been used to describe dozens of applications in the neuroinformatics domain. We expect Boutiques to improve the quality of application integration in computational platforms, to reduce redundancy of effort, to contribute to computational reproducibility, and to foster Open Science.

Molecular mechanism of DRP1 assembly studied in vitro by cryo-electron microscopy.

Mitochondria are dynamic organelles that continually adapt their morphology by fusion and fission events. An imbalance between fusion and fission has been linked to major neurodegenerative diseases, including Huntington's, Alzheimer's, and Parkinson's diseases. A member of the Dynamin superfamily, dynamin-related protein 1 (DRP1), a dynamin-related GTPase, is required for mitochondrial membrane fission. Self-assembly of DRP1 into oligomers in a GTP-dependent manner likely drives the division process. We show here that DRP1 self-assembles in two ways: i) in the presence of the non-hydrolysable GTP analog GMP-PNP into spiral-like structures of ~36 nm diameter; and ii) in the presence of GTP into rings composed of 13-18 monomers. The most abundant rings were composed of 16 monomers and had an outer and inner ring diameter of ~30 nm and ~20 nm, respectively. Three-dimensional analysis was performed with rings containing 16 monomers. The single-particle cryo-electron microscopy map of the 16 monomer DRP1 rings suggests a side-by-side assembly of the monomer with the membrane in a parallel fashion. The inner ring diameter of 20 nm is insufficient to allow four membranes to exist as separate entities. Furthermore, we observed that mitochondria were tubulated upon incubation with DRP1 protein in vitro. The tubes had a diameter of ~ 30nm and were decorated with protein densities. These findings suggest DRP1 tubulates mitochondria, and that additional steps may be required for final mitochondrial fission.

Electrosensory Midbrain Neurons Display Feature Invariant Responses to Natural Communication Stimuli.

Neurons that respond selectively but in an invariant manner to a given feature of natural stimuli have been observed across species and systems. Such responses emerge in higher brain areas, thereby suggesting that they occur by integrating afferent input. However, the mechanisms by which such integration occurs are poorly understood. Here we show that midbrain electrosensory neurons can respond selectively and in an invariant manner to heterogeneity in behaviorally relevant stimulus waveforms. Such invariant responses were not seen in hindbrain electrosensory neurons providing afferent input to these midbrain neurons, suggesting that response invariance results from nonlinear integration of such input. To test this hypothesis, we built a model based on the Hodgkin-Huxley formalism that received realistic afferent input. We found that multiple combinations of parameter values could give rise to invariant responses matching those seen experimentally. Our model thus shows that there are multiple solutions towards achieving invariant responses and reveals how subthreshold membrane conductances help promote robust and invariant firing in response to heterogeneous stimulus waveforms associated with behaviorally relevant stimuli. We discuss the implications of our findings for the electrosensory and other systems.

Algorithmic approaches to protein-protein interaction site prediction.

Interaction sites on protein surfaces mediate virtually all biological activities, and their identification holds promise for disease treatment and drug design. Novel algorithmic approaches for the prediction of these sites have been produced at a rapid rate, and the field has seen significant advancement over the past decade. However, the most current methods have not yet been reviewed in a systematic and comprehensive fashion. Herein, we describe the intricacies of the biological theory, datasets, and features required for modern protein-protein interaction site (PPIS) prediction, and present an integrative analysis of the state-of-the-art algorithms and their performance. First, the major sources of data used by predictors are reviewed, including training sets, evaluation sets, and methods for their procurement. Then, the features employed and their importance in the biological characterization of PPISs are explored. This is followed by a discussion of the methodologies adopted in contemporary prediction programs, as well as their relative performance on the datasets most recently used for evaluation. In addition, the potential utility that PPIS identification holds for rational drug design, hotspot prediction, and computational molecular docking is described. Finally, an analysis of the most promising areas for future development of the field is presented.

Transient protein-protein interface prediction: datasets, features, algorithms, and the RAD-T predictor.

BACKGROUND: Transient protein-protein interactions (PPIs), which underly most biological processes, are a prime target for therapeutic development. Immense progress has been made towards computational prediction of PPIs using methods such as protein docking and sequence analysis. However, docking generally requires high resolution structures of both of the binding partners and sequence analysis requires that a significant number of recurrent patterns exist for the identification of a potential binding site. Researchers have turned to machine learning to overcome some of the other methods' restrictions by generalising interface sites with sets of descriptive features. Best practices for dataset generation, features, and learning algorithms have not yet been identified or agreed upon, and an analysis of the overall efficacy of machine learning based PPI predictors is due, in order to highlight potential areas for improvement. RESULTS: The presence of unknown interaction sites as a result of limited knowledge about protein interactions in the testing set dramatically reduces prediction accuracy. Greater accuracy in labelling the data by enforcing higher interface site rates per domain resulted in an average 44% improvement across multiple machine learning algorithms. A set of 10 biologically unrelated proteins that were consistently predicted on with high accuracy emerged through our analysis. We identify seven features with the most predictive power over multiple datasets and machine learning algorithms. Through our analysis, we created a new predictor, RAD-T, that outperforms existing non-structurally specializing machine learning protein interface predictors, with an average 59% increase in MCC score on a dataset with a high number of interactions. CONCLUSION: Current methods of evaluating machine-learning based PPI predictors tend to undervalue their performance, which may be artificially decreased by the presence of un-identified interaction sites. Changes to predictors' training sets will be integral to the future progress of interface prediction by machine learning methods. We reveal the need for a larger test set of well studied proteins or domain-specific scoring algorithms to compensate for poor interaction site identification on proteins in general.