Comparison of Different Spike Train Synchrony Measures Regarding Their Robustness to Erroneous Data From Bicuculline-Induced Epileptiform Activity.

As synchronized activity is associated with basic brain functions and pathological states, spike train synchrony has become an important measure to analyze experimental neuronal data. Many measures of spike train synchrony have been proposed, but there is no gold standard allowing for comparison of results from different experiments. This work aims to provide guidance on which synchrony measure is best suited to quantify the effect of epileptiform-inducing substances (e.g., bicuculline, BIC) in in vitro neuronal spike train data. Spike train data from recordings are likely to suffer from erroneous spike detection, such as missed spikes (false negative) or noise (false positive). Therefore, different timescale-dependent (cross-correlation, mutual information, spike time tiling coefficient) and timescale-independent (Spike-contrast, phase synchronization (PS), A-SPIKE-synchronization, A-ISI-distance, ARI-SPIKE-distance) synchrony measures were compared in terms of their robustness to erroneous spike trains. For this purpose, erroneous spike trains were generated by randomly adding (false positive) or deleting (false negative) spikes (in silico manipulated data) from experimental data. In addition, experimental data were analyzed using different spike detection threshold factors in order to confirm the robustness of the synchrony measures. All experimental data were recorded from cortical neuronal networks on microelectrode array chips, which show epileptiform activity induced by the substance BIC. As a result of the in silico manipulated data, Spike-contrast was the only measure that was robust to false-negative as well as false-positive spikes. Analyzing the experimental data set revealed that all measures were able to capture the effect of BIC in a statistically significant way, with Spike-contrast showing the highest statistical significance even at low spike detection thresholds. In summary, we suggest using Spike-contrast to complement established synchrony measures because it is timescale independent and robust to erroneous spike trains.

The structure and resilience of financial market networks.

Financial markets can be viewed as a highly complex evolving system that is very sensitive to economic instabilities. The complex organization of the market can be represented in a suitable fashion in terms of complex networks, which can be constructed from stock prices such that each pair of stocks is connected by a weighted edge that encodes the distance between them. In this work, we propose an approach to analyze the topological and dynamic evolution of financial networks based on the stock correlation matrices. An entropy-related measurement is adopted to quantify the robustness of the evolving financial market organization. It is verified that the network topological organization suffers strong variation during financial instabilities and the networks in such periods become less robust. A statistical robust regression model is proposed to quantity the relationship between the network structure and resilience. The obtained coefficients of such model indicate that the average shortest path length is the measurement most related to network resilience coefficient. This result indicates that a collective behavior is observed between stocks during financial crisis. More specifically, stocks tend to synchronize their price evolution, leading to a high correlation between pair of stock prices, which contributes to the increase in distance between them and, consequently, decrease the network resilience.

Morphological Neuron Classification Based on Dendritic Tree Hierarchy.

The shape of a neuron can reveal interesting properties about its function. Therefore, morphological neuron characterization can contribute to a better understanding of how the brain works. However, one of the great challenges of neuroanatomy is the definition of morphological properties that can be used for categorizing neurons. This paper proposes a new methodology for neuron morphological analysis by considering different hierarchies of the dendritic tree for characterizing and categorizing neuronal cells. The methodology consists in using different strategies for decomposing the dendritic tree along its hierarchies, allowing the identification of relevant parts (possibly related to specific neuronal functions) for classification tasks. A set of more than 5000 neurons corresponding to 10 classes were examined with supervised classification algorithms based on this strategy. It was found that classification accuracies similar to those obtained by using whole neurons can be achieved by considering only parts of the neurons. Branches close to the soma were found to be particularly relevant for classification.

Chain motifs: the tails and handles of complex networks.

A great part of the interest in complex networks has been motivated by the presence of structured, frequently nonuniform, connectivity. Because diverse connectivity patterns tend to result in distinct network dynamics, and also because they provide the means to identify and classify several types of complex network, it becomes important to obtain meaningful measurements of the local network topology. In addition to traditional features such as the node degree, clustering coefficient, and shortest path, motifs have been introduced in the literature in order to provide complementary descriptions of the network connectivity. The current work proposes a different type of motif, namely, chains of nodes, that is, sequences of connected nodes with degree 2. These chains have been subdivided into cords, tails, rings, and handles, depending on the type of their extremities (e.g., open or connected). A theoretical analysis of the density of such motifs in random and scale-free networks is described, and an algorithm for identifying these motifs in general networks is presented. The potential of considering chains for network characterization has been illustrated with respect to five categories of real-world networks including 16 cases. Several interesting findings were obtained, including the fact that several chains were observed in real-world networks, especially the world wide web, books, and the power grid. The possibility of chains resulting from incompletely sampled networks is also investigated.

Gene regulatory and signaling networks exhibit distinct topological distributions of motifs.

The biological processes of cellular decision making and differentiation involve a plethora of signaling pathways and gene regulatory circuits. These networks in turn exhibit a multitude of motifs playing crucial parts in regulating network activity. Here we compare the topological placement of motifs in gene regulatory and signaling networks and observe that it suggests different evolutionary strategies in motif distribution for distinct cellular subnetworks.

Voronoi analysis uncovers relationship between mosaics of normally placed and displaced amacrine cells in the thraira retina.

Although neuronal dynamics is to a high extent a function of synapse strength, the spatial distribution of neurons is also known to play an important role, which is evidenced by the topographical organization of the main stations of the visual system: retina, lateral geniculate nucleus, and cortex. The coexisting systems of normally placed and displaced amacrine cells in the vertebrate retina provide interesting examples of retinotopic spatial organization. However, it is not clear whether these two systems are spatially interrelated or not. The current work applies two mathematical-computational methods-a new method involving Voronoi diagrams for local density quantification and a more traditional approach, the Ripley K function-in order to characterize the mosaics of normally placed and displaced amacrine cells in the retina of Hoplias malabaricus and search for possible spatial relationships between these two types of mosaics. The results obtained by the Voronoi local density analysis suggest that the two systems of amacrine cells are spatially interrelated through nearly constant local density ratios.

Exploring complex networks through random walks.

Most real complex networks--such as protein interactions, social contacts, and the Internet--are only partially known and available to us. While the process of exploring such networks in many cases resembles a random walk, it becomes a key issue to investigate and characterize how effectively the nodes and edges of such networks can be covered by different strategies. At the same time, it is critically important to infer how well can topological measurements such as the average node degree and average clustering coefficient be estimated during such network explorations. The present article addresses these problems by considering random, Barabási-Albert (BA), and geographical network models with varying connectivity explored by three types of random walks: traditional, preferential to untracked edges, and preferential to unvisited nodes. A series of relevant results are obtained, including the fact that networks of the three studied models with the same size and average node degree allow similar node and edge coverage efficiency, the identification of linear scaling with the size of the network of the random walk step at which a given percentage of the nodes/edges is covered, and the critical result that the estimation of the averaged node degree and clustering coefficient by random walks on BA networks often leads to heavily biased results. Many are the theoretical and practical implications of such results.

Effects of threshold on the topology of gene co-expression networks.

Several developments regarding the analysis of gene co-expression profiles using complex network theory have been reported recently. Such approaches usually start with the construction of an unweighted gene co-expression network, therefore requiring the selection of a suitable threshold defining which pairs of vertices will be connected. We aimed at addressing such an important problem by suggesting and comparing five different approaches for threshold selection. Each of the methods considers a respective biologically-motivated criterion for electing a potentially suitable threshold. A set of 21 microarray experiments from different biological groups was used to investigate the effect of applying the five proposed criteria to several biological situations. For each experiment, we used the Pearson correlation coefficient to measure the relationship between each gene pair, and the resulting weight matrices were thresholded considering several values, generating respective adjacency matrices (co-expression networks). Each of the five proposed criteria was then applied in order to select the respective threshold value. The effects of these thresholding approaches on the topology of the resulting networks were compared by using several measurements, and we verified that, depending on the database, the impact on the topological properties can be large. However, a group of databases was verified to be similarly affected by most of the considered criteria. Based on such results, it can be suggested that when the generated networks present similar measurements, the thresholding method can be chosen with greater freedom. If the generated networks are markedly different, the thresholding method that better suits the interests of each specific research study represents a reasonable choice.

Learning about knowledge: a complex network approach.

An approach to modeling knowledge acquisition in terms of walks along complex networks is described. Each subset of knowledge is represented as a node, and relations between such knowledge are expressed as edges. Two types of edges are considered, corresponding to free and conditional transitions. The latter case implies that a node can only be reached after visiting previously a set of nodes (the required conditions). The process of knowledge acquisition can then be simulated by considering the number of nodes visited as a single agent moves along the network, starting from its lowest layer. It is shown that hierarchical networks--i.e., networks composed of successive interconnected layers--are related to compositions of the prerequisite relationships between the nodes. In order to avoid deadlocks--i.e., unreachable nodes--the subnetwork in each layer is assumed to be a connected component. Several configurations of such hierarchical knowledge networks are simulated and the performance of the moving agent quantified in terms of the percentage of visited nodes after each movement. The Barabási-Albert and random models are considered for the layer and interconnecting subnetworks. Although all subnetworks in each realization have the same number of nodes, several interconnectivities, defined by the average node degree of the interconnection networks, have been considered. Two visiting strategies are investigated: random choice among the existing edges and preferential choice to so far untracked edges. A series of interesting results are obtained, including the identification of a series of plateaus of knowledge stagnation in the case of the preferential movement strategy in the presence of conditional edges.

Pattern formation in a gene network model with boundary shape dependence.

A fundamental task in developmental biology is to identify the mechanisms which drive morphogenesis. Traditionally pattern formation have been modeled mainly using Turing-type mechanisms, where complex patterns arise by symmetry breaking. However, there is a growing experimental evidence that the influence of signals derived from surrounding tissues can contribute to the patterning processes. In this paper, we show that the interplay between the shape of surrounding tissues and a hierarchically organized gene regulatory network can be able to induce stable complex patterns. The rise of these patterns depends strongly on the shape of the surrounding tissues.

A comparative analysis of highly conserved sex-determining genes between Apis mellifera and Drosophila melanogaster.

A comparison of the most conserved sex-determining genes between the fruit fly, Drosophila melanogaster, and the honey bee, Apis mellifera, was performed with bioinformatics tools developed for computational molecular biology. An initial set of protein sequences already described in the fruit fly as participants of the sex-determining cascade was retrieved from the Gene Ontology database (http://www.geneontology.org/) and aligned against a database of protein sequences predicted from the honey bee genome. The doublesex (dsx) gene is considered one of the most conserved sex-determining genes among metazoans, and a male-specific partial cDNA of putative A. mellifera dsx gene (Amdsx) was identified experimentally. The theoretical predictions were developed in the context of sequence similarity. Experimental evidence indicates that dsx is present in embryos and larvae, and that it encodes a transcription factor widely conserved in metazoans, containing a DM DNA-binding domain implicated in the regulation of the expression of genes involved in sexual phenotype formation.

Modular transcriptional repertoire and MicroRNA target analyses characterize genomic dysregulation in the thymus of Down syndrome infants.

Trisomy 21-driven transcriptional alterations in human thymus were characterized through gene coexpression network (GCN) and miRNA-target analyses. We used whole thymic tissue--obtained at heart surgery from Down syndrome (DS) and karyotipically normal subjects (CT)--and a network-based approach for GCN analysis that allows the identification of modular transcriptional repertoires (communities) and the interactions between all the system's constituents through community detection. Changes in the degree of connections observed for hierarchically important hubs/genes in CT and DS networks corresponded to community changes. Distinct communities of highly interconnected genes were topologically identified in these networks. The role of miRNAs in modulating the expression of highly connected genes in CT and DS was revealed through miRNA-target analysis. Trisomy 21 gene dysregulation in thymus may be depicted as the breakdown and altered reorganization of transcriptional modules. Leading networks acting in normal or disease states were identified. CT networks would depict the "canonical" way of thymus functioning. Conversely, DS networks represent a "non-canonical" way, i.e., thymic tissue adaptation under trisomy 21 genomic dysregulation. This adaptation is probably driven by epigenetic mechanisms acting at chromatin level and through the miRNA control of transcriptional programs involving the networks' high-hierarchy genes.

A comparison of morphometric characteristics of sperm from fertile Bos taurus and Bos indicus bulls in Brazil.

The current work has as main objective the systematic investigation of sperm morphometric characteristics of fertile Bos taurus and Bos indicus bulls living in Brazil by using several traditional as well as more modern and advanced computer vision concepts and methodologies. Ten smears of B. taurus semen and ten smears of B. indicus semen have been evaluated. Sperm morphology was quantified in terms of the following morphological features: head area, perimeter, width, length, width:length ratio, ellipticity, shape factor, width of sperm basis, the three first Fourier values, symmetry and hydrodynamics. Morphometric differences have been observed between the sperm cell of B. taurus and B. indicus bulls. The sperm cells of Zebu bulls tend to be smaller and less elliptic, however without modifying hydrodynamic, side symmetry and width of sperm head base. These differences clearly indicate that the geometrical characterization of bull sperm cells should take into account morphological peculiarities that are specific to each subspecies. Another important contribution is the identification that morphological differences implied by bulls of different fertility, as characterized by other authors, were found to be less as compared with those obtained in the current study where highly fertile animals from the two subspecies were studied.

A framework for analyzing the relationship between gene expression and morphological, topological, and dynamical patterns in neuronal networks.

BACKGROUND: A key point in developmental biology is to understand how gene expression influences the morphological and dynamical patterns that are observed in living beings. NEW METHOD: In this work we propose a methodology capable of addressing this problem that is based on estimating the mutual information and Pearson correlation between the intensity of gene expression and measurements of several morphological properties of the cells. A similar approach is applied in order to identify effects of gene expression over the system dynamics. Neuronal networks were artificially grown over a lattice by considering a reference model used to generate artificial neurons. The input parameters of the artificial neurons were determined according to two distinct patterns of gene expression and the dynamical response was assessed by considering the integrate-and-fire model. RESULTS: As far as single gene dependence is concerned, we found that the interaction between the gene expression and the network topology, as well as between the former and the dynamics response, is strongly affected by the gene expression pattern. In addition, we observed a high correlation between the gene expression and some topological measurements of the neuronal network for particular patterns of gene expression. COMPARISON WITH EXISTING METHODS: To our best understanding, there are no similar analyses to compare with. CONCLUSIONS: A proper understanding of gene expression influence requires jointly studying the morphology, topology, and dynamics of neurons. The proposed framework represents a first step towards predicting gene expression patterns from morphology and connectivity.

Community structure analysis of transcriptional networks reveals distinct molecular pathways for early- and late-onset temporal lobe epilepsy with childhood febrile seizures.

Age at epilepsy onset has a broad impact on brain plasticity and epilepsy pathomechanisms. Prolonged febrile seizures in early childhood (FS) constitute an initial precipitating insult (IPI) commonly associated with mesial temporal lobe epilepsy (MTLE). FS-MTLE patients may have early disease onset, i.e. just after the IPI, in early childhood, or late-onset, ranging from mid-adolescence to early adult life. The mechanisms governing early (E) or late (L) disease onset are largely unknown. In order to unveil the molecular pathways underlying E and L subtypes of FS-MTLE we investigated global gene expression in hippocampal CA3 explants of FS-MTLE patients submitted to hippocampectomy. Gene coexpression networks (GCNs) were obtained for the E and L patient groups. A network-based approach for GCN analysis was employed allowing: i) the visualization and analysis of differentially expressed (DE) and complete (CO) - all valid GO annotated transcripts - GCNs for the E and L groups; ii) the study of interactions between all the system's constituents based on community detection and coarse-grained community structure methods. We found that the E-DE communities with strongest connection weights harbor highly connected genes mainly related to neural excitability and febrile seizures, whereas in L-DE communities these genes are not only involved in network excitability but also playing roles in other epilepsy-related processes. Inversely, in E-CO the strongly connected communities are related to compensatory pathways (seizure inhibition, neuronal survival and responses to stress conditions) while in L-CO these communities harbor several genes related to pro-epileptic effects, seizure-related mechanisms and vulnerability to epilepsy. These results fit the concept, based on fMRI and behavioral studies, that early onset epilepsies, although impacting more severely the hippocampus, are associated to compensatory mechanisms, while in late MTLE development the brain is less able to generate adaptive mechanisms, what has implications for epilepsy management and drug discovery.

A percolation approach to neural morphometry and connectivity.

This article addresses the issues of neural shape characterization and analysis from the perspective of one of the main roles played by neural shapes, namely, connectivity. This study is oriented toward the geometry at the individual cell level and involves the use of the percolation concept from statistical mechanics, which is reviewed in an accessible fashion. The characterization of the neural cell geometry with respect to connectivity is performed in terms of critical percolation probability obtained experimentally while considering several types of geometrical interactions between cells, therefore directly expressing the potential for connections defined by each situation. Two basic situations are considered: dendrite-dendrite and dendrite-axon interactions. The obtained results corroborate the potential of the critical percolation probability as a valuable resource for characterizing, classifying, and analyzing the morphology of neural cells.

L -percolations of complex networks.

Given a complex network, its L-paths correspond to sequences of L+1 distinct nodes connected through L distinct edges. The L-conditional expansion of a complex network can be obtained by connecting all its pairs of nodes which are linked through at least one L-path, and the respective conditional L-expansion of the original network is defined as the intersection between the original network and its L-expansion. Such expansions are verified to act as filters enhancing the network connectivity, consequently contributing to the identification of communities in small-world models. It is shown in this paper for L=2 and 3, in both analytical and experimental fashions, that an evolving complex network with a fixed number of nodes undergoes successive phase transitions--the so-called L-percolations, giving rise to Eulerian giant clusters. It is also shown that the critical values of such percolations are a function of the network size and that the network percolates for L=3 before L=2 .

Reinforcing the resilience of complex networks.

Given a connected network, it can be augmented by applying a growing strategy (e.g., random- or preferential-attachment rules) over the previously existing structure. Another approach for augmentation, recently introduced, involves incorporating a direct edge between any two nodes which are found to be connected through at least one self-avoiding path of length L. This work investigates the resilience of random- and preferential-attachment models augmented by using the three schemes identified above. Considering random- and preferential-attachment networks, their giant cluster are identified and reinforced, then the resilience of the resulting networks with respect to highest-degree node attack is quantified through simulations. Statistical characterization of the effects of augmentations over some of the network properties is also provided. The results, which indicate that substantial reinforcement of the resilience of complex networks can be achieved by the expansions, also confirm the superior robustness of the random expansion. An important obtained result is that the initial growth scheme was found to have little effect over the possibilities of further enhancement of the network by subsequent reinforcement schemes.

Bioinformatics: perspectives for the future.

I give here a very personal perspective of Bioinformatics and its future, starting by discussing the origin of the term (and area) of bioinformatics and proceeding by trying to foresee the development of related issues, including pattern recognition/data mining, the need to reintegrate biology, the potential of complex networks as a powerful and flexible framework for bioinformatics and the interplay between bio- and neuroinformatics. Human resource formation and market perspective are also addressed. Given the complexity and vastness of these issues and concepts, as well as the limited size of a scientific article and finite patience of the reader, these perspectives are surely incomplete and biased. However, it is expected that some of the questions and trends that are identified will motivate discussions during the IcoBiCoBi round table (with the same name as this article) and perhaps provide a more ample perspective among the participants of that conference and the readers of this text.

An image processing approach to analyze morphological features of microscopic images of muscle fibers.

We present an image processing approach to automatically analyze duo-channel microscopic images of muscular fiber nuclei and cytoplasm. Nuclei and cytoplasm play a critical role in determining the health and functioning of muscular fibers as changes of nuclei and cytoplasm manifest in many diseases such as muscular dystrophy and hypertrophy. Quantitative evaluation of muscle fiber nuclei and cytoplasm thus is of great importance to researchers in musculoskeletal studies. The proposed computational approach consists of steps of image processing to segment and delineate cytoplasm and identify nuclei in two-channel images. Morphological operations like skeletonization is applied to extract the length of cytoplasm for quantification. We tested the approach on real images and found that it can achieve high accuracy, objectivity, and robustness.