RAD-6: pyrimidine synthesis and radiation sensitivity in Caenorhabditis elegans.

The Caenorhabditis elegans rad-6 (radiation-sensitive-6) mutant was isolated over 25 years ago in a genetic screen that identified mutants with enhanced sensitivity to DNA damaging agents. In the present paper we describe the molecular identification of the rad-6 gene and reveal that it encodes the bifunctional UMP synthase protein, which carries catalytic activities for OPRTase (orotate phosphoribosyltransferase) and ODCase (orotate monophosphate decarboxylase), key enzymes in the de novo pathway of pyrimidine synthesis. Mutations in genes encoding de novo pathway enzymes cause varying degrees of lethality and pleiotropic phenotypes in many organisms, including humans. We have examined how the absence of rad-6 activity leads to both UV-C hypersensitivity and a decline in both metabolic rate and lifespan. We discuss how rad-6 mutants adapt to the loss of the de novo pathway through a dependency on pyrimidine salvage. We establish further that rad-6(mn160) mutants lack ODCase activity because they are resistant to the cytotoxic effects of 5-FOA (5-fluoroorotic acid). Our results have also led to the identification of a metabolic sensor affecting survival and metabolism, which is dependent on the maternal rad-6 genotype.

Cortico-cardio-respiratory network interactions during anesthesia.

General anesthetics are used during medical and surgical procedures to reversibly induce a state of total unconsciousness in patients. Here, we investigate, from a dynamic network perspective, how the cortical and cardiovascular systems behave during anesthesia by applying nonparametric spectral techniques to cortical electroencephalography, electrocardiogram and respiratory signals recorded from anesthetized rats under two drugs, ketamine-xylazine (KX) and pentobarbital (PB). We find that the patterns of low-frequency cortico-cardio-respiratory network interactions may undergo significant changes in network activity strengths and in number of network links at different depths of anesthesia dependent upon anesthetics used.

Multistability of twisted states in non-locally coupled Kuramoto-type models.

A ring of N identical phase oscillators with interactions between L-nearest neighbors is considered, where L ranges from 1 (local coupling) to N/2 (global coupling). The coupling function is a simple sinusoid, as in the Kuramoto model, but with a minus sign which has a profound influence on its behavior. Without the limitation of the generality, the frequency of the free-running oscillators can be set to zero. The resulting system is of gradient type, and therefore, all its solutions converge to an equilibrium point. All so-called q-twisted states, where the phase difference between neighboring oscillators on the ring is 2πq/N, are equilibrium points, where q is an integer. Their stability in the limit N → ∞ is discussed along the line of Wiley et al. [Chaos 16, 015103 (2006)] In addition, we prove that when a twisted state is asymptotically stable for the infinite system, it is also asymptotically stable for sufficiently large N. Note that for smaller N, the same q-twisted states may become unstable and other q-twisted states may become stable. Finally, the existence of additional equilibrium states, called here multi-twisted states, is shown by numerical simulation. The phase difference between neighboring oscillators is approximately 2πq/N in one sector of the ring, -2πq/N in another sector, and it has intermediate values between the two sectors. Our numerical investigation suggests that the number of different stable multi-twisted states grows exponentially as N → ∞. It is possible to interpret the equilibrium points of the coupled phase oscillator network as trajectories of a discrete-time translational dynamical system where the space-variable (position on the ring) plays the role of time. The q-twisted states are then fixed points, and the multi-twisted states are periodic solutions of period N that are close to a heteroclinic cycle. Due to the apparently exponentially fast growing number of such stable periodic solutions, the system shows spatial chaos as N → ∞.

Network community-detection enhancement by proper weighting.

In this paper, we show how proper assignment of weights to the edges of a complex network can enhance the detection of communities and how it can circumvent the resolution limit and the extreme degeneracy problems associated with modularity. Our general weighting scheme takes advantage of graph theoretic measures and it introduces two heuristics for tuning its parameters. We use this weighting as a preprocessing step for the greedy modularity optimization algorithm of Newman to improve its performance. The result of the experiments of our approach on computer-generated and real-world data networks confirm that the proposed approach not only mitigates the problems of modularity but also improves the modularity optimization.

Mesoscale and clusters of synchrony in networks of bursting neurons.

We study the role of network architecture in the formation of synchronous clusters in synaptically coupled networks of bursting neurons. We give a simple combinatorial algorithm that finds the largest synchronous clusters from the network topology. We demonstrate that networks with a certain degree of internal symmetries are likely to have cluster decompositions with relatively large clusters, leading potentially to cluster synchronization at the mesoscale network level. We also address the asymptotic stability of cluster synchronization in excitatory networks of Hindmarsh-Rose bursting neurons and derive explicit thresholds for the coupling strength that guarantees stable cluster synchronization.

Attenuated asymmetry of functional connectivity in schizophrenia: a high-resolution EEG study.

The interhemispheric asymmetries that originate from connectivity-related structuring of the cortex are compromised in schizophrenia (SZ). Under the assumption that such abnormalities affect functional connectivity, we analyzed its correlate-EEG synchronization-in SZ patients and matched controls. We applied multivariate synchronization measures based on Laplacian EEG and tuned to various spatial scales. Compared to the controls who had rightward asymmetry at a local level (EEG power), rightward anterior and leftward posterior asymmetries at an intraregional level (1st and 2nd order S-estimator), and rightward global asymmetry (hemispheric S-estimator), SZ patients showed generally attenuated asymmetry, the effect being strongest for intraregional synchronization in the alpha and beta bands. The abnormalities of asymmetry increased with the duration of the disease and correlated with the negative symptoms. We discuss the tentative links between these findings and gross anatomical asymmetries, including the cerebral torque and gyrification pattern, in normal subjects and SZ patients.

Topography of EEG multivariate phase synchronization in early Alzheimer's disease.

Alzheimer's disease (AD) is likely to disrupt the synchronization of the bioelectrical processes in the distributed cortical networks underlying cognition. We analyze the surface topography of the multivariate phase synchronization (MPS) of multichannel EEG in 17 patients (Clinical Dementia Rating (CDR) Scale: 0.5-1; Functional Assessment Staging (FAST): 3-4) compared to 17 controls by applying a combination of global and regional MPS measures to the resting EEG. In early AD, whole-head mapping reveals a specific landscape of synchronization characterized by a decrease in MPS over the fronto-temporal region and an increase over the temporo-parieto-occipital region predominantly of the left hemisphere. These features manifest themselves through the EEG delta-beta bands and discriminate patients from controls with an accuracy of up to 94%. Moreover, the abnormal MPS in both anterior and posterior clusters correlates with the Mini Mental State Examination score, binding regional EEG synchronization to cognitive decline in AD patients. The MPS technique reveals that the EEG phenotype of early AD is relevant to the clinical picture and may ultimately become its sensitive and specific biomarker.

'Glocal' robustness analysis and model discrimination for circadian oscillators.

To characterize the behavior and robustness of cellular circuits with many unknown parameters is a major challenge for systems biology. Its difficulty rises exponentially with the number of circuit components. We here propose a novel analysis method to meet this challenge. Our method identifies the region of a high-dimensional parameter space where a circuit displays an experimentally observed behavior. It does so via a Monte Carlo approach guided by principal component analysis, in order to allow efficient sampling of this space. This 'global' analysis is then supplemented by a 'local' analysis, in which circuit robustness is determined for each of the thousands of parameter sets sampled in the global analysis. We apply this method to two prominent, recent models of the cyanobacterial circadian oscillator, an autocatalytic model, and a model centered on consecutive phosphorylation at two sites of the KaiC protein, a key circadian regulator. For these models, we find that the two-sites architecture is much more robust than the autocatalytic one, both globally and locally, based on five different quantifiers of robustness, including robustness to parameter perturbations and to molecular noise. Our 'glocal' combination of global and local analyses can also identify key causes of high or low robustness. In doing so, our approach helps to unravel the architectural origin of robust circuit behavior. Complementarily, identifying fragile aspects of system behavior can aid in designing perturbation experiments that may discriminate between competing mechanisms and different parameter sets.

Efficient rewirings for enhancing synchronizability of dynamical networks.

In this paper, we present an algorithm for optimizing synchronizability of complex dynamical networks. Starting with an undirected and unweighted network, we end up with an undirected and unweighted network with the same number of nodes and edges having enhanced synchronizability. To this end, based on some network properties, rewirings, i.e., eliminating an edge and creating a new edge elsewhere, are performed iteratively avoiding always self-loops and multiple edges between the same nodes. We show that the method is able to enhance the synchronizability of networks of any size and topological properties in a small number of steps that scales with the network size. For numerical simulations, an optimization algorithm based on simulated annealing is used. Also, the evolution of different topological properties of the network such as distribution of node degree, node and edge betweenness centrality is tracked with the iteration steps. We use networks such as scale-free, Strogatz-Watts and random to start with and we show that regardless of the initial network, the final optimized network becomes homogeneous. In other words, in the network with high synchronizability, parameters, such as, degree, shortest distance, node, and edge betweenness centralities are almost homogeneously distributed. Also, parameters, such as, maximum node and edge betweenness centralities are small for the rewired network. Although we take the eigenratio of the Laplacian as the target function for optimization, we show that it is also possible to choose other appropriate target functions exhibiting almost the same performance. Furthermore, we show that even if the network is optimized taking into account another interpretation of synchronizability, i.e., synchronization cost, the optimal network has the same synchronization properties. Indeed, in networks with optimized synchronizability, different interpretations of synchronizability coincide. The optimized networks are Ramanujan graphs, and thus, this rewiring algorithm could be used to produce Ramanujan graphs of any size and average degree.

Predicting single spikes and spike patterns with the Hindmarsh-Rose model.

Most simple neuron models are only able to model traditional spiking behavior. As physiologists discover and classify different electrical phenotypes, computational neuroscientists become interested in using simple phenomenological models that can exhibit these different types of spiking patterns. The Hindmarsh-Rose model is a three-dimensional relaxation oscillator which can show both spiking and bursting patterns and has a chaotic regime. We test the predictive powers of the Hindmarsh-Rose model on two different test databases. We show that the Hindmarsh-Rose model can predict the spiking response of rat layer 5 neocortical pyramidal neurons on a stochastic input signal with a precision comparable to the best known spiking models. We also show that the Hindmarsh-Rose model can capture qualitatively the electrical footprints in a database of different types of neocortical interneurons. When the model parameters are fit from sub-threshold measurements only, the model still captures well the electrical phenotype, which suggests that the sub-threshold signals contain information about the firing patterns of the different neurons.

Enhancing synchronizability of weighted dynamical networks using betweenness centrality.

By considering the eigenratio of the Laplacian of the connection graph as a synchronizability measure, we propose a procedure for weighting dynamical networks to enhance their synchronizability. The method is based on node and edge betweenness centrality measures and is tested on artificially constructed scale-free, Watts-Strogatz, and random networks as well as on some real-world graphs. It is also numerically shown that the same procedure could be used to enhance the phase synchronizability of networks of nonidentical oscillators.

Dysconnection topography in schizophrenia revealed with state-space analysis of EEG.

BACKGROUND: The dysconnection hypothesis has been proposed to account for pathophysiological mechanisms underlying schizophrenia. Widespread structural changes suggesting abnormal connectivity in schizophrenia have been imaged. A functional counterpart of the structural maps would be the EEG synchronization maps. However, due to the limits of currently used bivariate methods, functional correlates of dysconnection are limited to the isolated measurements of synchronization between preselected pairs of EEG signals. METHODS/RESULTS: To reveal a whole-head synchronization topography in schizophrenia, we applied a new method of multivariate synchronization analysis called S-estimator to the resting dense-array (128 channels) EEG obtained from 14 patients and 14 controls. This method determines synchronization from the embedding dimension in a state-space domain based on the theoretical consequence of the cooperative behavior of simultaneous time series-the shrinking of the state-space embedding dimension. The S-estimator imaging revealed a specific synchronization landscape in schizophrenia patients. Its main features included bilaterally increased synchronization over temporal brain regions and decreased synchronization over the postcentral/parietal region neighboring the midline. The synchronization topography was stable over the course of several months and correlated with the severity of schizophrenia symptoms. In particular, direct correlations linked positive, negative, and general psychopathological symptoms to the hyper-synchronized temporal clusters over both hemispheres. Along with these correlations, general psychopathological symptoms inversely correlated within the hypo-synchronized postcentral midline region. While being similar to the structural maps of cortical changes in schizophrenia, the S-maps go beyond the topography limits, demonstrating a novel aspect of the abnormalities of functional cooperation: namely, regionally reduced or enhanced connectivity. CONCLUSION/SIGNIFICANCE: The new method of multivariate synchronization significantly boosts the potential of EEG as an imaging technique compatible with other imaging modalities. Its application to schizophrenia research shows that schizophrenia can be explained within the concept of neural dysconnection across and within large-scale brain networks.

Synchronization in asymmetrically coupled networks with node balance.

We study global stability of synchronization in asymmetrically connected networks of limit-cycle or chaotic oscillators. We extend the connection graph stability method to directed graphs with node balance, the property that all nodes in the network have equal input and output weight sums. We obtain the same upper bound for synchronization in asymmetrically connected networks as in the network with a symmetrized matrix, provided that the condition of node balance is satisfied. In terms of graphs, the symmetrization operation amounts to replacing each directed edge by an undirected edge of half the coupling strength. It should be stressed that without node balance this property in general does not hold.

Synchronization of bursting neurons: what matters in the network topology.

We study the influence of coupling strength and network topology on synchronization behavior in pulse-coupled networks of bursting Hindmarsh-Rose neurons. Surprisingly, we find that the stability of the completely synchronous state in such networks only depends on the number of signals each neuron receives, independent of all other details of the network topology. This is in contrast with linearly coupled bursting neurons where complete synchrony strongly depends on the network structure and number of cells. Through analysis and numerics, we show that the onset of synchrony in a network with any coupling topology admitting complete synchronization is ensured by one single condition.