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1.  Unraveling Hidden Order in the Dynamics of Developed and Emerging Markets 
PLoS ONE  2014;9(11):e112427.
The characterization of asset price returns is an important subject in modern finance. Traditionally, the dynamics of stock returns are assumed to lack any temporal order. Here we present an analysis of the autocovariance of stock market indices and unravel temporal order in several major stock markets. We also demonstrate a fundamental difference between developed and emerging markets in the past decade - emerging markets are marked by positive order in contrast to developed markets whose dynamics are marked by weakly negative order. In addition, the reaction to financial crises was found to be reversed among developed and emerging markets, presenting large positive/negative autocovariance spikes following the onset of these crises. Notably, the Chinese market shows neutral or no order while being regarded as an emerging market. These findings show that despite the coupling between international markets and global trading, major differences exist between different markets, and demonstrate that the autocovariance of markets is correlated with their stability, as well as with their state of development.
doi:10.1371/journal.pone.0112427
PMCID: PMC4226548  PMID: 25383630
2.  Clique of Functional Hubs Orchestrates Population Bursts in Developmentally Regulated Neural Networks 
PLoS Computational Biology  2014;10(9):e1003823.
It has recently been discovered that single neuron stimulation can impact network dynamics in immature and adult neuronal circuits. Here we report a novel mechanism which can explain in neuronal circuits, at an early stage of development, the peculiar role played by a few specific neurons in promoting/arresting the population activity. For this purpose, we consider a standard neuronal network model, with short-term synaptic plasticity, whose population activity is characterized by bursting behavior. The addition of developmentally inspired constraints and correlations in the distribution of the neuronal connectivities and excitabilities leads to the emergence of functional hub neurons, whose stimulation/deletion is critical for the network activity. Functional hubs form a clique, where a precise sequential activation of the neurons is essential to ignite collective events without any need for a specific topological architecture. Unsupervised time-lagged firings of supra-threshold cells, in connection with coordinated entrainments of near-threshold neurons, are the key ingredients to orchestrate population activity.
Author Summary
To which extent a single neuron can influence brain circuits/networks dynamics? Why only a few neurons display such a strong power? These open questions are inspired by recent experimental observations in developing and adult neuronal circuits, as well as by classical debates within the framework of the single neuron doctrine. In this work we identify and present a mechanism which can explain in neuronal circuits, at some early stage of their development, how and why only a few specific neurons can exhibit such power. For this purpose, we consider a standard neuronal network model whose population activity is characterized by bursting behavior. The introduction of a distribution of correlated neuronal excitabilities and degrees, inspired by the simultaneous presence of younger and older neurons in the network, leads to the emergence of functional hub neurons. These critical cells, whenever perturbed, are capable of suppressing network synchronization. Notably, we show that their strong influence on the population dynamics is not related to their structural properties, but to their operational and structural integration into a clique. These results highlight how network-wide effects can be induced by single neurons without any need for a specific topological architecture.
doi:10.1371/journal.pcbi.1003823
PMCID: PMC4177675  PMID: 25255443
3.  The three-way switch operation of Rac1/RhoA GTPase-based circuit controlling amoeboid-hybrid-mesenchymal transition 
Scientific Reports  2014;4:6449.
Metastatic carcinoma cells exhibit at least two different phenotypes of motility and invasion - amoeboid and mesenchymal. This plasticity poses a major clinical challenge for treating metastasis, while its underlying mechanisms remain enigmatic. Transitions between these phenotypes are mediated by the Rac1/RhoA circuit that responds to external signals such as HGF/SF via c-MET pathway. Using detailed modeling of GTPase-based regulation to study the Rac1/RhoA circuit's dynamics, we found that it can operate as a three-way switch. We propose to associate the circuit's three possible states to the amoeboid, mesenchymal and amoeboid/mesenchymal hybrid phenotype. In particular, we investigated the range of existence of, and the transition between, the three states (phenotypes) in response to Grb2 and Gab1 - two downstream adaptors of c-MET. The results help to explain the regulation of metastatic cells by c-MET pathway and hence can contribute to the assessment of possible clinical interventions.
doi:10.1038/srep06449
PMCID: PMC4171704  PMID: 25245029
4.  Propagating Waves of Directionality and Coordination Orchestrate Collective Cell Migration 
PLoS Computational Biology  2014;10(7):e1003747.
The ability of cells to coordinately migrate in groups is crucial to enable them to travel long distances during embryonic development, wound healing and tumorigenesis, but the fundamental mechanisms underlying intercellular coordination during collective cell migration remain elusive despite considerable research efforts. A novel analytical framework is introduced here to explicitly detect and quantify cell clusters that move coordinately in a monolayer. The analysis combines and associates vast amount of spatiotemporal data across multiple experiments into transparent quantitative measures to report the emergence of new modes of organized behavior during collective migration of tumor and epithelial cells in wound healing assays. First, we discovered the emergence of a wave of coordinated migration propagating backward from the wound front, which reflects formation of clusters of coordinately migrating cells that are generated further away from the wound edge and disintegrate close to the advancing front. This wave emerges in both normal and tumor cells, and is amplified by Met activation with hepatocyte growth factor/scatter factor. Second, Met activation was found to induce coinciding waves of cellular acceleration and stretching, which in turn trigger the emergence of a backward propagating wave of directional migration with about an hour phase lag. Assessments of the relations between the waves revealed that amplified coordinated migration is associated with the emergence of directional migration. Taken together, our data and simplified modeling-based assessments suggest that increased velocity leads to enhanced coordination: higher motility arises due to acceleration and stretching that seems to increase directionality by temporarily diminishing the velocity components orthogonal to the direction defined by the monolayer geometry. Spatial and temporal accumulation of directionality thus defines coordination. The findings offer new insight and suggest a basic cellular mechanism for long-term cell guidance and intercellular communication during collective cell migration.
Author Summary
The fundamental mechanisms underlying intercellular coordination during collective cell migration remain elusive despite considerable research efforts. We present a novel analytical framework that considers spatiotemporal dynamics across several traits. Our approach was applied to discover new modes of organized collective dynamics of cancer and normal cells. Following disruption of a cell monolayer, a propagating wave of coordinated migration emerges as clusters of coordinately moving cells are formed away from the wound and disintegrate near the advancing front. Activation of Met signal transduction by hepatocyte growth factor/scatter factor, master regulators of cell motility in malignant and normal processes, generates coinciding waves of cellular acceleration and stretching that propagate backward from the wound front and trigger a delayed wave of directional migration. Amplified coordination is intrinsically associated with enhanced directionality suggesting that even a weak directional cue is sufficient to promote a coordinated response that is transmitted to cells within the cell sheet. Our findings provide important novel insights on the basic cellular organization during collective cell migration and establish a mechanism of long-range cell guidance, intercellular coordination and pattern formation during monolayer wound healing.
doi:10.1371/journal.pcbi.1003747
PMCID: PMC4109844  PMID: 25058592
6.  Astrocytic theory of working memory 
BMC Neuroscience  2014;15(Suppl 1):P206.
doi:10.1186/1471-2202-15-S1-P206
PMCID: PMC4126408
7.  Individual Pause-and-Go Motion Is Instrumental to the Formation and Maintenance of Swarms of Marching Locust Nymphs 
PLoS ONE  2014;9(7):e101636.
The principal interactions leading to the emergence of order in swarms of marching locust nymphs was studied both experimentally, using small groups of marching locusts in the lab, and using computer simulations. We utilized a custom tracking algorithm to reveal fundamental animal-animal interactions leading to collective motion. Uncovering this behavior introduced a new agent-based modeling approach in which pause-and-go motion is pivotal. The behavioral and modeling findings are largely based on motion-related visual sensory inputs obtained by the individual locust. Results suggest a generic principle, in which intermittent animal motion can be considered as a sequence of individual decisions as animals repeatedly reassess their situation and decide whether or not to swarm. This interpretation implies, among other things, some generic characteristics regarding the build-up and emergence of collective order in swarms: in particular, that order and disorder are generic meta-stable states of the system, suggesting that the emergence of order is kinetic and does not necessarily require external environmental changes. This work calls for further experimental as well as theoretical investigation of the neural mechanisms underlying locust coordinative behavior.
doi:10.1371/journal.pone.0101636
PMCID: PMC4079690  PMID: 24988464
8.  Sparse short-distance connections enhance calcium wave propagation in a 3D model of astrocyte networks 
Traditionally, astrocytes have been considered to couple via gap-junctions into a syncytium with only rudimentary spatial organization. However, this view is challenged by growing experimental evidence that astrocytes organize as a proper gap-junction mediated network with more complex region-dependent properties. On the other hand, the propagation range of intercellular calcium waves (ICW) within astrocyte populations is as well highly variable, depending on the brain region considered. This suggests that the variability of the topology of gap-junction couplings could play a role in the variability of the ICW propagation range. Since this hypothesis is very difficult to investigate with current experimental approaches, we explore it here using a biophysically realistic model of three-dimensional astrocyte networks in which we varied the topology of the astrocyte network, while keeping intracellular properties and spatial cell distribution and density constant. Computer simulations of the model suggest that changing the topology of the network is indeed sufficient to reproduce the distinct ranges of ICW propagation reported experimentally. Unexpectedly, our simulations also predict that sparse connectivity and restriction of gap-junction couplings to short distances should favor propagation while long–distance or dense connectivity should impair it. Altogether, our results provide support to recent experimental findings that point toward a significant functional role of the organization of gap-junction couplings into proper astroglial networks. Dynamic control of this topology by neurons and signaling molecules could thus constitute a new type of regulation of neuron-glia and glia-glia interactions.
doi:10.3389/fncom.2014.00045
PMCID: PMC3997029  PMID: 24795613
glial cells; astrocytes; gap-junctions; wave propagation; network topology
9.  The physics of bacterial decision making 
The choice that bacteria make between sporulation and competence when subjected to stress provides a prototypical example of collective cell fate determination that is stochastic on the individual cell level, yet predictable (deterministic) on the population level. This collective decision is performed by an elaborated gene network. Considerable effort has been devoted to simplify its complexity by taking physics approaches to untangle the basic functional modules that are integrated to form the complete network: (1) A stochastic switch whose transition probability is controlled by two order parameters—population density and internal/external stress. (2) An adaptable timer whose clock rate is normalized by the same two previous order parameters. (3) Sensing units which measure population density and external stress. (4) A communication module that exchanges information about the cells' internal stress levels. (5) An oscillating gate of the stochastic switch which is regulated by the timer. The unique circuit architecture of the gate allows special dynamics and noise management features. The gate opens a window of opportunity in time for competence transitions, during which the circuit generates oscillations that are translated into a chain of short intervals with high transition probability. In addition, the unique architecture of the gate allows filtering of external noise and robustness against variations in circuit parameters and internal noise. We illustrate that a physics approach can be very valuable in investigating the decision process and in identifying its general principles. We also show that both cell-cell variability and noise have important functional roles in the collectively controlled individual decisions.
doi:10.3389/fcimb.2014.00154
PMCID: PMC4214203  PMID: 25401094
gene circuits; computational modeling; noise management; cell fate determination; sporulation and competence; Bacillus subtilis; cell communication
10.  Collective navigation of cargo-carrying swarms 
Interface Focus  2012;2(6):786-798.
Much effort has been devoted to the study of swarming and collective navigation of micro-organisms, insects, fish, birds and other organisms, as well as multi-agent simulations and to the study of real robots. It is well known that insect swarms can carry cargo. The studies here are motivated by a less well-known phenomenon: cargo transport by bacteria swarms. We begin with a concise review of how bacteria swarms carry natural, micrometre-scale objects larger than the bacteria (e.g. fungal spores) as well as man-made beads and capsules (for drug delivery). A comparison of the trajectories of virtual beads in simulations (using different putative coupling between the virtual beads and the bacteria) with the observed trajectories of transported fungal spores implies the existence of adaptable coupling. Motivated by these observations, we devised new, multi-agent-based studies of cargo transport by agent swarms. As a first step, we extended previous modelling of collective navigation of simple bacteria-inspired agents in complex terrain, using three putative models of agent–cargo coupling. We found that cargo-carrying swarms can navigate efficiently in a complex landscape. We further investigated how the stability, elasticity and other features of agent–cargo bonds influence the collective motion and the transport of the cargo, and found sharp phase shifts and dual successful strategies for cargo delivery. Further understanding of such mechanisms may provide valuable clues to understand cargo-transport by smart swarms of other organisms as well as by man-made swarming robots.
doi:10.1098/rsfs.2012.0029
PMCID: PMC3499125  PMID: 24312731
collective behaviour; swarming intelligence; bacteria swarming; agent-based modelling; social behaviour of bacteria; bacteria cargo transport
11.  Periodic Reversals in Paenibacillus dendritiformis Swarming 
Journal of Bacteriology  2013;195(12):2709-2717.
Bacterial swarming is a type of motility characterized by a rapid and collective migration of bacteria on surfaces. Most swarming species form densely packed dynamic clusters in the form of whirls and jets, in which hundreds of rod-shaped rigid cells move in circular and straight patterns, respectively. Recent studies have suggested that short-range steric interactions may dominate hydrodynamic interactions and that geometrical factors, such as a cell's aspect ratio, play an important role in bacterial swarming. Typically, the aspect ratio for most swarming species is only up to 5, and a detailed understanding of the role of much larger aspect ratios remains an open challenge. Here we study the dynamics of Paenibacillus dendritiformis C morphotype, a very long, hyperflagellated, straight (rigid), rod-shaped bacterium with an aspect ratio of ∼20. We find that instead of swarming in whirls and jets as observed in most species, including the shorter T morphotype of P. dendritiformis, the C morphotype moves in densely packed straight but thin long lines. Within these lines, all bacteria show periodic reversals, with a typical reversal time of 20 s, which is independent of their neighbors, the initial nutrient level, agar rigidity, surfactant addition, humidity level, temperature, nutrient chemotaxis, oxygen level, illumination intensity or gradient, and cell length. The evolutionary advantage of this unique back-and-forth surface translocation remains unclear.
doi:10.1128/JB.00080-13
PMCID: PMC3697242  PMID: 23603739
12.  Hyperbaric Oxygen Therapy Can Improve Post Concussion Syndrome Years after Mild Traumatic Brain Injury - Randomized Prospective Trial 
PLoS ONE  2013;8(11):e79995.
Background
Traumatic brain injury (TBI) is the leading cause of death and disability in the US. Approximately 70-90% of the TBI cases are classified as mild, and up to 25% of them will not recover and suffer chronic neurocognitive impairments. The main pathology in these cases involves diffuse brain injuries, which are hard to detect by anatomical imaging yet noticeable in metabolic imaging. The current study tested the effectiveness of Hyperbaric Oxygen Therapy (HBOT) in improving brain function and quality of life in mTBI patients suffering chronic neurocognitive impairments.
Methods and Findings
The trial population included 56 mTBI patients 1–5 years after injury with prolonged post-concussion syndrome (PCS). The HBOT effect was evaluated by means of prospective, randomized, crossover controlled trial: the patients were randomly assigned to treated or crossover groups. Patients in the treated group were evaluated at baseline and following 40 HBOT sessions; patients in the crossover group were evaluated three times: at baseline, following a 2-month control period of no treatment, and following subsequent 2-months of 40 HBOT sessions. The HBOT protocol included 40 treatment sessions (5 days/week), 60 minutes each, with 100% oxygen at 1.5 ATA. “Mindstreams” was used for cognitive evaluations, quality of life (QOL) was evaluated by the EQ-5D, and changes in brain activity were assessed by SPECT imaging. Significant improvements were demonstrated in cognitive function and QOL in both groups following HBOT but no significant improvement was observed following the control period. SPECT imaging revealed elevated brain activity in good agreement with the cognitive improvements.
Conclusions
HBOT can induce neuroplasticity leading to repair of chronically impaired brain functions and improved quality of life in mTBI patients with prolonged PCS at late chronic stage.
Trial Registration
ClinicalTrials.gov
NCT00715052
doi:10.1371/journal.pone.0079995
PMCID: PMC3829860  PMID: 24260334
13.  Benchmark for multi-cellular segmentation of bright field microscopy images 
BMC Bioinformatics  2013;14:319.
Background
Multi-cellular segmentation of bright field microscopy images is an essential computational step when quantifying collective migration of cells in vitro. Despite the availability of various tools and algorithms, no publicly available benchmark has been proposed for evaluation and comparison between the different alternatives.
Description
A uniform framework is presented to benchmark algorithms for multi-cellular segmentation in bright field microscopy images. A freely available set of 171 manually segmented images from diverse origins was partitioned into 8 datasets and evaluated on three leading designated tools.
Conclusions
The presented benchmark resource for evaluating segmentation algorithms of bright field images is the first public annotated dataset for this purpose. This annotated dataset of diverse examples allows fair evaluations and comparisons of future segmentation methods. Scientists are encouraged to assess new algorithms on this benchmark, and to contribute additional annotated datasets.
doi:10.1186/1471-2105-14-319
PMCID: PMC3826518  PMID: 24195722
Collective cell migration; Wound healing assay; Segmentation; Benchmarking
14.  Semantic organization in children with cochlear implants: computational analysis of verbal fluency 
Purpose: Cochlear implants (CIs) enable children with severe and profound hearing impairments to perceive the sensation of sound sufficiently to permit oral language acquisition. So far, studies have focused mainly on technological improvements and general outcomes of implantation for speech perception and spoken language development. This study quantitatively explored the organization of the semantic networks of children with CIs in comparison to those of age-matched normal hearing (NH) peers.
Method: Twenty seven children with CIs and twenty seven age- and IQ-matched NH children ages 7–10 were tested on a timed animal verbal fluency task (Name as many animals as you can). The responses were analyzed using correlation and network methodologies. The structure of the animal category semantic network for both groups were extracted and compared.
Results: Children with CIs appeared to have a less-developed semantic network structure compared to age-matched NH peers. The average shortest path length (ASPL) and the network diameter measures were larger for the NH group compared to the CIs group. This difference was consistent for the analysis of networks derived from animal names generated by each group [sample-matched correlation networks (SMCN)] and for the networks derived from the common animal names generated by both groups [word-matched correlation networks (WMCN)].
Conclusions: The main difference between the semantic networks of children with CIs and NH lies in the network structure. The semantic network of children with CIs is under-developed compared to the semantic network of the age-matched NH children. We discuss the practical and clinical implications of our findings.
doi:10.3389/fpsyg.2013.00543
PMCID: PMC3759020  PMID: 24032018
cochlear implants; semantic networks; verbal fluency; network science; spreading activation; mental lexicon
16.  How High Frequency Trading Affects a Market Index 
Scientific Reports  2013;3:2110.
The relationship between a market index and its constituent stocks is complicated. While an index is a weighted average of its constituent stocks, when the investigated time scale is one day or longer the index has been found to have a stronger effect on the stocks than vice versa. We explore how this interaction changes in short time scales using high frequency data. Using a correlation-based analysis approach, we find that in short time scales stocks have a stronger influence on the index. These findings have implications for high frequency trading and suggest that the price of an index should be published on shorter time scales, as close as possible to those of the actual transaction time scale.
doi:10.1038/srep02110
PMCID: PMC3743071  PMID: 23817553
17.  Turning Oscillations Into Opportunities: Lessons from a Bacterial Decision Gate 
Scientific Reports  2013;3:1668.
Sporulation vs. competence provides a prototypic example of collective cell fate determination. The decision is performed by the action of three modules: 1) A stochastic competence switch whose transition probability is regulated by population density, population stress and cell stress. 2) A sporulation timer whose clock rate is regulated by cell stress and population stress. 3) A decision gate that is coupled to the timer via a special repressilator-like loop. We show that the distinct circuit architecture of this gate leads to special dynamics and noise management characteristics: The gate opens a time-window of opportunity for competence transitions during which it generates oscillations that are turned into a chain of transition opportunities – each oscillation opens a short interval with high transition probability. The special architecture of the gate also leads to filtering of external noise and robustness against internal noise and variations in the circuit parameters.
doi:10.1038/srep01668
PMCID: PMC3627974  PMID: 23591544
18.  Hyperbaric Oxygen Induces Late Neuroplasticity in Post Stroke Patients - Randomized, Prospective Trial 
PLoS ONE  2013;8(1):e53716.
Background
Recovery after stroke correlates with non-active (stunned) brain regions, which may persist for years. The current study aimed to evaluate whether increasing the level of dissolved oxygen by Hyperbaric Oxygen Therapy (HBOT) could activate neuroplasticity in patients with chronic neurologic deficiencies due to stroke.
Methods and Findings
A prospective, randomized, controlled trial including 74 patients (15 were excluded). All participants suffered a stroke 6–36 months prior to inclusion and had at least one motor dysfunction. After inclusion, patients were randomly assigned to "treated" or "cross" groups. Brain activity was assessed by SPECT imaging; neurologic functions were evaluated by NIHSS, ADL, and life quality. Patients in the treated group were evaluated twice: at baseline and after 40 HBOT sessions. Patients in the cross group were evaluated three times: at baseline, after a 2-month control period of no treatment, and after subsequent 2-months of 40 HBOT sessions. HBOT protocol: Two months of 40 sessions (5 days/week), 90 minutes each, 100% oxygen at 2 ATA. We found that the neurological functions and life quality of all patients in both groups were significantly improved following the HBOT sessions while no improvement was found during the control period of the patients in the cross group. Results of SPECT imaging were well correlated with clinical improvement. Elevated brain activity was detected mostly in regions of live cells (as confirmed by CT) with low activity (based on SPECT) – regions of noticeable discrepancy between anatomy and physiology.
Conclusions
The results indicate that HBOT can lead to significant neurological improvements in post stroke patients even at chronic late stages. The observed clinical improvements imply that neuroplasticity can still be activated long after damage onset in regions where there is a brain SPECT/CT (anatomy/physiology) mismatch.
Trial Registration
ClinicalTrials.gov NCT00715897
doi:10.1371/journal.pone.0053716
PMCID: PMC3546039  PMID: 23335971
19.  Quantifying the Behavior of Stock Correlations Under Market Stress 
Scientific Reports  2012;2:752.
Understanding correlations in complex systems is crucial in the face of turbulence, such as the ongoing financial crisis. However, in complex systems, such as financial systems, correlations are not constant but instead vary in time. Here we address the question of quantifying state-dependent correlations in stock markets. Reliable estimates of correlations are absolutely necessary to protect a portfolio. We analyze 72 years of daily closing prices of the 30 stocks forming the Dow Jones Industrial Average (DJIA). We find the striking result that the average correlation among these stocks scales linearly with market stress reflected by normalized DJIA index returns on various time scales. Consequently, the diversification effect which should protect a portfolio melts away in times of market losses, just when it would most urgently be needed. Our empirical analysis is consistent with the interesting possibility that one could anticipate diversification breakdowns, guiding the design of protected portfolios.
doi:10.1038/srep00752
PMCID: PMC3475344  PMID: 23082242
20.  Genome Sequence of the Pattern-Forming Social Bacterium Paenibacillus dendritiformis C454 Chiral Morphotype 
Journal of Bacteriology  2012;194(8):2127-2128.
Paenibacillus dendritiformis is a Gram-positive, soil-dwelling, spore-forming social microorganism. An intriguing collective faculty of this strain is manifested by its ability to switch between different morphotypes, such as the branching (T) and the chiral (C) morphotypes. Here we report the 6.3-Mb draft genome sequence of the P. dendritiformis C454 chiral morphotype.
doi:10.1128/JB.00158-12
PMCID: PMC3318481  PMID: 22461558
21.  The Role of the Neuro-Astro-Vascular Unit in the Etiology of Ataxia Telangiectasia 
The growing recognition that brain pathologies do not affect neurons only but rather are, to a large extent, pathologies of glial cells as well as of the vasculature opens to new perspectives in our understanding of genetic disorders of the CNS. To validate the role of the neuron-glial-vascular unit in the etiology of genome instability disorders, we report about cell death and morphological aspects of neuroglia networks and the associated vasculature in a mouse model of Ataxia Telangiectasia (A-T), a human genetic disorder that induces severe motor impairment. We found that A-T-mutated protein deficiency was consistent with aberrant astrocytic morphology and alterations of the vasculature, often accompanied by reactive gliosis. Interestingly similar findings could also be reported in the case of other genetic disorders. These observations bolster the notion that astrocyte-specific pathologies, hampered vascularization and astrocyte-endothelium interactions in the CNS could play a crucial role in the etiology of genome instability brain disorders and could underlie neurodegeneration.
doi:10.3389/fphar.2012.00157
PMCID: PMC3443819  PMID: 23060792
astrocyte; reactive gliosis; Ataxia Telangiectasia; DNA damage response
22.  Emergence of HGF/SF-Induced Coordinated Cellular Motility 
PLoS ONE  2012;7(9):e44671.
Collective cell migration plays a major role in embryonic morphogenesis, tissue remodeling, wound repair and cancer invasion. Despite many decades of extensive investigations, only few analytical tools have been developed to enhance the biological understanding of this important phenomenon. Here we present a novel quantitative approach to analyze long term kinetics of bright field time-lapse wound healing. Fully-automated spatiotemporal measures and visualization of cells' motility and implicit morphology were proven to be sound, repetitive and highly informative compared to single-cell tracking analysis. We study cellular collective migration induced by tyrosine kinase-growth factor signaling (Met-Hepatocyte Growth Factor/Scatter Factor (HGF/SF)). Our quantitative approach is applied to demonstrate that collective migration of the adenocarcinoma cell lines is characterized by simple morpho-kinetics. HGF/SF induces complex morpho-kinetic coordinated collective migration: cells at the front move faster and are more spread than those further away from the wound edge. As the wound heals, distant cells gradually accelerate and enhance spread and elongation –resembling the epithelial to mesenchymal transition (EMT), and then the cells become more spread and maintain higher velocity than cells located closer to the wound. Finally, upon wound closure, front cells halt, shrink and round up (resembling mesenchymal to epithelial transition (MET) phenotype) while distant cells undergo the same process gradually. Met inhibition experiments further validate that Met signaling dramatically alters the morpho-kinetic dynamics of the healing wound. Machine-learning classification was applied to demonstrate the generalization of our findings, revealing even subtle changes in motility patterns induced by Met-inhibition. It is concluded that activation of Met-signaling induces an elaborated model in which cells lead a coordinated increased motility along with gradual differentiation-based collective cell motility dynamics. Our quantitative phenotypes may guide future investigation on the molecular and cellular mechanisms of tyrosine kinase-induced coordinate cell motility and morphogenesis in metastasis.
doi:10.1371/journal.pone.0044671
PMCID: PMC3435317  PMID: 22970283
23.  Artificial Neural Networks Based Controller for Glucose Monitoring during Clamp Test 
PLoS ONE  2012;7(8):e44587.
Insulin resistance (IR) is one of the most widespread health problems in modern times. The gold standard for quantification of IR is the hyperinsulinemic-euglycemic glucose clamp technique. During the test, a regulated glucose infusion is delivered intravenously to maintain a constant blood glucose concentration. Current control algorithms for regulating this glucose infusion are based on feedback control. These models require frequent sampling of blood, and can only partly capture the complexity associated with regulation of glucose. Here we present an improved clamp control algorithm which is motivated by the stochastic nature of glucose kinetics, while using the minimal need in blood samples required for evaluation of IR. A glucose pump control algorithm, based on artificial neural networks model was developed. The system was trained with a data base collected from 62 rat model experiments, using a back-propagation Levenberg-Marquardt optimization. Genetic algorithm was used to optimize network topology and learning features. The predictive value of the proposed algorithm during the temporal period of interest was significantly improved relative to a feedback control applied at an equivalent low sampling interval. Robustness to noise analysis demonstrates the applicability of the algorithm in realistic situations.
doi:10.1371/journal.pone.0044587
PMCID: PMC3432111  PMID: 22952998
24.  Loss of Intrinsic Organization of Cerebellar Networks in Spinocerebellar Ataxia Type 1: Correlates with Disease Severity and Duration 
Cerebellum (London, England)  2011;10(2):218-232.
The spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of cerebellar degenerative disorders, characterized by progressive gait unsteadiness, hand incoordination, and dysarthria. The mutational mechanism in SCA1, a dominantly inherited form of SCA, consists of an expanded trinucleotide CAG repeat. In SCA1, there is loss of Purkinje cells, neuronal loss in dentate nucleus, olives, and pontine nuclei. In the present study, we sought to apply intrinsic functional connectivity analysis combined with diffusion tensor imaging to define the state of cerebellar connectivity in SCA1. Our results on the intrinsic functional connectivity in lateral cerebellum and thalamus showed progressive organizational changes in SCA1 noted as a progressive increase in the absolute value of the correlation coefficients. In the lateral cerebellum, the anatomical organization of functional clusters seen as parasagittal bands in controls is lost, changing to a patchy appearance in SCA1. Lastly, only fractional anisotropy in the superior peduncle and changes in functional organization in thalamus showed a linear dependence to duration and severity of disease. The present pilot work represents an initial effort describing connectivity biomarkers of disease progression in SCA1. The functional changes detected with intrinsic functional analysis and diffusion tensor imaging suggest that disease progression can be analyzed as a disconnection syndrome.
doi:10.1007/s12311-010-0214-5
PMCID: PMC3091958  PMID: 20886327
Networks; MRI; Biomarkers; Ataxia
25.  Evolvement of Uniformity and Volatility in the Stressed Global Financial Village 
PLoS ONE  2012;7(2):e31144.
Background
In the current era of strong worldwide market couplings the global financial village became highly prone to systemic collapses, events that can rapidly sweep throughout the entire village.
Methodology/Principal Findings
We present a new methodology to assess and quantify inter-market relations. The approach is based on the correlations between the market index, the index volatility, the market Index Cohesive Force and the meta-correlations (correlations between the intra-correlations.) We investigated the relations between six important world markets—U.S., U.K., Germany, Japan, China and India—from January 2000 until December 2010. We found that while the developed “western” markets (U.S., U.K., Germany) are highly correlated, the interdependencies between these markets and the developing “eastern” markets (India and China) are volatile and with noticeable maxima at times of global world events. The Japanese market switches “identity”—it switches between periods of high meta-correlations with the “western” markets and periods when it behaves more similarly to the “eastern” markets.
Conclusions/Significance
The methodological framework presented here provides a way to quantify the evolvement of interdependencies in the global market, evaluate a world financial network and quantify changes in the world inter market relations. Such changes can be used as precursors to the agitation of the global financial village. Hence, the new approach can help to develop a sensitive “financial seismograph” to detect early signs of global financial crises so they can be treated before they develop into worldwide events.
doi:10.1371/journal.pone.0031144
PMCID: PMC3275621  PMID: 22347444

Results 1-25 (50)