Influence of the Time Scale on the Construction of Financial Networks

Written by on September 30, 2010 – 7:00 am -

Background

In this paper we investigate the definition and formation of financial networks. Specifically, we study the influence of the time scale on their construction.

Methodology/Principal Findings

For our analysis we use correlation-based networks obtained from the daily closing prices of stock market data. More precisely, we use the stocks that currently comprise the Dow Jones Industrial Average (DJIA) and estimate financial networks where nodes correspond to stocks and edges correspond to none vanishing correlation coefficients. That means only if a correlation coefficient is statistically significant different from zero, we include an edge in the network. This construction procedure results in unweighted, undirected networks. By separating the time series of stock prices in non-overlapping intervals, we obtain one network per interval. The length of these intervals corresponds to the time scale of the data, whose influence on the construction of the networks will be studied in this paper.

Conclusions/Significance

Numerical analysis of four different measures in dependence on the time scale for the construction of networks allows us to gain insights about the intrinsic time scale of the stock market with respect to a meaningful graph-theoretical analysis.


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Functional Connectivity of the Posteromedial Cortex

Written by on September 30, 2010 – 7:00 am -

As different areas within the PMC have different connectivity patterns with various cortical and subcortical regions, we hypothesized that distinct functional modules may be present within the PMC. Because the PMC appears to be the most active region during resting state, it has been postulated to play a fundamental role in the control of baseline brain functioning within the default mode network (DMN). Therefore one goal of this study was to explore which components of the PMC are specifically involved in the DMN. In a sample of seventeen healthy volunteers, we performed an unsupervised voxelwise ROI-based clustering based on resting state functional connectivity. Our results showed four clusters with different network connectivity. Each cluster showed positive and negative correlations with cortical regions involved in the DMN. Progressive shifts in PMC functional connectivity emerged from anterior to posterior and from dorsal to ventral ROIs. Ventral posterior portions of PMC were found to be part of a network implicated in the visuo-spatial guidance of movements, whereas dorsal anterior portions of PMC were interlinked with areas involved in attentional control. Ventral retrosplenial PMC selectively correlated with a network showing considerable overlap with the DMN, indicating that it makes essential contributions in self-referential processing, including autobiographical memory processing. Finally, ventral posterior PMC was shown to be functionally connected with a visual network.

The paper represents the first attempt to provide a systematic, unsupervised, voxelwise clustering of the human posteromedial cortex (PMC), using resting-state functional connectivity data. Moreover, a ROI-based parcellation was used to confirm the results.


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Human MicroRNA Oncogenes and Tumor Suppressors Show Significantly Different Biological Patterns: From Functions to Targets

Written by on September 30, 2010 – 7:00 am -

MicroRNAs (miRNAs) are small noncoding RNAs which play essential roles in many important biological processes. Therefore, their dysfunction is associated with a variety of human diseases, including cancer. Increasing evidence shows that miRNAs can act as oncogenes or tumor suppressors, and although there is great interest in research into these cancer-associated miRNAs, little is known about them. In this study, we performed a comprehensive analysis of putative human miRNA oncogenes and tumor suppressors. We found that miRNA oncogenes and tumor suppressors clearly show different patterns in function, evolutionary rate, expression, chromosome distribution, molecule size, free energy, transcription factors, and targets. For example, miRNA oncogenes are located mainly in the amplified regions in human cancers, whereas miRNA tumor suppressors are located mainly in the deleted regions. miRNA oncogenes tend to cleave target mRNAs more frequently than miRNA tumor suppressors. These results indicate that these two types of cancer-associated miRNAs play different roles in cancer formation and development. Moreover, the patterns identified here can discriminate novel miRNA oncogenes and tumor suppressors with a high degree of accuracy. This study represents the first large-scale bioinformatic analysis of human miRNA oncogenes and tumor suppressors. Our findings provide help for not only understanding of miRNAs in cancer but also for the specific identification of novel miRNAs as miRNA oncogenes and tumor suppressors. In addition, the data presented in this study will be valuable for the study of both miRNAs and cancer.


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Crystal Structure of the Formin mDia1 in Autoinhibited Conformation

Written by on September 30, 2010 – 7:00 am -

Background

Formin proteins utilize a conserved formin homology 2 (FH2) domain to nucleate new actin filaments. In mammalian diaphanous-related formins (DRFs) the FH2 domain is inhibited through an unknown mechanism by intramolecular binding of the diaphanous autoinhibitory domain (DAD) and the diaphanous inhibitory domain (DID).

Methodology/Principal Findings

Here we report the crystal structure of a complex between DID and FH2-DAD fragments of the mammalian DRF, mDia1 (mammalian diaphanous 1 also called Drf1 or p140mDia). The structure shows a tetrameric configuration (4 FH2 + 4 DID) in which the actin-binding sites on the FH2 domain are sterically occluded. However biochemical data suggest the full-length mDia1 is a dimer in solution (2 FH2 + 2 DID). Based on the crystal structure, we have generated possible dimer models and found that architectures of all of these models are incompatible with binding to actin filament but not to actin monomer. Furthermore, we show that the minimal functional monomeric unit in the FH2 domain, termed the bridge element, can be inhibited by isolated monomeric DID. NMR data on the bridge-DID system revealed that at least one of the two actin-binding sites on the bridge element is accessible to actin monomer in the inhibited state.

Conclusions/Significance

Our findings suggest that autoinhibition in the native DRF dimer involves steric hindrance with the actin filament. Although the structure of a full-length DRF would be required for clarification of the presented models, our work here provides the first structural insights into the mechanism of the DRF autoinhibition.


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Building a Morphogen Gradient without Diffusion in a Growing Tissue

Written by on September 30, 2010 – 7:00 am -

In many developmental systems, spatial pattern arises from morphogen gradients, which provide positional information for cells to determine their fate. Typically, diffusion is thought to be the mechanism responsible for building a morphogen gradient. An alternative mechanism is investigated here. Using mathematical modeling, we demonstrate how a non-diffusive morphogen concentration gradient can develop in axially growing tissue systems, where growth is due to cell proliferation only. Two distinct cases are considered: in the first, all cell proliferation occurs in a localized zone where active transcription of a morphogen-producing gene occurs, and in the second, cell proliferation is uniformly distributed throughout the tissue, occurring in both the active transcription zone and beyond. A cell containing morphogen mRNA produces the morphogen protein, hence any gradient in mRNA transcripts translates into a corresponding morphogen protein gradient. Proliferation-driven growth gives rise to both advection (the transport term) and dilution (a reaction term). These two key mechanisms determine the resultant mRNA transcript distribution. Using the full range of uniform initial conditions, we show that advection and dilution due to cell proliferation are, in general, sufficient for morphogen gradient formation for both types of axially growing systems. In particular, mRNA transcript degradation is not necessary for gradient formation; it is only necessary with localized proliferation for one special value of the initial concentration. Furthermore, the morphogen concentration decreases with distance away from the transcription zone, except in the case of localized proliferation with the initial concentration sufficiently large, when the concentration can either increase with distance from the transcription zone or sustain a local minimum. In both localized and uniformly distributed proliferation, in order for a concentration gradient to form across the whole domain, transcription must occur in a zone equal to the initial domain size; otherwise, it will only form across part of the tissue.


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Competition on the Rocks: Community Growth and Tessellation

Written by on September 30, 2010 – 7:00 am -

Crustose lichen communities on rocks exhibit fascinating spatial mosaics resembling political maps of nations or municipalities. Although the establishment and development of biological populations are important themes in ecology, our understanding of the formation of such patterns on the rocks is still in its infancy. Here, we present a novel model of the concurrent growth, establishment and interaction of lichens. We introduce an inverse technique based on Monte Carlo simulations to test our model on field samples of lichen communities. We derive an expression for the time needed for a community to cover a surface and predict the historical spatial dynamics of field samples. Lichens are frequently used for dating the time of exposure of rocks in glacial deposits, lake retreats or rock falls. We suggest our method as a way to improve the dating.


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Inferring PDZ Domain Multi-Mutant Binding Preferences from Single-Mutant Data

Written by on September 30, 2010 – 7:00 am -

Many important cellular protein interactions are mediated by peptide recognition domains. The ability to predict a domain's binding specificity directly from its primary sequence is essential to understanding the complexity of protein-protein interaction networks. One such recognition domain is the PDZ domain, functioning in scaffold proteins that facilitate formation of signaling networks. Predicting the PDZ domain's binding specificity was a part of the DREAM4 Peptide Recognition Domain challenge, the goal of which was to describe, as position weight matrices, the specificity profiles of five multi-mutant ERBB2IP-1 domains. We developed a method that derives multi-mutant binding preferences by generalizing the effects of single point mutations on the wild type domain's binding specificities. Our approach, trained on publicly available ERBB2IP-1 single-mutant phage display data, combined linear regression-based prediction for ligand positions whose specificity is determined by few PDZ positions, and single-mutant position weight matrix averaging for all other ligand columns. The success of our method as the winning entry of the DREAM4 competition, as well as its superior performance over a general PDZ-ligand binding model, demonstrates the advantages of training a model on a well-selected domain-specific data set.


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Quantification of Three-Dimensional Cell-Mediated Collagen Remodeling Using Graph Theory

Written by on September 30, 2010 – 7:00 am -

Background

Cell cooperation is a critical event during tissue development. We present the first precise metrics to quantify the interaction between mesenchymal stem cells (MSCs) and extra cellular matrix (ECM). In particular, we describe cooperative collagen alignment process with respect to the spatio-temporal organization and function of mesenchymal stem cells in three dimensions.

Methodology/Principal Findings

We defined two precise metrics: Collagen Alignment Index and Cell Dissatisfaction Level, for quantitatively tracking type I collagen and fibrillogenesis remodeling by mesenchymal stem cells over time. Computation of these metrics was based on graph theory and vector calculus. The cells and their three dimensional type I collagen microenvironment were modeled by three dimensional cell-graphs and collagen fiber organization was calculated from gradient vectors. With the enhancement of mesenchymal stem cell differentiation, acceleration through different phases was quantitatively demonstrated. The phases were clustered in a statistically significant manner based on collagen organization, with late phases of remodeling by untreated cells clustering strongly with early phases of remodeling by differentiating cells. The experiments were repeated three times to conclude that the metrics could successfully identify critical phases of collagen remodeling that were dependent upon cooperativity within the cell population.

Conclusions/Significance

Definition of early metrics that are able to predict long-term functionality by linking engineered tissue structure to function is an important step toward optimizing biomaterials for the purposes of regenerative medicine.


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Stochastic Models of Lymphocyte Proliferation and Death

Written by on September 30, 2010 – 7:00 am -

Quantitative understanding of the kinetics of lymphocyte proliferation and death upon activation with an antigen is crucial for elucidating factors determining the magnitude, duration and efficiency of the immune response. Recent advances in quantitative experimental techniques, in particular intracellular labeling and multi-channel flow cytometry, allow one to measure the population structure of proliferating and dying lymphocytes for several generations with high precision. These new experimental techniques require novel quantitative methods of analysis. We review several recent mathematical approaches used to describe and analyze cell proliferation data. Using a rigorous mathematical framework, we show that two commonly used models that are based on the theories of age-structured cell populations and of branching processes, are mathematically identical. We provide several simple analytical solutions for a model in which the distribution of inter-division times follows a gamma distribution and show that this model can fit both simulated and experimental data. We also show that the estimates of some critical kinetic parameters, such as the average inter-division time, obtained by fitting models to data may depend on the assumed distribution of inter-division times, highlighting the challenges in quantitative understanding of cell kinetics.


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Age-Correlated Gene Expression in Normal and Neurodegenerative Human Brain Tissues

Written by on September 29, 2010 – 7:00 am -

Background

Human brain aging has received special attention in part because of the elevated risks of neurodegenerative disorders such as Alzheimer's disease in seniors. Recent technological advances enable us to investigate whether similar mechanisms underlie aging and neurodegeneration, by quantifying the similarities and differences in their genome-wide gene expression profiles.

Principal Findings

We have developed a computational method for assessing an individual's “physiological brain age” by comparing global mRNA expression datasets across a range of normal human brain samples. Application of this method to brains samples from select regions in two diseases – Alzheimer's disease (AD, superior frontal gyrus), frontotemporal lobar degeneration (FTLD, in rostral aspect of frontal cortex ~BA10) – showed that while control cohorts exhibited no significant difference between physiological and chronological ages, FTLD and AD exhibited prematurely aged expression profiles.

Conclusions

This study establishes a quantitative scale for measuring premature aging in neurodegenerative disease cohorts, and it identifies specific physiological mechanisms common to aging and some forms of neurodegeneration. In addition, accelerated expression profiles associated with AD and FTLD suggest some common mechanisms underlying the risk of developing these diseases.


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An Improved Strategy for Generating Forces in Steered Molecular Dynamics: The Mechanical Unfolding of Titin, e2lip3 and Ubiquitin

Written by on September 29, 2010 – 7:00 am -

One of the applications of Molecular Dynamics (MD) simulations is to explore the energetic barriers to mechanical unfolding of proteins such as occurs in response to the mechanical pulling of single molecules in Atomic Force Microscopy (AFM) experiments. Although Steered Molecular Dynamics simulations have provided microscopic details of the unfolding process during the pulling, the simulated forces required for unfolding are typically far in excess of the measured values. To rectify this, we have developed the Pulsed Unconstrained Fluctuating Forces (PUFF) method, which induces constant-momentum motions by applying forces directly to the instantaneous velocity of selected atoms in a protein system. The driving forces are applied in pulses, which allows the system to relax between pulses, resulting in more accurate unfolding force estimations than in previous methods. In the cases of titin, ubiquitin and e2lip3, the PUFF trajectories produce force fluctuations that agree quantitatively with AFM experiments. Another useful property of PUFF is that simulations get trapped if the target momentum is too low, simplifying the discovery and analysis of unfolding intermediates.


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Ontology-Based Meta-Analysis of Global Collections of High-Throughput Public Data

Written by on September 29, 2010 – 7:00 am -

Background

The investigation of the interconnections between the molecular and genetic events that govern biological systems is essential if we are to understand the development of disease and design effective novel treatments. Microarray and next-generation sequencing technologies have the potential to provide this information. However, taking full advantage of these approaches requires that biological connections be made across large quantities of highly heterogeneous genomic datasets. Leveraging the increasingly huge quantities of genomic data in the public domain is fast becoming one of the key challenges in the research community today.

Methodology/Results

We have developed a novel data mining framework that enables researchers to use this growing collection of public high-throughput data to investigate any set of genes or proteins. The connectivity between molecular states across thousands of heterogeneous datasets from microarrays and other genomic platforms is determined through a combination of rank-based enrichment statistics, meta-analyses, and biomedical ontologies. We address data quality concerns through dataset replication and meta-analysis and ensure that the majority of the findings are derived using multiple lines of evidence. As an example of our strategy and the utility of this framework, we apply our data mining approach to explore the biology of brown fat within the context of the thousands of publicly available gene expression datasets.

Conclusions

Our work presents a practical strategy for organizing, mining, and correlating global collections of large-scale genomic data to explore normal and disease biology. Using a hypothesis-free approach, we demonstrate how a data-driven analysis across very large collections of genomic data can reveal novel discoveries and evidence to support existing hypothesis.


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APBSmem: A Graphical Interface for Electrostatic Calculations at the Membrane

Written by on September 29, 2010 – 7:00 am -

Electrostatic forces are one of the primary determinants of molecular interactions. They help guide the folding of proteins, increase the binding of one protein to another and facilitate protein-DNA and protein-ligand binding. A popular method for computing the electrostatic properties of biological systems is to numerically solve the Poisson-Boltzmann (PB) equation, and there are several easy-to-use software packages available that solve the PB equation for soluble proteins. Here we present a freely available program, called APBSmem, for carrying out these calculations in the presence of a membrane. The Adaptive Poisson-Boltzmann Solver (APBS) is used as a back-end for solving the PB equation, and a Java-based graphical user interface (GUI) coordinates a set of routines that introduce the influence of the membrane, determine its placement relative to the protein, and set the membrane potential. The software Jmol is embedded in the GUI to visualize the protein inserted in the membrane before the calculation and the electrostatic potential after completing the computation. We expect that the ease with which the GUI allows one to carry out these calculations will make this software a useful resource for experimenters and computational researchers alike. Three examples of membrane protein electrostatic calculations are carried out to illustrate how to use APBSmem and to highlight the different quantities of interest that can be calculated.


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Neuroimaging Study Designs, Computational Analyses and Data Provenance Using the LONI Pipeline

Written by on September 28, 2010 – 7:00 am -

Modern computational neuroscience employs diverse software tools and multidisciplinary expertise to analyze heterogeneous brain data. The classical problems of gathering meaningful data, fitting specific models, and discovering appropriate analysis and visualization tools give way to a new class of computational challenges—management of large and incongruous data, integration and interoperability of computational resources, and data provenance. We designed, implemented and validated a new paradigm for addressing these challenges in the neuroimaging field. Our solution is based on the LONI Pipeline environment [3], [4], a graphical workflow environment for constructing and executing complex data processing protocols. We developed study-design, database and visual language programming functionalities within the LONI Pipeline that enable the construction of complete, elaborate and robust graphical workflows for analyzing neuroimaging and other data. These workflows facilitate open sharing and communication of data and metadata, concrete processing protocols, result validation, and study replication among different investigators and research groups. The LONI Pipeline features include distributed grid-enabled infrastructure, virtualized execution environment, efficient integration, data provenance, validation and distribution of new computational tools, automated data format conversion, and an intuitive graphical user interface. We demonstrate the new LONI Pipeline features using large scale neuroimaging studies based on data from the International Consortium for Brain Mapping [5] and the Alzheimer's Disease Neuroimaging Initiative [6]. User guides, forums, instructions and downloads of the LONI Pipeline environment are available at http://pipeline.loni.ucla.edu.


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Relating Mutant Genotype to Phenotype via Quantitative Behavior of the NADPH Redox Cycle in Human Erythrocytes

Written by on September 28, 2010 – 7:00 am -

Background

The NADPH redox cycle plays a key role in antioxidant protection of human erythrocytes. It consists of two enzymes: glucose-6-phosphate dehydrogenase (G6PD) and glutathione reductase. Over 160 G6PD variants have been characterized and associated with several distinct clinical manifestations. However, the mechanistic link between the genotype and the phenotype remains poorly understood.

Methodology/Principal Findings

We address this issue through a novel framework (design space) that integrates information at the genetic, biochemical and clinical levels. Our analysis predicts three qualitatively-distinct phenotypic regions that can be ranked according to fitness. When G6PD variants are analyzed in design space, a correlation is revealed between the phenotypic region and the clinical manifestation: the best region with normal physiology, the second best region with a pathology, and the worst region with a potential lethality. We also show that Plasmodium falciparum, by induction of its own G6PD gene in G6PD-deficient erythrocytes, moves the operation of the cycle to a region of the design space that yields robust performance.

Conclusions/Significance

In conclusion, the design space for the NADPH redox cycle, which includes relationships among genotype, phenotype and environment, illuminates the function, design and fitness of the cycle, and its phenotypic regions correlate with the organism's clinical status.


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