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PubMedDate not supplied

Visualizing Internet routing changes.

Today's Internet provides a global data delivery service to millions of end users and routing protocols play a critical role in this service. It is important to be able to identify and diagnose any problems occurring in Internet routing. However, the Internet's sheer size makes this task difficult. One cannot easily extract out the most important or relevant routing information from the large amounts of data collected from multiple routers. To tackle this problem, we have developed Link-Rank, a tool to visualize Internet routing changes at the global scale. Link-Rank weighs links in a topological graph by the number of routes carried over each link and visually captures changes in link weights in the form of a topological graph with adjustable size. Using Link-Rank, network operators can easily observe important routing changes from massive amounts of routing data, discover otherwise unnoticed routing problems, understand the impact of topological events, and infer root causes of observed routing changes.

Algorithms↗

PubMed2001

Reasoning counterfactually: combining and rending.

Counterfactual reasoning occurs when people are asked to assume for the sake of argument that a fact they previously thought was true is now false and to draw a conclusion on that basis. To accomplish this sort of reasoning requires a revising of one's beliefs, which was simulated in the present study. Students were shown a set of statements that they were to assure themselves was consistent. They were then asked to accept a counterfactual assumption as true and reconcile resulting inconsistencies among the set of statements. In these problems, one statement is a generality (e.g., All trees on the plaza are elms), another is a particular (e.g., This tree is a pine), and one is a counterfactual (e.g., Assume this tree is on the plaza). Students preferred to reconcile the inconsistency by identifying the generality as "true" and the particular as "false." They did this more often when the assumption combined categories than when it dislodged categories and when real beliefs were at stake rather than arbitrary generalities. This study tested current models of inference for their ability to account for counterfactual reasoning and found the results to be consistent with natural deduction system, mental models, and conceptual-integration network approaches to everyday reasoning.

Cognition↗

PubMed1999

Extensive intraspecific chloroplast DNA (cpDNA) variation in the alpine Draba aizoides L. (Brassicaceae): haplotype relationships and population structure.

Chloroplast DNA (cpDNA) sequence variation is currently the most widely used tool for the inference of phylogenetic relationships among plants at all taxonomic levels. Generally, noncoding regions tend to evolve faster than coding sequences and have recently been applied to the study of phylogenetic relationships among closely related taxa. An implicit assumption of many of these studies is that intraspecific cpDNA variation is either absent or low and therefore will not interfere with the reconstruction of interspecific relationships. A survey of cpDNA sequence variation in the common alpine plant species Draba aizoides L. was undertaken to assess levels of intraspecific cpDNA sequence variation. These levels were compared to levels of interspecific sequence divergence between D. aizoides and related alpine Draba species. Intraspecific cpDNA sequence divergence was extensive in D. aizoides, and intraspecific differences were often larger than interspecific differences. cpDNA haplotype relationships were explored using a maximum parsimony approach and minimum-spanning networks. Results from both methods were largely congruent but comparisons provided interesting insights into the presumed evolutionary history of cpDNA haplotypes. A combined effect of cpDNA introgression and complex lineage sorting was inferred to explain the pattern of cpDNA variation found in D. aizoides. Our results suggest that intraspecific cpDNA variation can be extensive and that intraspecific variation needs to be taken into account when inferring phylogenetic relationships among closely related taxa.

Brassicaceae↗

PubMed2006

One billion years of bZIP transcription factor evolution: conservation and change in dimerization and DNA-binding site specificity.

The genomic era has revealed that the large repertoire of observed animal phenotypes is dependent on changes in the expression patterns of a finite number of genes, which are mediated by a plethora of transcription factors (TFs) with distinct specificities. The dimerization of TFs can also increase the complexity of a genetic regulatory network manifold, by combining a small number of monomers into dimers with distinct functions. Therefore, studying the evolution of these dimerizing TFs is vital for understanding how complexity increased during animal evolution. We focus on the second largest family of dimerizing TFs, the basic-region leucine zipper (bZIP), and infer when it expanded and how bZIP DNA-binding and dimerization functions evolved during the major phases of animal evolution. Specifically, we classify the metazoan bZIPs into 19 families and confirm the ancient nature of at least 13 of these families, predating the split of the cnidaria. We observe fixation of a core dimerization network in the last common ancestor of protostomes-deuterostomes. This was followed by an expansion of the number of proteins in the network, but no major dimerization changes in interaction partners, during the emergence of vertebrates. In conclusion, the bZIPs are an excellent model with which to understand how DNA binding and protein interactions of TFs evolved during animal evolution.

Animals↗

PubMed2006

Recurrent insertion and duplication generate networks of transposable element sequences in the Drosophila melanogaster genome.

BACKGROUND: The recent availability of genome sequences has provided unparalleled insights into the broad-scale patterns of transposable element (TE) sequences in eukaryotic genomes. Nevertheless, the difficulties that TEs pose for genome assembly and annotation have prevented detailed, quantitative inferences about the contribution of TEs to genomes sequences. RESULTS: Using a high-resolution annotation of TEs in Release 4 genome sequence, we revise estimates of TE abundance in Drosophila melanogaster. We show that TEs are non-randomly distributed within regions of high and low TE abundance, and that pericentromeric regions with high TE abundance are mosaics of distinct regions of extreme and normal TE density. Comparative analysis revealed that this punctate pattern evolves jointly by transposition and duplication, but not by inversion of TE-rich regions from unsequenced heterochromatin. Analysis of genome-wide patterns of TE nesting revealed a 'nesting network' that includes virtually all of the known TE families in the genome. Numerous directed cycles exist among TE families in the nesting network, implying concurrent or overlapping periods of transpositional activity. CONCLUSION: Rapid restructuring of the genomic landscape by transposition and duplication has recently added hundreds of kilobases of TE sequence to pericentromeric regions in D. melanogaster. These events create ragged transitions between unique and repetitive sequences in the zone between euchromatic and beta-heterochromatic regions. Complex relationships of TE nesting in beta-heterochromatic regions raise the possibility of a co-suppression network that may act as a global surveillance system against the majority of TE families in D. melanogaster.

Animals↗

PubMed1997

The role of retinal bipolar cell in early vision: an implication with analogue networks and regularization theory.

A linear analogue network model is proposed to describe the neuronal circuit of the outer retina consisting of cones, horizontal cells, and bipolar cells. The model reflects previous physiological findings on the spatial response properties of these neurons to dim illumination and is expressed by physiological mechanisms, i.e., membrane conductances, gap-junctional conductances, and strengths of chemical synaptic interactions. Using the model, we characterized the spatial filtering properties of the bipolar cell receptive field with the standard regularization theory, in which the early vision problems are attributed to minimization of a cost function. The cost function accompanying the present characterization is derived from the linear analogue network model, and one can gain intuitive insights on how physiological mechanisms contribute to the spatial filtering properties of the bipolar cell receptive field. We also elucidated a quantitative relation between the Laplacian of Gaussian operator and the bipolar cell receptive field. From the computational point of view, the dopaminergic modulation of the gap-junctional conductance between horizontal cells is inferred to be a suitable neural adaptation mechanism for transition between photopic and mesopic vision.

Animals↗

PubMed2005

Learning yeast gene functions from heterogeneous sources of data using hybrid weighted Bayesian networks.

We developed a machine learning system for determining gene functions from heterogeneous sources of data sets using a Weighted Naive Bayesian Network (WNB). The knowledge of gene functions is crucial for understanding many fundamental biological mechanisms such as regulatory pathways, cell cycles and diseases. Our major goal is to accurately infer functions of putative genes or ORFs (Open Reading Frames) from existing databases using computational methods. However, this task is intrinsically difficult since the underlying biological processes represent complex interactions of multiple entities. Therefore many functional links would be missing when only one or two source of data is used in the prediction. Our hypothesis is that integrating evidence from multiple and complementary sources could significantly improve the prediction accuracy. In this paper, our experimental results not only suggest that the above hypothesis is valid, but also provide guidelines for using the WNB system for data collection, training and predictions. The combined training data sets contain information from gene annotations, gene expressions, clustering outputs, keyword annotations and sequence homology from public databases. The current system is trained and tested on the genes of budding yeast Saccharomyces cerevisiae. Our WNB model can also be used to analyze the contribution of each source of information toward the prediction performance through the weight training process. The contribution analysis could potentially lead to significant scientific discovery by facilitating the interpretation and understanding of the complex relationships between biological entities.

Artificial Intelligence↗

PubMed2004

Actin- and protein-4.1-containing filaments link nuclear pore complexes to subnuclear organelles in Xenopus oocyte nuclei.

We imaged the interiors of relatively intact Xenopus oocyte nuclei by field emission scanning electron microscopy (feSEM) and visualized a network of filaments that attach to nuclear pore complexes and extend throughout the nucleus. Within the nucleus, these 'pore-linked filaments' (PLFs) were embedded into spherical structures 100 nm to approximately 5 microm in diameter. A subset of spheres was identified as Cajal bodies by immuno-gold labeling; the rest were inferred to be nucleoli and snurposomes both of which are abundant in Xenopus oocyte nuclei. Most PLFs were independent of chromatin. The thickness of a typical PLF was 40 nm (range, approximately 12-100 nm), including the 4 nm chromium coat. PLFs located inside the nucleus merged, bundled and forked, suggesting architectural adaptability. The PLF network collapsed upon treatment with latrunculin A, which depolymerizes actin filaments. Jasplakinolide, which stabilizes actin filaments, produced PLFs with more open substructure including individual filaments with evenly-spaced rows of radially projecting short filaments. Immuno-gold labeling of untreated oocyte nuclei showed that actin and protein 4.1 each localized on PLFs. Protein 4.1-gold epitopes were spaced at approximately 120 nm intervals along filaments, and were often paired ( approximately 70 nm apart) at filament junctions. We suggest that protein 4.1 and actin contribute to the structure of a network of heterogeneous filaments that link nuclear pore complexes to subnuclear organelles, and discuss possible functions for PLFs in nuclear assembly and intranuclear traffic.

Actins↗

PubMed1996

An expert system based on causal knowledge: validation on post-cardiosurgical patients.

A new expert system for the analysis of post-cardiosurgical patients in Intensive Care Units is described, and a preliminary validation performed. The inference engine employs a hybrid reasoning method which integrates quantitative and qualitative simulation techniques in an original manner. The long-term knowledge consists of a causal network which reproduces the main relationships between physiological quantities involved in the course after cardiac surgery. Emphasis has been given to respiratory and metabolic, as well as cardiovascular quantities both in the systemic and pulmonary circulations. Preliminary system validation has been performed on a set of 40 cardiosurgical patients, previously classified either at normal-risk (17 patients) or at high-risk (23 patients) by means of statistical classification techniques. In most cases, predictions of the expert system substantially agree with those provided by the more traditional statistical method. The system, however, is also able to furnish detailed explanations on the possible physiological causes responsible for the patient status. In particular, simulation results indicate that a reduction in the cardiac index (19 cases) and an increase in the oxygen utilization coefficient (19 cases) are the most critical alterations in the high-risk patients. The system imputes the reduced cardiac index to a rise in total systemic resistance (15 high-risk patients), a decrease in cardiac strength (2 high-risk patients) or an insufficient filling volume of the systemic circulation (4 high-risk patients). Furthermore, in 6 high-risk patients the depressed cardiac outflow occurs with a reduction in the arterial oxygen content, mainly imputable to an insufficiency of blood hemoglobin content. Finally, two examples of the complete expert system explanatory capabilities are shown with reference to a pair of high-risk patients and discussed.

Blood Circulation↗

PubMed1990

Evidence for a power law intensity code in the coupled cones of the turtle.

The hyperpolarizing responses to light were recorded intracellularly from red cones of the turtle, Pseudemys scripta elegans. Pairs of slit stimuli were flashed alone or together at various intensities, one slit positioned on the receptive field center and the other displaced 30 microns. The peak amplitude of the response was measured, and the results analyzed to quantify the relationship between the light intensity and the size of the neural signal evoked prior to the spatial interactions occurring in the network of coupled cones. This signal, E, was found to be described by a compressive power law, E = k.I0.5, where I is slit intensity. Evidence that the inferred excitation function describes a local mechanism independent of the slit position was obtained by measuring the response and the sensitivity receptive field profiles. The response and the sensitivity fields both decreased exponentially, but with space constants that differed by a factor of two, indicating in still another way the existence of an early square-root transformation.

Animals↗

PubMed2003

Micromechanical studies of mitotic chromosomes.

We review micromechanical experiments studying mechanoelastic properties of mitotic chromosomes. We discuss the history of this field, starting from the classic in vivo experiments of Nicklas (1983). We then focus on experiments where chromosomes were extracted from prometaphase cells and then studied by micromanipulation and microfluidic biochemical techniques. These experiments reveal that chromosomes have a well-behaved elastic response over a fivefold range of stretching, with an elastic modulus similar to that of a loosely tethered polymer network. Perturbation by microfluidic "spraying" of various ions reveals that the mitotic chromosome can be rapidly and reversibly decondensed or overcondensed, i.e., that the native state is not maximally compacted. We compare our results for chromosomes from cells to results of experiments by Houchmandzadeh and Dimitrov (1999) on chromatids reconstituted using Xenopus egg extracts. Remarkably, while the stretching elastic response of reconstituted chromosomes is similar to that observed for chromosomes from cells, reconstituted chromosomes are far more easily bent. This result suggests that reconstituted chromatids have a large-scale structure that is quite different from chromosomes in somatic cells. Finally, we discuss microspraying experiments of DNA-cutting enzymes, which reveal that the element that gives mitotic chromosomes their mechanical integrity is DNA itself. These experiments indicate that chromatin-condensing proteins are not organized into a mechanically contiguous "scaffold," but instead that the mitotic chromosome is best thought of as a cross-linked network of chromatin. Preliminary results from restriction enzyme digestion experiments indicate a spacing between chromatin "cross-links" of roughly 15 kb, a size similar to that inferred from classical chromatin loop isolation studies. These results suggest a general strategy for the use of micromanipulation methods for the study of chromosome structure.

Animals↗

PubMedDate not supplied

Interpolation processes in the visual perception of objects.

Visual perception of objects depends on segmentation and grouping processes that act on fragmentary input. This paper gives a brief overview of these processes. A simple geometry accounting for contour interpolation is described, and its applications to 2D, 3D, and spatiotemporal object interpolation processes are considered. A method is described for distinguishing interpolation based on this geometry from more global or top-down influences. Results suggest a separation between interpolation based on relatively local stimulus relations, which give rise to precise boundary representations, and processes involving recognition from partial information, which do not. Aspects of the model-especially the unified treatment of illusory and occluded objects-raise questions about the nature of seeing. Although it is often believed that illusory objects are perceived, while occluded objects are inferred, I suggest that both research and theory converge in supporting a more unified account. Illusory and occluded contours and surfaces do not divide into the real, the perceived, and the inferred, but are all represented, and in key respects, derive from identical perceptual processes.

Neural Networks, Computer↗

PubMed2000

Organic-inorganic hybrids based on polyoxometalates. 6. Syntheses, structure, and reactivity of the bis(tert-butylsilyl)decatungstophosphate [(gamma-PW10O36)(t-BuSiOH)2]3-.

Bis(tert-butylsilyl)decatungstophosphate (n-Bu4N)3[(gamma-PW10O36)(t-BuSiOH)2] (1) has been synthesized through phase-transfer conditions, by reaction of t-BuSiCl3 with Cs7[(gamma-PW10O36)].xH2O. This new hybrid anion has been characterized by elemental analysis, X-ray crystallography, multinuclear solution and solid-state NMR, and infrared spectroscopy. Crystals of 1 are monoclinic, space group C2/c, with lattice constants a = 44.762(10) A, b = 19.032(4) A, c = 22.079(8) A, beta = 98.9(2) degrees, and Z = 8. Anion 1 has nominal Cs symmetry and displays an "open structure" with two t-BuSiOH groups anchored to the (gamma-PW10O36) framework. The two t-BuSiOH units are nonequivalent as confirmed by 29Si CP-MAS NMR and by diffuse reflection infrared spectroscopy. The two OH groups are linked through one H-bond (dO-O = 2.63 A). According to 29Si and 183W NMR, 1 adopts a more symmetrical conformation (C2v) in solution. Anion 1 reacts cleanly in homogeneous conditions with Me2SiCl2 to yield (n-Bu4N)3[(gamma-PW10O36)(t-BuSiO)2(SiMe2)] (2). The structure of 2 has been inferred from multinuclear NMR and infrared spectroscopy. The hybrid "closed-structure" anion 2 consists of the (gamma-PW10O36) framework on which is grafted a heterosilylated network composed of a capping fragment, Si(CH3)2, linked to the t-BuSi groups through two siloxane bridges.

Journal Article↗

PubMed2000

Phylogeography of the bullhead Cottus gobio (Pisces: Teleostei: Cottidae) suggests a pre-pleistocene origin of the major central European populations.

The bullhead Cottus gobio is a small, bottom-dwelling fish consisting of populations that have not been subject to transplantations or artificial stocking. It is therefore an ideal model species for studying the colonization history of central European freshwater systems, in particular with respect to the possible influences of the Pleistocene glaciation cycles. We sampled Cottus populations across most of its distribution range, with a special emphasis on southern Germany where the major European drainage systems are in closest contact. Mitochondrial D-loop sequencing of more than 400 specimens and phylogenetic network analysis allowed us to draw a detailed picture of the colonization of Europe by C. gobio. Moreover, the molecular distances between the haplotypes enabled us to infer an approximate time frame for the origin of the various populations. The founder population of C. gobio stems apparently from the Paratethys and invaded Europe in the Pliocene. From there, the first colonization into central Europe occurred via the ancient lower Danube, with a separate colonization of the eastern European territories. During the late Pliocene, one of the central European populations must have reached the North Sea in a second step after which it then started to colonize the Atlantic drainages via coastal lines. Accordingly, we found very distinct populations in the upper and lower Rhine, which can be explained by the fact that the lower Rhine was disconnected from the upper Rhine until approximately 1 million years ago (Ma). More closely related, but still distinct, populations were found in the Elbe, the Main and the upper Danube, all presumably of Pleistocene origin. Intriguingly, they have largely maintained their population identity, despite the strong disturbance caused by the glaciation cycles in these areas. On the other hand, a mixing of populations during postglacial recolonization could be detected in the lower Rhine and its tributaries. However, the general pattern that emerges from our analysis suggests that the glaciation cycles did not have a major impact on the general population structure of C. gobio in central Europe.

Animals↗

PubMed2006

Modular DAG-RNN architectures for assembling coarse protein structures.

We develop and test machine learning methods for the prediction of coarse 3D protein structures, where a protein is represented by a set of rigid rods associated with its secondary structure elements (alpha-helices and beta-strands). First, we employ cascades of recursive neural networks derived from graphical models to predict the relative placements of segments. These are represented as discretized distance and angle maps, and the discretization levels are statistically inferred from a large and curated dataset. Coarse 3D folds of proteins are then assembled starting from topological information predicted in the first stage. Reconstruction is carried out by minimizing a cost function taking the form of a purely geometrical potential. We show that the proposed architecture outperforms simpler alternatives and can accurately predict binary and multiclass coarse maps. The reconstruction procedure proves to be fast and often leads to topologically correct coarse structures that could be exploited as a starting point for various protein modeling strategies. The fully integrated rod-shaped protein builder (predictor of contact maps + reconstruction algorithm) can be accessed at http://distill.ucd.ie/.

Algorithms↗

PubMed2004

Coexpression analysis of human genes across many microarray data sets.

We present a large-scale analysis of mRNA coexpression based on 60 large human data sets containing a total of 3924 microarrays. We sought pairs of genes that were reliably coexpressed (based on the correlation of their expression profiles) in multiple data sets, establishing a high-confidence network of 8805 genes connected by 220,649 "coexpression links" that are observed in at least three data sets. Confirmed positive correlations between genes were much more common than confirmed negative correlations. We show that confirmation of coexpression in multiple data sets is correlated with functional relatedness, and show how cluster analysis of the network can reveal functionally coherent groups of genes. Our findings demonstrate how the large body of accumulated microarray data can be exploited to increase the reliability of inferences about gene function.

Cluster Analysis↗

PubMed2006

A fast learning algorithm for deep belief nets.

We show how to use "complementary priors" to eliminate the explaining-away effects that make inference difficult in densely connected belief nets that have many hidden layers. Using complementary priors, we derive a fast, greedy algorithm that can learn deep, directed belief networks one layer at a time, provided the top two layers form an undirected associative memory. The fast, greedy algorithm is used to initialize a slower learning procedure that fine-tunes the weights using a contrastive version of the wake-sleep algorithm. After fine-tuning, a network with three hidden layers forms a very good generative model of the joint distribution of handwritten digit images and their labels. This generative model gives better digit classification than the best discriminative learning algorithms. The low-dimensional manifolds on which the digits lie are modeled by long ravines in the free-energy landscape of the top-level associative memory, and it is easy to explore these ravines by using the directed connections to display what the associative memory has in mind.

Algorithms↗

PubMed2006

Genome-wide prediction of transcriptional regulatory elements of human promoters using gene expression and promoter analysis data.

BACKGROUND: A complete understanding of the regulatory mechanisms of gene expression is the next important issue of genomics. Many bioinformaticians have developed methods and algorithms for predicting transcriptional regulatory mechanisms from sequence, gene expression, and binding data. However, most of these studies involved the use of yeast which has much simpler regulatory networks than human and has many genome wide binding data and gene expression data under diverse conditions. Studies of genome wide transcriptional networks of human genomes currently lag behind those of yeast. RESULTS: We report herein a new method that combines gene expression data analysis with promoter analysis to infer transcriptional regulatory elements of human genes. The Z scores from the application of gene set analysis with gene sets of transcription factor binding sites (TFBSs) were successfully used to represent the activity of TFBSs in a given microarray data set. A significant correlation between the Z scores of gene sets of TFBSs and individual genes across multiple conditions permitted successful identification of many known human transcriptional regulatory elements of genes as well as the prediction of numerous putative TFBSs of many genes which will constitute a good starting point for further experiments. Using Z scores of gene sets of TFBSs produced better predictions than the use of mRNA levels of a transcription factor itself, suggesting that the Z scores of gene sets of TFBSs better represent diverse mechanisms for changing the activity of transcription factors in the cell. In addition, cis-regulatory modules, combinations of co-acting TFBSs, were readily identified by our analysis. CONCLUSION: By a strategic combination of gene set level analysis of gene expression data sets and promoter analysis, we were able to identify and predict many transcriptional regulatory elements of human genes. We conclude that this approach will aid in decoding some of the important transcriptional regulatory elements of human genes.

Algorithms↗