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How to quantify an arterial stenosis: a study on the femoral arteries of dog and man.

The blood supply to the femoral bed was studied in anaesthetised dogs before and after producing arterial stenoses. The blood supply system consisted of the vessels proximal to the site of measurement in the femoral artery and was characterised by a supply graph, which related mean perfusion pressure to mean flow. The different pressures and flows were obtained using an artificial periphery, the impedance of which was changed from beat to beat. The supply graph was approximated by a parabola with two parameters: the intercepts with the pressure and flow axes, the latter indicating the maximum mean flow. For constant aortic pressure the maximum mean flow appeared to be linearly related to the cross sectional area of the stenosed section (r = 0.98). Maximum mean flow was already considerably reduced before the stenosis became critical--that is, before physiological flow was measurably diminished. The change in maximum mean flow was therefore used to quantify the haemodynamic effects of stenoses that were less than critical. Blood supply graphs of the superficial femoral arteries were determined also in seven patients undergoing a femoropopliteal bypass operation. The maximum mean flow correlated well with the degree of obstruction determined from the preoperative angiograms (r = 0.90).

Adult↗

PSEUDOVIEWER2: Visualization of RNA pseudoknots of any type.

Visualizing RNA pseudoknot structures is computationally more difficult than depicting RNA secondary structures, because a drawing of a pseudoknot structure is a graph (and possibly a nonplanar graph) with inner cycles within the pseudoknot, and possibly outer cycles formed between the pseudoknot and other structural elements. We previously developed PSEUDOVIEWER for visualizing H-type pseudoknots. PSEUDOVIEWER2 improves on the first version in many ways: (i) PSEUDOVIEWER2 is more general because it can visualize a pseudoknot of any type, including H-type pseudoknots, as a planar graph; (ii) PSEUDOVIEWER2 computes a drawing of RNA structures much more efficiently and is an order of magnitude faster in actual running time; and (iii) PSEUDOVIEWER2 is a web-based application program. Experimental results demonstrate that PSEUDOVIEWER2 generates an aesthetically pleasing drawing of pseudoknots of any type and that the new representation offered by PSEUDOVIEWER2 ensures uniform and clear drawings, with no edge crossing, for all types of pseudoknots. The PSEUDOVIEWER2 algorithm is the first developed for the automatic drawing of RNA secondary structures, including pseudoknots of any type. PSEUDOVIEWER2 is accessible at http://wilab.inha.ac.kr/pseudoviewer2/.

Algorithms↗

BIOZON: a hub of heterogeneous biological data.

Biological entities are strongly related and mutually dependent on each other. Therefore, there is a growing need to corroborate and integrate data from different resources and aspects of biological systems in order to analyze them effectively. Biozon is a unified biological database that integrates heterogeneous data types such as proteins, structures, domain families, protein-protein interactions and cellular pathways, and establishes the relationships between them. All data are integrated on to a single graph schema centered around the non-redundant set of biological objects that are shared by each source. This integration results in a highly connected graph structure that provides a more complete picture of the known context of a given object that cannot be determined from any one source. Currently, Biozon integrates roughly 2 million protein sequences, 42 million DNA or RNA sequences, 32,000 protein structures, 150,000 interactions and more from sources such as GenBank, UniProt, Protein Data Bank (PDB) and BIND. Biozon augments source data with locally derived data such as 5 billion pairwise protein alignments and 8 million structural alignments. The user may form complex cross-type queries on the graph structure, add similarity relations to form fuzzy queries and rank the results based on analysis of the edge structure similar to Google PageRank, online at Biozon.org.

Computer Graphics↗

AliWABA: alignment on the web through an A-Bruijn approach.

UNLABELLED: Multiple sequence alignment programs are an invaluable tool in computational biology. A-Bruijn Alignment (ABA) is a method for multiple sequence alignment that represents an alignment as a directed graph and has proved useful in aligning nucleotide and amino acid sequences that are composed of repeated and shuffled subsequences. AliWABA is a web server that provides tools to generate alignments with ABA, visualize the resulting ABA graphs and extract subsequences from ABA graphs. AliWABA greatly simplifies the problem of analyzing multiple sequences for local similarities that may be reordered, as is common with the domain architectures of proteins. To facilitate the analysis of protein domains, AliWABA provides direct querying of the Conserved Domain Database. AVAILABILITY: http://aba.nbcr.net/

Algorithms↗

A new method that simultaneously aligns and reconstructs ancestral sequences for any number of homologous sequences, when the phylogeny is given.

Among the fundamental problems in molecular evolution and in the analysis of homologous sequences are alignment, phylogeny reconstruction, and the reconstruction of ancestral sequences. This paper presents a fast, combined solution to these problems. The new algorithm gives an approximation to the minimal history in terms of a distance function on sequences. The distance function on sequences is a minimal weighted path length constructed from substitutions and insertions-deletions of segments of any length. Substitutions are weighted with an arbitrary metric on the set of nucleotides or amino acids, and indels are weighted with a gap penalty function of the form gk = a + (bxk), where k is the length of the indel and a and b are two positive numbers. A novel feature is the introduction of the concept of sequence graphs and a generalization of the traditional dynamic sequence comparison algorithm to the comparison of sequence graphs. Sequence graphs ease several computational problems. They are used to represent large sets of sequences that can then be compared simultaneously. Furthermore, they allow the handling of multiple, equally good, alignments, where previous methods were forced to make arbitrary choices. A program written in C implemented this method; it was tested first on 22 5S RNA sequences.

Algorithms↗

Automating the identification and analysis of protein beta-barrels.

beta-Barrels are widespread and well-studied features of a great many protein structures. In this paper an unsupervised method for the detection of beta-barrels is developed based on techniques from graph theory. The hydrogen bonded connectivity of beta-sheets is derived using standard pattern recognition techniques and expressed as a graph. Barrels correspond to topological rings in these connectivity graphs and can thus be identified using ring perception algorithms. Following from this, the characteristic topological structure of a barrel can be expressed using a novel form of reduced nomenclature that counts sequence separations between successive members of the ring set. These techniques are tested by applying them to the detection of barrels in a non-redundant subset of the Brookhaven database. Results indicate that topological rings do seem to correspond uniquely to beta-barrels and that the technique, as implemented, finds the majority of barrels present in the dataset.

Algorithms↗

Common Structural Cliques: a tool for protein structure and function analysis.

Proposed is a method for locating functionally relevant atoms in protein structures and a representation of spatial arrangements of these atoms allowing for a flexible description of active sites in proteins. The search method is based on comparison of local structure features of proteins that share a common biochemical function. The method does not depend on overall similarity of structures and sequences of compared proteins or on previous knowledge about functionally relevant residues. The compared protein structures are condensed to a graph representation, with atoms as nodes and distances as edge labels. Protein graphs are then compared to extract all possible Common Structural Cliques. These cliques are merged to create Structural Templates: graphs that describe structural analogies between compared proteins. Structures of serine endopeptidases were compared in pairs using the presented algorithm with different geometrical parameters. Additionally, a Structural Template was extracted from the structures of aminotransferases, two different proteins that catalyze the same type of chemical reaction. The results presented show that the method works efficiently even in the case of large protein systems and allows for extraction of common structural features from proteins catalyzing a particular chemical reaction, but that evolved from different ancestors by convergent evolution.

Algorithms↗

Reliability of wound surface area measurements.

The purpose of this study was to establish intratester and intertester reliability of four methods of measuring wound surface area from transparency film tracings. Wound area measurements were obtained in 31 subjects with venous stasis ulcers. After tracing each wound on transparency film, wound area was calculated by (1) multiplying length and width measurements with a ruler, (2) placing the transparency film over graph paper and counting the squares, (3) using a planimeter, and (4) using a digitizer. Intraclass correlation coefficients (ICCs) for intratester measurements were .99 for each method. The ICC values for intertester measurements ranged from .97 to .99. The results of this study indicate that intratester and intertester wound measurements can be taken reliably with the graph paper, planimeter, and digitizer methods. The graph paper technique may be preferable in most clinical settings, because it is low in cost and easy to use.

Data Interpretation, Statistical↗

Charting of daily weight pattern reinforces maintenance of weight reduction in moderately obese patients.

To maintain reduced body weight by behavioral therapy in moderately obese patients, body weight was measured four times daily and charted in a weekly graph. Seventy-two female patients with simple obesity were divided into two groups: 55 patients with appliance of charting of weight pattern (group-I), and 17 patients without the charting (group-II). The percentage of patients followed for 2 years was different between group-I (87%) and group-II (65%) during 2 years after completion of weight reduction therapy interviews (p less than 0.05). Forty-eight of group-I patients succeeded in decreasing their weight by 15.2 +/- 1.5 (mean +/- SEM) kg during the 6.5 +/- 0.8 months of the therapy interviews. They were followed up for 3.8 years with no rebound weight gain. Eleven patients in group-II also succeeded in decreasing their weight by 16.8 +/- 1.9 kg during 7.8 +/- 1.3 months but their body weight rebounded by 9.0 kg during the 2-year followup period. Twelve of 15 male patients with weight charting maintained reduced weight during 4.3 years. It was easier and more effective for obese patients to maintain weight graphs for the longer period than to record no weight graphs. Obese patients could themselves monitor irregular weight patterns produced by overeating and correct the irregularities in food intake and daily lifestyles. This seems to explain why the illustration of daily fluctuations of weight measurements was useful for long-term maintenance of weight reduction.

Adult↗

Degree of accuracy in perceiving graphic and representational information through touch.

Two studies are reported in which comprehension and interpretation of raised-line images and graphs by touch were investigated. Experiment 1 required blind-folded sighted subjects and blind subjects to rate the veracity of raised-line drawings in conveying the nature of an image when the complexity of the depicted object was manipulated (from simple outlines to more complex exaggeration of salient features). Results showed no effect of complexity on veracity ratings. Experiment 2 involved the assessment of blind and visually impaired subjects of line-graphs, histograms and pie charts which varied in information content and perceptible detail (textured and untextured). Histograms were easier to interpret than line-graphs, but there were no differences between histograms and pie charts. An increase in information content had little effect on comprehension.

Adolescent↗

Trajectories of changing refractive status.

Refractive status can be represented as a point plotted on a three-dimensional graph. As the refractive status changes a curve is traced out on the graph. Trajectories of changing refractive status are illustrated in a number of representative ideal cases. The three-dimensional graphs are shown by means of stereo-pairs. Trajectories are constructed from clinical data and interpreted with reference to the ideal examples. They show changing refractive status with age, after cataract extraction, and after radial keratotomy. The trajectories may prove to be a useful tool for both clinician and researcher. They show overall trends and allow prediction of future changes. Certain types of trajectories could prove to be characteristic of certain conditions and thus be useful for diagnosis. Trajectories allow monitoring of change after intervention.

Adolescent↗

The small world inside large metabolic networks.

The metabolic network of the catabolic, energy and biosynthetic metabolism of Escherichia coli is a paradigmatic case for the large genetic and metabolic networks that functional genomics efforts are beginning to elucidate. To analyse the structure of previously unknown networks involving hundreds or thousands of components by simple visual inspection is impossible, and quantitative approaches are needed to analyse them. We have undertaken a graph theoretical analysis of the E. coli metabolic network and find that this network is a small-world graph, a type of graph distinct from both regular and random networks and observed in a variety of seemingly unrelated areas, such as friendship networks in sociology, the structure of electrical power grids, and the nervous system of Caenorhabditis elegans. Moreover, the connectivity of the metabolites follows a power law, another unusual but by no means rare statistical distribution. This provides an objective criterion for the centrality of the tricarboxylic acid cycle to metabolism. The small-world architecture may serve to minimize transition times between metabolic states, and contains evidence about the evolutionary history of metabolism.

Escherichia coli↗

ESTGenes: alternative splicing from ESTs in Ensembl.

We describe a novel algorithm for deriving the minimal set of nonredundant transcripts compatible with the splicing structure of a set of ESTs mapped on a genome. Sets of ESTs with compatible splicing are represented by a special type of graph. We describe the algorithms for building the graphs and for deriving the minimal set of transcripts from the graphs that are compatible with the evidence. These algorithms are part of the Ensembl automatic gene annotation system, and its results, using ESTs, are provided at www.ensembl.org as ESTgenes for the mosquito, Caenorhabditis briggsae, C. elegans, zebrafish, human, mouse, and rat genomes. Here we also report on the results of this method applied to the human and mouse genomes.

Alternative Splicing↗

Identifying loci under positive selection in complex population histories.

Detailed modeling of a species' history is of prime importance for understanding how natural selection operates over time. Most methods designed to detect positive selection along sequenced genomes, however, use simplified representations of past histories as null models of genetic drift. Here, we present the first method that can detect signatures of strong local adaptation across the genome using arbitrarily complex admixture graphs, which are typically used to describe the history of past divergence and admixture events among any number of populations. The method-called graph-aware retrieval of selective sweeps (GRoSS)-has good power to detect loci in the genome with strong evidence for past selective sweeps and can also identify which branch of the graph was most affected by the sweep. As evidence of its utility, we apply the method to bovine, codfish, and human population genomic data containing panels of multiple populations related in complex ways. We find new candidate genes for important adaptive functions, including immunity and metabolism in understudied human populations, as well as muscle mass, milk production, and tameness in specific bovine breeds. We are also able to pinpoint the emergence of large regions of differentiation owing to inversions in the history of Atlantic codfish.

Animals↗

A novel method for multiple alignment of sequences with repeated and shuffled elements.

We describe ABA (A-Bruijn alignment), a new method for multiple alignment of biological sequences. The major difference between ABA and existing multiple alignment methods is that ABA represents an alignment as a directed graph, possibly containing cycles. This representation provides more flexibility than does a traditional alignment matrix or the recently introduced partial order alignment (POA) graph by allowing a larger class of evolutionary relationships between the aligned sequences. Our graph representation is particularly well-suited to the alignment of protein sequences with shuffled and/or repeated domain structure, and allows one to construct multiple alignments of proteins containing (1) domains that are not present in all proteins, (2) domains that are present in different orders in different proteins, and (3) domains that are present in multiple copies in some proteins. In addition, ABA is useful in the alignment of genomic sequences that contain duplications and inversions. We provide several examples illustrating the applications of ABA.

Algorithms↗

Genome rearrangements in mammalian evolution: lessons from human and mouse genomes.

Although analysis of genome rearrangements was pioneered by Dobzhansky and Sturtevant 65 years ago, we still know very little about the rearrangement events that produced the existing varieties of genomic architectures. The genomic sequences of human and mouse provide evidence for a larger number of rearrangements than previously thought and shed some light on previously unknown features of mammalian evolution. In particular, they reveal that a large number of microrearrangements is required to explain the differences in draft human and mouse sequences. Here we describe a new algorithm for constructing synteny blocks, study arrangements of synteny blocks in human and mouse, derive a most parsimonious human-mouse rearrangement scenario, and provide evidence that intrachromosomal rearrangements are more frequent than interchromosomal rearrangements. Our analysis is based on the human-mouse breakpoint graph, which reveals related breakpoints and allows one to find a most parsimonious scenario. Because these graphs provide important insights into rearrangement scenarios, we introduce a new visualization tool that allows one to view breakpoint graphs superimposed with genomic dot-plots.

Algorithms↗

Structure function of passive scalars in two-dimensional turbulence.

The structure function of a scalar theta(x,t), passively advected in a two-dimensional turbulent flow u(x,t), is discussed by means of the fractal dimension delta1g of the passive-scalar graph. A relation between delta1g, the scaling exponent zeta(theta)(1) of the scalar structure function D1(theta)r, and the structure function D2(r) of the underlying flow field is derived. Different from the three-dimensional (3D) case, the 2D structure function also depends on an additional parameter, characteristic of the driving of the passive scalar. In the enstrophy inertial subrange a mean-field approximation for the velocity structure function gives a scaling of the passive scalar graph with delta1g<2 for intermediate and large values of the Prandtl number Pr. In the energy inertial subrange a model for the energy spectrum and thus D2(r) gives a passive-scalar graph scaling with exponent delta1g=5/3. Finally, we discuss an application to recent observations of scalar dispersion in nonuniversal 2D flows.

Journal Article↗

Beyond blobs in percolation cluster structure: the distribution of 3-blocks at the percolation threshold.

The incipient infinite cluster appearing at the bond percolation threshold can be decomposed into singly connected "links" and multiply connected "blobs." Here we decompose blobs into objects known in graph theory as 3-blocks. A 3-block is a graph that cannot be separated into disconnected subgraphs by cutting the graph at two or fewer vertices. Clusters, blobs, and 3-blocks are special cases of k-blocks with k=1, 2, and 3, respectively. We study bond percolation clusters at the percolation threshold on two-dimensional (2D) square lattices and three-dimensional cubic lattices and, using Monte Carlo simulations, determine the distribution of the sizes of the 3-blocks into which the blobs are decomposed. We find that the 3-blocks have fractal dimension d(3)=1.2+/-0.1 in 2D and 1.15+/-0.1 in 3D. These fractal dimensions are significantly smaller than the fractal dimensions of the blobs, making possible more efficient calculation of percolation properties. Additionally, the closeness of the estimated values for d(3) in 2D and 3D is consistent with the possibility that d(3) is dimension independent. Generalizing the concept of the backbone, we introduce the concept of a "k-bone," which is the set of all points in a percolation system connected to k disjoint terminal points (or sets of disjoint terminal points) by k disjoint paths. We argue that the fractal dimension of a k-bone is equal to the fractal dimension of k-blocks, allowing us to discuss the relation between the fractal dimension of k-blocks and recent work on path crossing probabilities.

Journal Article↗