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PubMed2002

Elastic properties of proteins: insight on the folding process and evolutionary selection of native structures.

We carry out a theoretical study of the vibrational and relaxation properties of naturally occurring proteins with the purpose of characterizing both the folding and equilibrium thermodynamics. By means of a suitable model, we provide a full characterization of the spectrum and eigenmodes of vibration at various temperatures by merely exploiting the knowledge of the protein native structure. It is shown that the rate at which perturbations decay at the folding transition correlates well with experimental folding rates. This validation is carried out on a list of about 30 two-state folders. Furthermore, the qualitative analysis of residues mean square displacements (shown to reproduce crystallographic data accurately) provides a reliable and statistically accurate method to identify crucial folding sites/contacts. This novel strategy is validated against clinical data for human immunodeficiency virus type 1 (HIV-1) protease. Finally, we compare the spectra and eigenmodes of vibration of natural proteins against randomly generated compact structures and regular random graphs. The comparison reveals a distinctive enhanced flexibility of natural structures accompanied by slow relaxation times at the folding temperature. The fact that these properties are connected intimately to the presence and assembly of secondary motifs hints at the special criteria adopted by evolution in the selection of viable folds.

Biological Evolution↗
PubMed2002

Topological and causal structure of the yeast transcriptional regulatory network.

Interpretation of high-throughput biological data requires a knowledge of the design principles underlying the networks that sustain cellular functions. Of particular importance is the genetic network, a set of genes that interact through directed transcriptional regulation. Genes that exert a regulatory role encode dedicated transcription factors (hereafter referred to as regulating proteins) that can bind to specific DNA control regions of regulated genes to activate or inhibit their transcription. Regulated genes may themselves act in a regulatory manner, in which case they participate in a causal pathway. Looping pathways form feedback circuits. Because a gene can have several connections, circuits and pathways may crosslink and thus represent connected components. We have created a graph of 909 genetically or biochemically established interactions among 491 yeast genes. The number of regulating proteins per regulated gene has a narrow distribution with an exponential decay. The number of regulated genes per regulating protein has a broader distribution with a decay resembling a power law. Assuming in computer-generated graphs that gene connections fulfill these distributions but are otherwise random, the local clustering of connections and the number of short feedback circuits are largely underestimated. This deviation from randomness probably reflects functional constraints that include biosynthetic cost, response delay and differentiative and homeostatic regulation.

Gene Expression Regulation, Fungal↗
PubMed1981

Systematic method of development in liquid chromatography applied to the determination of antiepileptic drugs.

The object of a liquid-chromatographic analysis is to separate, identify, and quantitate the constituents of interest in a sample mixture within an acceptable analysis time. This will be achieved by a systematic analysis development rather than by a trial-and-error approach. Such a systematic procedure requires a knowledge of the chromatographic parameters governing resolution and analysis time and their relative influences on resolution and its experimental implication. Furthermore, basic information about the mechanisms of the modes of liquid chromatography (adsorption, partition, ion exchange, and steric exclusion) and about the types of sample which can be preferentially analyzed by them is necessary. This information leads to a rational selection of the separation system that promises the best chance of success. In the subsequent experimental work, the analyst systematically measures and calculates resolution and analysis time as functions of selectivity, capacity, and efficiency of the phase system under selected chromatographic conditions. The essential chromatograms, tables, and graphs resulting from this systematic method of development are documented so that it is possible to replicate the analysis procedure in the laboratories involved. The result is a set of chromatographic conditions capable of achieving an optimum compromise between resolution and analysis time. The procedure is applied to routine therapeutic drug monitoring of antiepileptic drugs in patient serum.

Anticonvulsants↗
PubMedDate not supplied

[The role of social networks in exclusive breastfeeding].

OBJECTIVE: The purpose of the study was to explore the network that the social actors form around the mother with a neonate and the roles they play, either as support or as an obstacle of exclusive breast-feeding. MATERIAL AND METHODS: We applied a social network survey in two stages: in the first one, we asked mothers with babies under six months of age who had helped them breast-feed their babies and who had had a bearing on not letting them do it. Later, we asked other mothers who had told them to give formula, water, tea or solid food to the babies. With the answers we formed two "cases by actors" matrices. We computed the frequencies to find out those people that most influenced the mother for and against exclusive breast-feeding. We also graphed the results from the matrix to visualize the answers. RESULTS: The maternal grandmother of the child, the physician and the paternal grandmother appeared as those who most positively contributed with exclusive breast-feeding. Paradoxically, they are the same who most influenced its interruption. DISCUSSION: We were looking for a social network to support exclusive breast-feeding and another one to hinder it, but the two networks turned out to be very similar. The same characters who help a mother to breast-feed are the ones who make her stop. The implication for an intervention program is that it is necessary to strengthen some knowledge and inhibit some other within the same group of people.

Breast Feeding↗
PubMed2001

Perfect simulation from population genetic models with selection.

We consider using the ancestral selection graph (ASG) to simulate samples from population genetic models with selection. Currently the use of the ASG to simulate samples is limited. This is because the computational requirement for simulating samples increases exponentially with the selection rate and also due to needing to simulate a sample of size one from the population at equilibrium. For the only case where the distribution of a sample of size one is known, that of parent-independent mutations, more efficient simulation algorithms exist. We will show that by applying the idea of coupling from the past to the ASG, samples can be simulated from a general K-allele model without knowledge of the distribution of a sample of size one. Furthermore, the computation involved in generating such samples appears to be less than that of simulating the ASG until its ultimate ancestor. In particular, in the case of genic selection with parent-independent mutations, the computational requirement increases only quadratically with the selection rate. The algorithm is demonstrated by simulating samples at a microsatellite locus.

Algorithms↗
PubMed2004

Network analysis of protein structures identifies functional residues.

Identifying active site residues strictly from protein three-dimensional structure is a difficult task, especially for proteins that have few or no homologues. We transformed protein structures into residue interaction graphs (RIGs), where amino acid residues are graph nodes and their interactions with each other are the graph edges. We found that active site, ligand-binding and evolutionary conserved residues, typically have high closeness values. Residues with high closeness values interact directly or by a few intermediates with all other residues of the protein. Combining closeness and surface accessibility identified active site residues in 70% of 178 representative structures. Detailed structural analysis of specific enzymes also located other types of functional residues. These include the substrate binding sites of acetylcholinesterases and subtilisin, and the regions whose structural changes activate MAP kinase and glycogen phosphorylase. Our approach uses single protein structures, and does not rely on sequence conservation, comparison to other similar structures or any prior knowledge. Residue closeness is distinct from various sequence and structure measures and can thus complement them in identifying key protein residues. Closeness integrates the effect of the entire protein on single residues. Such natural structural design may be evolutionary maintained to preserve interaction redundancy and contribute to optimal setting of functional sites.

Allosteric Site↗
PubMed2006

Wheat EST resources for functional genomics of abiotic stress.

BACKGROUND: Wheat is an excellent species to study freezing tolerance and other abiotic stresses. However, the sequence of the wheat genome has not been completely characterized due to its complexity and large size. To circumvent this obstacle and identify genes involved in cold acclimation and associated stresses, a large scale EST sequencing approach was undertaken by the Functional Genomics of Abiotic Stress (FGAS) project. RESULTS: We generated 73,521 quality-filtered ESTs from eleven cDNA libraries constructed from wheat plants exposed to various abiotic stresses and at different developmental stages. In addition, 196,041 ESTs for which tracefiles were available from the National Science Foundation wheat EST sequencing program and DuPont were also quality-filtered and used in the analysis. Clustering of the combined ESTs with d2_cluster and TGICL yielded a few large clusters containing several thousand ESTs that were refractory to routine clustering techniques. To resolve this problem, the sequence proximity and "bridges" were identified by an e-value distance graph to manually break clusters into smaller groups. Assembly of the resolved ESTs generated a 75,488 unique sequence set (31,580 contigs and 43,908 singletons/singlets). Digital expression analyses indicated that the FGAS dataset is enriched in stress-regulated genes compared to the other public datasets. Over 43% of the unique sequence set was annotated and classified into functional categories according to Gene Ontology. CONCLUSION: We have annotated 29,556 different sequences, an almost 5-fold increase in annotated sequences compared to the available wheat public databases. Digital expression analysis combined with gene annotation helped in the identification of several pathways associated with abiotic stress. The genomic resources and knowledge developed by this project will contribute to a better understanding of the different mechanisms that govern stress tolerance in wheat and other cereals.

Acclimatization↗
PubMed1995

Representing clinical narratives using conceptual graphs.

The analysis of medical narratives and the generation of natural language expressions are strongly dependent on the existence of an adequate representation language. Such a language has to be expressive enough in order to handle the complexity of human reasoning in the domain. Sowa's Conceptual Graphs (CG) are an answer, and this paper presents a multilingual implementation, using French, English and German. Current developments demonstrate the feasibility of an approach to natural Language Understanding where semantic aspects are dominant, in contrast to syntax driven methods. The basic idea is to aggregate blocks of words according to semantic compatibility rules, following a method called Proximity Processing. The CG representation is gradually built, starting from single words in a semantic lexicon, to finally give a complete representation of the sentence under the form of a single CG. The process is dependent on specific rules of the medical domain, and for this reason is largely controlled by the declarative knowledge of the medical Linguistic Knowledge Base.

Artificial Intelligence↗
PubMedDate not supplied

Obesity in pre-school chldren: issuse and challenges for community based child health nurses.

Childhood obesity is becoming a topical issue in both the health literature and the popular media and increasingly child health nurses are observing preschool children who appear to be disproportionately heavy for their height when plotted on standardized growth charts. In this paper literature related to childhood obesity in New Zealand and internationally is explored to identify current issues, and the implications of these issues for nurses in community based child health practice are discussed. Themes that emerged from the literature relate to the measurement of obesity, links between childhood and adult obesity and issues for families. A theme in the literature around maternal perception was of particular interest. Studies that investigated maternal perceptions of childhood obesity found that mothers identified their child as being overweight or obese only when it imposed limitations on physical activity or when the children were teased rather than by referring to individual growth graphs. The implications for nursing in the area of child health practice is discussed as nurses working in this area need an understanding of the complex and often emotive issues surrounding childhood obesity and an awareness of the reality of people's lives when devising health promotion strategies.

Activities of Daily Living↗
PubMed1999

Information structure and the relative efficacy of tables and graphs.

Users and system designers often prefer to display information with graphs rather than with tables. However, empirical studies that compared task performance with the two display types frequently revealed either an advantage of tables over graphs or no differences between the displays. This apparent contradiction may result from previous studies in which the importance of the structure that usually exists in displayed information is overlooked. We predict that graphic displays will have an advantage over tables when the displayed information has structure and when this structure is relevant for the task. These conditions generally exist in the actual use of information displays, but have seldom been assessed in experiments. In the present study participants in an experiment performed an information extraction task and a prediction task with unstructured or structured data and with different levels of prior information about the structure. The results showed that the information structure and prior knowledge about the existence of structure affected the advantage of graphic displays over tables when task performance depended on the use of structure. Existing approaches to the study of displays were analyzed in view of these findings. Actual or potential applications of this research include the development of better displays for process control and decision support and better operator training programs.

Analysis of Variance↗
PubMed2002

The KEGG databases at GenomeNet.

The Kyoto Encyclopedia of Genes and Genomes (KEGG) is the primary database resource of the Japanese GenomeNet service (http://www.genome.ad.jp/) for understanding higher order functional meanings and utilities of the cell or the organism from its genome information. KEGG consists of the PATHWAY database for the computerized knowledge on molecular interaction networks such as pathways and complexes, the GENES database for the information about genes and proteins generated by genome sequencing projects, and the LIGAND database for the information about chemical compounds and chemical reactions that are relevant to cellular processes. In addition to these three main databases, limited amounts of experimental data for microarray gene expression profiles and yeast two-hybrid systems are stored in the EXPRESSION and BRITE databases, respectively. Furthermore, a new database, named SSDB, is available for exploring the universe of all protein coding genes in the complete genomes and for identifying functional links and ortholog groups. The data objects in the KEGG databases are all represented as graphs and various computational methods are developed to detect graph features that can be related to biological functions. For example, the correlated clusters are graph similarities which can be used to predict a set of genes coding for a pathway or a complex, as summarized in the ortholog group tables, and the cliques in the SSDB graph are used to annotate genes. The KEGG databases are updated daily and made freely available (http://www.genome.ad.jp/kegg/).

Animals↗
PubMedDate not supplied

Strategy to assess, develop, and evaluate critical thinking.

BACKGROUND: To care for patients with complex health problems, nurses need a strong knowledge base and critical thinking skills. Critical thinking enables the nurse to process and analyze information, solve clinical problems, and decide on actions to take. Teaching and evaluation, however, often focus on memorizing facts and details about clinical care rather than on critical thinking. METHOD: Context-dependent test items are designed to evaluate critical thinking and may be used in orientation, in competency testing, and by preceptors and others who work with beginning nurses for formative evaluation and discussions with them. A context-dependent item presents introductory material to analyze and determine a course of action. The introductory material may be a clinical scenario, an issue nurses might face in their practice, patient data, graphs or flow sheets, and other types of material for analysis. Carefully planned questions for assessing critical thinking are then asked. CONCLUSION: The article describes how to develop and use context-dependent items in nursing continuing education.

Clinical Competence↗
PubMed1990

Isotachophoretic separation of organic acids in biological fluids.

The operating conditions for the isotachophoretic separation of organic acids were evaluated. At pH values ranging from 2.90 to 4.25 both relative step heights and molar flow-rates were determined experimentally for 26 anions. Comparing the observed values with simulated data, highly significant (p = 0.0001) correlation coefficients of 0.993 and 0.920, respectively, were found at pH 3.50. Whereas the concentration of the leading electrolyte did not affect the relative step heights, it increased the molar flow-rates significantly. The same applied to the detection current. The time of analysis was observed to be a function of the concentration of the leading electrolyte. However, the time elapsed between injection of the analyte and its detection depended solely on the volume and not on the amount of analyte injected. In isotachophoresis, incomplete separation of two compounds is indicated by the occurrence of a mixed zone which can hardly be distinguished from a pure zone. Thus, knowledge of the separation capacity is a prime prerequisite in optimizing the system for the analysis of biological fluids. The separability of nine equimolar pairs of anions was determined at pH values ranging from 2.90 to 4.25. Although two ionogenic constituents would separate only when their migration rates in the mixed state were different, no clear correlation was observed between separation capacity and difference in relative mobility. Separability, however, was found to increase with increasing concentration of the leading electrolyte. While the separation capacity was not influenced by the electric current, it was significantly affected by the volume injected. In subsequent analyses of serum, cerebrospinal fluid, seminal plasma and prostatic fluid, a variety of organic acids could be detected. Calibration graphs for the detected anions revealed a detection limit of 1 nmol and linearity over their biological concentration ranges. Further, the isotachophoretic results correlated well with high-performance liquid chromatographic and enzymatic analyses of citric acid and lactic acid in human seminal plasma and cerebrospinal fluid, respectively.

Acids↗
PubMed1990

Adding meaning to a design copy task through representational stimuli.

Occupational therapists frequently use their knowledge of occupation to add meaning and purpose to therapeutic tasks. This study investigated the effects of an attempt to add meaning to a particular occupational situation--a design copy task. Added meaning was given to the design copy task through the use of stimulus figures that were representational of familiar objects--an arrow, a house, and a face. The control condition consisted of three nonrepresentational figures composed of the same geometric shapes, in the same locations on the paper as the representational figures, but combined differently. The order of presentation was controlled for. The study used 30 elderly subjects (22 women and 8 men) from six nursing homes. The accuracy of the drawings was measured by a blind rater using graph overlays and predetermined rules of scoring. A two-way analysis of variance with one repeated measure (Order X Type of Figure) indicated significant differences at the .01 level between the representational and nonrepresentational figures. This study demonstrates how added meaning can enhance performance on a visuomotor task in a vulnerable population.

Aged↗
PubMed2006

Mutation parameters from DNA sequence data using graph theoretic measures on lineage trees.

MOTIVATION: B cells responding to antigenic stimulation can fine-tune their binding properties through a process of affinity maturation composed of somatic hypermutation, affinity-selection and clonal expansion. The mutation rate of the B cell receptor DNA sequence, and the effect of these mutations on affinity and specificity, are of critical importance for understanding immune and autoimmune processes. Unbiased estimates of these properties are currently lacking due to the short time-scales involved and the small numbers of sequences available. RESULTS: We have developed a bioinformatic method based on a maximum likelihood analysis of phylogenetic lineage trees to estimate the parameters of a B cell clonal expansion model, which includes somatic hypermutation with the possibility of lethal mutations. Lineage trees are created from clonally related B cell receptor DNA sequences. Important links between tree shapes and underlying model parameters are identified using mutual information. Parameters are estimated using a likelihood function based on the joint distribution of several tree shapes, without requiring a priori knowledge of the number of generations in the clone (which is not available for rapidly dividing populations in vivo). A systematic validation on synthetic trees produced by a mutating birth-death process simulation shows that our estimates are precise and robust to several underlying assumptions. These methods are applied to experimental data from autoimmune mice to demonstrate the existence of hypermutating B cells in an unexpected location in the spleen.

Algorithms↗
PubMed1994

Affiliations among steroid receptors as revealed by multivariate analysis of steroid binding data.

To illustrate the informative value of descriptive multivariate analysis in biochemical screening, we have analyzed several data matrices relating to the binding of steroids to the estrogen, progestin, androgen, glucocorticoid and mineralocorticoid receptors in different organs and species. We first compared dendrograms of steroid hormone receptors, that were obtained by an automatic hierarchical classification analysis of the binding data, to published phylogenetic trees of nuclear receptors based on amino-acid sequence analysis. The former classification describes the affiliations among the receptors as given by the binding specificity of a population of 187 steroids in a traditional cytosol binding assay (an indirect comparison of ligand binding sites); the latter describes the affiliations among the receptors as given by a comparison of selected primary sequences involved in ligand-dependent regulation of transactivation and dimerization. A similar hierarchical classification was also performed on the binding data of 62 steroids to myometrium cytosol from different species in order to show to what extent the progesterone-binding proteins in these species are affiliated. Hierarchical clustering methods classify each type of variable (receptor or steroid) independently. In order to be able to correlate both types of variable (receptors and steroids) on single-display graphs, it is necessary to resort to correspondence factorial analysis (CFA). CFA ranks the information content within the experimental system, highlighting major correlations and disclosing secondary correlations by eliminating redundant information and background noise. This multivariate method, applied to the analysis of published data, illustrated the particular specificity of estrogen binding in human vagina and raised the question of the nature of the binding protein in this tissue. Our examples are based on small data tables that can and have been analyzed de visu. However, it is certain that such descriptive multivariate techniques are indispensable for the analysis of large data banks not only to define structure-activity relationships but to estimate the degrees of affiliation among the biological variables being measured. Knowledge of such affiliations will help to organize available information in a context where the complexity of the biological systems under study is becoming increasingly apparent.

Animals↗
PubMed2001

A MeSH based intelligent search intermediary for Consumer Health Information Systems.

GIN Austria (Gesundheitsinformationsnetz Austria) offers patients and consumers reliable medical knowledge about diseases, wellness and disease management in an easy understandable way and enables them to quick and incessant access to informations about the Austrian health system and Austrian health organizations. To achieve full customer (patients, citizens) satisfaction to find relevant information we propose a concept of a vector-model oriented IR-Tool based on the controlled vocabulary of the MeSH Thesaurus (german version). By this approach users who are often not used to scientific terms and expressions are supported to build up their own query with MeSH Main Headings. In a second step broader and narrower Main Headings are added to the query vector by the system. For this calculation an adapted version of the Floyd-Warshall algorithm for directed, azyclic graphs is used. The tool is part of the GIN Search Modul, which will ease gathering health information from different heterogenous internet datasources.

Austria↗
PubMed2004

Molecular triangulation: bridging linkage and molecular-network information for identifying candidate genes in Alzheimer's disease.

A major challenge in human genetics is identifying the molecular basis of common heritable disorders. In contrast to rare single-gene diseases, multifactorial disorders are thought to arise from the combined effect of multiple gene variants, such that any single variant may have only a modest effect on disease susceptibility. We present a method to identify genes that may harbor a significant proportion of the genetic variation that predisposes individuals to a given multifactorial disorder. First, we perform an automated literature analysis that predicts physical interactions (edges) among candidate disease genes (seed nodes, selected on the basis of prior information) and other molecular entities. We derive models of molecular networks from this analysis and map the seed nodes to them. We then compute the graph-theoretic distance (the minimum number of edges that must be traversed) between the seed nodes and all other nodes in the network. We assume that nodes that are found in close proximity to multiple seed nodes are the best disease-related candidate genes. To evaluate this approach, we selected four seed genes, each with a proven role in Alzheimer's disease (AD). The method performed well in predicting additional network nodes that match AD gene candidates identified manually by an expert. We also show that the method prioritizes among the seed nodes themselves, rejecting false-positive seeds that are derived from (noisy) whole-genome genetic-linkage scans. We propose that this strategy will provide a valuable means to bridge genetic and genomic knowledge in the search for genetic determinants of multifactorial disorders.

Algorithms↗