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At least 1,189 records · Page 66Linked to original sources
PubMed2001

Comparison of variance components, ANOVA and regression of offspring on midparent (ROMP) methods for SNP markers.

An extension of the traditional regression of offspring on midparent (ROMP) method was used to estimate the heritability of the trait, test for marker association, and estimate the heritability attributable to a marker locus. The fifty replicates of the Genetic Analysis Workshop (GAW) 12 simulated general population data were used to compare the ROMP method with the variance components method as implemented in SOLAR as a test for marker association, and to a standard analysis of variance (ANOVA) method. Large sample statistical properties of the ROMP and ANOVA methods were compared using 2,000 replicates resampled from the families of the original 50 replicates. Overall, the power to detect a completely associated single nucleotide polymorphism (SNP) marker was high, and the type I error rates were similar to nominal significance levels for all three methods. The standard deviations of the estimates of the heritability of the trait were large for both SOLAR and ROMP, but the estimates were, on average, close to those of the generating model for both methods. However, on average, SOLAR overestimated the heritability attributable to the associated SNP marker (by 256%) while ROMP underestimated it (by 26%).

Analysis of Variance↗
PubMed2005

Approaches to detecting gene x gene interaction in Genetic Analysis Workshop 14 pedigrees.

Whether driven by the general lack of success in finding single-gene contributions to complex disease, by increased knowledge about the potential involvement of specific biological interactions in complex disease, or by recent dramatic increases in computational power, a large number of approaches to detect locus x locus interactions were recently proposed and implemented. The six Genetic Analysis Workshop 14 (GAW14) papers summarized here each applied either existing or refined approaches with the goal of detecting gene x gene, or locus x locus, interactions in the GAW14 data. Five of six papers analyzed the simulated data; the other analyzed the Collaborative Study on the Genetics of Alcoholism data. The analytic strategies implemented for detecting interactions included multifactor dimensionality reduction, conditional linkage analysis, nonparametric linkage correlation, two-locus parametric linkage analysis, and a joint test of linkage and association. Overall, most of the groups found limited success in consistently detecting all of the simulated interactions due, in large part, to the nature of the generating model.

Alcoholism↗
PubMed2003

Meta-analysis of indels causing human genetic disease: mechanisms of mutagenesis and the role of local DNA sequence complexity.

A relatively rare type of mutation causing human genetic disease is the indel, a complex lesion that appears to represent a combination of micro-deletion and micro-insertion. In the absence of meta-analytical studies of indels, the mutational mechanisms underlying indel formation remain unclear. Data from the Human Gene Mutation Database (HGMD) were therefore used to compare and contrast 211 different indels underlying genetic disease in an attempt to deduce the processes responsible for their genesis. Each indel was treated as if it were the result of a two-step insertion/deletion process and was assessed in the context of 10 base-pairs DNA sequence flanking the lesion on either side. Several indel hotspots were noted and a GTAAGT motif was found to be significantly over-represented in the vicinity of the indels studied. Previously postulated mechanisms underlying micro-deletions and micro-insertions were initially explored in terms of local DNA sequence regularity as measured by its complexity. The change in complexity consequent to a mutation was found to be indicative of the type of repeat sequence involved in mediating the event, thereby providing clues as to the underlying mutational mechanism. Complexity analysis was then employed to examine the possible intermediates through which each indel could have occurred and to propose likely mechanisms and pathways for indel generation on an individual basis. Manual analysis served to confirm that the majority of indels (>90%) are explicable in terms of a two-step process involving established mutational mechanisms. Indels equivalent to double base-pair substitutions (22% of the total) were found to be mechanistically indistinguishable from the remainder and may therefore be regarded as a special type of indel. The observed correspondence between changes in local DNA sequence complexity and the involvement of specific mutational mechanisms in the insertion/deletion process, and the ability of generated models to account for both the number and identity of the bases deleted and/or inserted, makes this approach invaluable not only for the analysis of indel formation, but also for the study of other types of complex lesion.

Base Sequence↗
PubMed2003

Rosetta predictions in CASP5: successes, failures, and prospects for complete automation.

We describe predictions of the structures of CASP5 targets using Rosetta. The Rosetta fragment insertion protocol was used to generate models for entire target domains without detectable sequence similarity to a protein of known structure and to build long loop insertions (and N-and C-terminal extensions) in cases where a structural template was available. Encouraging results were obtained both for the de novo predictions and for the long loop insertions; we describe here the successes as well as the failures in the context of current efforts to improve the Rosetta method. In particular, de novo predictions failed for large proteins that were incorrectly parsed into domains and for topologically complex (high contact order) proteins with swapping of segments between domains. However, for the remaining targets, at least one of the five submitted models had a long fragment with significant similarity to the native structure. A fully automated version of the CASP5 protocol produced results that were comparable to the human-assisted predictions for most of the targets, suggesting that automated genomic-scale, de novo protein structure prediction may soon be worthwhile. For the three targets where the human-assisted predictions were significantly closer to the native structure, we identify the steps that remain to be automated.

Algorithms↗
PubMed2006

WHISCY: what information does surface conservation yield? Application to data-driven docking.

Protein-protein interactions play a key role in biological processes. Identifying the interacting residues is a first step toward understanding these interactions at a structural level. In this study, the interface prediction program WHISCY is presented. It combines surface conservation and structural information to predict protein-protein interfaces. The accuracy of the predictions is more than three times higher than a random prediction. These predictions have been combined with another interface prediction program, ProMate [Neuvirth et al. J Mol Biol 2004;338:181-199], resulting in an even more accurate predictor. The usefulness of the predictions was tested using the data-driven docking program HADDOCK [Dominguez et al. J Am Chem Soc 2003;125:1731-1737] in an unbound docking experiment, with the goal of generating as many near-native structures as possible. Unrefined rigid body docking solutions within 10 A ligand RMSD from the true structure were generated for 22 out of 25 docked complexes. For 18 complexes, more than 100 of the 8000 generated models were correct. Our results demonstrates the potential of using interface predictions to drive protein-protein docking.

Binding Sites↗
PubMed1993

An empirical energy function for threading protein sequence through the folding motif.

In this paper we present a new residue contact potential derived by statistical analysis of protein crystal structures. This gives mean hydrophobic and pairwise contact energies as a function of residue type and distance interval. To test the accuracy of this potential we generate model structures by "threading" different sequences through backbone folding motifs found in the structural data base. We find that conformational energies calculated by summing contact potentials show perfect specificity in matching the correct sequences with each globular folding motif in a 161-protein data set. They also identify correct models with the core folding motifs of hemerythrin and immunoglobulin McPC603 V1-domain, among millions of alternatives possible when we align subsequences with alpha-helices and beta-strands, and allow for variation in the lengths of intervening loops. We suggest that contact potentials reflect important constraints on nonbonded interaction in native proteins, and that "threading" may be useful for structure prediction by recognition of folding motif.

Amino Acid Sequence↗
PubMed2002

Utility of three types of mass spectrometers for determining elemental compositions of ions formed from chromatographically separated compounds.

Concentration factors of 1000 and more reveal dozens of compounds in extracts of water supplies. Library mass spectra for most of these compounds are not available, and alternative means of identification are needed. Determination of the elemental compositions of the ions in mass spectra makes feasible searches of commercial and chemical literature that often lead to compound identification. Instrumental capabilities that constrain the utility of a mass spectrometer for determining ion compositions for compounds that elute from a chromatographic column are scan speed, mass accuracy, linear dynamic range, and resolving power. Mass peak profiling from selected ion recording data (MPPSIRD) performed with a double-focusing mass spectrometer provides the best combination of these capabilities. This technique provides unique ion compositions for ions of higher mass from compounds eluting from a gas chromatograph than can be obtained by orthogonal acceleration time-of-flight (oa-TOF) or Fourier transform ion cyclotron resonance mass spectrometry. Multiple compositions are usually possible for an ion with a mass exceeding 150 Da within the error limits of the mass measurement. The correct composition is selected based on measured exact masses of the mass peak profiles resulting from isotopic ions higher in mass by 1 and 2 Da and accurate measurement of the summed abundances of these isotopic ions relative to the monoisotopic ion. A profile generation model (PGM) automatically determines which compositions are consistent with measured exact masses and relative abundances. The utility of oa-TOF and double-focusing mass spectrometry using ion composition elucidation (MPPSIRD plus the PGM) are considered for determining ion compositions of two compounds found in drinking water extracts and a third compound from a monitoring well at a landfill. Published in 2002 by John Wiley & Sons, Ltd.

Fourier Analysis↗
PubMed1997

Straight-line movement and competitive mate searching in prairie rattlesnakes, Crotalus viridis viridis

Males compete in various ways for mating and reproductive success. Phylogenetic factors and local ecology affect female spatial and temporal distributions, which in turn influence the form of male competition, sexual selection and mating systems. In prairie rattlesnake, Crotalus viridis viridispopulations where (1) males seek females during a brief reproductive period, (2) females are relatively few, and (3) females are widely and unpredictably distributed spatially into small discrete clusters, males should show efficient mate searching more so than time-consuming 'handling' (e.g. fighting, mate persuasion). Natural history studies and computer and mathematical modelling generate this expectation. This long-term field study of prairie rattlesnakes in Wyoming indicated that straight-line (i.e. fixed-bearing) movement by males is critical for mate location and, thus, for mating success. Males that searched along straight-line paths located and mated with more females than those having less straight movement paths. Fighting was observed rarely, and no relationship was found between males' success at mate location and body mass and/or snout-vent length. Thus a range of traits may mediate competition and mating success among male snakes.

Journal Article↗
PubMed2000

S100-annexin complexes: some insights from structural studies.

Several annexins have been shown to bind proteins that belong to the S100 calcium-binding protein family. The two best-characterized complexes are annexin II with p11 and annexin I with S100C, the former of which has been implicated in membrane fusion processes. We have solved the crystal structures of the complexes of p11 with annexin II N-terminus and of S100C with annexin I N-terminus. Using these structural results, as well as electron microscopy observations of liposome junctions formed in the presence of such complexes (Lambert et al., 1997 J Mol Biol 272, 42-55), we propose a computer generated model for the entire annexin II/p11 complex.

Annexin A2↗
PubMed2000

Tubal sterilization and risk of cancer of the endometrium.

OBJECTIVE: Surgical sterilization is a common method of contraception among U.S. women. Most surgical sterilizations are tubal ligations, but few studies have investigated their potential impact on endometrial cancer risk. METHODS: A case-control study included 405 women diagnosed with endometrial cancer at 5 U.S. medical centers between 1987 and 1990 and 297 age-, race-, and location-matched controls who were identified by random-digit-dialing. Questionnaires ascertained information on tubal sterilization, and logistic regression models generated odds ratios (ORs) to estimate relative risk. RESULTS: The OR and 95% confidence interval for tubal sterilization, which was reported by 47 cases and 40 controls, was 0.9 (0.6-1.4) before adjustment and 1. 4 (0.8-2.4) after adjustment for age, parity, and oral contraceptive use. Age at surgery, years since surgery, or calendar years of surgery were not associated with endometrial cancer, and associations did not vary according to parity or stage of disease at diagnosis. CONCLUSIONS: Tubal sterilization is not substantially associated with endometrial cancer.

Adult↗
PubMed2001

The importance of somatic mutations in the V(lambda) gene 2a2 in human monoclonal anti-DNA antibodies.

2a2 is the most commonly rearranged gene in the human V(lambda )locus. It has been postulated that certain immunoglobulin genes (including 2a2) are rearranged preferentially because their germline sequences encode structures capable of binding to a range of antigens. Somatic mutation could then increase the specificity and affinity of binding to a particular antigen. We studied the properties of five IgG molecules in which the same heavy chain was paired with different light chains derived from 2a2. The pattern of somatic mutations in 2a2 was shown to be crucial in conferring the ability to bind DNA, but two different patterns of mutation each conferred this ability.Computer-generated models of the three-dimensional structures of these antibodies illustrate the ability of 2a2 to form a DNA binding site in different ways. Somatic mutations at the periphery of the DNA binding site were particularly important. In two different light chains, mutations to arginine at different sites in the complementarity determining regions (CDRs) enhanced binding to DNA. In a third light chain, however, mutation to arginine at a different site blocked binding to DNA.

Amino Acid Sequence↗
PubMed1997

The Structure of Perceptual Categories

When presented with a small set of sample objects, human observers have the striking capacity to induce a more general class. Generalization can even proceed from a single object ("one-shot categorization"). The inference is apparently guided by the principle that a good categorical hypothesis is one in which the observed object would be a typcal, "non-accidental," or generic example; this idea is formalized here as the Genericity Constraint. In the theory proposed here, each categorical hypothesis is a "generative model," a sequence of transformations by which the object is interpreted as having been created; objects are considered to be in the same category if they were created by the same set of operations. The set of all available category models can be explicitly enumerated in a lattice, an explicit structure that partially orders the models by their degree of regularity or genericity-more abstract models are higher in the lattice, and more regular or constrained models are lower. The Genericity Constraint dictates that among all the models on the lattice that apply, the observer should choose the one in which the observed object is generic, which is simply the lowest in the partial order. A series of experiments are reported in which subjects are asked to generalize from simple figures. The results corroborate the role of the lattice and the Genericity Constraint in subjects' interpretations

Journal Article↗
PubMed1999

Experimental evaluation of a surface charge method for computing the induced magnetic field in trabecular bone.

The magnetic field induced in the pores of trabecular bone as a result of the susceptibility difference between bone and bone marrow was computed with the aid of magnetic surface charge models generated from images of trabecular bone specimens acquired at 78 and 63 microm resolution. The predicted field was compared with the values derived from 2D and 3D field maps obtained by echo-offset imaging techniques and excellent agreement was found between the two methods. Finally, from the slopes of regression between the experimental and computed fields, the absolute susceptibility of bone was nondestructively determined as -11.0 x 10(-6) (MKS), which is in close agreement with a reported value of -11.3 x 10(-6) obtained with powdered bone by means of a spectroscopic susceptibility matching technique (J. A. Hopkins and F. W. Wehrli, Magn. Reson. Med. 37, 494-500 (1997)).

Animals↗
PubMed1999

Coevolution of a plant host-pathogen gene-for-gene system in a metapopulation model without cost of resistance or cost of virulence

A metapopulation model of a one-locus gene-for-gene system in a plant host and a biotrophic pathogen is described. The model allows subpopulations to go extinct, and, due to characteristic differences in life-history strategies, the plant host is assumed to be recolonized from a seed bank, whereas the pathogen is recolonized by migration. It is shown that variation in the gene-for-gene system can be maintained at a noticeable level without assuming cost of resistance or cost of virulence, if the probability of extinction depends on the host mean fitness in the subpopulation. The level of variation in the pathogen population increases with increasing extinction rate, genetic drift and fitness of the infected host, but decreases with increasing migration rate. Generally, these effects are magnified for life cycles in which selection occur before genetic drift and after migration. The metapopulation model generates positive associations between the virulence allele and the resistance allele without assuming cost of resistance or cost of virulence. Copyright 1999 Academic Press.

Journal Article↗
PubMed1998

Computer modeling of size and shape descriptors of alpha 1-adrenergic receptor antagonists and quantitative structure-affinity/selectivity relationships.

Computational chemistry and molecular modeling procedures allow us to define and compute ad hoc size and shape descriptors on the different prototropic forms assumed by drugs in biotest solutions. Together with experimental data measured on a well-identified target receptor, these descriptors are essential elements for obtaining simple, consistent, comparable, and easily interpretable theoretical quantitative structure-activity relationship (QSAR) models based on the ligand similarity-target receptor complementarity paradigm. In this context, quantitative size and shape affinity/subtype selectivity relationships have been modeled for a large set of very heterogeneous alpha 1a-, alpha 1b-, and alpha 1c-adrenergic receptor antagonists. The linear QSAR models generated have been validated by predicting both binding affinity and selectivity of a test set of noncongeneric antagonists. The satisfactory results obtained highlight both the simplicity and the versatility of the approach presented.

Adrenergic alpha-Antagonists↗
PubMed1984

Cross-linking studies related to the location of the rigor compliance in glycerinated rabbit psoas fibers: is the SII portion of the cross-bridge compliant?

The muscle tension generation model of Huxley and Simmons (1971) postulates an independent elastic element in the cross-bridge. This elastic structure was tentatively placed in the SII portion of the cross-bridge in the model. To check this assumption, we fixed the SII portion onto the surface of the thick filament in glycerinated rabbit psoas fibers in rigor by chemically cross-linking with dimethyl suberimidate, and compared the stiffness of the cross-linked fibers with that of the fibers before cross-linking. The stiffness was determined by measuring the tension increment upon stretching a fiber segment in rigor. The contribution of the end compliance was found to be small. Cross-linking increased the rigor stiffness by 20 to 30%. Almost the same amount of the stiffness increase was also observed at a sarcomere length where there was no overlap between the thin and thick filaments, and in a fiber segment cross-linked in relaxing solution. Therefore, the 20 to 30% increase of the stiffness is not caused by the fixation of the SII portion onto the thick filament but caused by the cross-linking of some parallel elastic components. Since the rigor stiffness before cross-linking is almost proportional to the overlap between thick and thin filaments, we conclude that the muscle stiffness in rigor does not originate in the SII portion but reflects some compliance of the head portion of the cross-bridge.

Animals↗
PubMed1993

Cohort size and schooling choice.

"We develop a perfect-foresight overlapping generations model to investigate the effects of cohort size on schooling decisions and cohort-specific welfare measures.... We calibrate the partial equilibrium model using data on [U.S.] schooling investments and aggregate wages over the period 1920 through 1980, and use the parameters to assess the magnitude of lifetime cohort wealth and schooling elasticities computed with respect to the entire cohort size sequence. We find that the equilibrium response of schooling to perturbations in the cohort size sequence is small, so that the adverse effects of increases in the size of own and neighboring cohorts on cohort wealth are not significantly [mitigated] by adjustments in schooling investments within our modelling framework."

Americas↗
PubMed1994

Effect of murine interferon alpha/beta on tumour-induced suppressor function.

T-lymphocyte-mediated immunosuppression has been described in several animal models and in man. In animal models. T-cell-mediated immunosuppression can hasten the development of cancers, permit the growth of tumors in immunocompetent hosts, and inhibit otherwise effective antitumor immunotherapy. Cyclophosphamide can abrogate the T-cell-mediated immunosuppression. However, inappropriately administered cyclophosphamide can adversely affect antitumor immunity. On the basis of data showing that interferon alpha/beta (IFN alpha/beta) and IFN beta selectively abrogate the T-cell-mediated dinitrofluorobenzene-specific suppressor function, we investigated the efficacy of purified murine IFN alpha/beta in manipulating tumor-induced T-cell-mediated immunosuppression in the well-characterized P815 mastocytoma model. In this model, generation of cytotoxicity in vitro and its inhibition by T cells correlates with antitumor immunity in vivo. We report that IFN alpha/beta selectively diminishes the generation of tumor-induced suppressor activity.

Animals↗