Composite motifs integrating multiple protein structures increase sensitivity for function prediction.

The study of disease often hinges on the biological function of proteins, but determining protein function is a difficult experimental process. To minimize duplicated effort, algorithms for function prediction seek characteristics indicative of possible protein function. One approach is to identify substructural matches of geometric and chemical similarity between motifs representing known active sites and target protein structures with unknown function.

Deterministic and stochastic models of NFkappaB pathway.

In the article, we discuss the state of art and perspectives in deterministic and stochastic models of NFkappaB regulatory module. The NFkappaB is a transcription factor controlling various immune responses including inflammation and apoptosis. It is tightly regulated by at least two negative feedback loops involving IkappaBalpha and A20.

Single-site ventricular and biventricular pacing: investigation of latest depolarization strategy.

Aims Cardiac resynchronization therapy with biventricular pacing has proved beneficial in symptomatic heart failure patients, yet the effects in patients with structurally normal hearts remain unknown. We hypothesized that, in an acute swine model with normal anatomy and function, single-site right ventricular (RV) pacing would better preserve haemodynamic function and electrical activation compared to biventricular pacing. Methods Endocardial single-site pacing was performed in anesthetized swine (n = 7) from the RV septum and RV apex.

Single TNFalpha trimers mediating NF-kappaB activation: stochastic robustness of NF-kappaB signaling.

Background: The NF-kappaB regulatory network controls innate immune response by transducing variety of pathogen-derived and cytokine stimuli into well defined single-cell gene regulatory events.

Results: We analyze the network by means of the model combining a deterministic description for molecular species with large cellular concentrations with two classes of stochastic switches: cell-surface receptor activation by TNFalpha ligand, and IkappaBalpha and A20 genes activation by NF-kappaB molecules. Both stochastic switches are associated with amplification pathways capable of translating single molecular events into tens of thousands of synthesized or degraded proteins.

The MASH pipeline for protein function prediction and an algorithm for the geometric refinement of 3D motifs.

The development of new and effective drugs is strongly affected by the need to identify drug targets and to reduce side effects. Resolving these issues depends partially on a thorough understanding of the biological function of proteins. Unfortunately, the experimental determination of protein function is expensive and time consuming.

Adjoint systems for models of cell signaling pathways and their application to parameter fitting.

The paper concerns the problem of fitting mathematical models of cell signaling pathways. Such models frequently take the form of sets of nonlinear ordinary differential equations. While the model is continuous in time, the performance index used in the fitting procedure, involves measurements taken at discrete time moments.

Cavity scaling: automated refinement of cavity-aware motifs in protein function prediction.

Algorithms for geometric and chemical comparison of protein substructure can be useful for many applications in protein function prediction. These motif matching algorithms identify matches of geometric and chemical similarity between well-studied functional sites, motifs, and substructures of functionally uncharacterized proteins, targets. For the purpose of function prediction, the accuracy of motif matching algorithms can be evaluated with the number of statistically significant matches to functionally related proteins, true positives (TPs), and the number of statistically insignificant matches to functionally unrelated proteins, false positives (FPs).

Forward-time simulations of human populations with complex diseases.

Due to the increasing power of personal computers, as well as the availability of flexible forward-time simulation programs like simuPOP, it is now possible to simulate the evolution of complex human diseases using a forward-time approach. This approach is potentially more powerful than the coalescent approach since it allows simulations of more than one disease susceptibility locus using almost arbitrary genetic and demographic models. However, the application of such simulations has been deterred by the lack of a suitable simulation framework.

Cavity-aware motifs reduce false positives in protein function prediction.

Determining the function of proteins is a problem with immense practical impact on the identification of inhibition targets and the causes of side effects. Unfortunately, experimental determination of protein function is expensive and time consuming. For this reason, algorithms for computational function prediction have been developed to focus and accelerate this effort.

Robust association of the APOE epsilon4 allele with premature myocardial infarction especially in patients without hypercholesterolaemia: the Aachen study.

Background: Genetic influence on the manifestation of coronary artery disease (CAD) and myocardial infarction (MI) has been shown previously. From many candidate genes the APOE (apolipoprotein E) with the major alleles epsilon2/epsilon3/epsilon4 is in the focus of interest.

Materials And Methods: In 1817 patients admitted for their first left heart catheterization at a premature age (males < 55 and females < 65) the association of APOE alleles with MI was analysed.

Simulations provide support for the common disease-common variant hypothesis.

The success of mapping genes involved in complex diseases, using association or linkage disequilibrium methods, depends heavily on the number and frequency of susceptibility alleles of these genes. These methods will be economically and statistically feasible if common diseases are usually influenced by one or a few susceptibility alleles at each locus (common disease-common variant, CDCV, hypothesis), but not so if there is a high degree of allelic heterogeneity. Here, we use forward-time population simulations to investigate the impact of various genetic and demographic factors on the allelic spectra of human diseases, on the basis of two models proposed by Reich and Lander and by Pritchard.

Reaction-diffusion approach to modeling of the spread of early tumors along linear or tubular structures.

We consider a system composed of a tubular sheet of early tumor cells, occupying the surface of a structure existing in the organism. We assume that the cells have a potential for proliferation in response to a growth factor. This model can be thought of as representing an early stage (pre-in situ) of tumor evolution.

Extremely simple single-prism ultrashort- pulse compressor.

We have designed and demonstrated a very simple and compact ultrashort-pulse compressor using a single prism and a corner-cube. Our design is significantly easier to align and tune compared with previous designs. Angle-tuning the prism wavelength-tunes, and translating the corner cube varies the group-delay dispersion over a wide range.

Stochastic search gene suggestion: a Bayesian hierarchical model for gene mapping.

Mapping the genes for a complex disease, such as diabetes or rheumatoid arthritis (RA), involves finding multiple genetic loci that may contribute to the onset of the disease. Pairwise testing of the loci leads to the problem of multiple testing. Looking at haplotypes, or linear sets of loci, avoids multiple tests but results in a contingency table with sparse counts, especially when using marker loci with multiple alleles.

Recurrent use of evolutionary importance for functional annotation of proteins based on local structural similarity.

The annotation of protein function has not kept pace with the exponential growth of raw sequence and structure data. An emerging solution to this problem is to identify 3D motifs or templates in protein structures that are necessary and sufficient determinants of function. Here, we demonstrate the recurrent use of evolutionary trace information to construct such 3D templates for enzymes, search for them in other structures, and distinguish true from spurious matches.

APOE alleles are not associated with calcific aortic stenosis.

Objectives: To analyse the association of APOE alleles with aortic stenosis (AS) in a large study population.

Methods: Patients with AS (n = 538) and a control group of the same age without heart disease (n = 536) were recruited. Left heart catheterisation was performed and mean gradient, aortic valve area, presence of stenotic coronary artery disease (CAD) and cardiovascular risk factors (hypercholesterolaemia, hypertension, smoking, diabetes mellitus and family history of CAD) were assessed.

Strength of the purifying selection against different categories of the point mutations in the coding regions of the human genome.

Using available Information on the total absolute size of the coding region of the human genome, data on codon usage and pseudogene-derived mutation rates for different single nucleotide substitutions we have estimated, for the human genome, the potential numbers of mutation events capable to produce: (1) nonsense; (2) missense (radical and conservative); (3) silent; (4) splice; and (5) protein-elongating (those changing wild-type stop codon into an amino acid encoding codon) mutations. We used the NCBI dbSNP database to retrieve data on the observed number of polymorphisms of each category. The fraction of polymorphisms in each category among all potential events in the genome depends on the strength of selection: the higher the rate of polymorphism, the weaker the selection.

A simple model of linkage disequilibrium and genetic drift in human genomic SNPs: importance of demography and SNP age.

We propose a simple model of evolution at a pair of SNP loci, under mutation, genetic drift and recombination. The developed model allows to consider evolution of SNPs under different demographic scenarios. We applied it to SNP data containing polymorphisms spanning 19 gene regions.

Stochastic regulation in early immune response.

Living cells may be considered noisy or stochastic biochemical reactors. In eukaryotic cells, in which the number of protein or mRNA molecules is relatively large, the stochastic effects originate primarily in regulation of gene activity. Transcriptional activity of a gene can be initiated by transactivator molecules binding to the specific regulatory site(s) in the target gene.

The role of micro-inflammation in the pathogenesis of uraemic pruritus in haemodialysis patients.

Background: Uraemic pruritus (UP) is still one of the most vexing and disabling symptoms in chronic renal failure. The pathogenesis of UP is obscure and effective therapeutic strategies are elusive. Deduced from partial successful treatment modalities, there is evidence that an alteration of the immune system with a pro-inflammatory pattern along with a deranged T-helper-cell differentiation may be involved in the pathogenesis of UP.

Additive effects of the chemokine receptor 2, vitamin D receptor, interleukin-6 polymorphisms and cardiovascular risk factors on the prevalence of myocardial infarction in patients below 65 years.

Background: Cardiovascular risk factors (CRF) have been associated with myocardial infarction (MI), while the role of genetic risk factors (GRF) remains undetermined.

Methods: Cineventriculograms of 3436 were analyzed for presence of regional function impairment as sign of MI. Genotyping for genetic polymorphism (vitamin D receptor VDR BsmI, interleukin-6 IL6-174 G/C, chemokine receptor 2 CCR2 64 V/I) was performed.

Transcriptional stochasticity in gene expression.

Due to the small number of copies of molecular species involved, such as DNA, mRNA and regulatory proteins, gene expression is a stochastic phenomenon. In eukaryotic cells, the stochastic effects primarily originate in regulation of gene activity. Transcription can be initiated by a single transcription factor binding to a specific regulatory site in the target gene.

simuPOP: a forward-time population genetics simulation environment.

Summary: simuPOP is a forward-time population genetics simulation environment. The core of simuPOP is a scripting language (Python) that provides a large number of objects and functions to manipulate populations, and a mechanism to evolve populations forward in time. Using this R/Splus-like environment, users can create, manipulate and evolve populations interactively, or write a script and run it as a batch file.

Analysis of differences in amino acid substitution patterns, using multilevel G-tests.

In this paper, a new algorithm is presented, which makes possible multilevel comparison of BLOSUM protein substitution matrices based on data from different groups of organisms. As an example, a comparison between substitution matrices based on data from two groups of bacterial genomes with different GC content is presented. Our approach includes evaluating the number of amino acid pairs in BLOCKS databases created separately for the two groups of bacteria using protein sequences deposited in the COG database.

On fitting of mathematical models of cell signaling pathways using adjoint systems.

This paper concerns the problem of fitting of mathematical models of cell signaling pathways. Such models frequently take the form of a set of nonlinear ordinary differential equations. While the model is continuous-time, the performance index, used in the fitting procedure, involves measurements taken only at discrete-time moments.