Introducing the Multivariate Dale Model in Population‐Based Genetic Association Studies

Until recently, the most common parametric approaches to study the combined effects of several genetic polymorphisms located within a gene or in a small genomic region are, at the genotype level, logistic regressions and at the haplotype level, haplotype analyses. An alternative modeling approach, based on the case/control principle, is to regard exposures (e.g., genetic data such as derived from Single Nucleotide Polymorphisms – SNPs) as random and disease status as fixed and to use a marginal multivariate model that accounts for inter‐relationships between exposures. One such model is the multivariate Dale model. This model is based on multiple logistic regressions. That is why the model, applied in a case/control setting, leads to straightforward interpretations that are similar to those drawn in a classical logistic modeling framework. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)     

Scaling physiological measurements for individuals of different body size

This paper examines how selected physiological performance variables, such as maximal oxygen uptake, strength and power, might best be scaled for subject differences in body size. The apparent dilemma between using either ratio standards or a linear adjustment method to scale was investigated by considering how maximal oxygen uptake (l.min-1), peak and mean power output (W) might best be adjusted for differences in body mass (kg). A curvilinear power function model was shown to be theoretically, physiologically and empirically superior to the linear models. Based on the fitted power functions, the best method of scaling maximum oxygen uptake, peak and mean power output, required these variables to be divided by body mass, recorded in the units kg 2/3. Hence, the power function ratio standards (ml.kg-2/3.min-1) and (W.kg-2/3) were best able to describe a wide range of subjects in terms of their physiological capacity, i.e. their ability to utilise oxygen or record power maximally, independent of body size. The simple ratio standards (ml.kg-1.min-1) and (W.kg-1) were found to best describe the same subjects according to their performance capacities or ability to run which are highly dependent on body size. The appropriate model to explain the experimental design effects on such ratio standards was shown to be log-normal rather than normal. Simply by taking logarithms of the power function ratio standard, identical solutions for the design effects are obtained using either ANOVA or, by taking the unscaled physiological variable as the dependent variable and the body size variable as the covariate, ANCOVA methods.     

Multiple protein sequence alignment from tertiary structure comparison: assignment of global and residue confidence levels.

An algorithm is presented for the accurate and rapid generation of multiple protein sequence alignments from tertiary structure comparisons. A preliminary multiple sequence alignment is performed using sequence information, which then determines an initial superposition of the structures. A structure comparison algorithm is applied to all pairs of proteins in the superimposed set and a similarity tree calculated. Multiple sequence alignments are then generated by following the tree from the branches to the root. At each branchpoint of the tree, a structure-based sequence alignment and coordinate transformations are output, with the multiple alignment of all structures output at the root. The algorithm encoded in STAMP (STructural Alignment of Multiple Proteins) is shown to give alignments in good agreement with published structural accounts within the dehydrogenase fold domains, globins, and serine proteinases. In order to reduce the need for visual verification, two similarity indices are introduced to determine the quality of each generated structural alignment. Sc quantifies the global structural similarity between pairs or groups of proteins, whereas Pij' provides a normalized measure of the confidence in the alignment of each residue. STAMP alignments have the quality of each alignment characterized by Sc and Pij' values and thus provide a reproducible resource for studies of residue conservation within structural motifs.     

Michaelis complexes of porcine pancreatic elastase with 7-[(alkylcarbamoyl)amino]-4-chloro-3-ethoxyisocoumarins: translational sampling of inhibitor position and kinetic measurements.

A step leading to the formation of the covalent complexes between porcine pancreatic elastase (PPE) and 7-[(alkylcarbamoyl)amino]-4-chloro-3-ethoxyisocoumarins (alkylHNCO-EICs) is the formation of the noncovalent Michaelis complex. No average structures are available for the Michaelis complexes of PPE with alkylHNCO-EICs. We present the results of an initial step in obtaining these structures and have determined kinetic constants as well. The kinetic results indicate that formation of the Michaelis complex is what differentiates the effectiveness of these inhibitors in inactivating PPE. The structural and kinetic results together suggest that the structure of the Michaelis complex is necessary for the design of potent alkylHNCO-EIC inhibitors of PPE. Two novel alkylHNCO-EICs are predicted to be the best inhibitors of this series. An alternate mechanism for serine protease inhibition is also proposed. Evidence for, and studies that may add support to, the hypothesized mechanism are discussed.     

A method for determining overall protein fold from NMR distance restraints

Summary We describe a simple method for determining the overall fold of a polypeptide chain from NOE-derived distance restraints. The method uses a reduced representation consisting of two particles per residue, and a force field containing pseudo-bond and pseudo-angle terms, an electrostatic term, but no van der Waals or hard shell repulsive terms. The method is fast and robust, requiring relatively few distance restraints to approximate the correct fold, and the correct mirror image is readily determined. The method is easily implemented using commercially available molecular modeling software.     

The design of single-stranded nucleic acid knots

A general strategy is described for the synthesis of single-stranded nucleic acid knots. Control of nucleic acid sequence is used to direct the formation of secondary structures that produce the target topology. The key feature of the strategy is the equation of a half-turn of double helical DNA or RNA with a node in a knot. By forming nodes from complementary DNA sequences, it appears possible to direct the assembly of any simple knot. Stabilization of individual nodes may be achieved by constructing them from long regions containing both B-DNA and Z-DNA. Control over the braiding of DNA that acts as a link between node-forming domains can be realized by condensing the nodes into well-defined DNA structures, such as extended domains of linear duplex, branched junctions, antijunctions or mesojunctions. Further topological control may be derived from the pairing of linker regions to complementary single-stranded molecules, thereby preventing them from braiding in an undesirable fashion.