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We derive an algorithm for simulating the dynamical behavior of stochastic diffusive systems. We use this algorithm to simulate flux-lattice melting in thin slabs of type-II superconductor whose thickness is comparable to the penetration depth. The simulations show that the flux lattice can melt at temperatures well below the superconducting transition temperature. In addition we show that the melting behavior of the flux-line lattice is very similar to that seen in both low-density Lennard-Jones and hard-disk systems.

The maximum pinning force of a two-dimensional vortex lattice in a random potential is calculated. A connection is established between this threshold pinning force and the potential energy discontinuities due to elastic and plastic instabilities of the vortex lattice. Inspired by recent computer simulations, the authors assume that the fluctuations in the commensurability between the random potential and the vortex potential breaks the vortex system up into a set of flowing channels in between trapped regions. Two instability mechanisms and their contribution to the threshold force are discussed within this channel-flow picture. They find that three different regimes exist depending on, w, the width of the channels: w = /infinity/, a/sub 0/ < w < /infinity/, and finally w = a/sub 0/, where a/sub 0/ is the vortex lattice spacing. Weak pinning superconductors can pass through all three regimes as the reduced magnetic field is varied from 0 to 1, whereas strong pinning compounds can remain in the saturated region (w = a/sub 0/) for all values of the field. They compare the expression for the threshold force with experimental results for both strong and weak pinning samples. A satisfactory qualitative agreement is obtained between theory and experiment.

The deformations of a two-dimensional vortex lattice pinned by a random configuration of pinning centres are studied by a molecular dynamics annealing method. The pinning centres collectively induce a softening of the vortex lattice. The shear modulus decreases with increasing strength of the random potential. At a certain strength Aplas, the pinning centres start to induce plastic deformations in the vortex lattice. The lattice is distorted elastically only when the strength of the random potential is below Aplas. The vortex lattice is rapidly destroyed as the strength of the pinning centres is increased above Aplas. The cross-over value Aplas depends on the density of the pinning centres and decreases logarithmically with increasing system size. The dynamic response to an external applied force Fdr is investigated using diffusive dynamics. The time averaged centre of mass velocity, versus Fdr (corresponding to the current-voltage characteristics of a type II superconductor) is measured. The response exhibits a strong cross-over at Aplas. There is no significant non-linearity in the − Fdr curves for pinning strengths weaker than Aplas. At Aplas, a non-linear region appears whose size grows rapidly with increasing pinning strength. In the linear sections of the − Fdr curves the vortex system moves coherently as a lattice. The non-linearity is caused by a fluid-like flow of the vortices.

We have investigated the interplay of fractional statistics and magnetic field for anyons on a lattice, by exact calculation of ground-state energies and wave functions for small systems. We find that the two types of ``flux'' (magnetic and statistical) are to some extent interchangeable in determining the ground-state properties, and thus that mean-field theories, which replace statistical phase shifts by magnetic fields, may be an appropriate method for treating fractional statistics.

The deformations of a 2D vortex lattice pinned by a random potential are studied by a molecular-dynamics annealing method. All but very weak potentials produce a highly defective lattice, consisting of trapped lattice regions separated by channels in which the vortices flow plastically. It is argued that this type of deformation is the cause of the observed restricted applicability of collective pinning theory.

Large-scale molecular dynamics simulations have been performed on several fluorite structure crystals. As these simulations include 3630 ions the particle-particle/particle-mesh algorithm was used to model the Coulombic forces. The size of the simulations was large enough to enable the Frenkel defect behaviour of the crystals to be studied both above and below the superionic transition temperature t c, thereby enabling us to study the way in which the Frenkel defect model breaks down as the temperature of the crystals is increased through t c.

We have observed, in exact numerical solutions of small systems, the microscopic precursors of superconductive pairing of fermions and semions (half-statistics quasiparticles) in two dimensions. We recognize the paired state by flux quantization at intervals of {ital hc}/2{ital e}. We find that the fermions pair only for values of an interparticle potential {ital u} which is large and negative, while the semions pair for a wide range of {ital u}, including strong repulsion. We also find that the semions, in the paired state, prefer quantized flux in {ital odd} multiples of {ital hc}/4{ital e}.

It is argued that flux motion near threshold in a macroscopic, two-dimensional lattice with a random potential, under the influence of an external driving force, always involves plastic flow of moving portions of the lattice past regions that are pinned. Convincing evidence for this picture is obtained from a comparison of experimental measurements to computer simulations of the nonlinear current-voltage characteristics of finite systems.

Ligand-induced activation of the glucocorticoid receptor (GR) is not well understood. The GR ligand-binding domain was modeled, based on homology with the progesterone receptor. Tyrosine 735 interacts with the D ring of dexamethasone, and substitution of D ring functional groups results in partial agonist steroids with reduced ability to direct transactivation. Loss of the Tyr735 hydroxyl group by substitution to phenylalanine (Tyr735Phe) did not reduce ligand binding affinity [dissociation constant (Kd) 4.3 nM compared with Kd 4.6 nM for wild-type] and did not alter transrepression of an nuclear factor-kappaB (NF-kappaB reporter. But, there was a significant 30% reduction in maximal transactivation of a mouse mammary tumor virus (MMTV) reporter, although with an unchanged EC50 (8.6 nM compared with 6 nM). Substitution to a nonaromatic hydrophobic amino acid, valine (Tyr735Val), retained high-affinity ligand binding for dexamethasone (Kd 6 nM compared with 4.6 nM) and did not alter transrepression of NF-kappaB. However, there was a 36% reduction in MMTV activity with a right shift in EC50 (14.8 nM). The change to serine, a small polar amino acid (Tyr735Ser), caused significantly lower affinity for dexamethasone (10.4 nM). Maximal transrepression of NF-kappaB was unaltered, but the IC50 for this effect was increased. Tyr735Ser had a major shift in EC50 (118 nM) for transactivation of an MMTV reporter. Maximal transactivation of MMTV induced by the natural ligand cortisol was reduced to 60% by Tyr735Phe and Tyr735Val and was completely absent by Tyr735Ser. These data suggest that tyrosine 735 is important for ligand interpretation and transactivation.

The integrin adhesion receptor alpha 4 beta 1 binds two ligands, the extracellular matrix glycoprotein fibronectin and the immunoglobulin superfamily member VCAM-1. Ligand-binding sites are contained with the HepII/IIICS domain of fibronectin, and within the homologous immunoglobulin domains 1 and 4 of VCAM-1. Previous studies have shown that the binding of each ligand to alpha 4 beta 1 is mutually exclusive, suggesting that they may employ similar mechanisms to bind receptor. Fibronectin contains at least three distinct peptide sequences that are active sites for alpha 4 beta 1 binding, two homologous sequences Leu-Asp-Val-Pro (LDVP) and Ile-Asp-Ala-Pro (IDAP), and a third related to Arg-Gly-Asp (RGD). Using a combination of site-directed mutagenesis and synthetic peptide approaches in conjunction with VCAM-1-dependent cell adhesion assays, we now report the identification of a key alpha 4 beta 1-binding sequence in both domains 1 and 4 of VCAM-1 as the tetrapeptide Ile-Asp-Ser-Pro (IDSP). Mutagenesis studies also suggest that an additional sequence in domain 1, KLEK, participates in receptor binding. Since IDSP is homologous to the LDVP and IDAP fibronectin peptides, this therefore provides a molecular explanation for the promiscuity of ligand binding by alpha 4 beta 1 and has implications for the design of synthetic VCAM-1 antagonists. The extrapolation of these findings to other integrin-binding immunoglobulin ligands is also discussed.

Conducting bioinformatic analyses involves biologists in expressing requests over a range of highly heterogeneous information sources and software tools. Such activities are laborious, and require detailed knowledge of the data structures and call interfaces of the different sources. The TAMBIS (Transparent Access to Multiple Bioinformatics Information Sources) project seeks to make the diversity in data structures, call interfaces and locations of bioinformatics sources transparent to users. In TAMBIS, queries are expressed in terms of an ontology implemented using a description logic, and queries over the ontology are rewritten to a middleware level for execution over the diverse sources. The paper describes query processing in TAMBIS, focusing in particular on the way source-independent concepts in the ontology are related to source-dependent middleware calls, and describing how the planner identifies efficient ways of evaluating user queries.

A number of methods exist for the prediction of protein secondary structure from primary sequence. One method identifies variable charged and conserved hydrophobic residues within large multiple alignments as a means of indicating outside and inside sites respectively in the protein structure. These sites are then manually fitted to secondary structure templates to generate a secondary structure prediction. Using the existing theoretical bases of this method, we present an algorithm (STAMA) which automatically carries out the initial variation/conservation analysis of the alignment. We also test the accuracy of complete predictions carried out by manual fitting of the STAMA-derived assignments to structure templates, using five large multiple alignments each including a protein of known structure. The method was found on average to predict only 57% of residues in the correct secondary structure, and was only as accurate as predictions carried out using the established and automated method of Garnier, Osguthorpe and Robson (1978) applied to a single sequence. When used in conjunction with other secondary structure prediction methods, however, the resulting consensus predictions were found to be very accurate, with 78% of the elements (alpha helices or beta strands) for which a consensus could be obtained being predicted correctly. The algorithm presented here, plus the assessment of the accuracy of prediction generated by this method, should enable this predictive approach to receive informed general use.

1. Hyaluronan from mesothelioma fluid, rooster comb and streptococci was examined by rotary shadowing and electron microscopy. All preparations showed extensive branched networks, but high-viscosity hyaluronan networks were essentially infinite, with no individual ‘molecules’ that were not integrated via multiple branched points into the meshwork. Low-viscosity hyaluronan, recovered after papain digestion of mesothelioma fluid, showed occasional single filaments that were independent of the main aggregates, some of which were themselves independent of other aggregates. 2. Hyaluronan is a polymer with a very marked capability to form meshworks at very low dilution (less than 1 microgram/ml). The longer the hyaluronan molecule, the more branching is potentially possible, and the more extensive and coherent is the network, with every hyaluronan molecule in contact with every other in the solution, via the network. This behaviour accounts for the mechanical properties of the soft tissues (e.g. vitreous humour) and fluids (e.g. synovial fluid) of which hyaluronan is a major component. 3. The hyaluronan twofold helix, previously demonstrated to be present in solution [Heatley & Scott (1988) Biochem. J. 254, 489-493] was shown by computer simulation and energy calculations to be sterically capable of extensive duplex formation, probably driven by interactions between the large hydrophobic patches on alternate sides of the tape-like polymer, forming stable aggregates at biological temperatures in water. This ‘stickiness’ is postulated to be the basis of the network-forming and laterally aggregating behaviour of hyaluronan. 4. The tertiary structures formed by hyaluronan may not be possible in the case of chondroitin 4-sulphate.

This paper describes the Transparent Access to Multiple Bioinformatics Information Sources project, known as TAMBIS, in which a domain ontology for molecular biology and bioinformatics is used in a retrieval-based information integration system for biologists. The ontology, represented using a description logic and managed by a terminology server, is used both to drive a visual query interface and as a global schema against which complex intersource queries are expressed. These source-independent declarative queries are then rewritten into collections of ordered source-dependent queries for execution by a middleware layer. In bioinformatics, the majority of data sources are not databases but tools with limited accessible interfaces. The ontology helps manage the interoperation between these resources. The paper emphasizes the central role that is played by the ontology in the system. The project distinguishes itself from others in the following ways: the ontology, developed by a biologist, is substantial; the retrieval interface is sophisticated; the description logic is managed by a sophisticated terminology server. A full pilot application is available as a JavaTM applet integrating five sources concerned with proteins. This pilot is currently undergoing field trials with working biologists and is being used to answer real questions in biology, one of which is used as a case study throughout the paper.

BackgroundNatural human languages show a power law behaviour in which word frequency (in any large enough corpus) is inversely proportional to word rank - Zipf’s law. We have therefore asked whether similar power law behaviours could be seen in data from electronic patient records.ResultsIn order to examine this question, anonymised data were obtained from all general practices in Salford covering a seven year period and captured in the form of Read codes. It was found that data for patient diagnoses and procedures followed Zipf’s law. However, the medication data behaved very differently, looking much more like a referential index. We also observed differences in the statistical behaviour of the language used to describe patient diagnosis as a function of an anonymised GP practice identifier.ConclusionsThis works demonstrate that data from electronic patient records does follow Zipf’s law. We also found significant differences in Zipf’s law behaviour in data from different GP practices. This suggests that computational linguistic techniques could become a useful additional tool to help understand and monitor the data quality of health records.