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Identification of humans using gait.

We propose a view-based approach to recognize humans from their gait. Two different image features have been considered: the width of the outer contour of the binarized silhouette of the walking person and the entire binary silhouette itself. To obtain the observation vector from the image features, we employ two different methods. In the first method, referred to as the indirect approach, the high-dimensional image feature is transformed to a lower dimensional space by generating what we call the frame to exemplar (FED) distance. The FED vector captures both structural and dynamic traits of each individual. For compact and effective gait representation and recognition, the gait information in the FED vector sequences is captured in a hidden Markov model (HMM). In the second method, referred to as the direct approach, we work with the feature vector directly (as opposed to computing the FED) and train an HMM. We estimate the HMM parameters (specifically the observation probability B) based on the distance between the exemplars and the image features. In this way, we avoid learning high-dimensional probability density functions. The statistical nature of the HMM lends overall robustness to representation and recognition. The performance of the methods is illustrated using several databases.

Algorithms↗

Membrane topology of peripheral myelin protein 22.

Peripheral myelin protein 22 (PMP22) is a structural component of compact peripheral nerve myelin and is likely to play a role in the modulation of cell proliferation and cell spreading. Molecular genetics revealed that mutations affecting the PMP22 gene are responsible for the most common forms of hereditary motor and sensory neuropathies in humans. Computer analysis predicts a tetraspan-membrane structure for the PMP22 protein. We have assessed the topology of PMP22 experimentally using chimeric proteins consisting of different PMP22 domains fused to reporter genes and internally tagged molecules. Based on in vitro transcription/translation assays and immunohistochemical analysis of transfected cells, we propose that PMP22 can adopt a non-tetraspan topology that has functional implications in normal and disease processes.

Alkaline Phosphatase↗

Robust tracking and posture description for laboratory rodents using active shape models.

We are in the process of developing an automated image analysis system, which uses deformable models of shape, learned from image examples, to interpret video images of rodents. Active shape models provide a compact description of the shape of the animal in a way that enables the postures the differentiate various behaviors to be distinguished. They also model the image profile across the shape boundary. We show how these features allow automatic, robust segmentation of the explicit object of interest. Rather than just detecting movement or changes from background in the image, the system can focus on objects that are of the correct shape and appearance. The modeling of the image profiles also allows the system to distinguish between the actual animal and image artifacts. We show how these techniques are being extended to extract postural information, which can then be integrated with positional data to produce a model of behavior.

Animals↗

Solution structure of a common substrate mimetic of cyclooxygenase-downstream synthases bound to an engineered thromboxane A2 synthase using a high-resolution NMR technique.

Understanding the docking mechanism of the common substrate, prostaglandin H(2) (PGH(2)), into the active sites of different cyclooxygenase(COX)-downstream synthases is a key step toward uncovering the molecular basis of the isomerization of PGH(2) to different prostanoids. A high-resolution NMR spectroscopy was used to determine the conformational changes and solution 3D structure of U44069, a PGH(2) analogue, bound to one of the COX-downstream synthases-an engineered thromboxane A(2) synthase (TXAS). The dynamic binding was clearly observed by (1)D NMR titration. The detailed conformational change and 3D structure of U44069 bound to the TXAS were demonstrated by 2D (1)H NMR experiments using transferred NOEs. Through the assignments for the 2D (1)H NMR spectra, TOCSY, DQF-COSY, NOESY, and the structural calculations based on the NOE constraints, they demonstrated that the widely open conformation with a triangle shape of the free U44069 changed to a compact structure with an oval shape when bound to the TXAS. The putative substrate-binding pocket of the TXAS model fits the conformation of the TXAS-bound U44069 appropriately, but could not fit the free form of U44069. It was the first to provide structural information for the dynamic docking of the PGH(2) mimic of the TXAS in solution, and to imply that PGH(2) undergoes conformational changes when bound to different COX-downstream synthases, which may play important roles in the isomerization of PGH(2) to different prostanoids. The NMR technique can be used as a powerful tool to determine the conformations of PGH(2) bound to other COX-downstream synthases.

Binding Sites↗

Propagation with distributed Gaussians as a sparse, adaptive basis for higher-dimensional quantum dynamics.

A simple quantum wavepacket propagation algorithm is presented, designed to produce a very compact, non-direct product representation in higher-dimensional cases. Instead of moving basis functions around, localized basis functions at pre-defined centers are added to and deleted from the representation, generating an active basis function set strictly localized to the region where the moving wavepacket has significantly non-zero values. Simple one-dimensional examples prove this property, as well as the ability of the algorithm to accommodate splitting and rejoining of an arbitrary number of wavefunction pieces, and tunnelling through potential energy barriers. It is argued that future applications to higher-dimensional examples will be less expensive than with traditional direct-product bases, since making the basis adaptive has a lower scaling than the elementary steps necessary for any propagation algorithm itself.

Algorithms↗

Generating graphs for visual analytics through interactive sketching.

We introduce an interactive graph generator, GreenSketch, designed to facilitate the creation of descriptive graphs required for different visual analytics tasks. The human-centric design approach of GreenSketch enables users to master the creation process without specific training or prior knowledge of graph model theory. The customized user interface encourages users to gain insight into the connection between the compact matrix representation and the topology of a graph layout when they sketch their graphs. Both the human-enforced and machine-generated randomnesses supported by GreenSketch provide the flexibility needed to address the uncertainty factor in many analytical tasks. This paper describes more than two dozen examples that cover a wide variety of graph creations from a single line of nodes to a real-life small-world network that describes a snapshot of telephone connections. While the discussion focuses mainly on the design of GreenSketch, we include a case study that applies the technology in a visual analytics environment and a usability study that evaluates the strengths and weaknesses of our design approach.

Algorithms↗

Optimal deformable surface models for 3D medical image analysis.

We present a novel method for building an optimal statistical deformable model from a set of surfaces whose topological realization is homeomorphic to a compact 2D manifold with boundary. The optimal parameterization of each shape is recursively refined by using hierarchical PBMs and tensor product B-spline representation of the surface. A criterion based on MDL is used to define the internal correspondence of the training data. The strength of the proposed technique is demonstrated by deriving a concise statistical model of the human left ventricle which has principal modes of variation that correspond to intrinsic cardiac motions. We demonstrate how the derived model can be used for 3D dynamic volume segmentation of the left ventricle, with its accuracy assessed by comparing results obtained from manual delineation of 3D cine MR data of 8 asymptomatic subjects. The extension of the technique to shapes with complex topology is also discussed.

Algorithms↗

The high-resolution structure of DNA-binding protein HU from Bacillus stearothermophilus.

Protein HU is a ubiquitous prokaryotic protein which controls the architecture of genomic DNA. It binds DNA non-specifically and promotes the bending and supercoiling of the double helical structure. HU is involved in many DNA-associated cellular processes, including replication, transcription and the packaging of DNA into chromosome-like structures. Originally determined at medium resolution, the crystal structure of HU has now been refined at 2.0 A resolution. The high-resolution structure shows that the dimeric molecule is essentially a compact platform for two flexible and basic arms which wrap around the DNA molecule. To maximize the protein's stability, non-secondary structural regions are reduced to a minimum, there is an extensive aromatic hydrophobic core and several salt bridges and hydrogen-bonded water molecules knit together crucial regions. Based on the original medium-resolution structure of HU, several proposals were made concerning the structural basis of HU's ability to bind, bend and supercoil DNA. Each of these proposals is fully supported by the high-resolution structure. Most notably, the surfaces of the molecule which appear to mediate protein-DNA and protein-protein interactions have the ideal shapes and physicochemical properties to perform these functions.

Bacterial Proteins↗

Bayesian estimation of the shape skeleton.

Skeletal representations of shape have attracted enormous interest ever since their introduction by Blum [Blum H (1973) J Theor Biol 38:205-287], because of their potential to provide a compact, but meaningful, shape representation, suitable for both neural modeling and computational applications. But effective computation of the shape skeleton remains a notorious unsolved problem; existing approaches are extremely sensitive to noise and give counterintuitive results with simple shapes. In conventional approaches, the skeleton is defined by a geometric construction and computed by a deterministic procedure. We introduce a Bayesian probabilistic approach, in which a shape is assumed to have "grown" from a skeleton by a stochastic generative process. Bayesian estimation is used to identify the skeleton most likely to have produced the shape, i.e., that best "explains" it, called the maximum a posteriori skeleton. Even with natural shapes with substantial contour noise, this approach provides a robust skeletal representation whose branches correspond to the natural parts of the shape.

Algorithms↗

Analysis of the effect of local interactions on protein stability.

BACKGROUND: Protein stability appears to be governed by non-covalent interactions. These can be local (between residues close in sequence) or non-local (medium-range and long-range interactions). The specific role of local interactions is controversial. Statistical mechanics arguments point out that local interactions must be weak in stable folded proteins. However, site-directed mutagenesis has revealed that local interactions make a significant contribution to protein stability. Finally, computer simulations suggest that correctly folded proteins require a delicate balance between local and non-local contributions to protein stability. RESULT: To analyze experimentally the effect of local interactions on protein stability, each of the five Che Y alpha-helices was enhanced in its helical propensity. alpha-Helix-promoting mutations have been designed, using a helix/coil transition algorithm tuned for heteropolypeptides, that do not alter the overall hydrophobicity or protein packing. The increase in helical propensity has been evaluated by far-UV CD analysis of the corresponding peptides. Thermodynamic analysis of the five Che Y mutants reveals, in all cases, an increase in half urea ([urea]1/2) and in Tm, and a decrease in the sensitivity to chemical denaturants (m). ANS binding assays indicate that the changes in m are not due to the stabilization of an intermediate, and the kinetic analysis of the mutants shows that their equilibrium unfolding transition can be considered as following a two-state model, while the change in m is found in the refolding reaction (m(k)f). CONCLUSIONS: These results are explained by a variable two-state model in which the changes in half urea and Tm arise from the stabilization of the native state and the decrease in m from the compaction of the denatured state. Therefore, the net change in protein stability in aqueous solution produced by increasing the contribution of native-like local interactions in Che Y is the balance between these two conflicting effects. Our results support the idea that optimization of protein stability and cooperativity involve a specific ratio of local versus non-local interactions.

Amino Acid Sequence↗

Solvation of coumarin 314 at water/air interfaces containing anionic surfactants. I. Low coverage.

Through the use of molecular dynamics techniques, we analyze equilibrium and dynamical aspects of the solvation of Coumarin 314 adsorbed at water/air interfaces in the presence of sodium dodecyl sulfate surfactant molecules. Three different coverages in the submonolayer regime were considered, 500, 250, and 100 A(2)/SDS molecule. The surfactant promotes two well-differentiated solvation environments, which can be clearly distinguished in terms of their structures for the largest surfactant coverage considered. The first one is characterized by the probe lying adjacent or exterior to two-dimensional spatial domains formed by clustered surfactant molecules. A second type of solvation environment is found in which the coumarin appears embedded within compact surfactant domains. Equilibrium and dynamical aspects of the interfacial orientation of the probe are investigated. Our results show a gradual transition from parallel to perpendicular dipolar alignment of the probe with respect to the interface as the concentration of surfactant rho(s) increases. The presence of the surfactant leads to an increase in the roughness and in the characteristic width of the water/air interface. These modifications are also manifested by the decorrelation times for the probe reorientational dynamics, which become progressively slower with rho(s) in both solvation states, although much more pronounced for the embedded ones. The dynamical characteristics of the solvation responses of the charged interfaces are also analyzed, and the implications of our findings to the interpretation of available experimental measurements are discussed.

Air↗

Preliminary design of a Gd-NCT neutron beam based on compact D-T neutron source.

Gadolinium has been recently proposed, as neutron capture agent in NCT (Neutron Capture Therapy), due to both the nuclide high neutron capture cross section, and the remarkable selective uptake inside tumour tissue that Gd-loaded compounds, can provide. When a neutron external source is supplied, different Gd nuclear reactions, and the generated Auger electrons in particular, cause a high local energy deposition, which results in a tumour cell inactivation. Preliminary micro- as well as macrodosimetric Monte Carlo computational investigations show that the tumour-to-healthy tissue biological damage ratio is in close relation to the neutron beam energy spectrum. The results points out that the optimum neutron spectrum, to be used for Gd-NCT, seems to lie in the 1 to 10 keV energy range. In order to 'tailor' such spectra, an original, accelerator-driven, neutron source and spectrum shaping assembly for hospital-based Gd-NCT are presented and preliminary results are reported.

Brain Neoplasms↗

Ab initio study of sorption on pyrophyllite: structure and acidity of the edge sites.

Pyrophyllite, Al2[Si4O10](OH)2, is the simplest structural prototype for 2:1 dioctahedral phyllosilicates. Since it does not possess permanent structural charge as other clay minerals do, it is used to investigate sorption properties of the clay surfaces not related to the permanent structural charge. The bulk structure and surface geometries of pyrophyllite have been modeled using an orthorhombic constrained supercell. The results of the calculations are in excellent agreement with available experimental data and earlier ab initio simulations. It is shown that the symmetry-constrained model is able to accurately reproduce the basic structural characteristic of pyrophyllite. The electrostatic potential near the (001) surface was used to analyze a possible scenario for the water sorption on the basal plane of pyrophyllite. The calculations predict a slightly hydrophobic behavior of the basal plane. The hydronium ion was found to form a strongly bonded conformation in the siloxane cavity. The relative stability and composition of lateral facets of pyrophyllite have been studied using the supercell approach. The crystals of pyrophyllite are predicted to have a prismatic habit dominated by (110) and (-110) edge facets and basal plane. On the basis of the Fukui functions and the relative protonation/deprotonation enthalpies, the relative acidity and density of the reactive surface sites have been predicted. The triple bond Al-O-Si triple bond sites have the highest proton affinity on the (100), (110), and (130) facets and three line sign Al-OH groups on the (010) edges. The deprotonation of the triple bond Al-OH2 sites is followed by triple bond Al-OH and triple bond Si-OH groups. The calculations suggest a new scale for acidities of edge sites in pyrophyllite that should facilitate the thermodynamic modeling of the sorption processes in compacted clays.

Journal Article↗

Tetrameric mouse acetylcholinesterase: continuum diffusion rate calculations by solving the steady-state Smoluchowski equation using finite element methods.

The tetramer is the most important form for acetylcholinesterase in physiological conditions, i.e., in the neuromuscular junction and the nervous system. It is important to study the diffusion of acetylcholine to the active sites of the tetrameric enzyme to understand the overall signal transduction process in these cellular components. Crystallographic studies revealed two different forms of tetramers, suggesting a flexible tetramer model for acetylcholinesterase. Using a recently developed finite element solver for the steady-state Smoluchowski equation, we have calculated the reaction rate for three mouse acetylcholinesterase tetramers using these two crystal structures and an intermediate structure as templates. Our results show that the reaction rates differ for different individual active sites in the compact tetramer crystal structure, and the rates are similar for different individual active sites in the other crystal structure and the intermediate structure. In the limit of zero salt, the reaction rates per active site for the tetramers are the same as that for the monomer, whereas at higher ionic strength, the rates per active site for the tetramers are approximately 67%-75% of the rate for the monomer. By analyzing the effect of electrostatic forces on ACh diffusion, we find that electrostatic forces play an even more important role for the tetramers than for the monomer. This study also shows that the finite element solver is well suited for solving the diffusion problem within complicated geometries.

Acetylcholine↗

MONSSTER: a method for folding globular proteins with a small number of distance restraints.

The MONSSTER (MOdeling of New Structures from Secondary and TEritary Restraints) method for folding of proteins using a small number of long-distance restraints (which can be up to seven times less than the total number of residues) and some knowledge of the secondary structure of regular fragments is described. The method employs a high-coordination lattice representation of the protein chain that incorporates a variety of potentials designed to produce protein-like behaviour. These include statistical preferences for secondary structure, side-chain burial interactions, and a hydrogen-bond potential. Using this algorithm, several globular proteins (1ctf, 2gbl, 2trx, 3fxn, 1mba, 1pcy and 6pti) have been folded to moderate-resolution, native-like compact states. For example, the 68 residue 1ctf molecule having ten loosely defined, long-range restraints was reproducibly obtained with a C alpha-backbone root-mean-square deviation (RMSD) from native of about 4. A. Flavodoxin with 35 restraints has been folded to structures whose average RMSD is 4.28 A. Furthermore, using just 20 restraints, myoglobin, which is a 146 residue helical protein, has been folded to structures whose average RMSD from native is 5.65 A. Plastocyanin with 25 long-range restraints adopts conformations whose average RMSD is 5.44 A. Possible applications of the proposed approach to the refinement of structures from NMR data, homology model-building and the determination of tertiary structure when the secondary structure and a small number of restraints are predicted are briefly discussed.

Algorithms↗

Crystal structure of the Mus musculus cholesterol-regulated START protein 4 (StarD4) containing a StAR-related lipid transfer domain.

The x-ray structure of the mouse cholesterol-regulated START protein 4 (StarD4) has been determined at 2.2-A resolution, revealing a compact alpha/beta structure related to the START domain present in the cytoplasmic C-terminal portion of human MLN64. The volume of the putative lipid-binding tunnel was estimated at 847 A(3), which is consistent with the binding of one cholesterol-size lipid molecule. Comparison of the tunnel-lining residues in StarD4 and MLN64-START permitted identification of possible lipid specificity determinants in both molecular tunnels. Homology modeling of related proteins, and comparison of the StarD4 and MLN64-START structures, showed that StarD4 is a member of a large START domain superfamily characterized by the helix-grip fold. Additional mechanistic and evolutionary studies should be facilitated by the availability of a second START domain structure from a distant relative of MLN64.

Amino Acid Sequence↗

Finite element modeling for strain rate dependency of fracture resistance in compact bone.

Crack growths in compact bones driven by various strain rate levels were studied using finite element modeling. The energy resistance curves in bovine femur cortical bones were characterized, whereas the orthotropic viscoelasticity in bone materials was accounted for to assess the effect of strain rate on the energy resistance curve. The models were also used to justify the anticipated plane strain response as a result of rather thick specimens used in experiments. Similarities were found between the experimental and model results when crack resistance ability exhibited in bones with slow loading rates, while unstable crack growth existed in bones with rapid loading rates. The critical energy release rates slightly decreased with the increase in strain rates. The hybrid experimental and computational method introduced in this study could be beneficial for application in fracture study in which standard experiments cannot be validly performed.

Animals↗

Circular clustering of protein dihedral angles by Minimum Message Length.

Early work on proteins identified the existence of helices and extended sheets in protein secondary structures, a high-level classification which remains popular today. Using the Snob program for information-theoretic Minimum Message Length (MML) classification, we are able to take the protein dihedral angles as determined by X-ray crystallography, and cluster sets of dihedral angles into groups. Previous work by Hunter and States has applied a similar Bayesian classification method, AutoClass, to protein data with site position represented by 3 Cartesian co-ordinates for each of the alpha-Carbon, beta-Carbon and Nitrogen, totalling 9 co-ordinates. By using the von Mises circular distribution in the Snob program, we are instead able to represent local site properties by the two dihedral angles, phi and psi. Since each site can be modelled as having 2 degrees of freedom, this orientation-invariant dihedral angle representation of the data is more compact than that of nine highly-correlated Cartesian co-ordinates. Using the information-theoretic message length concepts discussed in the paper, such a more concise model is more likely to represent the underlying generating process from which the data came. We report on the results of our classification, plotting the classes in (phi, psi) space; and introducing a symmetric information-theoretic distance measure to build a minimum spanning tree between the classes. We also give a transition matrix between the classes and note the existence of three classes in the region phi approximately -1.09 rad and psi approximately -0.75 rad which are close on the spanning tree and have high inter-transition probabilities. This gives rise to a tight, abundant and self-perpetuating structure.

Computational Biology↗