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PubMedDate not supplied

Design and synthesis of an array of selective androgen receptor modulators.

We describe the design, using shape comparison and fast docking computer algorithms, and rapid parallel synthesis of a 1300 member array based on GSK7721, a 4-aminobenzonitrile androgen receptor (AR) antagonist identified by focused screening of the GSK compound collection. The array yielded 352 submicromolar and 17 subnanomolar AR agonists as measured by a cell-based reporter gene functional assay. The rapid synthesis of a large number of active compounds provided valuable information in the optimization of AR modulators, which may be useful in treating androgen deficiency in aging males.

Algorithms↗

PubMed2003

Inherent speedup limitations in multiple time step/particle mesh Ewald algorithms.

Multiple time step (MTS) algorithms present an effective integration approach to reduce the computational cost of dynamics simulations. By using force splitting to allow larger time steps for the more slowly varying force components, computational savings can be realized. The Particle-Mesh-Ewald (PME) method has been independently devised to provide an effective and efficient treatment of the long-range electrostatics interactions. Here we examine the performance of a combined MTS/PME algorithm previously developed for AMBER on a large polymerase beta/DNA complex containing 40,673 atoms. Our goal is to carefully combine the robust features of the Langevin/MTS (LN) methodology implemented in CHARMM-which uses position rather than velocity Verlet with stochasticity to make possible outer time steps of 150 fs-with the PME formulation. The developed MTS/PME integrator removes fast terms from the reciprocal-space Ewald component by using switch functions. We analyze the advantages and limitations of the resulting scheme by comparing performance to the single time step leapfrog Verlet integrator currently used in AMBER by evaluating different time-step protocols using three assessors for accuracy, speedup, and stability, all applied to long (i.e., nanosecond) simulations to ensure proper energy conservation. We also examine the performance of the algorithm on a parallel, distributed shared-memory computer (SGI Origin 2000 with 8 300-MHz R12000 processors). Good energy conservation and stability behavior can be demonstrated, for Newtonian protocols with outer time steps of up to 8 fs and Langevin protocols with outer time steps of up to 16 fs. Still, we emphasize the inherent limitations imposed by the incorporation of MTS methods into the PME formulation that may not be widely appreciated. Namely, the limiting factor on the largest outer time-step size, and hence speedup, is an intramolecular cancellation error inherent to PME. This error stems from the excluded-nonbonded correction term contained in the reciprocal-space component. This cancellation error varies in time and introduces artificial frequencies to the governing dynamics motion. Unfortunately, we find that this numerical PME error cannot be easily eliminated by refining the PME parameters (grid resolution and/or order of interpolating polynomial). We suggest that methods other than PME for fast electrostatics may allow users to reap the full advantages from MTS algorithms.

Algorithms↗

PubMed1996

The hippocampus as a cognitive graph.

A theory of cognitive mapping is developed that depends only on accepted properties of hippocampal function, namely, long-term potentiation, the place cell phenomenon, and the associative or recurrent connections made among CA3 pyramidal cells. It is proposed that the distance between the firing fields of connected pairs of CA3 place cells is encoded as synaptic resistance (reciprocal synaptic strength). The encoding occurs because pairs of cells with coincident or overlapping fields will tend to fire together in time, thereby causing a decrease in synaptic resistance via long-term potentiation; in contrast, cells with widely separated fields will tend never to fire together, causing no change or perhaps (via long-term depression) an increase in synaptic resistance. A network whose connection pattern mimics that of CA3 and whose connection weights are proportional to synaptic resistance can be formally treated as a weighted, directed graph. In such a graph, a "node" is assigned to each CA3 cell and two nodes are connected by a "directed edge" if and only if the two corresponding cells are connected by a synapse. Weighted, directed graphs can be searched for an optimal path between any pair of nodes with standard algorithms. Here, we are interested in finding the path along which the sum of the synaptic resistances from one cell to another is minimal. Since each cell is a place cell, such a path also corresponds to a path in two-dimensional space. Our basic finding is that minimizing the sum of the synaptic resistances along a path in neural space yields the shortest (optimal) path in unobstructed two-dimensional space, so long as the connectivity of the network is great enough. In addition to being able to find geodesics in unobstructed space, the same network enables solutions to the "detour" and "shortcut" problems, in which it is necessary to find an optimal path around a newly introduced barrier and to take a shorter path through a hole opened up in a preexisting barrier, respectively. We argue that the ability to solve such problems qualifies the proposed hippocampal object as a cognitive map. Graph theory thus provides a sort of existence proof demonstrating that the hippocampus contains the necessary information to function as a map, in the sense postulated by others (O'Keefe, J., and L. Nadel. 1978. The Hippocampus as a Cognitive Map. Clarendon Press, Oxford, UK). It is also possible that the cognitive mapping functions of the hippocampus are carried out by parallel graph searching algorithms implemented as neural processes. This possibility has the great attraction that the hippocampus could then operate in much the same way to find paths in general problem space; it would only be necessary for pyramidal cells to exhibit a strong nonpositional firing correlate.

Animals↗

PubMed1991

Recognition of the folding consensus in RNA secondary structures by the topological-filtering method.

Functionally homologous RNA sequences can substantially diverge in their primary sequences but it can be reasonably assumed that they are related in their higher-degree structures. The problem to find such structures and simultaneously satisfy as far as possible the free-energy-minimization criterion, is considered here in two aspects. Firstly a quantitative measure of the folding consensus among secondary structures is defined, translating each structure into a linear representation and using the correlation theorem to compare them. Secondly an algorithm for the parallel search for secondary structures according to the free-energy-minimization criterion, but with a filtering action on the basis of the folding consensus measure is presented. The method is tested on groups of RNA sequences different in origin and in functions, for which proposals of homologous secondary structures based on experimental data exist. A comparison of the results with a blank consisting of a search on the basis of the free energy minimization alone is always performed. In these tests the method shows its ability in obtaining, from different sequences, secondary structures characterized by a high-folding consensus measure also when lower free energy but not homologous structures are possible. Two applications are also shown. The first demonstrates the transfer of experimental data available for one sequence, to a functionally related and therefore homologous one. The second application is the possibility of using a topological probe in the search for precise structural motifs.

Algorithms↗

PubMed1999

Folding a protein by discretizing its backbone torsional dynamics.

The aim of this work is to provide a coarse codification of local conformational constraints associated with each folding motif of a peptide chain in order to obtain a rough solution to the protein folding problem. This is accomplished by implementing a discretized version of the soft-mode dynamics on a personal computer (PC). Our algorithm mimics a parallel process as it evaluates concurrent folding possibilities by pattern recognition. It may be implemented in a PC as a sequence of perturbation-translation-renormalization (p-t-r) cycles performed on a matrix of local topological constraints (LTM). This requires suitable representational tools and a periodic quenching of the dynamics required for renormalization. We introduce a description of the peptide chain based on a local discrete variable the values of which label the basins of attraction of the Ramachandran map for each residue. Thus, the local variable indicates the basin in which the torsional coordinates of each residue lie at a given time. In addition, a coding of local topological constraints associated with each secondary and tertiary structural motif is introduced. Our treatment enables us to adopt a computation time step of 81 ps, a value far larger than hydrodynamic drag time scales. Folding pathways are resolved as transitions between patterns of locally encoded structural signals that change within the 10 micros-100 ms time scale range. These coarse folding pathways are generated by the periodic search for structural patterns in the time-evolving LTM. Each pattern is recorded as a contact matrix, an operation subject to a renormalization feedback loop. The validity of our approach is tested vis-a-vis experimentally-probed folding pathways eventually generating tertiary interactions in proteins which recover their active structure under in vitro renaturation conditions. As an illustration, we focus on determining significant folding intermediates and late kinetic bottlenecks that occur within the first 10 ms of the bovine pancreatic trypsin inhibitor renaturation process. The probed cooperativity and nucleation effects, as well as diffusion-collision stabilization of secondary structure are shown to result from the persistence of relatively stable patterns through successive (p-t-r) cycles, thus acting as seeding patterns for further growth or hierarchical development.

Algorithms↗

PubMed2006

Time-resolved 3D contrast-enhanced MRA with GRAPPA on a 1.5-T system for imaging of craniocervical vascular disease: initial experience.

INTRODUCTION: For three-dimensional (3D) imaging with magnetic resonance angiography (MRA) of the cerebral and cervical circulation, both a high temporal and a high spatial resolution with isovolumetric datasets are of interest. In an initial evaluation, we analyzed the potential of contrast-enhanced (CE) time-resolved 3D-MRA as an adjunct for neurovascular MR imaging. METHODS: In ten patients with various cerebrovascular disorders and vascularized tumors in the cervical circulation, high-speed MR acquisition using parallel imaging with the GeneRalized Autocalibrating Partially Parallel Acquisitions (GRAPPA) algorithm on a 1.5-T system with a temporal resolution of 1.5 s per dataset and a nearly isovolumetric spatial resolution was applied. The results were assessed and compared with those from conventional MRA and digital subtraction angiography (DSA). RESULTS: CE time-resolved 3D-MRA enabled the visualization and characterization of high-flow arteriovenous shunts in cases of vascular malformations or hypervascularized tumors. In steno-occlusive disease, the method provided valuable additional information about altered vessel perfusion compared to standard MRA techniques such as time-of-flight (TOF) MRA. The use of a nearly isovolumetric voxel size allowed a free-form interrogation of 3D datasets. Its comparatively low spatial resolution was found to be the major limitation. CONCLUSION: In this preliminary analysis, CE time-resolved 3D-MRA was revealed to be a promising complementary MRA sequence that enabled the visualization of contrast flow dynamics in various types of neurovascular disorders and vascularized cervical tumors.

Adult↗

PubMed2003

TOUCHSTONE II: a new approach to ab initio protein structure prediction.

We have developed a new combined approach for ab initio protein structure prediction. The protein conformation is described as a lattice chain connecting C(alpha) atoms, with attached C(beta) atoms and side-chain centers of mass. The model force field includes various short-range and long-range knowledge-based potentials derived from a statistical analysis of the regularities of protein structures. The combination of these energy terms is optimized through the maximization of correlation for 30 x 60,000 decoys between the root mean square deviation (RMSD) to native and energies, as well as the energy gap between native and the decoy ensemble. To accelerate the conformational search, a newly developed parallel hyperbolic sampling algorithm with a composite movement set is used in the Monte Carlo simulation processes. We exploit this strategy to successfully fold 41/100 small proteins (36 approximately 120 residues) with predicted structures having a RMSD from native below 6.5 A in the top five cluster centroids. To fold larger-size proteins as well as to improve the folding yield of small proteins, we incorporate into the basic force field side-chain contact predictions from our threading program PROSPECTOR where homologous proteins were excluded from the data base. With these threading-based restraints, the program can fold 83/125 test proteins (36 approximately 174 residues) with structures having a RMSD to native below 6.5 A in the top five cluster centroids. This shows the significant improvement of folding by using predicted tertiary restraints, especially when the accuracy of side-chain contact prediction is >20%. For native fold selection, we introduce quantities dependent on the cluster density and the combination of energy and free energy, which show a higher discriminative power to select the native structure than the previously used cluster energy or cluster size, and which can be used in native structure identification in blind simulations. These procedures are readily automated and are being implemented on a genomic scale.

Algorithms↗

PubMed1994

Short-term but not long-term adrenalectomy modulates amplitude and frequency of the CRH41 episodic release in push-pull cannulated median eminence of free-moving rats.

CRH 41 release in push-pull cannulated median eminence (ME) was measured in unanesthetized male rats, 3 and 7 days after adrenalectomy (ADX) and in sham-lesioned controls. Perfusion started at 13.30 h and perfusate samples were collected at 5 min intervals for 3 h to estimate the mean release rate of CRH41. The major parameters of the neurohormone's episodic release pattern were analyzed using the Ultra algorithm. In a parallel study, 3 groups of similarly treated rats were used to measure plasma ACTH and hypothalamic CRH41. Three days after ADX, the plasma ACTH titers had risen 14-fold, the hypothalamic CRH41 content had decreased by 40%, while the CRH41 release in the ME had doubled as a result of a significant increase in most variables of the pulsatile release pattern: pulse frequency (+34%; P < 0.01), mean amplitude (+36%; P < 0.05), mean peak levels (+67%; P < 0.01) and mean pulse nadirs (x2.5; P < 0.01). Seven days after ADX, even though plasma ACTH had further increased to 30-times control levels, hypothalamic CRH41 content and CRH41 release in the ME had returned to almost control levels. The possible mechanisms of the discrepancy between the CRH and ACTH response time-courses following ADX are discussed.

Adrenal Glands↗

PubMed2003

A parallel optimization approach for controlling allele diversity in conservation schemes.

We propose a novel method to control allelic diversity in conservation schemes based on an optimization problem, characterized by a convex program subject to integer linear constraints. Departing from previous studies considering similar problems, we implement a parallel simulated annealing algorithm to minimize the number of alleles lost across generations. The proposed algorithm shows excellent timing and minimization performances. Execution time decreases linearly with the number of processors used, providing similar results in all cases.

Algorithms↗

PubMedDate not supplied

DNA solution of a graph coloring problem.

The graph-theoretic parameter that has probably received the most attention over the years is the chromatic number. As is well-known, the coloring problem is an NP-Complete problem. In this paper, it has been solved by means of molecular biology techniques. The algorithm is highly parallel and has satisfactory fidelity. This work shows further evidence for the ability of DNA computing to solve NP-Complete problems.

Base Sequence↗

PubMed2004

High spatial resolution whole-body MR angiography featuring parallel imaging: initial experience.

PURPOSE: To combine whole-body multi-station three-dimensional contrast enhanced magnetic resonance angiography (3D CE MRA) using a self-developed rolling table platform with parallel imaging strategies (PAT) in order to increase the spatial resolution of the 3D MRA data sets. MATERIALS AND METHODS: Whole-body multi-station MRA was performed with a rolling table platform (AngioSURF) on 5 volunteers in two imaging series: 1) standard imaging protocol, 2) modified high-resolution protocol employing PAT using the generalized autocalibrating partially parallel acquisitions (GRAPPA) algorithm with an acceleration factor of 3. For an intra-individual comparison of the two MR examinations, the arterial vasculature was divided into 30 segments. Signal-to-noise ratios (SNR) and contrast-to-noise ratios (CNR) were calculated for all 30 arterial segments of each subject. Vessel segment depiction was qualitatively assessed applying a 5-point scale to each of the segments. Image reconstruction times were recorded for the standard as well as the PAT protocol. RESULTS: Compared to the standard protocol, PAT allowed for increased spatial resolution through a 3-fold reduction in mean voxel size for each of the 5 stations. Mean SNR and CNR values over all specified vessel segments decreased by a factor of 1.58 and 1.56, respectively. Despite the reduced SNR and CNR, the depiction of all specified vessel segments increased in PAT images, reflecting the increased spatial resolution. Qualitative comparison of standard and PAT images showed an increase in vessel segment conspicuity with more detailed depiction of intramuscular arterial branches in all volunteers. The time for image data reconstruction of all 5 stations was significantly increased from about 10 minutes to 40 minutes when using the PAT acquisition. CONCLUSION: The implementation of PAT into the concept of whole-body MRA enabled to increase the spatial resolution in all examined territories, which resulted in more detailed MR angiograms.

Adult↗

PubMed2006

Online system for faster multipoint linkage analysis via parallel execution on thousands of personal computers.

Computation of LOD scores is a valuable tool for mapping disease-susceptibility genes in the study of Mendelian and complex diseases. However, computation of exact multipoint likelihoods of large inbred pedigrees with extensive missing data is often beyond the capabilities of a single computer. We present a distributed system called "SUPERLINK-ONLINE," for the computation of multipoint LOD scores of large inbred pedigrees. It achieves high performance via the efficient parallelization of the algorithms in SUPERLINK, a state-of-the-art serial program for these tasks, and through the use of the idle cycles of thousands of personal computers. The main algorithmic challenge has been to efficiently split a large task for distributed execution in a highly dynamic, nondedicated running environment. Notably, the system is available online, which allows computationally intensive analyses to be performed with no need for either the installation of software or the maintenance of a complicated distributed environment. As the system was being developed, it was extensively tested by collaborating medical centers worldwide on a variety of real data sets, some of which are presented in this article.

Algorithms↗

PubMed2004

Multiple sequence alignment in parallel on a workstation cluster.

SUMMARY: Multiple sequence alignment is the NP-hard problem of aligning three or more DNA or amino acid sequences in an optimal way so as to match as many characters as possible from the set of sequences. The popular sequence alignment program ClustalW uses the classical method of approximating a sequence alignment, by first computing a distance matrix and then constructing a guide tree to show the evolutionary relationship of the sequences. We show that parallelizing the ClustalW algorithm can result in significant speedup. We used a cluster of workstations using C and message passing interface for our implementation. Experimental results show that speedup of over 5.5 on six processors is obtainable for most inputs. AVAILABILITY: The software is available upon request from the second author.

Algorithms↗

PubMed2001

An evolutionary computational approach to the phase problem in macromolecular X-ray crystallography.

The ab initio computation of the molecular envelopes of two proteins exclusively from their corresponding diffraction amplitudes demonstrates that an efficient and inherently parallel evolutionary search algorithm can assist in the direct phasing of macromolecules for which almost no a priori structural information is available. The applicability of this evolutionary computational approach is general and should not be limited to the examples described nor to extremes of data resolution, symmetry or structural size.

Algorithms↗

PubMed2006

Structural basis for platelet collagen responses by the immune-type receptor glycoprotein VI.

Activation of circulating platelets by exposed vessel wall collagen is a primary step in the pathogenesis of heart attack and stroke, and drugs to block platelet activation have successfully reduced cardiovascular morbidity and mortality. In humans and mice, collagen activation of platelets is mediated by glycoprotein VI (GPVI), a receptor that is homologous to immune receptors but bears little sequence similarity to known matrix protein adhesion receptors. Here we present the crystal structure of the collagen-binding domain of human GPVI and characterize its interaction with a collagen-related peptide. Like related immune receptors, GPVI contains 2 immunoglobulin-like domains arranged in a perpendicular orientation. Significantly, GPVI forms a back-to-back dimer in the crystal, an arrangement that could explain data previously obtained from cell-surface GPVI inhibition studies. Docking algorithms identify 2 parallel grooves on the GPVI dimer surface as collagen-binding sites, and the orientation and spacing of these grooves precisely match the dimensions of an intact collagen fiber. These findings provide a structural basis for the ability of an immune-type receptor to generate signaling responses to collagen and for the development of GPVI inhibitors as new therapies for human cardiovascular disease.

Binding Sites↗

PubMed2005

Four-dimensional dynamic flow measurement by holographic particle image velocimetry.

The ultimate goal of holographic particle image velocimetry (HPIV) is to provide space- and time-resolved measurement of complex flows. Recent new understanding of holographic imaging of small particles, pertaining to intrinsic aberration and noise in particular, has enabled us to elucidate fundamental issues in HPIV and implement a new HPIV system. This system is based on our previously reported off-axis HPIV setup, but the design is optimized by incorporating our new insights of holographic particle imaging characteristics. Furthermore, the new system benefits from advanced data processing algorithms and distributed parallel computing technology. Because of its robustness and efficiency, for the first time to our knowledge, the goal of both temporally and spatially resolved flow measurements becomes tangible. We demonstrate its temporal measurement capability by a series of phase-locked dynamic measurements of instantaneous three-dimensional, three-component velocity fields in a highly three-dimensional vortical flow-the flow past a tab.

Journal Article↗

PubMed2000

Fecal incontinence: hope for an underdiagnosed condition.

Fecal incontinence is often suffered in silence leading one to become a social recluse. This has led to the belief that the problem does not exist and therefore underdiagnosed. In the last decade, much has been learnt about the understanding of continence and defecation. Quantification of appropriate physiological parameters associated with fecal incontinence have allowed the patients to be assessed using a logical algorithm. More importantly, parallel developments in management techniques of fecal incontinence now allow the categorised patients to be managed logically. The assessment is thus translated into appropriate management plans which range from simple nonoperative medical and dietary manipulation to pelvic floor retraining, sphincter augmentation and finally sphincter reconstruction.

Combined Modality Therapy↗

PubMed2002

Parallel Monte Carlo methods for physical mapping of chromosomes.

Reconstructing a physical map of a chromosome from a genomic library presents a central computational problem in genetics. Physical map reconstruction in the presence of errors is a problem of high computational complexity. Parallel Monte Carlo methods for a maximum likelihood estimation-based approach to physical map reconstruction are presented. The estimation procedure entails gradient descent search for determining the optimal spacings between probes for a given probe ordering. The optimal probe ordering is determined using a simulated Monte Carlo algorithm. A two-tier parallelization strategy is proposed wherein the gradient descent search is parallelized at the lower level and the simulated Monte Carlo algorithm is simultaneously parallelized at the higher level. Implementation and experimental results on a network of shared-memory symmetric multiprocessors (SMPs) are presented.

Algorithms↗