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PubMed2005

Optimization of intensity-modulated radiation therapy with biological objectives.

IMRT treatment planning via biological objectives gives rise to constrained nonlinear optimization problems. We consider formulations with nonlinear objectives based on the equivalent uniform dose (EUD), with bound constraints on the beamlet weights, and describe fast, flexible variants of the two-metric gradient-projection approach for solving them efficiently and in a mathematically sound manner. We conclude that an approach that calculates the Newton component of the step iteratively, by means of the conjugate-gradient algorithm and an implicit representation of the Hessian matrix, is most effective. We also present an efficient heuristic for obtaining an approximate solution with a smoother distribution of beamlet weights. The effectiveness of the methods is verified by testing on a medium-scale clinical case.

Algorithms↗

PubMed2000

Immunogenicity of a vaccine preparation representing the variable regions of the HIV type 1 envelope glycoprotein.

Variability of the major antigenic sites of the envelope glycoprotein of HIV-1 constitutes a major problem in the formulation of effective vaccines. We have prepared a synthetic peptide vaccine that represents the major hypervariable epitopes (V1 through V5) of the clade B HIV-1 envelope glycoprotein (gp120). We refer to this preparation as variable epitope immunogen or VEI vaccine. This construct takes into consideration the type and frequency of amino acid substitutions found at each epitope during the evolution of the virus in individual patients and in the target population. Immunization of mice, rabbits, and rhesus macaques with the VEI vaccine resulted in the induction of long-lasting, high-titered HIV-1 antibodies, including antibodies that neutralize primary isolates. We also documented lymphocyte proliferative responses to the VEI vaccine, its individual components, analogs, and subtype-specific peptides representing the major hypervariable regions of HIV-1 gp120. Delayed-type hypersensitivity responses to these antigens were also demonstrated in mice. Our results show that this vaccine is highly immunogenic and safe in animals. Our data suggest that this formulation could become an important component of combination vaccine approaches against HIV-1 and other antigenically variable pathogens.

AIDS Vaccines↗

PubMed2002

Quality control in manufacturing oligo arrays: a combinatorial design approach.

The advent of the DNA microarray technology has brought with it the exciting possibility of simultaneously observing the expression levels of all genes in an organism. One such microarray technology, called "oligo arrays," manufactures short single strands of DNA (called probes) onto a glass surface using photolithography. An altered or missed step in such a manufacturing protocol can adversely affect all probes using this failed step and is in general impossible to disentangle from experimental variation when using such a defective array. The idea of designing special quality control probes to detect a failed step was first formulated by Hubbell and Pevzner (1999). We consider an alternative formulation of this problem and use a combinatorial design approach to solve it. Our results improve over prior work in guaranteeing coverage of all protocol steps and in being able to tolerate a greater number of unreliable probe intensities.

Combinatorial Chemistry Techniques↗

PubMed2006

A polynomial-time algorithm for de novo protein backbone structure determination from nuclear magnetic resonance data.

We describe an efficient algorithm for protein backbone structure determination from solution Nuclear Magnetic Resonance (NMR) data. A key feature of our algorithm is that it finds the conformation and orientation of secondary structure elements as well as the global fold in polynomial time. This is the first polynomial-time algorithm for de novo high-resolution biomacromolecular structure determination using experimentally recorded data from either NMR spectroscopy or X-ray crystallography. Previous algorithmic formulations of this problem focused on using local distance restraints from NMR (e.g., nuclear Overhauser effect [NOE] restraints) to determine protein structure. This approach has been shown to be NP-hard, essentially due to the local nature of the constraints. In practice, approaches such as molecular dynamics and simulated annealing, which lack both combinatorial precision and guarantees on running time and solution quality, are used routinely for structure determination. We show that residual dipolar coupling (RDC) data, which gives global restraints on the orientation of internuclear bond vectors, can be used in conjunction with very sparse NOE data to obtain a polynomial-time algorithm for structure determination. Furthermore, an implementation of our algorithm has been applied to six different real biological NMR data sets recorded for three proteins. Our algorithm is combinatorially precise, polynomialtime, and uses much less NMR data to produce results that are as good or better than previous approaches in terms of accuracy of the computed structure as well as running time.

Algorithms↗

PubMed2003

Ab initio reconstruction of metabolic pathways.

We propose a new formulation for the problem of ab initio metabolic pathway reconstruction. Given a set of biochemical reactions together with their substrates and products, we consider the reactions as transfers of atoms between the chemical compounds and we look for successions of reactions transferring a maximal (or preset) number of atoms between a given source and sink compound. We state this problem as the one of finding a composition of partial injections that maximizes the image size. First, we study the theoretical complexity of this problem, state some related problems and then give a practical algorithm to solve them. Finally, we present two applications of this approach to the reconstruction of the tryptophan biosynthesis pathway and to the glycolysis.

Algorithms↗

PubMed2003

Codon adaptation index as a measure of dominating codon bias.

UNLABELLED: We propose a simple algorithm to detect dominating synonymous codon usage bias in genomes. The algorithm is based on a precise mathematical formulation of the problem that lead us to use the Codon Adaptation Index (CAI) as a 'universal' measure of codon bias. This measure has been previously employed in the specific context of translational bias. With the set of coding sequences as a sole source of biological information, the algorithm provides a reference set of genes which is highly representative of the bias. This set can be used to compute the CAI of genes of prokaryotic and eukaryotic organisms, including those whose functional annotation is not yet available. An important application concerns the detection of a reference set characterizing translational bias which is known to correlate to expression levels; in this case, the algorithm becomes a key tool to predict gene expression levels, to guide regulatory circuit reconstruction, and to compare species. The algorithm detects also leading-lagging strands bias, GC-content bias, GC3 bias, and horizontal gene transfer. The approach is validated on 12 slow-growing and fast-growing bacteria, Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. AVAILABILITY: http://www.ihes.fr/~materials.

Adaptation, Physiological↗

PubMed2003

MGraph: graphical models for microarray data analysis.

UNLABELLED: This paper introduces a MATLAB toolbox, MGraph, which applies graphical models as a natural environment to formulate and solve problems in microarray data analysis. MGraph with its graphical interface allows the user to predict genetic regulatory networks by a graphical gaussian model (GGM), and to quantify the effects of different experimental treatment conditions on gene expression profiles by a graphical log-linear model (GLM). The power of graphical models was explored and illustrated through two example applications. First, four MAPK pathways in yeast were meaningfully reconstructed through GGM. Second, GLM was used to quantify the contributions of sex, genotype and age to transcriptional variance in Drosophila melanogaster. This application may provide a valuable aid in the prediction of genetic regulatory networks, as well as in investigations of various experimental conditions that affect global gene expression profiles. AVAILABILITY: The MATLAB program MGraph is freely available at http://www.uio.no/~junbaiw/mgraph/mgraph.html for academics.

Algorithms↗

PubMed1995

Audit of sickness absence and fitness-for-work referrals.

Since referrals in relation to sickness absence and fitness to continue work constitute an important part of occupational physicians' workloads, a study was carried out to audit this activity. Randomly selected referrals (u = 162) were audited by external peer review in relation to the information provided in the referral request, the consultation records and responses of the occupational physicians, and the response times linking the referral, the consultation and the response. The study showed that the referral record was adequate when specifying or quantifying long-term absences (90% and 84% of relevant cases, respectively) but questions or information regarding other relevant issues were much less frequent, eg only 12% of the referral records provided a description of the job or task. The physicians' response rate was high in relation to likely date of return to work (96%) but lower for other relevant items. In all the issues audited, the frequency of the physicians' responses was higher than the frequency with which the relevant questions were posed to them, thus suggesting 'added value' in the formulation of the problem by the physicians. The response times (often interpreted as a measure of health care quality) did not correlate usefully with the completeness of the responses as determined by peer review audit. Occupational physicians should aspire to achieve a validated standard of assessment and communication which can be audited.

Absenteeism↗

PubMed1983

A national survey of performance objectives of physician's assistant training programs.

A nationwide survey of physician's assistant (PA) training programs was carried out to determine the performance expected of students upon graduation. A list of tasks reflecting primary medical care problems was sent to PA program directors asking whether they expected their graduates to be able to perform the task, only to know about the task, or neither to be able to perform nor to have knowledge of the task. The results indicated that all students were expected to perform a history and physical examination. Almost all of the program directors expected students to establish a working diagnosis for the most common problems and to formulate a management plan for many of them. Extensive skills in patient education and counseling were expected. There was considerable congruence among the directors in performance expectations of students. The expected performance of the PA student by graduation emerged as comprehensive and not merely technical.

Clinical Competence↗

PubMed1999

Multiple scattering from gyrotropic bianisotropic cylinders of arbitrary cross sections using the modeling technique.

Based on the principle of the equivolumetric model, the multiple scattering from two-dimensional composite gyrotropic bianisotropic cylinders (GBC's) possessing a certain magnetic group of symmetry is studied by using the indirect modeling technique. At first, a mathematical formulation for the problem is carried out and its solution expressed in terms of a system of simultaneous linear equations of infinite order. The normal incident wave can be either TE(z) or TM(z) polarization. The linear equation system is then numerically solved by truncating the infinite series. Its numerical results are obtained and presented to characterize the co- and cross-polarized scattering by some typical composite GBC's. Especially, the multiple interactions among all the modeling cylinders, i.e., the host and guest cylinders as well as the guest and guest cylinders, are examined. Some phenomena of the interactions are found and discussed.

Journal Article↗

PubMed2001

Nature of phase transitions in a probabilistic cellular automaton with two absorbing states.

We present a probabilistic cellular automaton with two absorbing states, which can be considered a natural extension of the Domany-Kinzel model. Despite its simplicity, it shows a very rich phase diagram, with two second-order and one first-order transition lines that meet at a bicritical point. We study the phase transitions and the critical behavior of the model using mean field approximations, direct numerical simulations and field theory. The second-order critical curves and the kink critical dynamics are found to be in the directed percolation and parity conservation universality classes, respectively. The first-order phase transition is put in evidence by examining the hysteresis cycle. We also study the "chaotic" phase, in which two replicas evolving with the same noise diverge, using mean field and numerical techniques. Finally, we show how the shape of the potential of the field-theoretic formulation of the problem can be obtained by direct numerical simulations.

Journal Article↗

PubMed2001

Dynamic model of base pair breathing in a DNA chain with a defect.

We model and analyze a short section of a DNA chain with a defect, with the aim of understanding how the frequency, amplitude, and localization of breathing events depend on the strength of the bonds between base pairs, both along the chain and between the chains. Our results show that the presence of a defect in the chain permits the existence of a localized breather mode. The models we analyze are linear and hence solvable, with solvability extending to the statistical mechanics formulation of the problem. Parameter values for the interaction energy of a base with its nearest neighbors are obtained from AMBER. The results indicate good agreement with both the amplitude and the number of base pairs affected by defect-induced breathing motion.

Base Pairing↗

PubMed2003

Is the concept of the non-Hermitian effective Hamiltonian relevant in the case of potential scattering?

We examine the notion and properties of the non-Hermitian effective Hamiltonian of an unstable system using as an example potential resonance scattering with a fixed angular momentum. We present a consistent self-adjoint formulation of the problem of scattering on a finite-range potential, which is based on the separation of the configuration space into two segments, internal and external. The scattering amplitude is expressed in terms of the resolvent of a non-Hermitian operator H. The explicit form of this operator depends on both the radius of separation and the boundary conditions at this place, which can be chosen in many different ways. We discuss this freedom and show explicitly that the physical scattering amplitude is, nevertheless, unique, although not all choices are equally adequate from the physical point of view. The energy-dependent operator H should not be confused with the non-Hermitian effective Hamiltonian H(eff) which is usually exploited to describe interference of overlapping resonances. We note that the simple Breit-Wigner approximation is as a rule valid for any individual resonance in the case of few-channel scattering on a flat billiardlike cavity, leaving no room for nontrivial H(eff) to appear. The physics is appreciably richer in the case of an open chain of L connected similar cavities whose spectrum has a band structure. For a fixed band of L overlapping resonances, the smooth energy dependence of H can be ignored so that the constant LxL submatrix H(eff) approximately describes the time evolution of the chain in the energy domain of the band and the complex eigenvalues of H(eff) define the energies and widths of the resonances. We apply the developed formalism to the problem of a chain of L delta barriers, whose solution is also found independently in a closed form. We construct H(eff) for the two commonly considered types of boundary conditions (Neumann and Dirichlet) for the internal motion. Although the final results are in perfect coincidence, somewhat different physical patterns arise of the trend of the system with growing openness. Formation in the outer well of a short-lived doorway state shifted in energy is explicitly demonstrated together with the appearance of L-1 long-lived states trapped in the inner part of the chain.

Journal Article↗

PubMed2004

Path integrals and fluctuations in irreversible thermodynamics.

We express the set of stochastic differential equations which describe fluctuations in linear irreversible thermodynamics in terms of path integrals. The stochastic terms which are added to the linearized macroscopic equations have a correlation matrix that is singular, which implies that the straightforward formulation of the problem in terms of path integrals fails. We therefore begin by constructing a path-integral representation which is valid whether or not the correlation matrix is singular. We apply this to linearized irreversible thermodynamics, but the technique is designed to be applicable to more general versions of the theory. The approach emphasizes the role of the response and correlation functions as basic elements of the theory, and we calculate these quantities explicitly for the case of density fluctuations in a fluid.

Journal Article↗

PubMed2005

Spin glasses in the limit of an infinite number of spin components.

We consider spin glass models in which the number of spin components m is infinite. In the formulation of the problem appropriate for numerical calculations proposed by several authors, we show that the order parameter defined by the long-distance limit of the correlation functions is actually zero and there is only "quasi-long-range order" below the transition temperature. Nonetheless, there can be a finite temperature phase transition where the decay of correlations changes from exponential to power law. We also show that the spin glass transition temperature is zero in three dimensions so power-law behavior only occurs at T=0 in this case. We also argue that the order of limits, m-->infinity and N-->infinity is important, where N is the number of spins.

Journal Article↗

PubMed2005

Membrane-bound Turing patterns.

Motivated by recent observations in biological cells, we study Turing patterns in bounded regions where the nonlinear chemical reactions occur on the boundary and where reagent transport occurs in the bulk. Within a generic model, we formulate the stability problem and discuss the conditions for the occurrence of a Turing instability. By choosing other model parameters to be unequal, we find that Turing patterns exist even in the case of equal diffusion constants. Finally, a recently introduced computation technique is utilized to follow the nascent pattern into the highly nonlinear regime.

Animals↗

PubMed2006

Spatial survival probability for one-dimensional fluctuating interfaces in the steady state.

We report numerical and analytic results for the spatial survival probability for fluctuating one-dimensional interfaces with Edwards-Wilkinson or Kardar-Parisi-Zhang dynamics in the steady state. Our numerical results are obtained from analysis of steady-state profiles generated by integrating a spatially discretized form of the Edwards-Wilkinson equation to long times. We show that the survival probability exhibits scaling behavior in its dependence on the system size and the "sampling interval" used in the measurement for both "steady-state" and "finite" initial conditions. Analytic results for the scaling functions are obtained from a path-integral treatment of a formulation of the problem in terms of one-dimensional Brownian motion. A "deterministic approximation" is used to obtain closed-form expressions for survival probabilities from the formally exact analytic treatment. The resulting approximate analytic results provide a fairly good description of the numerical data.

Journal Article↗

PubMed2006

Supercritical fluids in porous composite materials: direction-dependent flow properties.

The results of extensive nonequilibrium molecular dynamics simulations of flow and transport of a pure fluid, as well as a binary fluid mixture, through a porous material composed of a macropore, a mesopore, and a nanopore, in the presence of an external pressure gradient, are reported. We find that under supercritical conditions, unusual phenomena occur that give rise to direction-dependent and pressure-dependent permeabilities for the fluids' components. The results, which are also in agreement with a continuum formulation of the problem, indicate that the composite nature of the material, coupled with condensation, give rise to the direction-dependent permeabilities. Therefore, modeling flow and transport of fluids, in the supercritical regime, in porous materials with the type of morphology considered in this paper (such as supported porous membranes) would require using effective permeabilities that depend on both the external pressure drop and the direction along which it is applied to the materials.

Journal Article↗