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A risk assessment approach applied to the growth of Erwinia carotovora in vegetable juice for variable temperature conditions.

Risk assessment for food spoilage relies on probabilistic models of microbial growth to predict the likelihood that microbial populations will exceed predefined spoilage levels. To assist in the design and management of industrial food quality systems, predictive microbiological models have to incorporate major risk factors such as the variability in the microbial strain, environment and initial contamination levels. In addition, the application of results measured under laboratory conditions to the less controlled environment of an industrial process usually also involves uncertainty. Extra information regarding this uncertainty must be factored into industrial microbial risk assessment. In this paper, based on our previous analysis of the growth of Erwinia carotovora we show how different factors contribute to the risk of microbial spoilage of vegetable juice and we demonstrate an effective way of including these factors into risk assessment models. The association of risk components with different unavoidable and manageable factors is also valuable for the development of optimal strategies for reducing microbial risk.

Beverages↗

Quantitation in SPECT using an effective model of the scattering.

A new method for correcting simultaneously the attenuation, scatter and resolution effects in SPECT has been developed for the case of a homogeneous medium. It is based on an effective model of the scatter process. This model depends on only four parameters which are determined experimentally and remain independent of the geometry and of the dimensions of the scatter medium. The method uses the data from the peak events and does not need additional energy windows on the scattered events. An original filter is proposed to remove the noise due to the poor statistics of clinical data. Tests on phantoms varying in size and activity show that the model allows absolute activity determination with an accuracy of a few per cent.

Algorithms↗

Long-lived conformational isomerism of protein dimers: the role of the free energy of subunit association.

The association of protein subunits to form N-mers (N >or= 3) does not follow the dependence on the law of mass action predicted by the classical thermodynamic description used for the equilibrium of association of small molecules. For those anomalous cases, a so-called deterministic model has been previously proposed. The latter model was based on the empirical observation that the dynamics of subunit exchange between protein oligomers can be very slow, leading to the existence of long-lived conformational isomers and to a persistently heterogeneous ensemble of oligomers in solution. Contrary to the expectation for a protein dimer, we have recently shown that the subunit association of triosephosphate isomerase (TIM) could also be described as a deterministic process and that long-lived conformational isomers of TIM could be isolated in solution. Here we show that a), observation of hysteresis in pressure dissociation curves is an additional indicator of deterministic behavior; b), the extent of deviation from the classical thermodynamic behavior correlates with the free-energy change of subunit association; and c), experimental manipulation of the free energy of subunit association through the addition of a subdenaturing concentration of a chaotropic agent restores the concentration dependence of subunit association of TIM. A model that explains these features and its biological relevance is discussed.

Dimerization↗

On approximations of Stein's neuronal model.

Stein's model represents a commonly-used description of spontaneous neuronal activity. Substituting Stein's model by the Ornstein-Uhlenbeck diffusion process increases the model tractability. A diffusion approximation of Stein's model is summarized in the present paper. It is proved that the cumulative distribution functions of interspike intervals under Stein's model converge to the cumulative distribution function of interspike intervals which are generated in accordance with the limiting Ornstein-Uhlenbeck diffusion model. The approach used allows us to determine to what extent Stein's model modifications and generalizations affect the possibility of diffusion approximation. It can be seen that non-diffusion approximations exist and they are also studied here. The results achieved can be considered as complementary to the numerical study published recently.

Action Potentials↗

Evolution of lamivudine resistance in human immunodeficiency virus type 1-infected individuals: the relative roles of drift and selection.

Human immunodeficiency virus type 1 (HIV-1) rapidly develops resistance to lamivudine during monotherapy, typically resulting in the appearance at position 184 in reverse transcriptase (RT) of isoleucine instead of the wild-type methionine (M184I) early in therapy, which is later replaced by valine (M184V). M184V reduces viral susceptibility to drug in vitro by approximately 100-fold, but also results in a lower processivity of RT. We show that a drop in absolute viral fitness associated with the outgrowth of M184V results in a drop in viral load only in individuals with high CD4(+) counts, from whom we estimate the relative fitness of M184V in the presence of drug to be approximately 10% of that of the wild type prior to therapy. The timing of emergence of the M184V mutant varies widely between infected individuals. From analysis of the frequency of M184I and M184V mutants determined at multiple time points in seven individuals during lamivudine therapy, we estimated the fitness advantage of M184V over M184I during therapy to be approximately 23% on average. We have also estimated the average ratio of the frequencies of the two mutants prior to therapy to be 0. 2:1, with a range from 0.12:1 to 0.33:1. We have found that the differences between individuals in the rate of evolution of lamivudine resistance arise due to genetic drift affecting the relative frequency of M184I and M184V prior to therapy. These results show that stochastic effects can be significant in HIV evolution, even when there is large fitness difference between mutant and wild-type variants.

Anti-HIV Agents↗

Computational engine for development of complex cascaded models of signal and noise in X-ray imaging systems.

The detective quantum efficiency (DQE) is generally accepted as the primary metric of signal-to-noise performance in medical X-ray imaging systems. Simple theoretical models of the Wiener noise power spectrum (NPS) and DQE can be developed using a cascaded-systems approach to assess particular system designs and establish operational benchmarks. However, the cascaded approach is often impractical for the development of comprehensive models due to the complexity and extremely large number of algebraic terms that must be manipulated to describe signal and noise transfer. We have developed a computational engine that overcomes this limitation. Using a predefined library of elementary physical processes, complex models are assembled and input-output relationships established using a graphical interface. A novel recursive algorithm is described that allows the signal and noise analyses of models with arbitrary complexity including the use of multiple parallel cascades. Symbolic mathematics is used to develop analytic expressions for the NPS and DQE. The algorithm is validated by manual calculation for simple models and by Monte Carlo calculation for complex models. We believe our approach enables the use of complex cascaded models to design better detectors with improved image quality.

Computer Simulation↗

[Kinetics of ligand binding to nucleic acids at random fillings].

Ligand binding with nucleic acids is described in frames of the theory of random processes. It is shown that the probabilistic description of binding of a ligand to nucleic acid allows one to describe not only the kinetics of changes in the number of bound ligands at arbitrary fillings but also to calculate stationary values of the number of bound ligands and its dispersion. A general analysis of absorption isotherms and the kinetics of ligand binding with nucleic acids allows one to determine the rate constants of formation and decomposition of the ligand-nucleic acid complex. A comparison of the results obtained with the case of low fillings is conducted.

Kinetics↗

Predictive controller evaluation including non-stationary high frequency noise and outliers for batch solid substrate fermentation bioreactors.

Optimum operation and automatic control of large-scale solid substrate fermentation (SSF) bioreactors is difficult. Though advanced control algorithms can handle most challenges encountered properly, for real-time SSF processes such controllers are expensive and time consuming to design and tune. With these considerations, advanced control algorithm tests using realistic simulations appear more appropriate. We used a phenomenological process model of an SSF pilot bioreactor, coupled with a realistic noise model, to test linear model predictive controllers. We focused on the effect noise has on the performance of the control algorithms, and how to enhance performance using a combination of low-pass (Butterworth) and outlier shaving (Hampel) filters. In simulations undertaken directly with the phenomenological model it was relatively straightforward to achieve good control performance. Nevertheless, control degraded sharply when the output of the phenomenological model was contaminated with noise using our realistic noise model, even with proper signal filtering.

Artifacts↗

Chance, explanation, and causation in evolutionary theory.

Chance comes into plays at many levels of the explanation of the evolutionary process; but the unity of sense of this category is problematic. The purpose of this talk is to clarify the meaning of chance at various levels in evolutionary theory: mutations, genetic drift, genetic revolutions, ecosystems, macroevolution. Three main concepts of chance are found at these various levels: luck (popular concept), randomness (probabilistic concept), and contingency relative to a given theoretical system (epistemological concept). After identifying which concept(s) of chance fit(s) with these levels, the question is raised whether these concepts can be reduced to a smaller number, and whether chance in evolutionary theory has a subjective or an objective sense.

Adaptation, Biological↗

Role of temperature in quanta mechanisms of facilitation in the frog neuromuscular junction.

The results of computer simulations on the Double Barrier Synapse (DBS) model are presented which quantify the relationship between the synapse parameters and the quanta transfer process. The DBS model is applicable to a variety of states of synaptic activity, and by changing the synapse parameters it is possible to simulate various conditions of quanta transmission. The influence of the bathing solution temperature change on the synaptic parameters under different conditions of transmitter release in the frog neuromuscular junction is investigated. Simulations demonstrate that several synaptic parameters, including the parameters of the presynaptic membrane, are not affected by the temperature change. It is shown that a stimulation frequency exists at which the steady-state level of facilitation during a long train of stimuli is the same for a wide range of temperatures.

Animals↗

The spontaneous-rate histogram of the auditory nerve can be explained by only two or three spontaneous rates and long-range dependence.

Estimates of the spontaneous discharge rate (SR) of auditory-nerve (AN) fibers are often based on measurements of the average rate over a long (e.g., 30 s) interval. These measurements are important because SR is apparently correlated with other AN properties, such as threshold to acoustic stimuli, shape of rate-level function, recovery from prior stimulation, and certain anatomical characteristics. Furthermore, histograms of SR estimates from large numbers of fibers suggest that they can be divided into two (i.e., low and high) or three (i.e., low, medium, and high) SR classes. Yet, even "simple" statistical estimates, such as average rate, can behave surprisingly poorly for processes with long-range dependence (LRD), which has been found in the spontaneous activity of AN fibers. In particular, LRD greatly increases the variability of estimates of mean discharge rate. We investigated the implications of this effect of LRD for our understanding of the SRs of AN fibers. The fractional-Gaussian-noise-driven Poisson process (fGnDP) was originally developed to model the LRD action-potential trains of AN fibers. Using rate estimates computed from this model, we were able to reproduce the shape of published histograms of SR using only three fixed SR values. Moreover, by using a Poisson-equivalent integrate-and-fire (IF) model in place of the inhomogeneous Poisson process in the fGnDP model, we were able to reproduce SR histograms using only two fixed SR values. These results suggest that AN fibers may have only two or three possible values for their long-term average spontaneous discharge rates. In other words, all "high-SR" neurons may actually have the same underlying SR. Furthermore, both "low-SR" and "medium-SR" neurons may have a single "true" SR value, or these two classes may have two different "true" SR values. Furthermore, the Poisson-equivalent IF model may prove useful in other applications involving the modeling of trains of action potentials.

Action Potentials↗

Statistical and heuristic image noise extraction (SHINE): a new method for processing Poisson noise in scintigraphic images.

Poisson noise is one of the factors degrading scintigraphic images, especially at low count level, due to the statistical nature of photon detection. We have developed an original procedure, named statistical and heuristic image noise extraction (SHINE), to reduce the Poisson noise contained in the scintigraphic images, preserving the resolution, the contrast and the texture. The SHINE procedure consists in dividing the image into 4 x 4 blocks and performing a correspondence analysis on these blocks. Each block is then reconstructed using its own significant factors which are selected using an original statistical variance test. The SHINE procedure has been validated using a line numerical phantom and a hot spots and cold spots real phantom. The reference images are the noise-free simulated images for the numerical phantom and an extremely high counts image for the real phantom. The SHINE procedure has then been applied to the Jaszczak phantom and clinical data including planar bone scintigraphy, planar Sestamibi scintigraphy and Tl-201 myocardial SPECT. The SHINE procedure reduces the mean normalized error between the noisy images and the corresponding reference images. This reduction is constant and does not change with the count level. The SNR in a SHINE processed image is close to that of the corresponding raw image with twice the number of counts. The visual results with the Jaszczak phantom SPECT have shown that SHINE preserves the contrast and the resolution of the slices well. Clinical examples have shown no visual difference between the SHINE images and the corresponding raw images obtained with twice the acquisition duration. SHINE is an entirely automatic procedure which enables halving the acquisition time or the injected dose in scintigraphic acquisitions. It can be applied to all scintigraphic images, including PET data, and to all low-count photon images.

Algorithms↗

Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture.

The process of metastasis is not random. Rather, it consists of a series of linked, sequential steps that must be completed by tumor cells if a metastasis is to develop. Although some of the steps in this process contain stochastic elements, as a whole, metastasis favors the survival and growth of a few subpopulations of cells that preexist within the parent neoplasm. Moreover, metastases can have a clonal origin, and different metastases can originate from the proliferation of single cells. The outcome of metastasis depends on the interaction of metastatic cells with different organ environments. Organ-specific metastases have been demonstrated in a variety of experimental tumor systems. Moreover, we have found tumor growth that is specific to a particular site within one organ. Whether the same conclusions can be reached for human cancers remained unanswered until very recently. Studies from our laboratory and from others have shown that the implantation of human cancer cells derived from surgical specimens into correct anatomical sites of nude mice can provide a suitable model of metastasis of human tumors. Clonal analysis of a human renal carcinoma, colon carcinomas, and melanomas has revealed that these tumors are indeed heterogeneous for metastatic properties, an observation made only after orthotopic implantation. Thus, growth in the environment of specific organs can be selective and the environment per se influences this process. While it is clear that vascularity and local immunity can facilitate or retard tumor growth, we have concentrated on understanding how damage to an organ and the subsequent repair process can facilitate tumor cell proliferation. Accelerated growth of human colon cancer cells was found in hepatectomized nude mice, whereas accelerated growth of human renal cancer cells was found in nephrectomized nude mice. These data suggest that systemic physiological signals can be recognized by neoplastic cells presumably by mechanisms similar to those shared by their normal cell counterparts. In summary, the critical factors that regulate metastasis are the intrinsic properties of metastatic cells and host factors involved in homeostasis. The recent increase in our understanding of metastasis should provide important leads for developing more effective approaches to the treatment of disseminated cancer.

Animals↗

A new Smith predictor and controller for control of processes with long dead time.

Good control of processes with long dead time is often achieved using a Smith predictor configuration. Typically a PI or PID controller is used; however, it is shown in this paper that for some situations improved set point and disturbance responses can be obtained if a PI-PD controller is used. Several methods are possible for selecting the parameters of the PI-PD controller but when the plant transfer function has no zeros, the use of the standard forms provides a simple algebraic approach, and also reveals why difficulties may be encountered if a PID controller is used. Some examples are given to show the value of the approach presented.

Computer Simulation↗

Properties of phylogenetic trees generated by Yule-type speciation models.

We investigate some discrete structural properties of evolutionary trees generated under simple null models of speciation, such as the Yule model. These models have been used as priors in Bayesian approaches to phylogenetic analysis, and also to test hypotheses concerning the speciation process. In this paper we describe new results for three properties of trees generated under such models. Firstly, for a rooted tree generated by the Yule model we describe the probability distribution on the depth (number of edges from the root) of the most recent common ancestor of a random subset of k species. Next we show that, for trees generated under the Yule model, the approximate position of the root can be estimated from the associated unrooted tree, even for trees with a large number of leaves. Finally, we analyse a biologically motivated extension of the Yule model and describe its distribution on tree shapes when speciation occurs in rapid bursts.

Animals↗

Statistical analysis of nonlinearly reconstructed near-infrared tomographic images: Part II--Experimental interpretation.

Image error analysis of a diffuse near-infrared tomography (NIR) system has been carried out on simulated data using a statistical approach described in Part I of this paper (Pogue et al., 2002). The methodology is used here with experimental data acquired on phantoms with a prototype imaging system intended for characterizing breast tissue. Results show that imaging performance is not limited by random measurement error, but rather by calibration issues. The image error over the entire field of view is generally not minimized when an accurate homogeneous estimate of the phantom properties is available; however, local image error over a target region of interest (ROI) is reduced. The image reconstruction process which includes a Levenberg-Marquardt style regularization provides good minimization of the objective function, yet its reduction is not always correlated with an overall image error decrease. Minimization of the bias in an ROI which contains localized changes in the optical properties can be achieved through five to nine iterations of the algorithm. Precalibration of the algorithm through statistical evaluation of phantom studies may provide a better measure of the image accuracy than that implied by minimization of the standard objective function.

Breast↗

A three-dimensional computer model of four hypothetical mechanisms protecting biofilms from antimicrobials.

Four hypothetical mechanisms for protection of biofilms against antimicrobials were incorporated into a three-dimensional model of biofilm growth and development. The model integrated processes of substrate utilization, diffusion, growth, cell migration, death, and detachment in a cellular automaton framework. Compared to simulations of unprotected biofilms, each of the protective mechanisms provided some tolerance to antimicrobial action. When the mechanisms were compared to each other, the behaviors of the four protective mechanisms produced distinct shapes of killing curves, nonuniform spatial patterns of survival and cell type distribution, and anticipated susceptibility patterns for dispersed biofilm cells. The differences between the protective mechanisms predicted in these simulations could guide the design of experiments to discriminate antimicrobial tolerance mechanisms in biofilms. Each of the mechanisms could be a plausible avenue of biofilm protection.

Anti-Infective Agents↗

Field parameterization and experimental test of the neutral theory of biodiversity.

Ecologists would like to explain general patterns observed across multi-species communities, such as species-area and abundance-frequency relationships, in terms of the fundamental processes of birth, death and migration underlying the dynamics of all constituent species. The unified neutral theory of biodiversity and related theories based on these fundamental population processes have successfully recreated general species-abundance patterns without accounting for either the variation among species and individuals or resource-releasing processes such as predation and disturbance, long emphasized in ecological theory. If ecological communities can be described adequately without estimating variation in species and their interactions, our understanding of ecological community organization and the predicted consequences of reduced biodiversity and environmental change would shift markedly. Here, I introduce a strong method to test the neutral theory that combines field parameterization of the underlying population dynamics with a field experiment, and apply it to a rocky intertidal community. Although the observed abundance-frequency distribution of the system follows that predicted by the neutral theory, the neutral theory predicts poorly the field experimental results, indicating an essential role for variation in species interactions.

Animals↗