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PubMed1993

Quantum mechanical properties of biosystems: a framework for complexity, structural stability, and transformations.

Internal quantum non-demolition measurements are inherent for biological organization and determine the essential features of living systems. Low energy dissipation in these measurements provided by slow conformational relaxation of biomacromolecular complexes (regarded as measuring devices) is the main precondition of enzyme operation and information transfer determining the steady non-equilibrium state of biosystems. The presence of an internal formal description inside a biosystem, expressed in genetic structures (developmental program), is a consequence of its quantum properties. Incompleteness of this formal description provides the possibility of the generation of new functional relations and interconnections inside the system. This is a logical precondition of an evolutionary process. The quantum mechanical uncertainty that underlies the appearance of bifurcations is considered to be the main physical foundation of complication and irreversible transformation of biosystems.

Biological Evolution↗
PubMed2002

Enhanced bio-manufacturing through advanced multivariate statistical technologies.

The paper describes the interrogation of data, from a reaction vessel producing an active pharmaceutical ingredient (API), using advanced multivariate statistical techniques. Due to the limited number of batches available, data augmentation was used to increase the number of batches thereby enabling the extraction of more subtle process behaviour from the data. A second methodology investigated was that of multi-group modelling. This allowed between cluster variability to be removed, thus allowing attention to focus on within process variability. The paper describes how the different approaches enabled the realisation of a better understanding of the factors causing the onset of an impurity formation to be obtained as well demonstrating the power of multivariate statistical data analysis techniques to provide an enhanced understanding of the process.

Artifacts↗
PubMed2005

A numerical solution to the nonhomogeneous two-stage MVK model of cancer.

In this article, we describe a straightforward method for solving the probability of at least one malignant cell by time t, and the associated hazard function, in the general (i.e., nonhomogeneous) two-stage Moolgavkar-Venzon-Knudson (MVK) model of cancer. The method consists of solving four coupled ordinary differential equations derived from the Kolmogorov backward equations for this process. The relationship of this method to previously proposed solutions is discussed.

Cell Transformation, Neoplastic↗
PubMed2004

Modeling senescence in hypotrichous ciliates.

A sexually reproducing hypotrichous ciliates undergo senescence which is in general attributed to degenerative processes in the macronucleus, assuming that loss of viability is based on loss of genetic elements. It is generally accepted that the genetic elements in the macronucleus of hypotrichs segregate randomly, a process which potentially can lead to aneuploid imbalances in the distribution of gene copies. It is, however, unclear whether there are mechanisms which compensate for such imbalances such that each genetic element regains its predetermined copy number (regulatory model, conserving euploidy), or whether the genetic elements only double, so that genetic imbalances can be inherited to further generations (stochastic model, allowing aneuploidy). By means of mathematical modeling and simulations, we investigate these two models with respect to the number of generations a lineage of hypotrichs can survive under asexual conditions. Whereas the regulatory model cannot explain senescence in hypotrichs, the stochastic model provides plausible results which, however, strongly depend on the assumed distribution of copy numbers which we investigate by means of three examples. For both models, simple prediction formulae for the approximate survival time of asexually reproducing ciliates are provided.

Aging↗
PubMed1995

Evidence for a cooperative learning mechanism in the vestibulo-ocular reflex.

The vestibulo-ocular reflex (VOR) stabilizes vision by producing eye rotations that counterbalance head rotations. It receives input from a pair of vestibular receptors, and becomes unbalanced when input from one side is removed, producing spontaneous eye rotation in the absence of head rotation (SVOR). SVOR can be eliminated by the process of vestibular compensation. In mammals, SVOR elimination occurs over a period of days, and follows an exponential time course. We show that SVOR elimination in goldfish occurs in a matter of minutes, and its time course is not exponential but is characterized by a sigmoid function suggesting a cooperative mechanism. This time course is reproduced in a stochastic neural network model that has nonspecific reinforcement related to the level of VOR imbalance.

Adaptation, Physiological↗
PubMed2003

Coalescent patterns in diploid exchangeable population models.

A class of two-sex population models is considered with N females and equal number N of males constituting each generation. Reproduction is assumed to undergo three stages: 1) random mating, 2) exchangeable reproduction, 3) random sex assignment. Treating individuals as pairs of genes at a certain locus we introduce the diploid ancestral process (the past genealogical tree) for n such genes sampled in the current generation. Neither mutation nor selection are assumed. A convergence criterium for the diploid ancestral process is proved as N goes to infinity while n remains unchanged. Conditions are specified when the limiting process (coalescent) is the Kingman coalescent and situations are discussed when the coalescent allows for multiple mergers of ancestral lines.

Algorithms↗
PubMed2004

Measuring information transfer in the spike generator of crayfish sustaining fibers.

We present a method based on information-theoretic distances for measuring the information transfer efficiency of voltage to impulse encoders. In response to light pulses, we simultaneously recorded the EPSP and spiking output of crayfish sustaining fibers. To measure the distance between analog EPSP responses, we developed a membrane noise model that accurately captures stimulus-induced nonstationarities. By comparing the EPSP and spike responses, we found encoding efficiencies on the order of 10(-4), with interesting dynamics occurring during initial transients. A simple analog to point-process converter predicted the small information transfer efficiencies and dynamic properties we measured.

Action Potentials↗
PubMedDate not supplied

Automated production support for the bioprocess industry.

This paper describes the application of Artificial Intelligence and Multivariate Statistical Techniques to two industrial fermentation systems. In the first example, an Expert System is shown to provide tighter control of an important process parameter. This is shown to lead to improved consistency of operation. In the second application, Principal Component Analysis is applied to a final stage fermentation production facility. The results presented indicate that the algorithm can provide concise indicators of process faults that can be presented to the operators to assist them in taking suitable corrective actions.

Algorithms↗
PubMed2004

Image enhancement and denoising by complex diffusion processes.

The linear and nonlinear scale spaces, generated by the inherently real-valued diffusion equation, are generalized to complex diffusion processes, by incorporating the free Schrödinger equation. A fundamental solution for the linear case of the complex diffusion equation is developed. Analysis of its behavior shows that the generalized diffusion process combines properties of both forward and inverse diffusion. We prove that the imaginary part is a smoothed second derivative, scaled by time, when the complex diffusion coefficient approaches the real axis. Based on this observation, we develop two examples of nonlinear complex processes, useful in image processing: a regularized shock filter for image enhancement and a ramp preserving denoising process.

Algorithms↗
PubMed1995

Specific compositional patterns of synonymous positions in homologous mammalian genes.

All 69 homologous coding sequences that are currently available in four mammalian orders were aligned and the synonymous (ie., third) positions of quartet (fourfold degenerate) codons were divided into three classes (that will be called conserved, intermediate, and variable), according to whether they show no change, one change, and more than one change, respectively. The three classes were analyzed in their compositional patterns. In the majority of GC-rich genes, the three classes of positions (but especially conserved positions) exhibited significantly different base compositions compared to expectations based on a "random" substitution process from the "ancestral" (consensus) sequence to the present-day (actual) sequences. Significant differences were rare in GC-poor genes. An analysis of the present results indicates that natural selection plays a role in the synonymous nucleotide substitution process, especially in GC-rich genes which represent the vast majority of mammalian genes.

Animals↗
PubMed2003

Using network models to approximate spatial point-process models.

Spatial effects are fundamental to ecological and epidemiological systems, yet the incorporation of space into models is potentially complex. Fixed-edge network models (i.e. networks where each edge has the same fixed strength of interaction) are widely used to study spatial processes but they make simplistic assumptions about spatial scale and structure. Furthermore, it can be difficult to parameterize such models with empirical data. By comparison, spatial point-process models are often more realistic than fixed-edge network models, but are also more difficult to analyze. Here we develop a moment closure technique that allows us to define a fixed-edge network model which predicts the prevalence and rate of epidemic spread of a continuous spatial point-process epidemic model. This approach provides a systematic method for accurate parameterization of network models using data from continuously distributed populations (such as data on dispersal kernels). Insofar as point-process models are accurate representations of real spatial biological systems, our example also supports the view that network models are realistic representations of space.

Animals↗
PubMed2005

A latent markov model for the analysis of longitudinal data collected in continuous time: states, durations, and transitions.

Markov models provide a general framework for analyzing and interpreting time dependencies in psychological applications. Recent work extended Markov models to the case of latent states because frequently psychological states are not directly observable and subject to measurement error. This article presents a further generalization of latent Markov models to allow for the analysis of rating data that are collected at arbitrary points in time. This extension offers new ways of investigating change processes by focusing explicitly on the durations that are spent in latent states. In an experience sampling application the author shows that such duration analyses can provide valuable insights about chronometric features of emotions.

Humans↗
PubMed2004

An autonomous molecular computer for logical control of gene expression.

Early biomolecular computer research focused on laboratory-scale, human-operated computers for complex computational problems. Recently, simple molecular-scale autonomous programmable computers were demonstrated allowing both input and output information to be in molecular form. Such computers, using biological molecules as input data and biologically active molecules as outputs, could produce a system for 'logical' control of biological processes. Here we describe an autonomous biomolecular computer that, at least in vitro, logically analyses the levels of messenger RNA species, and in response produces a molecule capable of affecting levels of gene expression. The computer operates at a concentration of close to a trillion computers per microlitre and consists of three programmable modules: a computation module, that is, a stochastic molecular automaton; an input module, by which specific mRNA levels or point mutations regulate software molecule concentrations, and hence automaton transition probabilities; and an output module, capable of controlled release of a short single-stranded DNA molecule. This approach might be applied in vivo to biochemical sensing, genetic engineering and even medical diagnosis and treatment. As a proof of principle we programmed the computer to identify and analyse mRNA of disease-related genes associated with models of small-cell lung cancer and prostate cancer, and to produce a single-stranded DNA molecule modelled after an anticancer drug.

Antineoplastic Agents↗
PubMed2000

A model for influence of exercise on formation and growth of tissue bubbles during altitude decompression.

In response to exercise performed before or after altitude decompression, physiological changes are suspected to affect the formation and growth of decompression bubbles. We hypothesized that the work to change the size of a bubble is done by gas pressure gradients in a macro- and microsystem of thermodynamic forces and that the number of bubbles formed through time follows a Poisson process. We modeled the influence of tissue O(2) consumption on bubble dynamics in the O(2) transport system in series against resistances, from the alveolus to the microsystem containing the bubble and its surrounding tissue shell. Realistic simulations of experimental decompression procedures typical of actual extravehicular activities were obtained. Results suggest that exercise-induced elevation of O(2) consumption at altitude leads to bubble persistence in tissues. At the same time, exercise-enhanced perfusion leads to an overall suppression of bubble growth. The total volume of bubbles would be reduced unless increased tissue motion simultaneously raises the rate of bubble formation through cavitation processes, thus maintaining or increasing total bubble volume, despite the exercise.

Altitude↗
PubMed2003

Influence of membrane properties on spike synchronization in neurons: theory and experiments.

In the brain spike synchronization in neurons is involved in information transfer and certain forms of dysfunction. The theory of random point processes was used to relate the statistical properties of input point processes to synchronization between firing in neurons viewed as threshold devices. Derived analytical relations describe normalized synchronization in the case of shared input with balanced excitation and inhibition. For neuronal models with unbalanced shared input and spike generating Hodgkin-Huxley type conductances, the theory satisfactorily describes the temporal dependence of spike synchronization on the delay between spikes. Computer generated stochastic stimulus current was used to stimulate motoneurons in turtle spinal cord slices. Theory was able to approximate the temporal dependence of spike synchronization on the delay between spikes when the membrane time constant and the relative spike threshold measured were used in calculations. In agreement with the theoretical prediction, normalized spike synchrony was reduced when the threshold for spike generation was lowered by injection of steady depolarizing bias current. In spinal motoneurons the relative spike threshold can be lowered by a persistent inward current facilitated by activation of certain metabotropic transmitter receptors. After induction of this inward current spike synchronization was reduced several times. It is suggested that downregulation of the persistent inward current in motoneurons by disruption of brainstem modulatory systems, as in Parkinson disease, can facilitate tremor due to the increased synchrony between motoneurons.

Action Potentials↗
PubMed1979

Force predictions relating to tremor and other consequences of a 'distributed' model of skeletal muscle.

In this brief report, a 'distributed' computer model of skeletal muscle is described, and its predictions regarding muscle force and EMG are presented. The force and myo-electric signals are produced as the sum of the contributions of independently activated motor units possessing a distribution of properties. The results of the simulation as well as theoretical study show that: (a) asynchronous activity of motor units can be responsible for the fairly regular oscillations observed in muscle tremor; (b) the use, in the case of muscle, of the limit theorem for the superposition of independent point processes leads to erroneous conclusions with respect to the frequency characteristics of the muscle force waveform, and possibly, with regard to those of the EMG.

Electromyography↗
PubMed2004

The evolution of reproductive restraint through social communication.

The evolution of altruistic behavior through group selection is generally viewed as possible in theory but unlikely in reality, because individual selection favoring selfish strategies should act more rapidly than group selection favoring cooperation. Here we demonstrate the evolution of altruism, in the form of conditional reproductive restraint based on an explicitly social mechanism, modulated by intrapopulation communication comprising signal and evolved response, in a spatially distributed predatory/parasitic/pathogenic model system. The predatory species consistently comes to exploit a signal implying overcrowding, individuals constraining their reproduction in response, with a corresponding increase in equilibrium reproduction rate in the absence of signal. This signaled restraint arises in a robust way for a range of model spatial systems; it outcompetes non-signal-based restraint and is not vulnerable to subversion by noncooperating variants. In these systems, communication is used to evaluate population density and regulate reproduction accordingly, consistent with central ideas of Wynne-Edwards [Wynne-Edwards, V. C. (1962) Animal Dispersion in Relation to Social Behavior (Hafner, New York)], whose claims about the evolutionary importance of group selection helped ignite decades of controversy. This quantitative simulation model shows how the key evolutionary transition from solitary living to sociality can occur. The process described here of cooperation evolving through communication may also help to explain other major evolutionary transitions such as intercellular communication leading to multicellular organisms.

Altruism↗
PubMed2002

Log-normal distribution of the trace element data results from a mixture of stocahstic input and deterministic internal dynamics.

In previous article, we showed a log-normal distribution of boron and lithium in human urine. This type of distribution is common in both biological and nonbiological applications. It can be observed when the effects of many independent variables are combined, each of which having any underlying distribution. Although elemental excretion depends on many variables, the one-compartment open model following a first-order process can be used to explain the elimination of elements. The rate of excretion is proportional to the amount present of any given element; that is, the same percentage of an existing element is eliminated per unit time, and the element concentration is represented by a deterministic negative power function of time in the elimination time-course. Sampling is of a stochastic nature, so the dataset of time variables in the elimination phase when the sample was obtained is expected to show Normal distribution. The time variable appears as an exponent of the power function, so a concentration histogram is that of an exponential transformation of Normally distributed time. This is the reason why the element concentration shows a log-normal distribution. The distribution is determined not by the element concentration itself, but by the time variable that defines the pharmacokinetic equation.

Adult↗