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PubMed2006

Nonlinear analysis of cerebral hemodynamic and intracranial pressure signals for characterization of autoregulation.

The objective of this study was to determine whether or not the underlying physiological systems that generates spontaneous arterial blood pressure (ABP), cerebral blood flow velocity (CBFV), and intracranial pressure signals could be adequately approximated as a linear stochastic process. Furthermore, a new measure (C) capable of capturing the degree of nonlinear dependency between two ABP and CBFV signals (including a time-varying situation) was proposed for quantifying the degree of cerebral blood flow autoregulation. A surrogate data test of fifteen ABP, CBFV, and intracranial pressure (ICP) segments was conducted for detecting whether there exists a statistically significant deviation from the null hypothesis of linear signals. The extension of the established block computation method of C measure to an adaptive one was achieved. This new algorithm was then applied to study the C evolution using brain injury patients data from a hyperventilation study and two propofol studies. Nonlinearity has not been detected for all the fifteen recordings, neither has nonlinear dependency between CBFV and ABP. However, their presences in some of the signal segments justified the adoption of a nonlinear measure of dependency capable of characterizing both linear and nonlinear correlations for inferring autoregulation status. C measure started to decrease with the introduction of hypocapnia state indicating that hyperventilation may reduce the dependency of CBFV on ABP fluctuations. On the other hand, complex patterns of C measure evolution were observed among 14 cases of propofol data indicating a nontrivial effect of propofol on the dependency of CBFV on ABP.

Adaptation, Physiological↗
PubMed2000

Genetic structure in the nonrewarding, bumblebee-pollinated orchid Calypso bulbosa.

Among- and within-population variation at neutral loci is governed by an interaction between stochastic processes and gene flow. A previous study of pollen dispersal in which the transfer of individually marked pollinia was monitored, indicated not only that populations of the nonrewarding, bumblebee-pollinated orchid Calypso bulbosa are connected by substantial levels of gene flow, but also that seed production may be the result of self-fertilization to a considerable extent. We examined the genetic structure of 21 C. bulbosa populations in northern Sweden by F-statistics analyses of variation at three polymorphic allozyme loci. Four populations each consisted of two or three distinct patches, which also allowed us to evaluate among-patch differentiation. The inbreeding coefficient over all loci within populations was high (FIS=0.283). F-statistics indicated that the level of genetic differentiation among patches within populations varied among populations. FST among patches within populations ranged between -0.021 and 0.119 and was significantly different from zero in two of the populations. There was low to moderate genetic differentiation among populations (FST=0. 072). A Mantel test indicated a positive correlation between geographical and genetic distances among populations, but this correlation was dependent on the difference in allele frequencies between the southernmost population sampled and all other populations. Self-fertilization and substructuring within sampling units (within patches and populations) may have contributed to the high inbreeding coefficients observed in many C. bulbosa populations. Long-distance seed and pollen dispersal may account for the low to moderate genetic differentiation among populations.

Animals↗
PubMed2000

Comparative single-molecule and ensemble myosin enzymology: sulfoindocyanine ATP and ADP derivatives.

Single-molecule and macroscopic reactions of fluorescent nucleotides with myosin have been compared. The single-molecule studies serve as paradigms for enzyme-catalyzed reactions and ligand-receptor interactions analyzed as individual stochastic processes. Fluorescent nucleotides, called Cy3-EDA-ATP and Cy5-EDA-ATP, were derived by coupling the dyes Cy3.29.OH and Cy5.29.OH (compounds XI and XIV, respectively, in, Bioconjug. Chem. 4:105-111)) with 2'(3')-O-[N-(2-aminoethyl)carbamoyl]ATP (EDA-ATP). The ATP(ADP) analogs were separated into their respective 2'- and 3'-O-isomers, the interconversion rate of which was 30[OH(-)] s(-1) (0.016 h(-1) at pH 7.1) at 22 degrees C. Macroscopic studies showed that 2'(3')-O-substituted nucleotides had properties similar to those of ATP and ADP in their interactions with myosin, actomyosin, and muscle fibers, although the ATP analogs did not relax muscle as well as ATP did. Significant differences in the fluorescence intensity of Cy3-nucleotide 2'- and 3'-O-isomers in free solution and when they interacted with myosin were evident. Single-molecule studies using total internal reflection fluorescence microscopy showed that reciprocal mean lifetimes of the nucleotide analogs interacting with myosin filaments were one- to severalfold greater than predicted from macroscopic data. Kinetic and equilibrium data of nucleotide-(acto)myosin interactions derived from single-molecule microscopy now have a biochemical and physiological framework. This is important for single-molecule mechanical studies of motor proteins.

Actins↗
PubMed2001

Ratcheting in post-translational protein translocation: a mathematical model.

We have developed a non-steady-state mathematical model describing post-translational protein translocation across the endoplasmic reticulum membrane. Movement of the polypeptide chain through the channel in the endoplasmic reticulum membrane is considered to be a stochastic process which is biased at the lumenal side of the channel by the binding of BiP (Kar2p), a member of the Hsp70 family of ATPases (ratcheting model). Assuming that movement of the chain through the channel is caused by passive diffusion (Brownian ratchet), the model describes all available experimental data. The optimum set of model parameters indicates that the ratcheting mechanism functions at near-maximum rate, being relatively insensitive to variations of the association or dissociation rate constants of BiP or its concentration. The estimated rate constant for diffusion of a polypeptide inside the channel indicates that the chain makes contact with the walls of the channel. Since fitting of the model to the data required that the backward rate constant be larger than the forward constant during early diffusion steps, translocation must occur against a force. The latter may arise, for example, from the unfolding of the polypeptide chain in the cytosol. Our results indicate that the ratchet can transport polypeptides against a free energy of about 25 kJ/mol without significant retardation of translocation. The modeling also suggests that the BiP ratchet is optimized, allowing fast translocation to be coupled with minimum consumption of ATP and rapid dissociation of BiP in the lumen of the ER. Finally, we have estimated the maximum hydrophobicity of a polypeptide segment up to which lateral partitioning from the channel into the lipid phase does not result in significant retardation of translocation.

Adenosine Triphosphate↗
PubMed1994

Evaluation of cancer prevention strategies by computerized simulation model: methodological issues.

A computerized simulation model developed to evaluate the potential impact of primary and secondary prevention is discussed from methodologic perspectives. In the simulation model, named CANSAVE (Cancer Strategy Analysis and Validation of Effect), the natural history of cancer was modeled as a Markovian stochastic process from cancer-free state to death. The lung cancer death rate among Japanese males was projected for 50 years to the year 2041. The simulation showed that the age-adjusted death rate would increase and reach a peak of 166 per 100,000 in 1989 and then decrease to 148 in 2003. It then shows a tendency to increase again, up to 255 in 2028. This change may be attributed to a lower smoking initiation rate among those born in the 1930s. Promotion of mass screening programs exhibits a more prompt effect than antismoking efforts, but the reduction in annual deaths is expected to be only 11%, even if a 100% participation is realized by the year 2000. The reduction in smoking initiation rate, on the other hand, begins to show a visible effect very slowly. It was predicted that a 1% annual reduction in smoking initiation rate would result in a 20% decrease in the number of deaths in 2041. The smoking cessation program is in the middle with regard to promptness. The predicted reductions in lung cancer deaths in 2041 were 13, 47, and 66%, respectively, when the annual smoking cessation rate was increased from 0.46% (present status) to 1, 3, and 5%. The combined application of all three preventive measures seems essential to realize the most effective reduction in lung cancer deaths.

Adult↗
PubMed2005

Non-homogeneous Markov processes for biomedical data analysis.

Some time ago, the Markov processes were introduced in biomedical sciences in order to study disease history events. Homogeneous and Non-homogeneous Markov processes are an important field of research into stochastic processes, especially when exact transition times are unknown and interval-censored observations are present in the analysis. Non-homogeneous Markov process should be used when the homogeneous assumption is too strong. However these sorts of models increase the complexity of the analysis and standard software is limited. In this paper, some methods for fitting non-homogeneous Markov models are reviewed and an algorithm is proposed for biomedical data analysis. The method has been applied to analyse breast cancer data. Specific software for this purpose has been implemented.

Algorithms↗
PubMed2026

Increased precipitation decelerates temporal succession of grassland soil microbial communities.

Global precipitation regimes have been shifted in recent decades, imposing significant consequences in water-limited grassland ecosystems. However, the effects of increased precipitation on the succession of soil microbial communities remain unclear, mainly due to the scarcity of long-term experiments with time-series data. Here, we examined temporal succession of grassland soil microbial communities in a long-term increased precipitation experiment. Both soil microbial taxonomic and functional structures were significantly altered by increased precipitation. Increased precipitation significantly decelerated the succession rates of soil microbial functional structure (i.e. time-decay relationships). Consistent with the increased microbial decomposition and heterotrophic respiration, the abundances of soil microbial carbon decomposition genes were markedly enhanced by increased precipitation. Furthermore, increased precipitation stimulated genes involved in nutrient cycling processes, potentially promoting plant growth. Collectively, the contributions of stochastic processes in shaping microbial communities were increased under increased precipitation, suggesting that microbial successional trajectories may shift toward multiple alternative states characterized by greater stochasticity under future altered precipitation regimes.

Soil Microbiology↗
PubMed2006

Stochastically driven genetic circuits.

Transcriptional regulation in small genetic circuits exhibits large stochastic fluctuations. Recent experiments have shown that a significant fraction of these fluctuations is caused by extrinsic factors. In this paper we review several theoretical and computational approaches to modeling of small genetic circuits driven by extrinsic stochastic processes. We propose a simplified approach to this problem, which can be used in the case when extrinsic fluctuations dominate the stochastic dynamics of the circuit (as appears to be the case in eukaryots). This approach is applied to a model of a single nonregulated gene that is driven by a certain gating process that affects the rate of transcription, and to a simplified version of the galactose utilization circuit in yeast.

Animals↗
PubMed1991

Periaqueductal gray spike trains recorded in frontal or horizontal mesencephalic brain slices from the rat.

Spontaneous spike trains were recorded from the periaqueductal gray matter (PAG) in frontal and horizontal mesencephalic slices in order to compare spontaneous activity of the slice preparation to previous in vivo records. The firing rates resembled those recorded in vivo. They were low notwithstanding the fact that the slicing procedure removed tonic inhibitory input to the PAG. The firing rates increased caudo-rostrally, a fact that had not been reported in vivo, and were lower in frontal sections. Several different spike trains were found, described and classified according to their temporal firing patterns. The spike sequences were usually simple stochastic processes, distributed as a Gaussian function with or without stochastic deletion of spikes.

Animals↗
PubMed2005

Development of cancer chemopreventive drugs based on mechanistic approaches.

One of the most important medical practices of the 21st century is the chemoprevention of cancer. Much progress has been made in this new emerging field, but much work remains before widespread use and practice of cancer prevention becomes commonplace. Cancer chemoprevention includes the concepts of inhibition, reversal, and retardation of the cancer process. The process of carcinogenesis requires 20-40 years to reach invasive cancer. This process follows multiple, diverse, and complex pathways in a stochastic process, called clonal evolution. Many of these pathways appear amenable to inhibition, reversal, or retardation at various points. It is urgent that we identify key pathways in the evolution of the cancer cell, which can be exploited to prevent this carcinogenesis process. Basic researchers are identifying many genetic lesions and epigenetic processes associated with the progression of precancer to invasive disease. These precancer lesions are also called intraepithelial neoplasia (IEN). Many of these early precancerous lesions favor cell division over quiescence and protect cells against apoptosis when signals are present. Many oncogenes, which are active during early development, are reactivated in adulthood by aberrant gene promoting errors. Normal regulatory genes can become mutated, making them insensitive to normal regulatory signals. Tumor suppressor genes are deleted or mutated rendering them inactive. These are several of a wide range of defects in cellular machinery, which can lead to evolution of the cancer phenotype. Errors may not have to appear in a defined order for cells to progress along the cancer pathway. To conquer this diverse disease, it is necessary to attack multiple key pathways at once for a predetermined period of time. Agent combination prevention strategies are, therefore, essential to decrease cancer morbidity. Each cancer type, organ location, or individual genetic background may require a custom combination of prevention strategies to be successful.

Anticarcinogenic Agents↗
PubMed1994

Spatial non-uniformities in [Ca2+]i during excitation-contraction coupling in cardiac myocytes.

The intracellular calcium ([Ca2+]i) transient in adult rat heart cells was examined using the fluorescent calcium indicator fluo-3 and a laser scanning confocal microscope. We find that the electrically evoked [Ca2+]i transient does not rise at a uniform rate at all points within the cell during the [Ca2+]i transient. These spatial non-uniformities in [Ca2+]i are observed immediately upon depolarization and largely disappear by the time the peak of the [Ca2+]i transient occurs. Importantly, some of the spatial non-uniformity in [Ca2+]i varies randomly in location from beat to beat. Analysis of the spatial character of the non-uniformities suggests that they arise from the stochastic nature of the activation of SR calcium-release channels. The non-uniformities in [Ca2+]i are markedly enhanced by low concentrations of Cd2+, suggesting that activation of L-type calcium channels is the primary source of activator calcium for the calcium transient. In addition, the pattern of calcium release in these conditions was very similar to the spontaneous calcium sparks that are observed under resting conditions and which are due to spontaneous calcium release from the SR. The spatial non-uniformity in the evoked [Ca2+]i transient under normal conditions can be explained by the temporal and spatial summation of a large number of calcium sparks whose activation is a stochastic process. The results are discussed with respect to a stochastic local control model for excitation-contraction (E-C) coupling, and it is proposed that the fundamental unit of E-C coupling consists of one dihydropyridine receptor activating a small group of ryanodine receptors (possibly four) in a square packing model.

Animals↗
PubMed1983

Variance reduction in analytical processes in the clinical laboratory by digital filtering.

A model is postulated describing the fluctuations in analytical chemical processes in the clinical laboratory. In this model the process variations are described by a non-stationary stochastic process with a significant time-varying mean value. Experiments short-term variance within a run and a long-term variance between runs determined by the time-varying mean value. For four different analytical systems used for determining six serum analytes between-run variance was demonstrated to be significantly greater than within-run variance. Based on the model a digital filtering procedure is presented which in each run estimates the process mean and subsequently corrects serum samples for its deviation. Thus significant variance reductions are obtained. The filtering procedure was tested for the determination in inorganic phosphate with a continuous-flow system in an experimental environment.

Analysis of Variance↗
PubMed1999

Harmonic potential driven by long-range correlated noise.

The probability distribution of a particle in a quadratic potential driven by Gaussian long-range correlated noise has been obtained. The long-time asymptotic relaxation of the stochastic process has been characterized in terms of the long-range correlated noise appearing in the corresponding stochastic differential equation defining the process. The particular case when the particle is driven by a Gaussian color noise has also been revisited, in this way giving its exact probability distribution for all time. By using a characteristic functional technique reported previously, results for a non-Gaussian long-range correlated noise are also shown. Emphasis has been placed on solving the plane rotator in the presence of arbitrary random torques having long-range correlations. In order to show strong and weak non-Markovian effects coming from different sources of noise, the undamped free particle under the influence of arbitrary accelerations has been analyzed. We also analyze in detail the structure of the trajectories of the overdamped and undamped free particle.

Journal Article↗
PubMed2005

Nonergodicity of blinking nanocrystals and other Lévy-walk processes.

We investigate the nonergodic properties of blinking nanocrystals modeled by a Lévy-walk stochastic process. Using a nonergodic mean field approach we calculate the distribution functions of the time averaged intensity correlation function. We show that these distributions are not delta peaked on the ensemble average correlation function values; instead they are W or U shaped. Beyond blinking nanocrystals our results describe ergodicity breaking in systems modeled by Lévy walks , for example, certain types of chaotic maps and spin dynamics to name a few.

Journal Article↗
PubMed2005

Uncertainty analysis of penicillin V production using Monte Carlo simulation.

Uncertainty and variability affect economic and environmental performance in the production of biotechnology and pharmaceutical products. However, commercial process simulation software typically provides analysis that assumes deterministic rather than stochastic process parameters and thus is not capable of dealing with the complexities created by variance that arise in the decision-making process. Using the production of penicillin V as a case study, this article shows how uncertainty can be quantified and evaluated. The first step is construction of a process model, as well as analysis of its cost structure and environmental impact. The second step is identification of uncertain variables and determination of their probability distributions based on available process and literature data. Finally, Monte Carlo simulations are run to see how these uncertainties propagate through the model and affect key economic and environmental outcomes. Thus, the overall variation of these objective functions are quantified, the technical, supply chain, and market parameters that contribute most to the existing variance are identified and the differences between economic and ecological evaluation are analyzed. In our case study analysis, we show that final penicillin and biomass concentrations in the fermenter have the highest contribution to variance for both unit production cost and environmental impact. The penicillin selling price dominates return on investment variance as well as the variance for other revenue-dependent parameters.

Fermentation↗
PubMed1984

Intercompartmental transport in the Golgi complex is a dissociative process: facile transfer of membrane protein between two Golgi populations.

The transfer of the vesicular stomatitis virus-encoded glycoprotein (G protein) between Golgi populations in fused cells (Rothman, J. E., L. J. Urbani, and R. Brands. 1984. J. Cell Biol. 99:248-259) is exploited here to study and to help define the compartmental organization of the Golgi stack and to characterize the mechanism of intercompartmental transport. We find that G protein that has just received its peripheral N-acetylglucosamine in the Golgi complex of one cell is efficiently transferred to the Golgi complex of another cell to receive galactose (Gal). Remarkably, this transport occurs at the same rate between these two compartments whether they are present in the same or different Golgi populations. Therefore, a dissociative (presumably vesicular) transport step moves G protein from one part of the Golgi in which N-acetylglucosamine is added to another in which Gal is added. Minutes later, upon receiving Gal, the same G protein molecules are very poorly transferred to an exogenous Golgi population after cell fusion. Therefore, once this intercompartmental transfer has already taken place (before fusion), it cannot take place again (after fusion); i.e., transport across the compartment boundary in the Golgi complex that separates the sites of N-acetylglucosamine and Gal incorporation is a vectorial process. We conclude that transfers between Golgi cisternae occur by a stochastic process in which transport vesicles budding from cisternae dissociate, can diffuse away, and then attach to and fuse with the appropriate target cisterna residing in the same or in a different stack, based on a biochemical pairing after a random encounter. Under these circumstances, a transported protein would almost always randomize among stacks with each intercisternal transfer; it would not progress systematically through a single stack. Altogether, our studies define three sequential compartments in the Golgi stack.

Acetylglucosamine↗
PubMed2006

Generic multifractality in exponentials of long memory processes.

We find that multifractal scaling is a robust property of a large class of continuous stochastic processes, constructed as exponentials of long-memory processes. The long memory is characterized by a power law kernel with tail exponent phi+1/2, where phi>0. This generalizes previous studies performed only with phi=0(with a truncation at an integral scale) by showing that multifractality holds over a remarkably large range of dimensionless scales for phi>0. The intermittency multifractal coefficient can be tuned continuously as a function of the deviation phi from 1/2 and of another parameter sigma2 embodying information on the short-range amplitude of the memory kernel, the ultraviolet cutoff ("viscous") scale, and the variance of the white-noise innovations. In these processes, both a viscous scale and an integral scale naturally appear, bracketing the "inertial" scaling regime. We exhibit a surprisingly good collapse of the multifractal spectra zeta(q) on a universal scaling function, which enables us to derive high-order multifractal exponents from the small-order values and also obtain a given multifractal spectrum zeta(q) by different combinations of phi and sigma2.

Journal Article↗