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PubMed2003

A populationwide coalescent analysis of Icelandic matrilineal and patrilineal genealogies: evidence for a faster evolutionary rate of mtDNA lineages than Y chromosomes.

Historical inferences from genetic data increasingly depend on assumptions about the genealogical process that shapes the frequencies of alleles over time. Yet little is known about the structure of human genealogies over long periods of time and how they depart from expectations of standard demographic models, such as that attributed to Wright and Fisher. To obtain such information and to examine the recent evolutionary history of mtDNA and Y-chromosome haplotypes in the Icelandic gene pool, we traced the matrilineal and patrilineal ancestry of all 131,060 Icelanders born after 1972 back to two cohorts of ancestors, one born between 1848 and 1892 and the other between 1798 and 1742. This populationwide coalescent analysis of Icelandic genealogies revealed highly positively skewed distributions of descendants to ancestors, with the vast majority of potential ancestors contributing one or no descendants and a minority of ancestors contributing large numbers of descendants. The expansion and loss of matrilines and patrilines has caused considerable fluctuation in the frequencies of mtDNA and Y-chromosome haplotypes, despite a rapid population expansion in Iceland during the past 300 years. Contrary to a widespread assumption, the rate of evolution caused by this lineage-sorting process was markedly faster in matrilines (mtDNA) than in patrilines (Y chromosomes). The primary cause is a 10% shorter matrilineal generation interval. Variance in the number of offspring produced within each generation was not an important differentiating factor. We observed an intergenerational correlation in offspring number and in the length of generation intervals in the matrilineal and patrilineal genealogies, which was stronger in matrilines and thus contributes to their faster evolutionary rate. These findings may have implications for coalescent date estimates based on mtDNA and Y chromosomes.

Alleles↗
PubMed1998

Control of alternative behavioral states by serotonin in Caenorhabditis elegans.

Serotonin has been implicated in the regulation of a wide range of brain functions involving alternative behavioral states, including the control of mood, aggression, sex, and sleep. Here, we report that in the nematode Caenorhabditis elegans, serotonin controls a switch between two distinct, on/off states of egg-laying behavior. Through quantitative analysis of the temporal pattern of egg-laying events, we determined that egg laying can be modeled as a novel random process, in which animals fluctuate between discrete behavioral states: an active state, during which eggs are laid in clusters, and an inactive state, during which eggs are retained. Single-cell ablation experiments indicate that two pairs of motor neurons, HSNL/HSNR and VC4/VC5, can induce the active phase by releasing serotonin. These neurons also release acetylcholine, which appears to trigger individual egg-laying events within the active phase. Genetic experiments suggest that determination of the behavioral states observed for C. elegans egg laying may be mediated through protein kinase C-dependent (PKC-dependent) modulation of voltage-gated calcium channels.

Acetylcholine↗
PubMed2006

Allometric scaling of the active hematopoietic stem cell pool across mammals.

BACKGROUND: Many biological processes are characterized by allometric relations of the type Y = Y(0)M(b) between an observable Y and body mass M, which pervade at multiple levels of organization. In what regards the hematopoietic stem cell pool, there is experimental evidence that the size of the hematopoietic stem cell pool is conserved in mammals. However, demands for blood cell formation vary across mammals and thus the size of the active stem cell compartment could vary across species. METHODOLOGY/PRINCIPLE FINDINGS: Here we investigate the allometric scaling of the hematopoietic system in a large group of mammalian species using reticulocyte counts as a marker of the active stem cell pool. Our model predicts that the total number of active stem cells, in an adult mammal, scales with body mass with the exponent 3/4. CONCLUSION/SIGNIFICANCE: The scaling predicted here provides an intuitive justification of the Hayflick hypothesis and supports the current view of a small active stem cell pool supported by a large, quiescent reserve. The present scaling shows excellent agreement with the available (indirect) data for smaller mammals. The small size of the active stem cell pool enhances the role of stochastic effects in the overall dynamics of the hematopoietic system.

Adult↗
PubMed1993

Spatial and temporal characteristics of rapid cursor-positioning movements with electromechanical mice in human-computer interaction.

This research examines how people make movements with pointing devices during human-computer interaction. It specifically concerns the perceptual-motor processes that mediate the speed and accuracy of cursor positioning with electromechanical mice. In three experiments we investigated the spatial and temporal characteristics of positioning movements made with a mouse, analyzing subjects' speed and accuracy as a function of the types of targets that the movements had to reach. Experiment 1 required rapid and accurate horizontal movements to targets that were vertical ribbons located at various distances from the mouse's starting location. The targets for Experiments 2 and 3, respectively, were vertical lines having various heights and rectangular boxes having various heights and widths. Constraints on movement distance along the primary (that is, horizontal) line of motion had the greatest effects on total positioning times. However, constraints on movement distance along a secondary (vertical) line of motion also affected total positioning times significantly. These effects may be localized in different phases of movements (e.g., movement execution and verification). The duration of movement execution (i.e., physical motion) depends primarily on the target distance, whereas the duration of movement verification (i.e., check for endpoint accuracy) depends primarily on target height and width. A useful account of movement execution is provided by stochastic optimized-submovement models, which have significant implications for designing mice and menu-driven displays.

Adult↗
PubMed2005

Information processing in noisy burster models of sensory neurons.

Processing of external stimuli by sensory neurons often involves bursting, when epochs of fast firing alternate with intervals of quiescence. In particular, sensory neurons of electroreceptors in paddlefish (Polyodon spathula) undergo bursting when stimulated externally with broad-band noise, but otherwise fire spontaneously in a quasiperiodic tonic manner. We use a simple phenomenological model for noise-induced bursting to quantify analytically, by means of the Kullback entropy and Fisher information, the gain in information transfer and electroreceptor sensitivity for external noisy stimuli. A good agreement between theoretical predictions, numerical simulations and experimental data is shown.

Animals↗
PubMed2006

Nonhomogeneous birth and death models for epidemic outbreak data.

In this paper, generalized nonlinear models are proposed in order to incorporate the following considerations in modeling an epidemic disease outbreak statistically. (1) The dependence of the data is handled with a nonhomogeneous death or a nonhomogeneous birth process. (2) The first stage of the outbreak is described with an epidemic susceptibles-infectives-removed (SIR) model. Soon the control measures taken will dominate the process. These measures are in addition to the natural epidemic removal process. The prevalence is related to the censored infection times in such a way that the distribution function and thus the survival function satisfy approximately the first equation of the SIR model. This leads in a natural way to the Burr family of distributions. (3) The nonhomogeneous birth process handles the fact that in practice, with some delay, infecteds are registered, but not susceptibles. (4) Finally, the ending of the epidemic caused by the measures taken is incorporated through a modification of the survival function with a final-size parameter, in the same way as is done in long-term survival models. These models are applied to three outbreaks: The Dutch classical swine fever outbreak from 1997 to 1998, the foot- and-mouth disease outbreak in Great Britain from 2001, and the Dutch avian influenza (H7N7) outbreak from 2003.

Animals↗
PubMed1999

A computer model of the spread of hepatitis C virus among injecting drug users.

A number of behavioural and clinical parameters influence the transmission of an infectious agent through direct contact between two individuals. The behavioural parameters encountered in such situations are also likely to exhibit an enormous amount of variability. With the spread of hepatitis C among injecting drug users, the parameters associated with injecting behaviour play an important role in the modelling of the transmission process. Computer simulation modelling is an ideal approach to deal with a large number of parameters as well as high levels of variability without excessive simplification. The simulation model presented in this paper is tested on data from a cohort of injecting drug users and the results obtained are very encouraging from a public health perspective. The model clearly indicates that the rate at which HCV spreads through a population of injecting drug users is extremely sensitive to the interaction rate and to the probability of infection through a single contact with an infective. At the same time it shows that rate of spread is not very sensitive to initial prevalence, which is very encouraging from a public health perspective.

Computer Simulation↗
PubMed2006

Quadratic weighted median filters for edge enhancement of noisy images.

Quadratic Volterra filters are effective in image sharpening applications. The linear combination of polynomial terms, however, yields poor performance in noisy environments. Weighted median (WM) filters, in contrast, are well known for their outlier suppression and detail preservation properties. The WM sample selection methodology is naturally extended to the quadratic sample case, yielding a filter structure referred to as quadratic weighted median (QWM) that exploits the higher order statistics of the observed samples while simultaneously being robust to outliers arising in the higher order statistics of environment noise. Through statistical analysis of higher order samples, it is shown that, although the parent Gaussian distribution is light tailed, the higher order terms exhibit heavy-tailed distributions. The optimal combination of terms contributing to a quadratic system, i.e., cross and square, is approached from a maximum likelihood perspective which yields the WM processing of these terms. The proposed QWM filter structure is analyzed through determination of the output variance and breakdown probability. The studies show that the QWM exhibits lower variance and breakdown probability indicating the robustness of the proposed structure. The performance of the QWM filter is tested on constant regions, edges and real images, and compared to its weighted-sum dual, the quadratic Volterra filter. The simulation results show that the proposed method simultaneously suppresses the noise and enhances image details. Compared with the quadratic Volterra sharpener, the QWM filter exhibits superior qualitative and quantitative performance in noisy image sharpening.

Algorithms↗
PubMed2002

Biomedical challenges of human senescence: a review.

OBJECTIVE: To summarise and discuss the progress made in the study of human senescence over the past one hundred years and assess the achievements to date. DATA SOURCES: Published original research and reviews during the past one hundred years. STUDY SELECTION: The summary focused on those contributions that tested the various hypotheses that attempt to identify and explain the factors that are involved in the ageing process. DATA EXTRACTION AND SYNTHESIS: Online and manual library searches provided a body of data on which the summaries and discussions were based. Specific questions were addressed: Why does ageing occur? What are the key mechanisms? To what extent are genetic and environmental factors involved in the ageing process? How does the immune system behave during ageing and especially against infectious agents? Answers to these questions were discussed against the background of major improvements in life expectancy in most parts of the world except for sub-Saharan Africa where the HIV/AIDS pandemic has reversed the trend. CONCLUSION: Biological and clinical studies over the past century clearly reflect a better understanding of the major factors involved in human senescence. It is appreciated that human life expectancy has improved dramatically over the period through achievements in public health, therapy, nutrition and general living standards. A great deal remains to be done through multidisciplinary research before the quality of life can be improved further.

Aging↗
PubMed2006

Using journal impact factors to correct for the publication bias of medical studies.

Publication bias of the results of medical studies can invalidate evidence-based medicine. The existing methodology for modeling this essentially relies upon the symmetry of the funnel plot. We present a new method of modeling publication bias that uses this information plus the impact factors of the publishing journals. A simple model of the publication process enables the estimation of bias-corrected intervention effects. The procedure is illustrated using a meta-analysis of the effectiveness of single-dose oral aspirin for acute pain, and results are also obtained for five other meta-analyses. The method enables the fitting of a wide range of models and is considered more flexible than other ways of compensating for publication bias. The model also provides the basis of a statistical test for the existence of publication bias. Use of the new methodology to supplement existing methods is recommended, in the context of a sensitivity analysis.

Analgesics, Non-Narcotic↗
PubMed2003

Force generation by actin polymerization II: the elastic ratchet and tethered filaments.

The motion of many intracellular pathogens is driven by the polymerization of actin filaments. The propulsive force developed by the polymerization process is thought to arise from the thermal motions of the polymerizing filament tips. Recent experiments suggest that the nucleation of actin filaments involves a phase when the filaments are attached to the pathogen surface by a protein complex. Here we extend the "elastic ratchet model" of Mogilner and Oster to incorporate these new findings. We apply this "tethered ratchet" model to derive the force-velocity relation for Listeria and discuss relations of our theoretical predictions to experimental measurements. We also discuss "symmetry breaking" dynamics observed in ActA-coated bead experiments, and the implications of the model for lamellipodial protrusion in migrating cells.

Actins↗
PubMed2000

Mechanisms of visual motion detection.

Visual motion is processed by neurons in primary visual cortex that are sensitive to spatial orientation and speed. Many models of local velocity computation are based on a second stage that pools the outputs of first-stage neurons selective for different orientations, but the nature of this pooling remains controversial. In a human psychophysical detection experiment, we found near-perfect summation of image energy when it was distributed uniformly across all orientations, but poor summation when it was concentrated in specific orientation bands. The data are consistent with a model that integrates uniformly over all orientations, even when this strategy is sub-optimal.

Adaptation, Physiological↗
PubMed2005

A non-stationary model for functional mapping of complex traits.

SUMMARY: Understanding the genetic control of growth is fundamental to agricultural, evolutionary and biomedical genetic research. In this article, we present a statistical model for mapping quantitative trait loci (QTL) that are responsible for genetic differences in growth trajectories during ontogenetic development. This model is derived within the maximum likelihood context, implemented with the expectation-maximization algorithm. We incorporate mathematical aspects of growth processes to model the mean vector and structured antedependence models to approximate time-dependent covariance matrices for longitudinal traits. Our model has been employed to map QTL that affect body mass growth trajectories in both male and female mice of an F2 population derived from the Large and Small mouse strains. The results from this model are compared with those from the autoregressive-based functional mapping approach. Based on results from computer simulation studies, we suggest that these two models are alternative to one another and should be used simultaneously for the same dataset.

Aging↗
PubMed2007

Calibration of visually guided reaching is driven by error-corrective learning and internal dynamics.

The sensorimotor calibration of visually guided reaching changes on a trial-to-trial basis in response to random shifts in the visual feedback of the hand. We show that a simple linear dynamical system is sufficient to model the dynamics of this adaptive process. In this model, an internal variable represents the current state of sensorimotor calibration. Changes in this state are driven by error feedback signals, which consist of the visually perceived reach error, the artificial shift in visual feedback, or both. Subjects correct for > or =20% of the error observed on each movement, despite being unaware of the visual shift. The state of adaptation is also driven by internal dynamics, consisting of a decay back to a baseline state and a "state noise" process. State noise includes any source of variability that directly affects the state of adaptation, such as variability in sensory feedback processing, the computations that drive learning, or the maintenance of the state. This noise is accumulated in the state across trials, creating temporal correlations in the sequence of reach errors. These correlations allow us to distinguish state noise from sensorimotor performance noise, which arises independently on each trial from random fluctuations in the sensorimotor pathway. We show that these two noise sources contribute comparably to the overall magnitude of movement variability. Finally, the dynamics of adaptation measured with random feedback shifts generalizes to the case of constant feedback shifts, allowing for a direct comparison of our results with more traditional blocked-exposure experiments.

Adaptation, Physiological↗
PubMed2005

Diffusion-limited phase separation in eukaryotic chemotaxis.

The ability of cells to sense spatial gradients of chemoattractant factors governs the development of complex eukaryotic organisms. Cells exposed to shallow chemoattractant gradients respond with strong accumulation of the enzyme phosphatidylinositol 3-kinase (PI3K) and its D3-phosphoinositide product (PIP(3)) on the plasma membrane side exposed to the highest chemoattractant concentration, whereas PIP(3)-degrading enzyme PTEN and its product PIP(2) localize in a complementary pattern. Such an early symmetry-breaking event is a mandatory step for directed cell movement elicited by chemoattractants, but its physical origin is still mysterious. Here, we propose that directional sensing is the consequence of a phase-ordering process mediated by phosphoinositide diffusion and driven by the distribution of chemotactic signal. By studying a realistic reaction-diffusion lattice model that describes PI3K and PTEN enzymatic activity, recruitment to the plasma membrane, and diffusion of their phosphoinositide products, we show that the effective enzyme-enzyme interaction induced by catalysis and diffusion introduces an instability of the system toward phase separation for realistic values of physical parameters. In this framework, large reversible amplification of shallow chemotactic gradients, selective localization of chemical factors, macroscopic response timescales, and spontaneous polarization arise naturally. The model is robust with respect to order-of-magnitude variations of the parameters.

Chemotaxis↗
PubMed1999

Models for antigen receptor gene rearrangement. I. Biased receptor editing in B cells: implications for allelic exclusion.

Recent evidence suggests that lymphocyte Ag receptor gene rearrangement does not always stop after the expression of the first productively rearranged receptor. Light chain gene rearrangement in B cells, and alpha-chain rearrangement in T cells can continue, which raises the question: how is allelic exclusion maintained, if at all, in the face of continued rearrangement? In this and the accompanying paper, we present comprehensive models of Ag receptor gene rearrangement and the interaction of this process with clonal selection. Our B cell model enables us to reconcile observations on the kappa:lambda ratio and on kappa allele usage, showing that B cell receptor gene rearrangement must be a highly ordered, rather than a random, process. We show that order is exhibited on three levels: a preference for rearranging kappa rather than lambda light chain genes; a preference to make secondary rearrangements on the allele that has already been rearranged, rather than choosing the location of the next rearrangement at random; and a sequentiality of J segment choice within each kappa allele. This order, combined with the stringency of negative selection, is shown to lead to effective allelic exclusion.

Alleles↗
PubMed1993

Mathematical models for multidrug resistance and its reversal.

Mathematical models describing drug resistance are briefly reviewed. One model which describes the molecular function of the P-glycoprotein pump in multidrug resistant (MDR) cell lines has been developed and is presented in detail. The pump is modeled as an energy dependent facilitated diffusion process. A partial differential equation linked to a pair of ordinary differential equations forms the core of the model. To describe MDR reversal, the model is extended to add an inhibitor. Equations for competitive, one-site noncompetitive, and two-site noncompetitive inhibition are derived. Numerical simulations have been run to describe P-glycoprotein dynamics both in the presence and absence of these kinds of inhibition. These results are briefly reviewed. The character of the pump and its response to inhibition are discussed within the context of the models. All discussions, descriptions, and conclusions are presented in nonmathematical terms. The paper is aimed at a scientifically sophisticated but mathematically innocent audience.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

SpikeNET: an event-driven simulation package for modelling large networks of spiking neurons.

Many biological neural network models face the problem of scalability because of the limited computational power of today's computers. Thus, it is difficult to assess the efficiency of these models to solve complex problems such as image processing. Here, we describe how this problem can be tackled using event-driven computation. Only the neurons that emit a discharge are processed and, as long as the average spike discharge rate is low, millions of neurons and billions of connections can be modelled. We describe the underlying computation and implementation of such a mechanism in SpikeNET, our neural network simulation package. The type of model one can build is not only biologically compliant, it is also computationally efficient as 400 000 synaptic weights can be propagated per second on a standard desktop computer. In addition, for large networks, we can set very small time steps (< 0.01 ms) without significantly increasing the computation time. As an example, this method is applied to solve complex cognitive tasks such as face recognition in natural images.

Action Potentials↗