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PubMed2005

Seismology: dynamic triggering of earthquakes.

After an earthquake, numerous smaller shocks are triggered over distances comparable to the dimensions of the mainshock fault rupture, although they are rare at larger distances. Here we analyse the scaling of dynamic deformations (the stresses and strains associated with seismic waves) with distance from, and magnitude of, their triggering earthquake, and show that they can cause further earthquakes at any distance if their amplitude exceeds several microstrain, regardless of their frequency content. These triggering requirements are remarkably similar to those measured in the laboratory for inducing dynamic elastic nonlinear behaviour, which suggests that the underlying physics is similar.

Journal Article↗

PubMed2006

Theodor Bücher Lecture. Metabolomics, modelling and machine learning in systems biology - towards an understanding of the languages of cells. Delivered on 3 July 2005 at the 30th FEBS Congress and the 9th IUBMB conference in Budapest.

The newly emerging field of systems biology involves a judicious interplay between high-throughput 'wet' experimentation, computational modelling and technology development, coupled to the world of ideas and theory. This interplay involves iterative cycles, such that systems biology is not at all confined to hypothesis-dependent studies, with intelligent, principled, hypothesis-generating studies being of high importance and consequently very far from aimless fishing expeditions. I seek to illustrate each of these facets. Novel technology development in metabolomics can increase substantially the dynamic range and number of metabolites that one can detect, and these can be exploited as disease markers and in the consequent and principled generation of hypotheses that are consistent with the data and achieve this in a value-free manner. Much of classical biochemistry and signalling pathway analysis has concentrated on the analyses of changes in the concentrations of intermediates, with 'local' equations - such as that of Michaelis and Menten v=(Vmax x S)/(S+K m) - that describe individual steps being based solely on the instantaneous values of these concentrations. Recent work using single cells (that are not subject to the intellectually unsupportable averaging of the variable displayed by heterogeneous cells possessing nonlinear kinetics) has led to the recognition that some protein signalling pathways may encode their signals not (just) as concentrations (AM or amplitude-modulated in a radio analogy) but via changes in the dynamics of those concentrations (the signals are FM or frequency-modulated). This contributes in principle to a straightforward solution of the crosstalk problem, leads to a profound reassessment of how to understand the downstream effects of dynamic changes in the concentrations of elements in these pathways, and stresses the role of signal processing (and not merely the intermediates) in biological signalling. It is this signal processing that lies at the heart of understanding the languages of cells. The resolution of many of the modern and postgenomic problems of biochemistry requires the development of a myriad of new technologies (and maybe a new culture), and thus regular input from the physical sciences, engineering, mathematics and computer science. One solution, that we are adopting in the Manchester Interdisciplinary Biocentre (http://www.mib.ac.uk/) and the Manchester Centre for Integrative Systems Biology (http://www.mcisb.org/), is thus to colocate individuals with the necessary combinations of skills. Novel disciplines that require such an integrative approach continue to emerge. These include fields such as chemical genomics, synthetic biology, distributed computational environments for biological data and modelling, single cell diagnostics/bionanotechnology, and computational linguistics/text mining.

Artificial Intelligence↗

PubMed1988

Tube law for the intrapulmonary airway.

A semiempirical model of a pressure-area relationship for the bronchial airways is developed. It is described by a single similarity law consistent in form with the nonlinear elastic behavior of biological tissue. The tethering effect of the parenchyma is lumped into the wall properties of the bronchi and is included in an effective wall stiffness. The model, which is fitted to the experimental data of Takishima and his associates (J. Appl. Physiol. 38: 875-881, 1975), is lung-volume dependent and is therefore suitable for the analyses of airflow at different lung volumes, especially for modeling of forced expiration.

Airway Resistance↗

PubMed2006

Interaction dynamics of neuronal oscillations analysed using wavelet transforms.

This paper describes the use of a computational tool based on the Morlet wavelet transform to investigate the interaction dynamics between oscillations generated by two anatomically distinct neuronal populations. The tool uses cross wavelet transform, coherence, bi-spectrum/bi-coherence and phase synchronization. Using specimen data recorded from the hippocampus of a rat with experimentally induced focal epilepsy, linear and non-linear correlations between neuronal oscillations in the CA1 and CA3 regions have been computed. The results of this real case study show that the computational tool can successfully analyse and quantify the temporal interactions between neuronal oscillators and could be employed to investigate the mechanisms underlying epilepsy.

Animals↗

PubMedDate not supplied

Air pollution and cause-specific mortality in Milan, Italy, 1980-1989.

In several studies, investigators have reported associations among air pollution, weather, and daily deaths, usually from all causes. In the current study, we focused on the difference in lag time between exposure to total suspended particulates or extreme weather and cause-specific mortality in an effort to understand the potential underlying mechanism. We used a robust Poisson regression in a generalized additive model to investigate the association between air pollution and daily mortality. We used a loess smooth function to model season, weather, and humidity; indicator variables for hot days were also used. To examine the relationship in a currently meaningful range, we excluded all days with a total suspended particulate concentration higher than 200 microg/m3. We found a significant association on the concurrent day, both for respiratory infection deaths (11% increase/100 microg/m3 increase in total suspended particulate; 95% confidence interval = 5, 17) and for heart-failure deaths (7% increase; 95% confidence interval = 3, 11). The associations with myocardial infarction (i.e., 10% increase; 95% confidence interval = 3, 18) and chronic obstructive pulmonary disease (12% increase, 95% confidence interval = 6, 17) were found for the means of 3 and 4 d prior to death. We observed an effect of cold weather at lag 1 for respiratory infections and an effect of hot weather at lag 0 for heart failure and myocardial infarctions. The association for all causes and cause-specific deaths was almost identical to that noted previously in Philadelphia, Pennsylvania. Smoothed functions of total suspended particulates suggested a higher slope at lower concentrations, and this finding may account for differences noted between European and U.S. studies. Given that both the dependence between weather and daily mortality and the lag between exposure and death varies by cause of death, analyses by specific causes of death would be very useful in the future.

Air Pollution↗

PubMed1978

Elasticity of excised dog lung parenchyma.

An experimental procedure was developed to measure the stress-strain relationship on rectangular slabs (5.0 X 5.0 X 0.5 cm) of excised dog's lung. The slabs were subjected to biaxial loading and the resulting triaxial deformations were measured. Deformations were measured in the central portion of the specimen by video dimension analysers in order to minimize boundary effects. Specimen thickness was measured with a magnetic reluctance proximeter system. The data were sampled and stored on-line by a PDP-8E computer. An electromechanical servo system was used to control the lateral force. Tests were performed at several pH values and at 20 and 37 degrees C. The tissue exhibited a highly nonlinear stress-strain relationship, compliant at low stress levels and stiff when the stress was high. Hysteresis was observed to be about 28% and was unaffected by a 250-fold change in strain rate. Biaxial loading revealed a new characteristic: there is a change in elastic behavior when the tissue undergoes a compressive strain. When the tissue was in tension increasing the lateral load decreased the compliance, but the opposite was true when compressive strain was present.

Animals↗

PubMed2002

Cancer patients' desires for communication of prognosis information.

A mail survey was sent to cancer patients to determine how often they want, request, and receive a qualitativeprognosis (i.e., will they die from the disease?) and a quantitative estimate (how long they will survive). The survey included measures of social and psychological characteristics that were hypothesized to be associated with their desire for and willingness to request prognosis information (N = 352). Major findings are as follows: (a) Whereas about 80% of patients wanted a qualitative prognosis, only about one half wanted a quantitative one; (b) over 90% of those who wanted a qualitative prognosis were given one, but only about one half of those who wanted a quantitative prognosis were given one; and (c) about 15% ofthose who wanted a qualitative prognosis failed to ask for it, and over one third of those who wanted a quantitative prognosis failed to ask for it. Multivariate analyses indicate that the effects of education on wanting, asking for, and receiving prognosis information are slight, and the effects of sex are essentially nil. Older people were significantly less likely to request and to be given prognosis information. Those who had greater anxiety and who needed to avoid thinking about death wanted, requested, and received significantly less information. Fear had significant nonlinear effects on desire, request, and receipt of quantitative information. Those whose prognosis was worse were less likely to want, ask for, and receive quantitative information. Those least likely to want, request, and be given qualitative information were those who combined a bad prognosis with a need to avoid thinking about death.

Communication↗

PubMedDate not supplied

Skull distortion of bone conducted signals.

A previously essentially unknown type of distortion of bone conduction (BC) signal has been studied on the skulls of four human cadavers. The method was based on a miniature accelerometer, rigidly attached to the cranial bone, converting the skull vibration close to the cochlea into an electrical signal which was analysed with regard to harmonic distortion. The BC signals, pure tones, were presented by means of a high-quality vibrator. The distortion was found to be limited to the lower audiometric frequencies, with a maximum around 500 Hz, and of such a degree as to be able to significantly influence the results of BC audiometry. The distortion is probably caused by nonlinear mechanical properties of the human skull.

Audiometry↗

PubMed2000

Adapting to remapped auditory localization cues: a decision-theory model.

This paper describes a model of adaptation to remapped auditory localization cues that is based on previous decision-theory models of psychophysical performance. The present model extends earlier work by explicitly assuming that past experience affects subject perception and by quantifying how training causes subjects' responses to evolve over time. The model makes quantitative predictions of total sensitivity, bias, and resolution for subjects involved in experiments investigating spatial auditory adaptation. One assumption of the model is that subjects cannot adapt to nonlinear rearrangements of localization cues, which is consistent with previous experimental reports in both audition (Shinn-Cunningham, Durlach, & Held, 1998b) and vision (Bedford, 1993). The model assumes that, in spatial adaptation experiments, subjects learn to interpret a continuous internal decision variable differently than normal; they do not learn to associate discrete stimulus-response pairs. This view is consistent with previous analyses of results from experiments investigating adaptation to visual rearrangement, as well as with the McCullough effect in vision (Bedford, 1993, 1995).

Cues↗

PubMed2006

[The resistance of acupoint and its measurement].

We have analysed the significance of acupoint resistance and some probable problems in its measurement according to biophysics theories and we believe that the skin resistance plays an important role in acupoint resistance. The Volt-ampere curve should be used to describe acupoint resistance, and only when the measurements are under the same condition should the results be compared, because acupoint resistance is nonlinear. The acupoint resistance could be detected only in vivo. In this paper is presented a simple and easy method with which we can connect acupoint into electric circle. Also reported here is how to control the circumstance condition while measurements are taken.

Acupuncture Points↗

PubMed1978

Nonlinear (amplified) relationship between nuclear occupancy by triiodothyronine and the appearance rate of hepatic alpha-glycerophosphate dehydrogenase and malic enzyme in the rat.

Three separate approaches were applied to examine the general relationship between R, the rate of induction of specific enzymes (mitochondrial alpha-glycero-phosphate dehydrogenase and cytosolic malic enzyme) and q, the fractional nuclear occupancy by triiodothyronine in male Sprague-Dawley rats. Daily 200-microgram injections of triiodothyronine per 10u g body wt for 7 days resulted in saturation of the hepatic nuclear sites and the achievement of an apparent new steady state of enzyme levels. The increase achieved over base-line hypothyroid levels was then compared with the increment over hypothyroid base line characteristic of intact euthyroid animals with 47% of nuclear sites occupied. The maximal theoretical reate of steady-state enzyme induction could be protected on the basis of the observed maximal increase in enzyme activity observed 1 day after the injection of graded doses of hormone and lambda, the known fractional rate of enzyme dissipation. The 24-h dose-response studies were used to generate R as a continuous function of q, both in hypothyroid as well as in euthyroid animals. This approach involved the numerical solution of an ordinary differential equation describing the rate of change of enzyme as a function of R, which was assumed to be uniquely related to q. Results of these analyses indicated that the ratio of the maximal rate of induction of enzyme at full occupancy to the rate of induction under euthyroid conditions assumes a value between 9.0 and 19.5, depending on the precise analytic and experimental approach applied. This value is far in excess of the theoretical ratio 2.13 which on would anticipate if R were linearly related to q and 47% of the nuclear sites occupied under physiological conditions. Thus, the signal for enzyme induction appears to undergo progressjive amplification with increasing nuclear occupancy. Moreover, the curve describing the relationship between R and q appears highly nonlinear throughout (concave upwards). Although the molecular mechanism responsible for amplification is unknown, recognition of this phenomenon may be helpful in understanding tissue effects of thyroid hormone excess. Moreover, the analytic technique for determining R as a function of q may be of general applicability in studying hormonal response systems under nonsteady-state conditions.

Animals↗

PubMed2004

Force transmission of one- and two-piece morse-taper oral implants: a nonlinear finite element analysis.

PURPOSE: To compare force transmission behaviors of one-piece (1-P) and two-piece (2-P) morse-taper oral implants. MATERIAL AND METHODS: A three-dimensional finite element model of a morse-taper oral implant and a solid abutment was constructed separately. The implant-abutment complex was embedded in a phi 1.5 cm x 1.5 cm acrylic resin cylinder. Vertical and oblique forces of 50 N and 100 N were applied on the abutment and solved by two different analyses. First, contact analysis was performed in the implant-abutment complex to evaluate a 2-P implant. Then, the components were bonded with a separation force of 10(20) N to analyze a 1-P implant. RESULTS: Von Mises stresses in the implant, principal stresses, and displacements in the resin were the same for both designs under vertical loading. Under oblique loading, principal stresses and displacement values in the resin were the same, but the magnitudes of Von Mises stresses were higher in the 2-P implant. The principal stress distributions around both implants in the acrylic bone were similar under both loading conditions. CONCLUSION: 2-P implants experience higher mechanical stress under oblique loading. Nevertheless, the 1-P- or 2-P morse-taper nature of an implant is not a decisive factor for the magnitude and distribution of stresses, and displacements in supporting tissues.

Compressive Strength↗

PubMed2003

A longitudinal study of brain volume changes in normal aging using serial registered magnetic resonance imaging.

OBJECTIVE: To investigate the effect of age on global and regional brain volumes and rates of atrophy, and to compare directly results based on cross-sectional and longitudinal data. METHODS: Thirty-nine healthy control subjects (age range, 31-84 years) underwent serial magnetic resonance imaging assessments. Measurements included the whole-brain, temporal lobe, hippocampal, and ventricular volumes at baseline and for repeat scans. RESULTS: We found significant decreases in cross-sectional whole-brain (P<.001), temporal lobe (P<.001), and hippocampal (P =.003) volumes and a significant increase in ventricular volume (P<.001) with increasing age. Cross-sectional and longitudinal estimates of atrophy rates were similar. We also found directional evidence of acceleration in atrophy rates with increasing age in all analyses, with the most marked changes occurring after 70 years of age. This increase in rates after 70 years of age was particularly marked in the ventricles (P<.001) and the hippocampi (P =.01). CONCLUSIONS: We found a significant age-associated decrease in global and regional brain volumes. Some evidence indicates that this decline in brain volumes may be due to a nonlinear acceleration in rates of atrophy with increasing age. A better understanding of this process may help to discriminate normal age-related changes from neurodegenerative diseases.

Adult↗

PubMed2006

Bioengineering Functional Copolymers. IX. Poly[(maleic anhydride-co-hexene-1)-g-poly(ethylene oxide)].

Amphiphilic bioengineering copolymers having a combination of hydrophilic/hydrophobic linkages and polyelectrolyte behavior, along with an ability to interact with biomacromolecules, in particular with the invertase enzyme, have been synthesized by (a) complex-radical copolymerization of maleic anhydride (MA, the acceptor) and hexene-1 (H-1, the donor) monomers with benzoyl peroxide as the initiator in 1,4-dioxane at 65 degrees C under high-conversion conditions and (b) subsequent grafting (polyesterification) of synthesized poly(MA-alt-H-1) with alpha-methoxy-omega-hydroxy-poly(ethylene oxide) (PEO). Copolymerizations were also carried out in the steady state, in order to essentially reduce the effect of copolymer composition drift. The values of the monomer reactivity ratios (r(1) and r(2)) determined by using the known terminal models of Fineman-Ross (FR) and Kelen-Tüdös (KT), as well as by nonlinear regression (NLR) analysis, are: r(1) = 0.16 and r(2) = 0.30 (FR), r(1) = 0.14 and r(2) = 0.27 (KT), and r(1) = 0.15 and r(2) = 0.29 (NLR), respectively. All the copolymers and graft copolymers were characterized by FTIR spectroscopy, (1)H{(13)C} NMR spectroscopy, viscometric measurements, and chemical (acid number), thermal (DSC and TGA), and X-ray diffraction analyses. Unlike poly(MA-alt-H-1)s, PEO macrobranched graft copolymers exhibit expressed polyelectrolyte and swelling behavior in diluted and concentrated dioxane solutions, respectively. The copolymer and its PEO hyperbranched derivatives can be used as carriers for enzyme immobilization.

Enzymes, Immobilized↗

PubMed1998

Nonlinear ribosome migration on cauliflower mosaic virus 35S RNA in transgenic tobacco plants.

Cauliflower mosaic virus (CaMV) uses a specialised translation mechanism to bypass the long leader sequence of the 35S RNA. The effect of the CaMV 35S RNA leader sequence on the expression of a downstream beta-glucuronidase (GUS) reporter gene was studied in transgenic tobacco plants. Enzymatic GUS assays of these transgenic plants show that a shunt mechanism of translation indeed occurs in planta with an average efficiency of 5% compared with the leaderless construct. Histological GUS analyses indicate that the shunt mechanism occurs throughout the whole plant and at all developmental stages.

Blotting, Southern↗

PubMed1983

Experimental study of the conducted action potential in cardiac Purkinje strands.

Conduction velocity is a complex physiological process that integrates the active and passive properties of the excitable cell. The relations between these properties in determining the conduction velocity are not intuitively obvious, and models have been used frequently to illustrate important relationships. To study the relationships of important parameters and to evaluate commonly used models, we changed conduction velocity experimentally in sheep cardiac Purkinje strands by reducing extracellular Na systematically. Cable analyses were also performed to obtain passive membrane and cable properties. Resting membrane resistance and capacitance did not change, nor did core resistance. Active properties measured in addition to conduction velocity included maximal upstroke velocity, action potential height, time constant of the foot, peak inward current, and upstroke power. With reduction in extracellular Na, all of these parameters of the action potential changed nonlinearly and not in direct proportion to the change in conduction velocity. The only simple relation found was a linear relationship between maximal upstroke velocity and peak inward current, normalized by the capacity of the foot. Models based on the cable equation and the wave equation offer a basis for quantitative analysis of conduction, and these data can be used to test the models.

Animals↗

PubMed2000

Population pharmacokinetics of tiagabine in epileptic patients on monotherapy.

A retrospective study of the population pharmacokinetics of tiagabine was performed from sparse data collected in a multicentre clinical trial in patients with newly diagnosed partial seizures. The purpose was to estimate the inter patient variability and to study the influence of various demographic, environmental and pathophysiological parameters on the pharmacokinetics of tiagabine in patients on monotherapy. A total of 593 plasma concentrations from 130 patients dosed with 2.5, 5, 7.5 or 10 mg tiagabine twice daily were used for modelling. A one-compartment open model with first-order absorption and elimination was fitted to the concentration-time data using the NONMEM program. Selection of covariates was initially performed using stepwise linear regression analyses. The selected covariates were incorporated in the population model and the importance of each covariate was investigated by means of backwards elimination. A one-compartment model with first-order absorption and elimination adequately described the tiagabine concentration-time profile. The apparent clearance as well as the apparent volume of distribution were both significantly correlated to body height in a nonlinear relationship. No other demographic, environmental or clinical chemical parameters were identified as covariates although only a few pathological values of the latter were present in the data. The mean values of CL/f was 6.10 l/h, of V/f was 62.0 l and of k(a) was 1.25 h(-1) for a subject of 170-cm height. The population half-life was 5.72 h. The apparent clearance and volume of distribution of tiagabine in epilepsy patients on monotherapy were both dependent on body height. Prospective studies are required in order to reveal if dose adjustments based on body height will result in improved therapeutic outcome.

Adolescent↗

PubMed2006

Improving source detection and separation in a spatiotemporal Bayesian inference dipole analysis.

Most existing spatiotemporal multi-dipole approaches for MEG/EEG source localization assume that the dipoles are active for the full time range being analysed. If the actual time range of activity of sources is significantly shorter than the time range being analysed, the detectability, localization and time-course determination of such sources may be adversely affected, especially for weak sources. In order to improve detectability and reconstruction of such sources, it is natural to add active time range information (starting time point and ending time point of source activation) for each candidate source as unknown parameters in the analysis. However, this adds additional nonlinear free parameters that could burden the analysis and could be unfeasible for some methods. Recently, we described a spatiotemporal Bayesian inference multi-dipole analysis for the MEG/EEG inverse problem. This approach treated the number of dipoles as a free parameter, produced realistic uncertainty estimates using a Markov chain Monte Carlo numerical sampling of the posterior distribution and included a method to reduce the unwanted effects of local minima. In this paper, our spatiotemporal Bayesian inference multi-dipole analysis is extended to incorporate active time range parameters of starting and stopping time points. The properties of this analysis in comparison to the previous one without active time range parameters are demonstrated through extensive studies using both simulated and empirical MEG data.

Action Potentials↗