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PubMed2006

Genome-wide prediction of G4 DNA as regulatory motifs: role in Escherichia coli global regulation.

The role of nonlinear DNA in replication, recombination, and transcription has become evident in recent years. Although several studies have predicted and characterized regulatory elements at the sequence level, very few have investigated DNA structure as regulatory motifs. Here, using G-quadruplex or G4 DNA motifs as a model, we have researched the role of DNA structure in transcription on a genome-wide scale. Analyses of >61,000 open reading frames (ORFs) across 18 prokaryotes show enrichment of G4 motifs in regulatory regions and indicate its predominance within promoters of genes pertaining to transcription, secondary metabolite biosynthesis, and signal transduction. Based on this, we predict that G4 DNA may present regulatory signals. This is supported by conserved G4 motifs in promoters of orthologous genes across phylogenetically distant organisms. We hypothesized a regulatory role of G4 DNA during supercoiling stress, when duplex destabilization may result in G4 formation. This is in line with our observations from target site analysis for 55 DNA-binding proteins in Escherichia coli, which reveals significant (P<0.001) association of G4 motifs with target sites of global regulators FIS and Lrp and the sigma factor RpoD (sigma70). These factors together control >1000 genes in the early growth phase and are believed to be induced by supercoiled DNA. We also predict G4 motif-induced supercoiling sensitivity for >30 operons in E. coli, and our findings implicate G4 DNA in DNA-topology-mediated global gene regulation in E. coli.

Conserved Sequence↗

PubMed1984

A nonlinear hyperelastic model of pressure volume function of cranial components.

The pressure-volume relationship (PVR) in the intracranial cerebrospinal fluid space has been a matter of investigation for quite sometime. The quantitative considerations of the PVR are believed to have important clinical implications, and attempts have been made to study the pressure-volume characteristics associated with a variety of disease states. Efforts have been made by researchers to understand the phenomenon in terms of mechanics. The major drawback has been that almost all researchers have invoked in their analyses, concepts from linear infinitesimal elasticity to explain the intracranial PVR. In this paper we have proposed a more realistic hyperelastic model to explain the observed PVR of the intracranial complex. The proposed model provides a better approximation to the intracranial P-V response than those proposed by previous investigators. The model highlights also the parameters that are relevant to characterise the intracranial tissues.

Animals↗

PubMed1986

Alternative interpretation for the osmotic response of human erythrocytes.

In a recent publication, Heubusch et al. (J Cell. Physiol, 122:266-272, 1985) reported changes of erythrocyte volume measured by the Coulter counter technique over a wide range of osmolalities (160 to 3000 m0sm). Their results showed a partially hindered, nonlinear response, in contrast to classical observations made over more restricted osmolality ranges, using other methods. The authors suggested the underlying cause of this behavior to be a mechanical resistance of the membrane cytoskeleton. In this paper, we wish to offer a different interpretation of their results on erythrocyte osmotic behavior, based on similar experiments carried out in our laboratory, and supported by previous analyses from the literature. In particular, it is shown that the shape-factor correction to the electronic sizing measurement can correctly account for the observed deviations from linearity in the hypotonic range. In contrast, increased chemical nonideality and eventual hemolysis are the likely factors responsible for the behavior in the hypertonic range.

Erythrocytes↗

PubMed2003

A population pharmacokinetic model for paclitaxel in the presence of a novel P-gp modulator, Zosuquidar Trihydrochloride (LY335979).

AIMS: To develop a population pharmacokinetic model for paclitaxel in the presence of a MDR modulator, zosuquidar 3HCl. METHODS: The population approach was used (implemented with NONMEM) to analyse paclitaxel pharmacokinetic data from 43 patients who received a 3-h intravenous infusion of paclitaxel (175 mg x m(-2) or 225 mg x m(-2)) alone in cycle 2 or concomitantly with the oral administration of zosuquidar 3HCl in cycle 1. RESULTS: The structural pharmacokinetic model for paclitaxel, accounting for the Cremophor ELTM impact, was a three-compartment model with a nonlinear model for paclitaxel plasma clearance (CL), involving a linear decrease in this parameter during the infusion and a sigmoidal increase with time after the infusion. The final model described the effect of Zosuquidar 3HCl on paclitaxel CL by a categorical relationship. A 25% decrease in paclitaxel CL was observed, corresponding to an 1.3-fold increase in paclitaxel AUC (from 14829 microg x l(-1) x h to 19115 microg x l(-1) x h following paclitaxel 175 mg x m(-2)) when zosuquidar Cmax was greater than 350 microg x l(-1). This cut-off concentration closely corresponded to the IC50 of a sigmoidal Emax relationship (328 microg x l(-1)). A standard dose of 175 mg x m(-2) of paclitaxel could be safely combined with doses of zosuquidar 3HCl resulting in plasma concentrations known, from previous studies, to result in maximal P-gp inhibition. CONCLUSIONS: This analysis provides a model which accurately characterized the increase in paclitaxel exposure, which is most likely to be due to P-gp inhibition in the bile canaliculi, in the presence of zosuquidar 3HCl (Cmax > 350 microg x l(-1)) and is predictive of paclitaxel pharmacokinetics following a 3 h infusion. Hence the model could be useful in guiding therapy for paclitaxel alone and also for paclitaxel administered concomitantly with a P-gp inhibitor, and in designing further clinical trials.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1993

The association of blood lead and blood pressure in population surveys.

Several reports from large population surveys have indicated that blood lead is positively related to blood pressure. We assessed this relation in 1,703 men (median blood lead = 83 micrograms per liter) and 1,661 women (median blood lead = 60 micrograms per liter), age 28 to 67 years, who participated in the first follow-up examination of the MONICA Augsburg cohort study in 1987-1988. Crude analyses confirmed a strong, positive association of blood lead concentrations with systolic and diastolic blood pressure. We identified age, body mass index, hematocrit, and alcohol consumption as the quantitatively most important confounders of this association. Adjustment for these variables, in particular for hematocrit and alcohol consumption, considerably reduced the magnitude of the blood lead effect on blood pressure. There were no indications for marked nonlinearity or threshold effects. After control of confounders, a difference of 100 micrograms per liter in blood lead levels, corresponding to rather extreme positions in the lower and upper end of the population blood lead distribution, related to estimated blood pressure increases of less than 3 mmHg. The appropriateness of treating hematocrit and alcohol consumption as confounders of the blood lead-blood pressure relation is discussed on the basis of current pathophysiologic concepts. We conclude that hematocrit should always be taken into account as a relevant confounder. On the other hand, the interrelation of alcohol consumption, blood lead, and blood pressure is presently not clearly understood; that is, its appropriate analytic handling cannot be determined. The consequences of these considerations on estimates of the blood lead effect on blood pressure may be both over- and underestimations.

Adult↗

PubMed2000

Lumbar-pelvic coordination is influenced by lifting task parameters.

STUDY DESIGN: Low back kinematics, including relative lumbar and pelvic motions, were quantified during controlled lifting tasks. OBJECTIVES: To evaluate the influence of load and lifting velocity on lumbar-pelvic (LP) coordination. SUMMARY OF BACKGROUND DATA: Sagittal trunk extension is achieved through the coordinated motion of the pelvis and lumbar spine. There are no data to indicate whether lifting task design influences lumbar-pelvic coordination. METHODS: Lumbar and pelvic motions were recorded from 18 healthy subjects while performing isokinetic lifting tasks of 0.1 kg and 10 kg. Coordinated motions of the pelvis (sacral spine) and low-thoracic spine were evaluated using eigenvector analyses and a ratio of lumbar and pelvic angles (L/P). RESULTS: Eigenvector models of the lumbar-pelvic coordination accurately represented empirical coordination profiles. Weight significantly influenced lumbar-pelvic coordination. Trunk extension velocity demonstrated a small but statistically significant influence on lumbar-pelvic coordination. Weight and trunk flexion angle significantly influenced lumbar/pelvic angle ratios. CONCLUSIONS: Trunk extension was achieved through simultaneous but nonlinear contributions from both the pelvis and lumbar spine throughout the range of motion. The lumbar spine accounted for 70% of the total, with increased pelvic contributions in flexed postures. Task weight increased the lumbar contribution to total trunk motion. When performing clinical evaluations of spinal kinematics, it is necessary to recognize that unloaded motions may not fully represent loaded behavior of spinal coordination.

Adult↗

PubMed1991

Non-equilibrium thermodynamic sensitivity of oxidative phosphorylation.

A new method was developed to analyse the dynamic properties of oxidative phosphorylation, in particular the sensitivity of the phosphate potential with respect to fluctuating cellular ATP utilization. This treatment is based on the eigenvalue sensitivity analysis of an experimentally supported non-equilibrium thermodynamic model of oxidative phosphorylation. Such an analysis allows direct access to the kinetic information, while circumventing the awkward conventional numerical integration of a set of nonlinear differential equations. This procedure revealed, for the parameters characteristic for liver of starved rats in vivo, that the sensitivity of oxidative phosphorylation to a fluctuating ATP utilization is minimal at a degree of coupling q = 0.95. This means that the phosphate potential is highly buffered with respect to fluctuating energy demands at the degree of coupling. This value of q agrees well with the degree of coupling qeef, at which net ATP production of oxidative phosphorylation--at optimal efficiency--occurs in the most economic way. This simultaneous maximization of kinetic stability and economic thermodynamic efficiency at the same degree of coupling appears to be a coincidence.

Adenosine Triphosphate↗

PubMed1998

Quadratic dose-response relationship between caffeine (1,3,7-trimethylxanthine) and EEG correlation dimension.

Many studies have failed to determine a systematic dose-response relationship across different cognitive tasks between caffeine and EEG power spectra. However, a nonlinear approach to EEG analysis, which reconstructs a multi-dimensional state space from each electrode recording, can be used to compute the number of active degrees of freedom in the signal (the correlation dimension, D2), and can be interpreted as a measure of signal complexity. This study attempted to determine a consistent dose-response relationship between caffeine and EEG D2, across six oral caffeine doses (100-600 mg), with each subject acting as their own control, to create a probabilistic bias against finding any consistent linear or nonlinear dose-response relationship across different cognitive tasks. The experiment (n = 10) was conducted with three within-subjects explanatory variables, 2 (experimental, placebo) x 8 (caffeine level) x 4 (type of cognitive task performed), with EEG D2 as the response variable, measured from Fz, F3, F4 and Cz. A significant three-way interaction was found [F(21,245.3) = 3.65, P = 0.001]. Regression analyses revealed a linear trend for the response variable across trials for the placebo condition (average R2 = 0.54), whereas linear+quadratic trends explained an average 30% of the variance for the experimental condition, compared to 0.01% for the linear fit, indicating a robust quadratic dose-response relationship between caffeine and EEG D2. Three conditions had positive quadratic co-efficients, and one condition had a negative quadratic co-efficient. These results are discussed in terms of the implications for brain dynamics, and with respect to recent criticisms of the computation of D2 from EEG.

Adult↗

PubMed2006

Periodic oscillations in leukopoiesis models with two delays.

The term leukopoiesis describes processes leading to the production and regulation of white blood cells. It is based on stem cells differentiation and may exhibit abnormalities resulting in severe diseases, such as cyclical neutropenia and leukemias. We consider a nonlinear system of two equations, describing the evolution of a stem cell population and the resulting white blood cell population. Two delays appear in this model to describe the cell cycle duration of the stem cell population and the time required to produce white blood cells. We establish sufficient conditions for the asymptotic stability of the unique nontrivial positive steady state of the model by analysing roots of a second degree exponential polynomial characteristic equation with delay-dependent coefficients. We also prove the existence of a Hopf bifurcation which leads to periodic solutions. Numerical simulations of the model with parameter values reported in the literature demonstrate that periodic oscillations (with short and long periods) agree with observations of cyclical neutropenia in patients.

Animals↗

PubMed2003

Mathematical modelling and simulation for planning critical care capacity.

Using average number of patients expected in a year, average length of stay and a target occupancy level to calculate the number of critical care beds needed is mathematically incorrect because of nonlinearity and variability in the factors that control length of stay. For a target occupancy in excess of 80%, this simple calculation will typically underestimate the number of beds required. More seriously, it provides no quantitative guidance information about other aspects of critical care demand such as the numbers of emergency patients transferred, deferral rates for elective patients and overall utilisation. The combination of appropriately analysing raw data and detailed mathematical modelling provides a much better method for estimating numbers of beds required. We describe this modelling approach together with evidence of its performance.

Bed Occupancy↗

PubMed2001

Multiple CD4+ cell kinetic patterns and their relationships with baseline factors and virological responses in HIV type 1 patients receiving highly active antiretroviral therapy.

This exploratory analyses characterizes patterns of lymphocyte recovery in HIV-1-infected patients treated with highly active antiretroviral therapy (HAART) and investigates their relationship with baseline indices and virologic responses. We modeled kinetics of total CD4+ lymphocytes, as well as naive (CD45RA+ CD62L+), and memory (CD45RA- CD45RO+) subsets in 48 patients treated with AZT/3TC/Ritonavir for 48 weeks in ACTG protocol 315. Cell kinetic indices were estimated by nonlinear regression methods and were correlated with baseline factors and virologic responses. Five different kinetic patterns were identified, including biphasic growth, growth-plateau, growth-depletion, decay-recovery, and biphasic decay. Although overall mean lymphocyte responses showed a biphasic increase in cell number, a careful investigation reveals that only one-third of patients actually followed the biphasic growth pattern in CD4+ cell response, while 44% of 48 patients from this study followed the growth-depletion pattern. CD4+ cell recovery during the first phase and the 48-week study period were negatively correlated with baseline CD4+ cell counts, and positively correlated with baseline viral load. Memory CD4+ cell recovery during the first phase was also negatively correlated with baseline memory CD4+ and total CD4+ cell number, but the recovery rate of memory CD4+ cells during the second phase was positively correlated with baseline CD4+ cell number. Patients with a decay in CD4+ cell count during treatment were more likely to have experienced virological rebound (58%) than patients with nondecay patterns (24%). The rate and magnitude of the absolute increase in total CD4+ and memory CD4+ cell number (but not naive CD4+ cells) during the second phase were lower in patients with viral rebound compared with patients with persistent viral suppression. These results show that the kinetics of lymphocyte reconstitution in response to potent antiretroviral therapy in individual patients vary considerably from the "classic" biphasic increase that characterizes the mean or median response pattern. Pattern analysis of lymphocyte kinetics may be useful for testing relationships among factors that modulate the response to treatment.

Anti-HIV Agents↗

PubMed2000

Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk.

The association between anthropometric indices and the risk of breast cancer was analyzed using pooled data from seven prospective cohort studies. Together, these cohorts comprise 337,819 women and 4,385 incident invasive breast cancer cases. In multivariate analyses controlling for reproductive, dietary, and other risk factors, the pooled relative risk (RR) of breast cancer per height increment of 5 cm was 1.02 (95% confidence interval (CI): 0.96, 1.10) in premenopausal women and 1.07 (95% CI: 1.03, 1.12) in postmenopausal women. Body mass index (BMI) showed significant inverse and positive associations with breast cancer among pre- and postmenopausal women, respectively; these associations were nonlinear. Compared with premenopausal women with a BMI of less than 21 kg/m2, women with a BMI exceeding 31 kg/m2 had an RR of 0.54 (95% CI: 0.34, 0.85). In postmenopausal women, the RRs did not increase further when BMI exceeded 28 kg/m2; the RR for these women was 1.26 (95% CI: 1.09, 1.46). The authors found little evidence for interaction with other breast cancer risk factors. Their data indicate that height is an independent risk factor for postmenopausal breast cancer; in premenopausal women, this relation is less clear. The association between BMI and breast cancer varies by menopausal status. Weight control may reduce the risk among postmenopausal women.

Adult↗

PubMed1993

Estimation and Analysis of Cucumber (Cucumis sativus L.) Leaf Cellular Heat Sensitivity.

Triphenyl tetrazolium chloride (TTC) reduction by cucumber (Cucumis sativus L. cv Poinsett 76 and cv Ashley) leaf discs was used as a viability assay to examine the effect of temperature pretreatment on the tissue response to acute hyperthermia. Semi-logarithmic plots of TTC reduction as a function of incubation time at different temperatures from 40 to 60[deg]C resembled the heat survival curves of animal cells. Heat inactivation rates were obtained and subjected to "quasi" Arrhenius analyses by analytical methods derived from the animal studies. The Arrhenius plots of TTC reduction rates for cv Ashley leaf discs preincubated at 25 or 37[deg]C and for cv Poinsett 76 preincubated at 37[deg]C were linear with the same activation energy (Ea) of about 80 kcal mol-1. The Arrhenius plot of cv Poinsett 76 preincubated at 25[deg]C was nonlinear with an Ea of about 80 kcal mol-1 at temperatures below 46[deg]C and an Ea of about 27.5 kcal mol-1 at temperatures above 47[deg]C. The significance of these differences is discussed in terms of the role of protein denaturation in the thermal sensitivity of cucumber disc reduction of TTC and the applicability of these methods to the analysis of plant cellular heat sensitivity.

Journal Article↗

PubMed2004

Quantitative genetics of continuous reaction norms: thermal sensitivity of caterpillar growth rates.

A continuous reaction norm or performance curve represents a phenotypic trait of an individual or genotype in which the trait value may vary with some continuous environmental variable. We explore patterns of genetic variation in thermal performance curves of short-term caterpillar growth rate in a population of Pieris rapae. We compare multivariate methods, which treat performance at each test temperature as a distinct trait, with function-valued methods that treat a performance curve as a continuous function. Mean growth rate increased with increasing temperatures from 8 to 35 degrees C, was highest at 35 degrees C, and declined at 40 degrees C. There was substantial and significant variation among full-sib families in their thermal performance curves. Estimates of broad-sense genetic variances and covariances showed that genetic variance in growth rate increased more than 30-fold from low (8-11 degrees C) to high (35-40 degrees C) temperatures, even after differences in mean growth rate across temperatures were removed. Growth rate at 35 and 40 degrees C was negatively correlated genetically, suggesting a genetic trade-off in growth rate at these temperatures; this trade-off may represent either a generalist-specialist trade-off and/or variation in the optimal temperature for growth. The estimated genetic variance-covariance function (G function), the function-valued analog of the variance-covariance matrix (G matrix), was quite bumpy compared with the estimated G matrix; and results of principal component analyses of the G function were difficult to interpret. The use of orthogonal polynomials as the basis functions in current function-valued estimation methods may generate artifacts when the true G function has prominent local features, such as strong negative covariances at nearby temperatures (e.g. at 35 and 40 degrees C); this may be a particular issue for thermal performance curves and other highly nonlinear reaction norms.

Analysis of Variance↗

PubMed1998

Statistical modeling of carcinogenic risks in dogs that inhaled 238PuO2.

Combined analyses of data on 260 life-span beagle dogs that inhaled 238PuO2 at the Inhalation Toxicology Research Institute (ITRI) and at Pacific Northwest National Laboratory (PNNL) were conducted. The hazard functions (age-specific risks) for incidence of lung, bone and liver tumors were modeled as a function of cumulative radiation dose, and estimates of lifetime risks based on the combined data were developed. For lung tumors, linear-quadratic functions provided an adequate fit to the data from both laboratories, and linear functions provided an adequate fit when analyses were restricted to doses less than 20 Gy. The estimated risk coefficients for these functions were significantly larger when based on ITRI data compared to PNNL data, and dosimetry biases are a possible explanation for this difference. There was also evidence that the bone tumor response functions differed for the two laboratories, although these differences occurred primarily at high doses. These functions were clearly nonlinear (even when restricted to average skeletal doses less than 1 Gy), and evidence of radiation-induced bone tumors was found for doses less than 0.5 Gy in both laboratories. Liver tumor risks were similar for the two laboratories, and linear functions provided an adequate fit to these data. Lifetime risk estimates for lung and bone tumors derived from these data had wide confidence intervals, but were consistent with estimates currently used in radiation protection. The dog-based lifetime liver tumor risk estimate was an order of magnitude larger than that used in radiation protection, but the latter also carries large uncertainties. The application of common statistical methodology to data from two studies has allowed the identification of differences in these studies and has provided a basis for common risk estimates based on both data sets.

Administration, Inhalation↗

PubMed2007

Time trends of esophageal cancer in Hong Kong: age, period and birth cohort analyses.

This study was to examine the time trend of the incidence rates of esophageal cancer during the period 1979-2003 in Hong Kong and to identify the effects of year of diagnosis (period) and year of birth (cohort) on the observed time trends using regression models. Cancer incidence data were obtained from Hong Kong Cancer Registry and population data were from the Census and Statistics Department. Age-standardized incidence rates were computed by the direct method using the World population of 1966. Annual percentage change (APC) in incidence rate was calculated using nonlinear regression. Period and cohort effects were assessed using 2 separate Poisson regression models after adjusting for age. During the period 1979-2003, a steady decrease in the age-standardized incidence rate was observed for both males (APC = -3.38%, 95% confidence interval [CI]: -2.89%, -3.86%) and females (APC = -3.92%, 95% CI: -3.15%, -4.69%). The incidence rates were consistently higher among males than females. After the adjustment for age and with the period 1989-1993 or birth cohort of 1934-1938 as reference, the relative risk of more recent periods or birth cohorts significantly decreased. The age-cohort model provided a better description of the data than the age-period model. Given reasonable latency between exposures and esophageal cancer incidence, the declining birth cohort effects in the recent generations were in line with the increased intakes of fresh vegetables and decreased consumptions of alcohol drinking, tobacco smoking, and preserved foods observed in population, thus supported their importance in influencing the burden of esophageal cancer.

Adult↗

PubMed2003

Dynamic causal modelling.

In this paper we present an approach to the identification of nonlinear input-state-output systems. By using a bilinear approximation to the dynamics of interactions among states, the parameters of the implicit causal model reduce to three sets. These comprise (1) parameters that mediate the influence of extrinsic inputs on the states, (2) parameters that mediate intrinsic coupling among the states, and (3) [bilinear] parameters that allow the inputs to modulate that coupling. Identification proceeds in a Bayesian framework given known, deterministic inputs and the observed responses of the system. We developed this approach for the analysis of effective connectivity using experimentally designed inputs and fMRI responses. In this context, the coupling parameters correspond to effective connectivity and the bilinear parameters reflect the changes in connectivity induced by inputs. The ensuing framework allows one to characterise fMRI experiments, conceptually, as an experimental manipulation of integration among brain regions (by contextual or trial-free inputs, like time or attentional set) that is revealed using evoked responses (to perturbations or trial-bound inputs, like stimuli). As with previous analyses of effective connectivity, the focus is on experimentally induced changes in coupling (cf., psychophysiologic interactions). However, unlike previous approaches in neuroimaging, the causal model ascribes responses to designed deterministic inputs, as opposed to treating inputs as unknown and stochastic.

Arousal↗

PubMed1987

Characteristics of neuronal systems in the visual cortex.

The coupling complexity of cortical areas makes it very difficult to analyse them experimentally. Studies of model systems provide the possibility of adapting the analysis to the available data base and elaborating the fundamental properties that depend on the structure of the system. We propose a model system of variable complexity that is spatially two-dimensional and time-dependent, uses feedback for iteration and smoothing, includes the mapping of the cortical networks and can be nonlinear as the case requires. Combining such elementary systems on the basis of neuroanatomical findings enables us to simulate cortical mappings and to interpret neurophysiological data. The decisive factor is that the dynamics of the system and the neuroanatomically based spatial coupling are closely connected with each other.

Animals↗