An experimental approach to identify dynamical models of transcriptional regulation in living cells.

We describe an innovative experimental approach, and a proof of principle investigation, for the application of System Identification techniques to derive quantitative dynamical models of transcriptional regulation in living cells. Specifically, we constructed an experimental platform for System Identification based on a microfluidic device, a time-lapse microscope, and a set of automated syringes all controlled by a computer. The platform allows delivering a time-varying concentration of any molecule of interest to the cells trapped in the microfluidics device (input) and real-time monitoring of a fluorescent reporter protein (output) at a high sampling rate. We tested this platform on the GAL1 promoter in the yeast Saccharomyces cerevisiae driving expression of a green fluorescent protein (Gfp) fused to the GAL1 gene. We demonstrated that the System Identification platform enables accurate measurements of the input (sugars concentrations in the medium) and output (Gfp fluorescence intensity) signals, thus making it possible to apply System Identification techniques to obtain a quantitative dynamical model of the promoter. We explored and compared linear and nonlinear model structures in order to select the most appropriate to derive a quantitative model of the promoter dynamics. Our platform can be used to quickly obtain quantitative models of eukaryotic promoters, currently a complex and time-consuming process.

Pinning control of complex networks via edge snapping.

In this paper, we propose a hierarchy of novel decentralized adaptive pinning strategies for controlled synchronization of complex networks. This hierarchy addresses the fundamental need of selecting the sites to pin through a fully decentralized approach based on edge snapping. Specifically, we present three different strategies of increasing complexity which use a combination of network evolution and adaptation of the coupling and control gains. Theoretical results are complemented by extensive numerical investigations of the performance of the proposed strategies on a set of testbed examples.

Comparing different ODE modelling approaches for gene regulatory networks.

A fundamental step in synthetic biology and systems biology is to derive appropriate mathematical models for the purposes of analysis and design. For example, to synthesize a gene regulatory network, the derivation of a mathematical model is important in order to carry out in silico investigations of the network dynamics and to investigate parameter variations and robustness issues. Different mathematical frameworks have been proposed to derive such models. In particular, the use of sets of nonlinear ordinary differential equations (ODEs) has been proposed to model the dynamics of the concentrations of mRNAs and proteins. These models are usually characterized by the presence of highly nonlinear Hill function terms. A typical simplification is to reduce the number of equations by means of a quasi-steady-state assumption on the mRNA concentrations. This yields a class of simplified ODE models. A radically different approach is to replace the Hill functions by piecewise-linear approximations [Casey, R., de Jong, H., Gouze , J.-L., 2006. Piecewise-linear models of genetic regulatory networks: equilibria and their stability. J. Math. Biol. 52 (1), 27-56]. A further modelling approach is the use of discrete-time maps [Coutinho, R., Fernandez, B., Lima, R., Meyroneinc, A., 2006. Discrete time piecewise affine models of genetic regulatory networks. J. Math. Biol. 52, 524-570] where the evolution of the system is modelled in discrete, rather than continuous, time. The aim of this paper is to discuss and compare these different modelling approaches, using a representative gene regulatory network. We will show that different models often lead to conflicting conclusions concerning the existence and stability of equilibria and stable oscillatory behaviours. Moreover, we shall discuss, where possible, the viability of making certain modelling approximations (e.g. quasi-steady-state mRNA dynamics or piecewise-linear approximations of Hill functions) and their effects on the overall system dynamics.

Handgrip Strength Predicts Longitudinal Changes in Clock Drawing Test Performance. An Observational Study in a Sample of Older Non-Demented Adults.

OBJECTIVE: Impairment of physical performance might identify older people at higher risk of dementia over time. The present study evaluated handgrip strength as independent predictor of cognitive decline. DESIGN: Observational, prospective. Follow-up duration: 11.2 ± 0.8 months. SETTING AND PARTICIPANTS: Geriatric outpatients center. 104 consecutive stroke- and dementia-free older adults (44% men, ages 80.2 ± 5.4 years). METHODS: The Clinical Dementia Rating scale and the Clock Drawing Test (CDT) were administered. Handgrip strength was assessed using a Jamar hand dynamometer. Brain magnetic resonance imaging studies at 1.5 T were performed. White matter damage was expressed as severity of white matter hyperintensities (WMHs). Longitudinal changes in cognitive function were expressed as 1-year decline in CDT performance. RESULTS: A robust association was observed between baseline handgrip strength and 1-year cognitive decline after multiple adjustment. Of note, the strength of such association was only minimally attenuated after adjusting for deep WMHs extent (ß coefficient for handgrip strength = 0.183, SE= 0.038, p= 0.007, R2= 0.58). CONCLUSIONS: Handgrip strength predicted accelerated 1-year decline in cognitive function, assessed by CDT, in a sample of older adults. Future studies are needed to elucidate the causal mechanisms linking limitations in physical function with dementia risk.

Decision landscapes: visualizing mouse-tracking data.

Computerized paradigms have enabled gathering rich data on human behaviour, including information on motor execution of a decision, e.g. by tracking mouse cursor trajectories. These trajectories can reveal novel information about ongoing decision processes. As the number and complexity of mouse-tracking studies increase, more sophisticated methods are needed to analyse the decision trajectories. Here, we present a new computational approach to generating decision landscape visualizations based on mouse-tracking data. A decision landscape is an analogue of an energy potential field mathematically derived from the velocity of mouse movement during a decision. Visualized as a three-dimensional surface, it provides a comprehensive overview of decision dynamics. Employing the dynamical systems theory framework, we develop a new method for generating decision landscapes based on arbitrary number of trajectories. This approach not only generates three-dimensional illustration of decision landscapes, but also describes mouse trajectories by a number of interpretable parameters. These parameters characterize dynamics of decisions in more detail compared with conventional measures, and can be compared across experimental conditions, and even across individuals. The decision landscape visualization approach is a novel tool for analysing mouse trajectories during decision execution, which can provide new insights into individual differences in the dynamics of decision making.

Homeobox genes and sea urchin development.

We describe the expression of three Paracentrotus lividus homeobox-containing genes of the dispersed class during sea urchin embryogenesis and discuss their possible roles in the mechanisms of cell specification and embryo morphogenesis. PlHbox12 represents the first regulator identified in sea urchin that belongs to the zygotic class of transcription factors. Its early and transient expression and the localization of transcripts suggests that PlHbox12 is involved in cell fate specification of the oral or aboral ectodermal territories at the early cleavage stages. PlHbox9 is expressed just after the completion of gastrulation in a narrow stripe of cells at the ectoderm-endoderm boundary. It probably organizes a novel spatial boundary which definitely separates the archenteron and the aboral ectoderm. Finally, the spatial and temporal expression of the PlOtp gene strongly indicate that this regulator is conditionally activated in few cells of the oral ectoderm and is involved in patterning of this territory at late stages. Furthermore, our data indicate that PlOtp acts upstream of signaling systems that lead to the activation of the primary mesenchyme cell gene expression program and skeletal morphogenesis.

Pulsatile versus steady-state component of blood pressure in elderly females: an independent risk factor for cardiovascular disease?

OBJECTIVE: To evaluate whether the pulsatile component of blood pressure can be a risk factor independent of the steady component in elderly females. DESIGN: Fifty-two elderly hypertensive female patients were compared with 32 normotensive control subjects of the same age. According to the results of that first study, a cohort of 126 elderly females was studied over a 3-year period to evaluate whether the pulsatile and steady-state components of blood pressure correlated with the same parameters and could predict the occurrence of cardiovascular events. RESULTS: In the first study the hypertensive patients with elevated pulse pressure had significantly higher triglycerides level and lower urinary sodium excretion than the hypertensive patients with lower pulse pressure and than the control subjects of the same age. The incidence of cardiovascular events over a 3-year period was significantly higher in the elderly hypertensive females with increased pulse pressure. In the cohort of 126 females mean arterial pressure (MAP) and pulse pressure did not show the same degree of correlation with the biological parameters tested (plasma triglycerides: MAP r = 0.162, P < 0.05; pulse pressure r = 0.314, P < 0.0005; urinary sodium excretion: MAP r = -0.365, P < 0.0001; pulse pressure r = -0.257, P < 0.002). Furthermore, for the same MAP level, patients with cardiovascular accidents in a 3-year period had significantly higher pulse pressure values. Pulse pressure (and not MAP) was a strong predictor of cardiovascular accidents. CONCLUSIONS: In elderly hypertensive females the pulsatile and the steady-state components of blood pressure did not correlate with the same biological parameters. Furthermore, the pulsatile component, when explored by pulse pressure, seemed to be a strong independent cardiovascular risk factor.

Effects of chronic lithium treatment on the peripheral nervous system.

BACKGROUND: Although lithium carbonate is widely used in the treatment of mood disorders, symptoms suggesting toxic effects on the peripheral nervous system may emerge even in subjects whose serum lithium levels remain within the recommended therapeutic range. METHOD: Electroneuronographic (ENG) parameters (motor nerve conduction velocity of peroneal and median nerves, sensory nerve conduction velocity of sural and median nerves, amplitude of motor potential of peroneal and median nerves, and amplitude of sensory action potential of the median nerve at the wrist and the sural nerve) were investigated in 2 groups (N = 34) of patients suffering from bipolar affective disorder (DSM-III-R, DSM-IV) undergoing maintenance treatment with lithium carbonate for at least 1 year (mean = 2.06 years) in monotherapy. For 12 patients, ENG results were compared with pretreatment values, whereas in the other 22 cases, only data relevant to posttreatment were available. Fifty-four healthy subjects and 20 patients with recurrent major affective disorder (unipolar and bipolar) never treated with lithium made up the comparison groups. RESULTS: Compared with the 2 comparison groups, patients on chronic lithium treatment showed significant reduction of motor nerve conduction velocity of peroneal and median nerves, sensory nerve conduction velocity of sural and median nerves, amplitude of motor potential of peroneal and median nerves, and amplitude of sensory action potential of the median nerve at the wrist and the sural nerve. The comparison with the assessment made prior to lithium treatment also showed significant changes; after a period of treatment with lithium varying from 2 to 8 years (mean = 5.2 years), significant reductions were found on motor and sensory nerve conduction velocity and on amplitude motor potentials and sensory action potentials. CONCLUSION: Chronic maintenance treatment with lithium affects the peripheral nerves, even if the impairment rarely is such as to warrant discontinuation of treatment. Monitoring of ENG results could be useful for the early detection of neurotoxicity of lithium.

Insulin effects on the left ventricle in older hypertensive subjects.

BACKGROUND: To evaluate the effects of hyperinsulinemia on left ventricular (LV) structure and function in older hypertensive subjects METHODS: Thirty-seven hypertensive subjects (17 men/20 women) aged 50 to 80, were studied. LV mass were evaluated echocardiographically according to the Penn convention. A 75-g oral glucose tolerance test (OGTT) was performed after overnight fasting, and both blood glucose and insulin concentrations were assayed at 0, 30, 60, 90, 120, and 180 minutes. Comparison between groups was performed by analysis of variance. A P value of .05 was considered statistically significant. RESULTS: When the hypertensive patients were divided into two groups according to the median value of 2-hour post-loading plasma insulin, there was no difference in blood pressure levels between the groups. However, hyperinsulinemic hypertensive subjects had an increased LV mass (P < .05), mean wall thickness, and interventricular septum thickness (P < .05 for both parameters) and had better systolic function-ejection and shortening fractions (P < .0001 for both indices). CONCLUSIONS: Hyperinsulinemia may be associated with increased left ventricular mass and with a better systolic performance in older hypertensive subjects.

Quality of life and overweight: the obesity related well-being (Orwell 97) questionnaire.

The development and validation of a self-reported measure of obesity-related quality of life, the Obesity Related Well-Being (ORWELL 97), were undertaken to examine the intensity and the subjective relevance of physical and psychosocial distress. The questionnaire was validated in a sample of 147 obese patients (99 females, 48 males). The Eating Disorder Examination 12.0D interview, a structured diagnostic interview for DSM-III-R (DSM-IV criteria for binge eating disorder), Beck Depression Inventory, Binge Eating Scale, and the State-Trait Anxiety Inventory 1 and 2 scales were also applied. Internal consistency and test-retest reliability were satisfactory. Factor analysis allowed the identification of two subscales: ORWELL 97-1 related to psychological status and social adjustment, and ORWELL 97-2 related to physical symptoms impairment. Obese female patients showed a lower quality of life, and the severity of obesity appeared to interfere with physical functioning rather than psychological status and social adjustment. The ORWELL 97 questionnaire appears to be a simple and reliable measure of obesity-related quality of life, which can be used in current clinical practice.

Is blood pressure the major determinant of left ventricular mass in subjects over 50 years of age?

The weak relation of systolic blood pressure to left ventricular (LV) mass in hypertension has frequently been regarded as evidence of non-hemodynamic stimuli to muscle growth. Anyway, left ventricular hypertrophy (LVH) is associated with a significantly increased risk for cardiovascular events. Data were obtained from M-mode echocardiograms in 10 normotensives and 58 hypertensives over 50 years (range 50-85 years); 18 hypertensives; were without (LVH -) and 40 were with LVH (LVH +) - when LV mass, normalized for body surface area, was calculated according to the Penn's Convention. Cardiac output was derived by Teicholz formula for LV volumes. End-systolic stress/end-systolic dimension ratio (ESS/ ESD r), an index of myocardial contractility, was calculated as previously validated in the literature. We found that, in subjects ranging from 50 to 85 years of age, the presence of LV hypertrophy is not necessarily associated with raised blood pressure levels. Systolic function was substantially preserved among the study groups, irrespective of their age, hypertensive condition and/or presence of LVH. The increased wall thickness in subjects with LVH was associated with a significant reduction in wall stress (thus suggesting an adequateness of the compensatory role of LVH - at least at the observed stage of the hypertrophy process) and with a significant decrease of the contractile performance. On the multivariate analysis, the observed relation of LV mass to blood pressure and myocardial contractility (r = 0.621, P < 0.001) may explain some apparently conflicting findings, such as the lack of LV hypertrophy in a number of hypertensive patients.

[Effect of cooper supplementation on blood pressure values in patients with stable moderate hypertension]. / Efecto de la suplementación con cobre sobre los valores de presión arterial en pacientes con hipertensión moderada estable.

Copper (Cu) deficiency is associated with changes in arterial pressure. The effect depends of the age of initiation of the copper-deficient diet. Copper deficiency started at a young age causes hypotension. When initiated in older or adult animals, copper deficiency can cause hypertension. A case-control study was carried out to investigate the effect of administrating 5 mg Cu/d in 60 subjects, both genders, with mild stable hypertension, pharmacologically untreated (treated group) and compared with 60 hypertensives (control group) who were matched by gender, age, body weight, smoking habits, calories, fat and salt intake (NaCl), and physical activity. Hypertension was diagnosed when the blood pressure was > 150/95 mm Hg. Mean age, mean corporal weight and risk factors were similar in both groups. The results suggested the existence of a marginal deficiency of the trace element in 62% of subjects and demonstrated that Cu decreases systolic (r = -0.963) and diastolic (r = -0.981) blood pressures in treated group (p < 0.05). Control patients did not show significant changes in their arterial pressures. These findings indicate a functional alteration in human blood pressure regulation during mild copper depletion and suggest that Cu could be used in the treatment of stable moderate arterial hypertension. Further investigation is needed to determine the extent of this influence.

[Effect of copper supplementation on lipid profile of Venezuelan hyperlipemic patients]. / Efecto de la suplementación oral con cobre en el perfil lipídico de pacientes Venezolanos hiperlipémicos.

It has been assumed that most Western diets satisfy the requirement of copper/day because of ubiquitous presence of this element in most foods. Recent studies have shown that dietary copper (Cu) may often fall below the estimated daily requirements, what could determine a deficiency of this trace element. This deficiency is associated with hypercholesterolemia and hypertrigliceridemia, both in human and experimental animals. In the present intervention study was examined the effect of the administration of 5 mg of Cu/day in 73 patients (treated group), of both genders, with ages between 26 and 48 years, with high serum levels of total cholesterol and triglycerides without pharmacological treatment and compared with 73 hyperlipemic subjects non-treated with copper (control group) who were matched by gender, age, body weight, smoking habits, calories and fat intake, and physical activity. Before copper administration, a sample of blood was obtained for serum determinations of copper, zinc and lipids. At the end of the experimental period (45 days), a new sample of blood was taken for the corresponding determinations. The results suggest the existence of a marginal deficiency of the trace element in 38% of the subjects and demonstrate that copper supplementation decreases (p < 0.05) serum levels of total cholesterol (r = -0.976), triglycerides (r = -0.972), LDL-cholesterol (r = -0.961) and zinc (r = -0.980) with a slight increment (r = 0.894) of HDL-cholesterol. These findings demonstrate that copper can be used in the treatment of the patients with hypercholesterolemia and hypertriglyceridemia. The mechanisms by which Cu determines these changes are not known.

Discontinuity-induced bifurcations of piecewise smooth dynamical systems.

This paper presents an overview of the current state of the art in the analysis of discontinuity-induced bifurcations (DIBs) of piecewise smooth dynamical systems, a particularly relevant class of hybrid dynamical systems. Firstly, we present a classification of the most common types of DIBs involving non-trivial interactions of fixed points and equilibria of maps and flows with the manifolds in phase space where the system is non-smooth. We then analyse the case of limit cycles interacting with such manifolds, presenting grazing and sliding bifurcations. A description of possible classification strategies to predict and analyse the scenarios following such bifurcations is also discussed, with particular attention to those methodologies that can be applied to generic n-dimensional systems.

Catastrophic sliding bifurcations and onset of oscillations in a superconducting resonator.

This paper presents a general analysis and a concrete example of the catastrophic case of a discontinuity-induced bifurcation in so-called Filippov nonsmooth dynamical systems. Such systems are characterized by discontinuous jumps in the right-hand sides of differential equations across a phase space boundary and are often used as physical models of stick-slip motion and relay control. Sliding bifurcations of periodic orbits have recently been shown to underlie the onset of complex dynamics including chaos. In contrast to previously analyzed cases, in this work a periodic orbit is assumed to graze the boundary of a repelling sliding region, resulting in its abrupt destruction without any precursive change in its stability or period. Necessary conditions for the occurrence of such catastrophic grazing-sliding bifurcations are derived. The analysis is illustrated in a piecewise-smooth model of a stripline resonator, where it can account for the abrupt onset of self-modulating current fluctuations. The resonator device is based around a ring of NbN containing a microbridge bottleneck, whose switching between normal and super conducting states can be modeled as discontinuous, and whose fast temperature versus slow current fluctuations are modeled by a slow-fast timescale separation in the dynamics. By approximating the slow component as Filippov sliding, explicit conditions are derived for catastrophic grazing-sliding bifurcations, which can be traced out as parameters vary. The results are shown to agree well with simulations of the slow-fast model and to offer a simple explanation of one of the key features of this experimental device.

How to synchronize biological clocks.

This paper is concerned with a novel algorithm to study networks of biological clocks. A new set of conditions is established that can be used to verify whether an existing network synchronizes or to give guidelines to construct a new synthetic network of biological oscillators that synchronize. The methodology uses the so-called contraction theory from dynamical system theory and Gershgorin disk theorem. The strategy is validated on two examples: a model of glycolisis in yeast cells and a synthetic network of Repressilators that synchronizes.

Minimal control synthesis adaptive control of nonlinear systems: utilizing the properties of chaos.

This paper discusses a novel approach to the control of chaos based on the use of the adaptive minimal control synthesis algorithm. The strategies presented are based on the explicit exploitation of different properties of chaotic systems including the boundedness of the chaotic attractors and their topological transitivity (or ergodicity). It is shown that chaos can be exploited to synthesize more efficient control techniques for nonlinear systems. For instance, by using the ergodicity of the chaotic trajectory, we show that a local adaptive control strategy can be used to synthesize a global controller. An application is to the swing-up control of a double inverted pendulum.