A model integration approach linking signalling and gene-regulatory logic with kinetic metabolic models.

Systems biology has to increasingly cope with large- and multi-scale biological systems. Many successful in silico representations and simulations of various cellular modules proved mathematical modelling to be an important tool in gaining a solid understanding of biological phenomena. However, models spanning different functional layers (e.g. metabolism, signalling and gene regulation) are still scarce. Consequently, model integration methods capable of fusing different types of biological networks and various model formalisms become a key methodology to increase the scope of cellular processes covered by mathematical models. Here we propose a new integration approach to couple logical models of signalling or/and gene-regulatory networks with kinetic models of metabolic processes. The procedure ends up with an integrated dynamic model of both layers relying on differential equations. The feasibility of the approach is shown in an illustrative case study integrating a kinetic model of central metabolic pathways in hepatocytes with a Boolean logical network depicting the hormonally induced signal transduction and gene regulation events involved. In silico simulations demonstrate the integrated model to qualitatively describe the physiological switch-like behaviour of hepatocytes in response to nutritionally regulated changes in extracellular glucagon and insulin levels. A simulated failure mode scenario addressing insulin resistance furthermore illustrates the pharmacological potential of a model covering interactions between signalling, gene regulation and metabolism.

p53 as a potential predictive factor of response to chemotherapy: feasibility of p53 assessment using a functional test in yeast from trucut biopsies in breast cancer patients.

Assessment of the predictive value of p53 requires the testing of large numbers of samples from patients enrolled in prospective phase III clinical trials. The goal of this study was to determine whether p53 status can be determined by p53 yeast functional assay using the limiting amounts of material that can typically be obtained in prospective phase III trials (particularly when chemotherapy is given before surgery). All patients presenting with a clinically palpable tumour which could be considered large enough to perform a trucut biopsy (> or =2 cm breast tumour) were eligible for this study. Two trucut biopsies and one incisional biopsy were performed on the surgical specimens (mastectomy or tumourectomy). Samples were snap frozen and cryostat sections were taken for histology and p53 testing. Thirty patients were included. Three samples out of 90 failed to give any p53 PCR products, probably because these samples contained almost entirely fibrous tissue. Of the 87 samples that could be tested, the incisional and trucut biopsies results were fully concordant in every case. p53 could be defined in 97% of patients by double trucut biopsy. Eight out of 30 tumours tested were mutant for p53 (27%). p53 status can be reliably determined by yeast assay from single frozen sections of trucut biopsies. Histological examination before p53 testing is essential to exclude cases where the p53 result may reflect only the status of the normal cells in the biopsy.

Adrenocorticotropin responses to interpersonal stress: effects of overt anger expression style and defensiveness.

This study evaluated the influence of overt anger expression style and defensiveness on the hypothalamic-pituitary-adrenocortical (HPA) responses to acute psychological stress. These personality traits are thought to modulate the stress cardiovascular response and influence disease risk, however, little is known about their influence on HPA responses. Forty-six young, healthy male volunteers worked on counterbalanced extended public-speaking and mental arithmetic. The sample was dichotomitized into groups low vs. high in anger-out, using Spielberger's Anger-Expression Inventory, and in defensiveness, using the Marlowe-Crown Social Desirability Scale. Serum cortisol and adrenocorticotropic hormone (ACTH) concentrations were measured before and after performing each task. Heart rate (HR) and blood pressures (BP) were obtained continuously in 2-min intervals before, during and after the tasks. Public speaking produced greater adrenocortical and cardiovascular stress responses than mental arithmetic, and the greatest increases in ACTH occurred in subjects high in anger-out and defensiveness. These preliminary findings provide evidence that a mismatch between traits of preferred anger expression style and defensive style produces pronounced adrenocorticotropic responses during socially salient stress.

Interactive effects of trait hostility and anger expression on cardiovascular reactivity in young men.

Hostility and anger-expression style are personality traits often associated with elevated cardiovascular reactivity and potential heightened risk for cardiovascular disease. In the present study a sample of 50 young, healthy men were divided into groups low or high on the Cook-Medley Hostility scale and on anger-out from Spielberger's Anger Expression scale. Subjects worked on mental arithmetic and public speaking tasks in counterbalanced order. Heart rate, systolic and diastolic blood pressure and hemodynamic indices were measured at baseline and during the tasks. Hostility and anger-out interacted in their effects on cardiovascular responses. The High Anger-Out/Low-Hostile group displayed the greatest increases in heart rate and blood pressures, while the High Anger-Out/High-Hostile group was least reactive. Furthermore, the High Anger-Out/Low-Hostile group showed a distinct fight/flight response pattern during public speaking, indicated by increases in stroke volume and cardiac output and a decrease in systemic vascular resistance. These results suggest that a mismatch between hostile cognitions and habitual anger expression leads to greater cardiovascular reactivity to challenging tasks, potentially enhancing risk for development of cardiovascular diseases.

Cardiovascular responses during effortful active coping and acute experience of anger in women.

This study addresses the question of whether effortful active coping and anger provocation add in their effects on cardiovascular responses. Heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) responses of 64 female students were collected during an active versus nonactive coping task with and without provocation. After a baseline period, women did mental arithmetic (active coping) or read numbers aloud (nonactive coping). Half of each group was then additionally provoked. Ratings of the emotional states (Positive and Negative Affect Scale) indicate that provocation led to an increase in anger, but not in fear or negative or positive affect. Effortful active coping and provocation elevated cardiovascular activity. Although active coping enhanced all cardiovascular variables, provocation particularly affected HR and DBP. The effects of active coping and provocation on HR and DBP but not on SBP were additive and probably were produced by different physiological mechanisms.

Cardiovascular and neuroendocrine adjustment to public speaking and mental arithmetic stressors.

In this study, we evaluated cardiovascular, neuroendocrine, and psychological adjustment to repeated presentations of a public speaking and a mental arithmetic task. Brief versions of mental arithmetic tasks have been used widely in previous reactivity studies, and growing attention to more socially salient tasks has led to the increased use of public speaking tasks. However, psychophysiological adjustment during extended and repeated exposure to these tasks has not been delineated. In the present study, 52 healthy men worked on three 8-min presentations of public speaking and of mental arithmetic in a repeated measure design. Both tasks produced substantial cardiovascular, adrenocorticotropic hormone, and cortisol responses; public speaking produced greater changes. Repeated presentations of public speaking produced a stable pattern of cardiac activation, whereas repetitions of the mental arithmetic initially produced large cardiac responses that changed to a more vascular tonus across task periods. Both tasks increased negative moods. However, correlations between the endocrine, cardiovascular, and negative moods were significant only during the public speaking stressor. The public speaking task is a socially relevant experimental protocol for studying reactivity in the laboratory setting and elicits relatively high, stable, and homogeneous responses.

Mental effort during active and passive coping: a dual-task analysis.

This study was designed to examine the invested mental effort during active and passive coping by means of performance data. Dual-task performance was measured while subjects coped with a situation, either actively or passively. Thirty-six male students worked on a primary mental arithmetic task (MAT) and a secondary choice reaction time task simultaneously. Half of the sample could avoid an aversive tone by performing well on the MAT. For the remaining half, their performance had no influence on the tone. The aversive tone stimulation of these subjects was yoked to a "partner," in the first group. Subjects with control showed elevated cardiovascular responses and inferior secondary task performance than subjects without control. No differences were found in the performance on the MAT. These results were in line with the assumption that subjects with control spent more effort on the primary task. Subjects under the active coping condition probably payed more attention to the tone, which consumed more cognitive resources.

A study of the University of Connecticut's criteria for admission into medical school.

Scores on nineteen pre-admission and post-admission performance variables for four classes of medical students were analysed using canonical correlation and regression methods. Detailed interviews with 138 clinical preceptors were included among the criterion variables. National Board Part I scores could be predicted readily from conventional data such as Medical College Admission Test scores and grade point average. However, these same predictors generally correlated negatively with measures of clinical performance. Evidence supports pre-admission interviews and careful analysis of letters of recommendation as useful predictors of the clinical performance variables.