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Upstream operators enhance repression of the lac promoter.

To study regulation of transcription by distant elements, a wild-type lac operator was inserted upstream of a promoter-constitutive operator control region. The upstream operator is shown to aid in repression of transcription from the mutant control region. The effectiveness of the upstream operator as a function of its distance from the mutant control region parallels the length dependence observed for DNA cyclization. A quantitative model is proposed for action-at-a-distance of DNA control sites in which protein-protein and protein-DNA interactions are mediated by DNA looping. In this model, the effective concentrations of interacting proteins that are tethered by DNA are determined by the length of the intervening DNA and by its inherent bending and torsional stiffness. This model makes a number of predictions for both eukaryotic and prokaryotic control sequences located far from their sites of action.

Galactokinase↗

Computer simulation of the hemodynamic determinants of myocardial oxygen supply and demand.

A computer program was developed that uses a mathematical model of the cardiovascular system to predict myocardial oxygen supply and demand as well as cardiac hemodynamics. This model combines the time-varying elastance model of the left ventricle, the modified Windkessel model of the arterial system, and the left ventricular pressure-volume area prediction of myocardial oxygen demand. The computer simulation permits independent control of variables, thus providing the opportunity to design "experiments" and to observe the results. The model predicts that tachycardia leads to reduced myocardial oxygen supply and increased demand. Hypertension caused by increased systemic vascular resistance increases supply more than it increases demand. On the other hand, increased contractility or left ventricular end-diastolic pressure increases demand more than supply, and may cause ischemia in the presence of coronary artery stenosis. The model is an aid in understanding how hemodynamic variables affect the balance between myocardial oxygen supply and demand. It can be used for education and to analyze study protocols prior to animal experimentation.

Animals↗

A method to guide community planning and evaluation efforts in tobacco control using data on smoking during pregnancy.

BACKGROUND: Effective community based tobacco control programmes are critical for state and nationwide impact. However, there is little discussion in the literature of methods for setting local objectives which use locally collected data and account for historical variation in progress. OBJECTIVES: To develop and illustrate a method that uses locally available birth certificate data to model trends in tobacco use during pregnancy among women giving birth, predict future prevalence, and use predictions to set community specific tobacco control objectives. DATA SOURCE: Vital statistics. Wisconsin standard birth certificates, 1990-2000, which record the smoking status of the mother during pregnancy. DATA ANALYSIS: Trends in the prevalence of smoking during pregnancy in Wisconsin statewide and in all counties (n = 72) were modelled using linear regression of log prevalence on year. Model fit was assessed using R(2). Regression slopes, indicating estimated relative annual percentage change in prevalence, were used to predict prevalence in 2005, and objectives were calculated as a 20% reduction from the predicted prevalence in 2005. CONCLUSIONS: Modelling trends in the prevalence of smoking using locally collected data enables communities to set reasonable future tobacco control objectives that account for historical trends in progress.

Community Health Planning↗

Effects of gravitational load on jaw movements in speech.

External loads arising as a result of the orientation of body segments relative to gravity can affect the achievement of movement goals. The degree to which subjects adjust control signals to compensate for these loads is a reflection of the extent to which forces affecting motion are represented neurally. In the present study we assessed whether subjects, when speaking, compensate for loads caused by the orientation of the head relative to gravity. We used a mathematical model of the jaw to predict the effects of control signals that are not adjusted for changes to head orientation. The simulations predicted a systematic change in sagittal plane jaw orientation and horizontal position resulting from changes to the orientation of the head. We conducted an empirical study in which subjects were tested under the same conditions. With one exception, empirical results were consistent with the simulations. In both simulation and empirical studies, the jaw was rotated closer to occlusion and translated in an anterior direction when the head was in the prone orientation. When the head was in the supine orientation, the jaw was rotated away from occlusion. The findings suggest that the nervous system does not completely compensate for changes in head orientation relative to gravity. A second study was conducted to assess possible changes in acoustical patterns attributable to changes in head orientation. The frequencies of the first (F1) and second (F2) formants associated with the steady-state portion of vowels were measured. As in the kinematic study, systematic differences in the values of F1 and F2 were observed with changes in head orientation. Thus the acoustical analysis further supports the conclusion that control signals are not completely adjusted to offset forces arising because of changes in orientation.

Biomechanical Phenomena↗

Social learning theory and the Health Belief Model.

The Health Belief Model, social learning theory (recently relabelled social cognitive theory), self-efficacy, and locus of control have all been applied with varying success to problems of explaining, predicting, and influencing behavior. Yet, there is conceptual confusion among researchers and practitioners about the interrelationships of these theories and variables. This article attempts to show how these explanatory factors may be related, and in so doing, posits a revised explanatory model which incorporates self-efficacy into the Health Belief Model. Specifically, self-efficacy is proposed as a separate independent variable along with the traditional health belief variables of perceived susceptibility, severity, benefits, and barriers. Incentive to behave (health motivation) is also a component of the model. Locus of control is not included explicitly because it is believed to be incorporated within other elements of the model. It is predicted that the new formulation will more fully account for health-related behavior than did earlier formulations, and will suggest more effective behavioral interventions than have hitherto been available to health educators.

Attitude to Health↗

Modeling of the sedative and airway obstruction effects of propofol in patients with Parkinson disease undergoing stereotactic surgery.

BACKGROUND: Functional stereotactic surgery requires careful titration of sedation since patients with Parkinson disease need to be rapidly awakened for testing. This study reports a population pharmacodynamic model of propofol sedation and airway obstruction in the Parkinson disease population. METHODS: Twenty-one patients with advanced Parkinson disease undergoing functional stereotactic surgery were included in the study and received propofol target-controlled infusion to achieve an initial steady state concentration of 1 microg/ml. Sedation was measured using the Ramsay Sedation Scale. Airway obstruction was measured using a four-category score. Blood samples were drawn for propofol measurement. Individual pharmacokinetic profiles were constructed nonparametrically using linear interpolation. Time course of sedation and respiratory effects were described with population pharmacodynamic models using NONMEM. The probability (P) of a given level of sedation or airway obstruction was related to the estimated effect-site concentration of propofol (Ce) using a logistic regression model. RESULTS: The concentrations predicted by the target-controlled infusion system generally exceeded the measured concentrations. The estimates of C(50) for Ramsay scores 3, 4, and 5 were 0.1, 1.02, and 2.28 microg/ml, respectively. For airway obstruction scores 2 and 3, the estimates of C(50) were 0.32 and 2.98 microg/ml, respectively. Estimates of k(e0) were 0.24 and 0.5 1/min for the sedation and respiratory effects, respectively. CONCLUSIONS: The pharmacokinetic behavior of propofol in patients with Parkinson disease differs with respect to the population from which the model used by the target-controlled infusion device was developed. Based on the results from the final models, a typical steady state plasma propofol concentration of 0.35 microg/ml eliciting a sedation score of 3 with only minimal, if any, airway obstruction has been defined as the therapeutic target.

Adult↗

Perceptions of disease severity and barriers to self-care predict glycemic control in Aboriginal persons with type 2 diabetes mellitus.

The Health Belief Model (HBM) was evaluated for secondary prevention of type 2 diabetes mellitus in an Aboriginal population in British Columbia. Glycemic markers (glycated hemoglobin [HbA1c]), insulin and post-load glucose), diabetes health beliefs (susceptibility, severity, benefits and barriers), knowledge and behaviour were measured for 16 men and 18 women with diabetes (age [SD]=57.7 [11.6]). Eighteen months later, HbA1c and behaviour were measured for all participants, and health beliefs obtained for 17 of them. Perceived severity and perceived barriers were related to glycemic status at baseline and follow up, and predicted reduction in HbA1c (b[SE] |0.40| [0.18], p <0.05). The results support a therapeutic emphasis on belief in the severity of diabetes complications, and the complementary belief that barriers to therapeutic behaviour can be overcome in efforts to support Aboriginal persons with diabetes to manage their disease. The empirical utility of the HBM in glycemic control was partially upheld.

Adult↗

Host MHC class I gene control of NK-cell specificity in the mouse.

The missing self model predicts that NK cells adapt somatically to the type as well as levels of MHC class I products expressed by their host. Transgenic and gene knock-out mice have provided conclusive evidence that MHC class I genes control specificity and tolerance of NK cells. The article describes this control and discusses the possible mechanisms behind it, starting from a genetic model to study how natural resistance to tumors is influenced by MHC class I expression in the host as well as in the target cells. Data on host gene regulation of NK-cell functional specificity as well as Ly49 receptor expression are reviewed, leading up to the central question: how does the system develop and maintain "useful" NK cells, while avoiding "harmful" and "useless" ones? The available data can be fitted within each of two mutually none-exclusive models: cellular adaptation and clonal selection. Recent studies supporting cellular adaptation bring the focus on different possibilities within this general mechanism, such as anergy, receptor calibration and, most importantly, whether the specificity of each NK cell is permanently fixed or subject to continuous regulation.

Animals↗

Predictive control of body mass trajectory in a two-step sequence.

During a step, the body enters a state of falling as a foot is lifted from the ground. This has important implications for the control of body trajectory when stepping in different directions. A model has been proposed in which the central nervous system controls body trajectory by a predictive, ballistic "throw" of the body occurring just before the stepping foot leaves the ground. Here we investigate this model and ask how far into the future the body trajectory is predetermined by this initial ballistic throw. We measured body centre-of-mass (CoM) and foot trajectories during two-step sequences involving stepping onto illuminated targets, one for each foot. The targets were varied spatially such that leading foot placement could be dissociated from final CoM position. The results showed that the body throw was altered when stepping in different directions. However, the throw varied only with leading foot placement and not with final CoM position. Thus, provided the leading foot was placed identically, the same throw was used for steps in which body trajectories would later diverge. Furthermore, these trajectories did not diverge while the stepping foot was in the air but occurred after it touched down. The results are consistent with the ballistic stepping model. However, they suggest that the throw is limited in its predictive capacity, being concerned only with where the stepping foot is to be placed rather than final CoM position. This constitutes a one-step-at-a-time strategy that allows the body to be safely "caught" between steps.

Biomechanical Phenomena↗

Transient antiretroviral treatment during acute simian immunodeficiency virus infection facilitates long-term control of the virus.

Experimental evidence and mathematical models indicate that CD4+ T-cell help is required to generate memory cytotoxicT-lymphocyte precursors (CTLp) that are capable of persisting without ongoing antigenic stimulation, and that such responses are necessary to clear an infection or to control it in the long term. Here we analyse mathematical models of simian immunodeficiency virus (SIV) replication in macaques, assuming that SIV impairs specific CD4+ T-cell responses. According to the models, fast viral replication during the initial stages of primary infection can result in failure to generate sufficient long-lived memory CTLp required to control the infection in the long term. Modelling of drug therapy during the acute phase of the infection indicates that transient treatment can minimize the amount of virus-induced immune impairment, allowing a more effective initial immune sensitization. The result is the development of high levels of memory CTLp that are capable of controlling SIV replication in the long term, in the absence of continuous treament. In the model, the success of treatment depends crucially on the timing and duration of antiretroviral therapy. Data on SIV-infected macaques receiving transient drug therapy during acute infection support these theoretical predictions. The data and modelling suggest that among subjects controlling SIV replication most efficiently after treatment, there is a positive correlation between cellular immune responses and virus load in the post-acute stage of infection. Among subjects showing less-efficient virus control, the correlation is negative. We discuss our findings in relation to previously published data on HIV infection.

Acute Disease↗

Experimentally confirmed mathematical model for human control of a non-rigid object.

Determining the principles used to plan and execute movements is a fundamental question in neuroscience research. When humans reach to a target with their hand, they exhibit stereotypical movements that closely follow an optimally smooth trajectory. Even when faced with various perceptual or mechanical perturbations, subjects readily adapt their motor output to preserve this stereotypical trajectory. When humans manipulate non-rigid objects, however, they must control the movements of the object as well as the hand. Such tasks impose a fundamentally different control problem than that of moving one's arm alone. Here, we developed a mathematical model for transporting a mass-on-a-spring to a target in an optimally smooth way. We demonstrate that the well-known "minimum-jerk" model for smooth reaching movements cannot accomplish this task. Our model extends the concept of smoothness to allow for the control of non-rigid objects. Although our model makes some predictions that are similar to minimum jerk, it predicts distinctly different optimal trajectories in several specific cases. In particular, when the relative speed of the movement becomes fast enough or when the object stiffness becomes small enough, the model predicts that subjects will transition from a uni-phasic hand motion to a bi-phasic hand motion. We directly tested these predictions in human subjects. Our subjects adopted trajectories that were well-predicted by our model, including all of the predicted transitions between uni- and bi-phasic hand motions. These findings suggest that smoothness of motion is a general principle of movement planning that extends beyond the control of hand trajectories.

Algorithms↗

Numerical models for calculating the blood level of a drug with oral controlled release forms.

Controlled release dosage forms offer advantages over conventional dosage forms and a more constant and prolonged therapeutic effect. These new dosage forms are tested by using in-vitro tests or in-vivo tests; however, a great problem appears with the establishment of correlations between these tests. A new way of working is able to resolve the problem. It consists of coupling either experiments or models based on numerical analysis and computerization. In-vitro tests performed at various pH are used to determine the kinetics of release and the parameters characterizing diffusion or erosion. From the knowledge of the certain data (the gastrointestinal tract-time history, the kinetics of release of the drug out of the dosage form, the rate constants of absorption and elimination, and the plasmatic volume), it is possible to obtain, by calculation, the kinetics of the drug in the plasmatic volume, as well as other pieces of information. Not only is the model able to predict the pharmacokinetics of a drug from a controlled release dosage form, but it also optimizes the characteristics of the dosage form. The validity of the model is successfully tested by comparing the blood level of Theophylline, obtained either by in-vivo tests or calculation.

Absorption↗

The use of mathematical models to simulate control options for echinococcosis.

In many parts of the world Echinococcus granulosus is a widespread infection in sheep and dogs with a consequential spill over into the human population. In the past, mathematical models have been derived to define the transmission dynamics of this parasite, principally in the sheep-dog life cycle. These models have characterized the cycles of infection as lacking in density dependent constraints in both the definitive or intermediate hosts. This suggested that there was little, if any, induced host immunity by the parasite in either host in natural infections. However, recent evidence from both Tunisia and Kazakhstan, where young dogs are the most heavily parasitised, suggests the possibility of significant definitive host immunity. This may have an effect on the control effort needed to destabilize the parasite. A preliminary computer simulation model (based on an Excel spreadsheet) to attempt to predict the results of a control programme has been written. This demonstrates that there could be significantly different results if there is indeed protective immunity in the dog than in the absence of immunity. In the former the parasite needs a greater control effort to push the parasite towards extinction than in the latter. The computer simulation is based on a mathematical model of the parasite's life cycle and is flexible so that different values of parameters can be used in different situations where the transmission of the parasite may be at different levels. Because of the flexibility of the computer simulation it is anticipated that this programme can be applied in most situations, although initial parameters for a particular location or strain of the parasite will have to be first predetermined with base line field surveys and possibly experimental infections. The programme also has an additional flexibility to enable simulations if some parameters cannot be accurately estimated through Monte-Carlo techniques. In the latter situation, worst and best case scenarios can be estimated and likely frequency distributions of the unknown parameters can be included in the model.

Animals↗

College students' memory for vocabulary in their majors: evidence for a nonlinear relation between knowledge and memory.

The effect of domain knowledge on students' memory for vocabulary terms was investigated. Participants were 142 college students (94 education majors and 48 business majors). The measure of domain knowledge was the number of courses completed in the major. Students recalled three different lists (control, education, and business) of 20 words. Knowledge effects were estimated controlling for academic aptitude, academic achievement, and general memory ability. Domain-specific knowledge consistently predicted recall, above and beyond the effect of these control variables. Moreover, nonlinear models better represented the relation between knowledge and memory, with very similar functions predicting recall in both knowledge domains. Specifically, early in the majors more classes corresponded with increased memory performance, but a plateau period, when more classes did not result in higher recall, was evident for both majors. Longitudinal research is needed to explore at what point in learning novices' performance begins to resemble experts' performance.

Adolescent↗

Transcriptional regulation in constraints-based metabolic models of Escherichia coli.

Full genome sequences enable the construction of genome-scale in silico models of complex cellular functions. Genome-scale constraints-based models of Escherichia coli metabolism have been constructed and used to successfully interpret and predict cellular behavior under a range of conditions. These previous models do not account for regulation of gene transcription and thus cannot accurately predict some organism functions. Here we present an in silico model of the central E. coli metabolism that accounts for regulation of gene expression. This model accounts for 149 genes, the products of which include 16 regulatory proteins and 73 enzymes. These enzymes catalyze 113 reactions, 45 of which are controlled by transcriptional regulation. The combined metabolic/regulatory model can predict the ability of mutant E. coli strains to grow on defined media as well as time courses of cell growth, substrate uptake, metabolic by-product secretion, and qualitative gene expression under various conditions, as indicated by comparison with experimental data under a variety of environmental conditions. The in silico model may also be used to interpret dynamic behaviors observed in cell cultures. This combined metabolic/regulatory model is thus an important step toward the goal of synthesizing genome-scale models that accurately represent E. coli behavior.

Aerobiosis↗

Factors influencing the coping effort of mothers of hospitalized children.

The purpose of this study was to test a theoretical model predicting the relationships among four concepts: predictability of events, control, anxiety, and coping effort of mothers of children hospitalized with acute physical conditions. The sample consisted of 45 mothers of acutely ill, hospitalized children from 1-24 months of age. For each of the concepts, 16 events commonly associated with hospitalization of a child were proportionately ranked using magnitude estimation measurement technique. The psychometric properties of the instrument were estimated through reliability assessment and cross modality matching. Multiple regression analysis indicated that 97% of the dependent variable, coping effort, was explained by two of the three predictor variables--predictability of events and anxiety. Mothers who knew what events to expect experienced less anxiety and reported expending less effort to cope with the stressful events. Control was not a significant factor in predicting the mothers' coping effort.

Adaptation, Psychological↗

Comparison of vaccination strategies for the control of dog rabies in Machakos District, Kenya.

Demographic and epidemiological field data were used in a deterministic model to describe dog rabies transmission in Machakos District, Kenya and to predict the impact of potential vaccination strategies for its control. The basic reproduction number (R0) was estimated to be 2.44 (1.52-3.36, 95% confidence limits). There were three key model predictions. The first was that a threshold dog density (K(T)) of 4.5 dogs km(-2) (3.8-5.2 dogs km(-2), 95% confidence limits) was required to maintain transmission. The second was that the estimated annual vaccination rate of 24% failed to decrease incidence and actually increased the stability of transmission and may be counter-productive. Thirdly, to control rabies, it was predicted that 59% (34%-70%, 95% confidence limits) of dogs should be vaccinated at any one time. This requires approximately 70% coverage for annual but only 60% coverage for semi-annual vaccination campaigns. Community-level vaccination trials are needed to test these predictions.

Animals↗

Formation of the triple helix of type I procollagen in cellulo. Temperature-dependent kinetics support a model based on cis in equilibrium trans isomerization of peptide bonds.

The kinetics of triple-helix formation in type I procollagen at 37 degrees C in cellulo have been found to agree with predictions from the following model: triple-helix formation is initiated after completion of the synthesis of the procollagen polypeptide chains and after the chains associate to form interchain disulfide bonds within the C-propeptide; triple-helix formation propagates from this single nucleation site toward the N terminus of the molecule, interrupted by the random occurrence of peptide bonds in the cis configuration; cis-trans isomerization controls the rate of triple-helix formation. This model predicts that the activation energy of the rate-limiting process should be strongly positive. However, studies of triple-helix formation in vitro using thermally denatured material have shown only a low, or even negative, dependence of the rate on temperature in the physiological range. Here we report the temperature dependence of the rate of triple-helix formation in cellulo and a novel procedure for analyzing the resulting data to give an estimate of the Arrhenius activation energy of the rate-controlling process. It was found that this rate showed a strong, positive dependence on temperature, as expected, and that the activation energy was in satisfactory agreement with independent direct determinations of this parameter for cis-trans isomerizations. These findings lend further support to the model of triple-helix formation described above.

Animals↗