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At least 721 records · Page 40Linked to original sources
PubMed1998

Current theories of neuronal information processing performed by Ca2+/calmodulin-dependent protein kinase II with support and insights from computer modelling and simulation.

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is concentrated in brain, and is particularly enriched in synaptic structures where it comprises 20-50% of all proteins. The abundant nature of CaMKII and its ability to phosphorylate a wide range of substrate proteins, including itself, earmarks it as a protein kinase that may have a vital role in neuronal information processing and memory. A computer model of CaMKII is investigated that incorporates recent findings about the geometrical arrangement of subunits, the mechanism of Ca(2+)-dependent subunit activation, and Ca(2+)-independent autophosphorylation. The model is framed as a system of nonlinear differential equations. It is demonstrated numerically that (1) CaMKII is tuned to be activated by stimulation protocols associated with the induction of long-term potentiation; (2) the observed slow dissociation of trapped Ca2+/calmodulin may require the autonomy site to be protected from dephosphorylation; and (3) Ca(2+)-independent kinase activity is expressed in a manner akin to a graded switch. The model validates current theories concerning how CaMKII may be a Ca2+ pulse frequency detector, a molecular switch, or a mediator of the threshold for long-term synaptic plasticity.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed2004

A 3-D computational model predicts that cell deformation affects selectin-mediated leukocyte rolling.

Leukocyte recruitment to sites of inflammation is initiated by their tethering and rolling on the activated endothelium under flow. Even though the fast kinetics and high tensile strength of selectin-ligand bonds are primarily responsible for leukocyte rolling, experimental evidence suggests that cellular properties such as cell deformability and microvillus elasticity actively modulate leukocyte rolling behavior. Previous theoretical models either assumed cells as rigid spheres or were limited to two-dimensional representations of deformable cells with deterministic receptor-ligand kinetics, thereby failing to accurately predict leukocyte rolling. We therefore developed a three-dimensional computational model based on the immersed boundary method to predict receptor-mediated rolling of deformable cells in shear flow coupled to a Monte Carlo method simulating the stochastic receptor-ligand interactions. Our model predicts for the first time that the rolling of more compliant cells is relatively smoother and slower compared to cells with stiffer membranes, due to increased cell-substrate contact area. At the molecular level, we show that the average number of bonds per cell as well as per single microvillus decreases with increasing membrane stiffness. Moreover, the average bond lifetime decreases with increasing shear rate and with increasing membrane stiffness, due to higher hydrodynamic force experienced by the cell. Taken together, our model captures the effect of cellular properties on the coupling between hydrodynamic and receptor-ligand bond forces, and successfully explains the stable leukocyte rolling at a wide range of shear rates over that of rigid microspheres.

Biophysics↗
PubMedDate not supplied

[Capacitive sensor for environmental monitoring based on thin films of molecularly imprinted polymers. Computer modeling for optimization of the composition of synthetic analogs of bioreceptors].

A capacitive sensor for environmental monitoring based on thin films of desmetryn-selective molecularly imprinted polymer (MIP) was developed. The method of modification of gold electrodes with the thin film of herbicide-selective MIP using the grafting polymerization approach was developed. The method of computational modeling was used to optimize the composition of desmetryn-selective MIPs. It was shown that 2-acrylamido-2-methyl-1-propan-sulfonic acid is the optimal functional monomer for desmetryn. Formation of synthetic binding sites in MIPs was demonstrated to be determined by the binding energy between the template and functional monomers as well as the number of functional groups taking part in the recognition of the template molecule. Electrochemical processes occurring at the MIP-modified electrode were analyzed. The detection limit for desmetryn comprised 100 nM. High selectivity of the capacitive sensor towards structural analogues of desmetryn as well as high operational and storage stabilities was demonstrated.

Biomimetic Materials↗
PubMed1995

Computer modeling of intracranial saccular and lateral aneurysms for the study of their hemodynamics.

There is strong evidence indicating hemodynamic stress as an underlying cause for saccular intracranial aneurysm growth, thrombosis, and/or rupture. We examined flow fields encountered in models of cerebral aneurysms having a lateral (originating from the side of an artery, not at a branch point) geometric configuration. Shear stress and pressure gradients acting on aneurysm walls under a variety of flow and geometric conditions were evaluated. For this purpose, a two-dimensional finite-element computer model of lateral aneurysms in a steady-flow state was developed. Three idealized aneurysm shapes were studied, half-spherical, spherical, and pear-shaped. The ostium width of the cerebral aneurysm, relative to the radius of the parent artery and the Reynolds number, were also varied. Maximal shear stresses and maximum pressures (for an ostium width of 2 times the radius of the parent artery) were typically found at the downstream site of the ostium, rather than at the dome of the aneurysm. In general, the highest shear stresses and the lowest pressures (at the distal portion of the ostium) were obtained in the spherical aneurysm, whereas the lowest shear stresses and the highest pressures were found in the half-spherical aneurysm. The location of maximal stresses (shear and pressure) at the distal region of the ostium suggests that growth and/or rupture may well proceed from this point. Such findings are in contrast to the commonly held opinion that aneurysm rupture occurs at the dome. Careful pathological investigation will need to be performed to clarify this finding. The results of this preliminary investigation also indicate that the flow field in lateral aneurysms is highly dependent on a number of factors related to flow and geometric parameters. Geometry seems to be a significant mediator of local magnitudes of stress. Thus, the tendency for growth or thrombosis may be influenced by variations in size or shape.

Aneurysm, Ruptured↗
PubMed1995

How many trainees are needed in general surgery? A computer model to facilitate planning.

As a consequence of the reduction in junior doctors' hours, the intention to shorten training and the freedom of Trusts to appoint additional consultants, the requirement for trained surgeons has increased sharply. Whether this consultant expansion will be sustained, so as to reach the target of one general surgeon to 30,000 population, is uncertain. To improve the planning of the number of trainees in this unstable environment, a computer model has been established for the numbers of higher surgical trainees (HSTs) and consultants. Using a series of scenarios the model demonstrates that the existing number of HST posts, with a six-year duration of training, cannot deliver the intended 1767 consultant posts until about 2016. The target can be reached in 2009 by shortening HST to five years or by the conversion of visiting registrar posts to career HST; both measures combined can achieve the target by 2006. Thus urgent action is needed to increase the output of HSTs in general surgery. In view of the uncertain demand for additional consultants, the number of trainees, in each year of HST, should be monitored frequently. The number entering training may then be adjusted appropriately.

Computer Simulation↗
PubMed1990

Structure of donor side components in photosystem II predicted by computer modelling.

Thirty-one and eleven sequences for the photosystem II reaction centre proteins D1 and D2 respectively, were compared to identify conserved single amino acid residues and regions in the sequences. Both proteins are highly conserved. One important difference is that the lumenal parts of the D1 protein are more conserved than the corresponding parts in the D2 protein. The three-dimensional structures around the electron donors tyrosineZ and tyrosineD on the oxidizing side of photosystem II have been predicted by computer modelling using the photosynthetic reaction centre from purple bacteria as a framework. In the model the tyrosines occupy two cavities close to the lumenal surface of the membrane. They are symmetrically arranged around the primary donor P680 and the distances between the centre of the tyrosines and the closest Mg ion in P680 are around 14 A. Both tyrosineZ and tyrosineD are suggested to form a hydrogen bond with histidine 190 from the loop connecting helices C and D in the D1 and D2 proteins, respectively. The Mn cluster in the oxygen evolving complex has been localized by using known and estimated distances from the tyrosine radicals. It is suggested that a binding region for the Mn cluster is constituted by the lumenal ends of helices A and B and the loop connecting them in the D1 protein. This part of the D1 protein contains a large number of strictly conserved carboxylic acid residues and histidines which could participate in the Mn binding. There is little probability that the Mn cluster binds on the lumenal surface of the D2 protein.

Amino Acid Sequence↗
PubMed1989

Accuracy of decisions to withdraw therapy in critically ill patients: clinical judgment versus a computer model.

Two clinicians and the nursing sisters working in the ICU evaluated the chance of survival of ICU patients every day. Patients were assessed either as "outcome unknown or will die." These predictions were compared with those made by computerized trend analysis of daily acute physiology and chronic health evaluation (APACHE II) scores corrected for the presence and duration of major organ system failure. The predictions were not acted upon during the study. Comparing the predictions with actual hospital outcome, the doctors and nurses had a false-positive diagnosis rate for dying of between 7.7% and 16.7%, while there were no false predictions by the computer model. The patients predicted to die by the doctors and nurses were not completely identical to those predicted by the computer. Predictions of doctors and nurses that were confirmed by the computer had a sensitivity of 20% and no false predictions of death.

Decision Making, Computer-Assisted↗
PubMed1992

Heat stress in protective clothing: validation of a computer model and the heat-humidity index (HHI).

Ability to work while wearing protective clothing is often limited by rising body temperature. Peterson analyzed the combined effects of heat, humidity and workload using the Texas Model of Thermoregulation and suggested that environmental heat load imposed on a person wearing heavy, semipermeable clothing could be predicted using the Heat-Humidity Index (HHI = 0.5 Tdb + 0.5 Twb), where Tdb = dry bulb temperature and Twb = wet bulb temperature. Our study was designed to: 1) test the validity of this computer model; and 2) evaluate the applicability of the HHI to heavily clothed subjects working in a variety of thermal environments. Nine men wearing chemical defense clothing were each studied under eight conditions over the range Tdb = 20 - 40 degrees C, Tbg = Tdb + 5 degrees C, relative humidity = 9-75%, and oxygen uptake = 14-27 ml.kg-1 x min-1. Variables analyzed included tolerance time (TT), rectal temperature (Tre), skin temperature, heart rate (HR), weight loss, sweat rate, evaporation rate, and evaporative efficiency. Experiments were designed to last 30-180 min, and continued until Tre = 39 degrees C except when subjective tolerance limits occurred first (12 of 72 experiments). The observed time to reach Tre = 39 degrees C bracketed the predicted time in the more severe conditions, but the model seriously underestimated heat storage in the milder conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Acclimatization↗
PubMed2002

Elimination of a human T-cell region in staphylokinase by T-cell screening and computer modeling.

Staphylokinase is a potent highly fibrin-selective thrombolytic agent, but it induces a humoral immune response in most treated patients. Staphylokinase-specific T-lymphocytes can be found in normal healthy individuals, from whom a large panel of staphylokinase-specific T-cells were cloned. The staphylokinase amino acid sequence 71-87 was widely recognized, as it induced proliferation of T-cell clones isolated from 90% of the donors. Computer modeling of this area, threaded as 11-mer peptides within the peptide-binding groove of the major HLA-DR alleles, indicated two putative partially overlapping binding sequences. The region-(71-87)-specific T-cell clones recognized either one or the other minimal peptide, confirming that both sequences could be functional T-cell epitopes. Furthermore, to guide the mutagenesis to eliminate T-cell reactivity, the contribution of each residue to the HLA-DR-anchoring and T-cell receptor exposure was evaluated for both binding motifs. Computer calculations combined with functional assays resulted in the design of staphylokinase-variants, including 2 to 4 amino acid substitutions in the region 71-87. These variants were no longer recognized by the region-(71-87)-specific T-cell clones, and importantly no new staphylokinase-variant-specific cellular immune response could be measured.

Amino Acid Sequence↗
PubMed2001

Computer modelling and experimental evidence for two steady states in the photosynthetic Calvin cycle.

We present observations of photosynthetic carbon dioxide assimilation, and leaf starch content from genetically modified tobacco (Nicotiana tabacum) plants in which the activity of the Calvin cycle enzyme, sedoheptulose-1,7-bisphosphatase, is reduced by an antisense construct. The measurements were made on leaves of varying ages and used to calculate the flux control coefficients of sedoheptulose-1,7-bisphosphatase over photosynthetic assimilation and starch synthesis. These calculations suggest that control coefficients for both are negative in young leaves, and positive in mature leaves. This behaviour is compared to control coefficients obtained from a detailed computer model of the Calvin cycle. The comparison demonstrates that the experimental observations are consistent with bistable behaviour exhibited by the model, and provides the first experimental evidence that such behaviour in the Calvin cycle occurs in vivo as well as in silico.

Carbon Dioxide↗
PubMed1995

A computational model for the neurobiological substrates of visual attention.

Two interesting and complex tasks are performed by the brain in the process of perception: the integration of characteristics leading to an easier recognition of a pattern as a whole (binding), and the extraction of properties that need to be detailed and analyzed (attention). Attention seems to have a reciprocal relation with binding, inasmuch as the latter promotes the composition of features and their dependencies, while the former selects a single characteristic independently of the remainder. Classically, binding is viewed as a process whereby sets of properties are gathered in representative entities, which are themselves linked to form higher level structures, in a sequence that culminates in the total integration of the pattern features in a localized construct. The convergent axonal projections from one cortical area to another would be the neurobiological mechanism through which binding is achieved. Attention comprises the selective excitation of neuronal networks or pathways that stand for specific pattern properties. The thalamus and its reticular nucleus would then be the anatomical substrate of the attentional focus. In this paper we propose a computational model aiming at bringing together the main (and apparently diverging) ideas about binding and attention. Based on experimental data, a neuronal network representing cortical pyramidal cells is assembled, and its structure and function are related to the binding and attention phenomena. Actually, the convergent projections that enlarge the visual receptive field are associated to binding, while a specific change in the pyramidal cell behavior is responsible for attention. Computer simulations are shown which reproduce the electrophysiology of pyramidal cells and mimic some interesting experimental results in visual attention. We conclude by conjecturing that attention is a driven interruption in the regular process of binding.

Algorithms↗
PubMedDate not supplied

Cost-effectiveness analysis of interventions to enhance mammography compliance using computer modeling (CAN*TROL).

OBJECTIVE: Tailored telephone counseling and physician-based and clinic-based interventions have been shown to be cost-effective in enhancing utilization of mammography among nonadherent women. The objective of this study was to evaluate the costs and benefits of a broad implementation of these interventions from a health payer perspective. METHODS: CAN*TROL computer modeling was employed in the cost-effectiveness analysis of interventions in a 2000 Texas female population. The estimated effects of the various interventions and their related costs derived from the literature were applied to a hypothetical scenario of a broad implementation of these interventions. RESULTS: Seven studies were identified from the literature, six of them employed tailored telephone counseling (TC), whereas two used comprehensive physician-based (PB) or clinic-based (CB) interventions. The estimated intervention cost per women was 43 dollars for TC, 71 dollars for PB, and 151 dollars for CB. CAN*TROL model showed that after 15 years of implementation, TC, PB, and CB could reduce cancer mortality by 6.5, 2.2, and 10.7%, respectively. The cumulative net costs of interventions, mammography screening, and medical care costs were lower for TC (TC vs. PB vs. CB, 1.05 million vs. 1.06 million vs. 1.60 million). Nevertheless, CB resulted in more life-years saved (TC vs. PB vs. CB, 11,413 vs. 8515 vs. 14,559). The incremental cost-effectiveness ratio was more favorable for tailored telephone counseling interventions. One-way sensitivity analysis indicated that compliance rates and intervention costs had the most significant impact on the incremental cost-effectiveness ratio. CONCLUSION: Tailored telephone counseling interventions may be the preferred first-line intervention for getting nonadherent women aged 50 to 79 years on schedule for mammography screening.

Aged↗
PubMed1995

A computer model of uterine contractions based on discrete contractile elements.

OBJECTIVE: To predict uterine contraction waveforms using a microcomputer-based model of uterine activity based on discrete contractile elements, varying the shape of the model, total number of cells, and pacemaker locations. METHODS: The model is a hollow ovoid composed of discrete contractile elements (cells) that propagate electrical impulses, generate tension, and have defined contracting and refractory periods. Each cell contacts eight surrounding cells and propagates impulses iteratively from cell to cell. Contraction pressure is the sum of the tension contributions by contracting cells. Sample contraction waveforms were generated based on various numbers of cells organized in ovoids with long:short axis ratios of 1:1, 3:2, and 2:1, with one or two pacemakers at varying positions. RESULTS: Contraction waveforms are altered by altering the shape of the matrix, but not by increasing the number of contractile elements. The vertical placement of the pacemaker has a dramatic effect on the shape and symmetry of contractions, including the development of patterns characteristic of "dysfunctional" uterine contractions. CONCLUSION: Abnormal uterine contraction patterns may result from pacemaker activity in unusual locations, such as mid-uterus. Further refinement of this computer model of uterine activity may contribute to a better understanding of the genesis of normal and abnormal intrauterine pressure waveforms and their relationship to the progress of labor.

Computer Simulation↗
PubMed1989

A computer model for unconscious spread of anxiety-linked inhibition in cognitive networks.

Unconscious inhibitory processes, triggered by a potential anxiety reaction, are reviewed in the context of an emerging rapprochement between psychodynamic and cognitive approaches in experimental psychology. Conditions underlying spread of inhibitory action to other cognitive networks are first explored in three tachistoscopic experiments utilizing words posthypnotically tied to a potential anxiety, pleasure, or neutral reaction. Response times of subjects, instructed to ignore those words while naming pictures or solving anagrams as quickly as possible, reveal a highly differentiated pattern of circumstances governing likelihood of inhibitory spread from anxiety-linked words to target stimuli. Next a computer model is constructed to simulate cognitive processes from onset of display to eventual response, and the model is then tested for its fit to the empirical data. Finally, an illustrative study shows that a subset of computer-generated predictions for spread of inhibitory action is verifiable experimentally.

Adult↗
PubMed2026

Integrating structure and experimental data annotations with computational modeling framework for predicting micro-nanoplastics toxicities.

The wide use of plastic materials leads to increased emissions of micro-nanoplastics (MNPs) into the environment, raising significant concerns about their impact on human health. Traditional experimental approaches for assessing MNPs toxicity are costly, time-consuming, and there are no experimental protocols that are universally acceptable. Computational modeling using machine learning (ML) approaches provides an efficient alternative to MNP toxicity assessment. However, most modeling studies of MNPs are limited due to the lack of high-quality data and there are few previous modeling studies considering complex structures of MNPs for model training. To address this challenge, we constructed three MNP datasets with popular toxicity endpoints from various resources and used nanostructure annotation techniques to create virtual MNPs (vMNPs) for all MNP structures. The MNP structures were digitalized from annotated vMNPs, and geometrical descriptors were calculated using the Delaunay Tessellation approach. Moreover, important experimental information, such as concentrations and cell lines, were transformed into extra training variables. Partial least squares regression (PLSR) models were built using both experimental and geometrical descriptors and validated through a leave-one-out cross validation procedure. The resulting models showed reasonable performance in predicting toxicity potentials of MNPs for the three endpoints in the present datasets. Moreover, an additional library of vMNPs with their predicted properties and bioactivities was constructed, directing further research of new MNPs. This study provides three novel ML models for MNPs by integrating geometrical and experimental descriptors, which have the potential to assess new MNPs for their toxicity. The modeling strategy developed in this study can be easily expanded to model other MNP toxicity endpoints and create promising new models for MNP toxicity assessments.

Data annotation↗
PubMed1999

Role of feedback in mammalian vision: a new hypothesis and a computational model.

This paper presents a novel hypothesis on the function of massive feedback pathways in mammalian visual systems. We propose that the cortical feature detectors compete not for the right to represent the output at a point, but for exclusive rights to abstract and represent part of the underlying input. Feedback can do this very naturally. A computational model that implements the above idea for the problem of detection is presented and based on that we suggest a functional role for the thalamo-cortical loop during perception of lines. We show that the model successfully tackles the so called Cross problem. Based on some recent experimental results, we discuss the biological plausibility of our model. We also comment on the relevance of our hypothesis (on the role of feedback) to general sensory information processing and recognition.

Algorithms↗
PubMed2006

Esophageal temperature during radiofrequency-catheter ablation of left atrium: a three-dimensional computer modeling study.

INTRODUCTION: There is current interest in finding a way to minimize thermal injury in the esophagus during radiofrequency-catheter ablation of the left atrium. Despite the fact that the esophageal temperature is now being monitored during ablation, the influence of different anatomic and technical factors on the temperature rise remains unknown. METHODS AND RESULTS: We implemented a three-dimensional computational model that included atrial tissue, epicardial fat, esophagus, aorta, and lung, all linked by connective tissue. The finite-element method was used to calculate the esophageal temperature distribution during a procedure of constant-temperature ablation with an 8-mm electrode, under different tissue conditions. Results showed that the distance between electrode and esophagus was the most important anatomic factor in predicting the esophageal temperature rise, the composition of the different tissues being of lesser importance. The measurement of the esophageal temperature in different sites of the lumen offered differences up to 3.7 degrees C, especially for a short electrode-esophagus distance (5 mm). The difference in the convective cooling by circulating blood around electrode and endocardium did not show a significant influence on the esophageal temperature rise. CONCLUSION: Computer results suggest that (1) the electrode-esophagus distance is the most important anatomic factor; (2) the incorrect positioning of an esophageal temperature probe could give a low reading for the maximum temperature reached in the esophagus; and (3) the different cooling effect of the circulating blood flow at different atrial sites has little impact on the esophageal temperature rise.

Atrial Fibrillation↗
PubMed1997

Tuberculosis control in Asia and the western Pacific: a role for computer modelling.

Despite the availability of effective treatment, tuberculosis (TB) causes more deaths than any other infection. Most of the world's TB cases and deaths occur in Asia and the Western Pacific, and the growing prevalence of multiple drug-resistant TB and the spread of human immunodeficiency virus (HIV) present ever greater obstacles to effective TB control. The management of TB remains difficult, and epidemiologic studies to assess control programmes require significant time and expense and may not be generalizable to other regions. Computer models are powerful and relatively inexpensive tools for rapidly planning and evaluating TB control strategies. Models have demonstrated the value of targeted chemoprophylaxis strategies for the prevention of TB among HIV-infected individuals, and programmes to ensure that all HIV-infected individuals receive TB chemoprophylaxis should be considered in Asia and the Western Pacific. Though directly observed therapy (DOT) is effective when designed to be attractive to patients, modelling has shown that DOT, if poorly accepted by patients, may lead to fewer patients seeking care and thus to paradoxical rises in TB case rates. Models may be used to make accurate predictions of TB morbidity and programme costs using local epidemiologic and demographic inputs. The use of models in Asia and the Western Pacific offers a low-cost way to compare programmes, to improve the evaluation of programmes, to project future cases, and to examine programme needs while providing insights into TB control helpful to countries in and out of the region.

AIDS-Related Opportunistic Infections↗