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PubMed2005

Adaptation of the Folts and electrolytic methods of arterial thrombosis for the study of anti-thrombotic molecules in small animals.

INTRODUCTION: Animal preparations of arterial thrombosis play a crucial role in the discovery and validation of novel drug targets in vivo, aiding in the selection of new drugs for clinical evaluation. The Folts and electrolytic methods of arterial thrombosis are two of the most commonly used techniques to investigate drugs with novel anti-thrombotic potential. However, these techniques often involved the use of large animals such as dogs, and their application to small animals was limited. The aim of the present study was to adapt the Folts and electrolytic methods previously described in large animals to create highly reproducible, quantitative models of arterial thrombosis in mice, rats and rabbits. METHODS: Carotid artery blood flow was measured in anaesthetised mice, rats and rabbits. In the Folts-like method, a silk suture was tied around one carotid artery distal to a flow probe and tightened to cause a concentric stenosis sufficient to decrease blood flow by 50%. Intimal damage was induced by pinching the artery at the site of stenosis using forceps. The sequential formation and mechanical dislodgement of the resultant platelet-rich occlusive thrombus caused cyclic carotid artery flow reductions. In the electrolytic method in mice, a platinum hook electrode was placed distal to a flow probe on one carotid artery. The artery was clamped distally to the electrode to cause stasis and an electrical current (4 mA for 1.25 min) was applied before clamp release. This induced vascular injury resulting in occlusive thrombus (platelet- and fibrin-rich) formation. CONCLUSION: The Folts-like method of arterial thrombosis was successfully adapted for use in mice, rats and rabbits, and the electrolytic technique for use in mice. Compared with larger animals, these methods are highly reproducible and ideal for pre-clinical, cost-effective, low-cost routine screening of novel anti-thrombotic drugs.

Animals↗

PubMed2006

The effect of genome length on ejection forces in bacteriophage lambda.

A variety of viruses tightly pack their genetic material into protein capsids that are barely large enough to enclose the genome. In particular, in bacteriophages, forces as high as 60 pN are encountered during packaging and ejection, produced by DNA bending elasticity and self-interactions. The high forces are believed to be important for the ejection process, though the extent of their involvement is not yet clear. As a result, there is a need for quantitative models and experiments that reveal the nature of the forces relevant to DNA ejection. Here, we report measurements of the ejection forces for two different mutants of bacteriophage lambda, lambdab221cI26 and lambdacI60, which differ in genome length by approximately 30%. As expected for a force-driven ejection mechanism, the osmotic pressure at which DNA release is completely inhibited varies with the genome length: we find inhibition pressures of 15 atm and 25 atm, for the short and long genomes, respectively, values that are in agreement with our theoretical calculations.

Bacteriophage lambda↗

PubMed2004

Attention enhances adaptability: evidence from motion adaptation experiments.

Several previous psychophysical and neurophysiological studies have investigated the separate effects of attention and adaptation on visual processing. Here, we investigated the combined effects of attention and adaptation on motion processing by measuring the effects of spatial attention on the duration of the motion after-effect (MAE) over a wide range of stimulus contrasts. MAE duration was compared between two conditions: full-attention, subjects were required to pay attention to the adapting motion stimulus, and poor-attention, subjects performed a difficult vowel detection task at the center of gaze and ignored the adapting motion stimulus. Attention was found to increase the MAE duration by a factor of 1.4, which was approximately constant over a wide range of stimulus contrasts (3.22-80.6%). Notably, this included contrasts for which the MAE duration had reached its asymptotic value. We show that a quantitative model based on known properties of directionally selective MT neurons can explain these results by assuming that attention enhances the effects of adaptation, a phenomenon we refer to as "adaptation gain". Specifically, attending to an adapting motion stimulus shifts the semi-saturation point (C50) of the underlying contrast response function (CRF) of motion detectors roughly 1.4-fold more to the right than does ignoring that same stimulus. By enhancing the effects of adaptation in this fashion, attention is predicted to enhance the adaptability of the visual motion system.

Adaptation, Physiological↗

PubMed2004

The remote distractor effect in saccade programming: channel interactions and lateral inhibition.

We explored the dependency of the saccadic remote distractor effect (RDE) on the spatial frequency content of target and distractor Gabor patches. A robust RDE was obtained with low-medium spatial frequency distractors, regardless of the spatial frequency of the target. High spatial frequency distractors interfered to a similar extent when the target was of the same spatial frequency. We developed a quantitative model based on lateral inhibition within an oculomotor decision unit. This lateral inhibition mechanism cannot account for the interaction observed between target and distractor spatial frequency, pointing to the existence of channel interactions at an earlier level.

Adult↗

PubMed2003

School climate and implementation of the Pathways study.

BACKGROUND: Pathways was a multisite school-based study to prevent obesity in American Indian school children by encouraging healthy eating and physical activity. METHODS: Over the 3-year study, a total of 290 in-depth interviews were conducted with school administrators, food service managers, classroom teachers, and physical education instructors in all 21 intervention schools to examine support and barriers for Pathways. Analysis included qualitative assessment of key themes using NUD*IST and quantitative modeling of the impact of a school climate score on implementation of intervention components. RESULTS: Overall, teachers, food service managers, and physical education instructors were supportive of the Pathways interventions. School administration and lack of family participation were perceived barriers at some schools. Attitudes toward the program ranged from neutral to positive during the first year, with about two-thirds giving positive ratings, with greater variation in successive years. Overall, the mean score was 3.5 on a 5-point scale (1=very negative, 5=very positive). School climate score was positively associated with classroom curriculum and student exposure indices, but not with family attendance, food service, or physical activity implementation indices. The latter two indices were associated with site. CONCLUSIONS: An assessment of school climate through interviews is useful in understanding successes and failures in a school-based health intervention and can predict implementation success for some programs.

Child↗

PubMed2000

Dynamics of protein and mixed protein/surfactant adsorption layers at the water/fluid interface.

The adsorption behaviour of proteins and systems mixed with surfactants of different nature is described. In the absence of surfactants the proteins mainly adsorb in a diffusion controlled manner. Due to lack of quantitative models the experimental results are discussed partly qualitatively. There are different types of interaction between proteins and surfactant molecules. These interactions lead to protein/surfactant complexes the surface activity and conformation of which are different from those of the pure protein. Complexes formed with ionic surfactants via electrostatic interaction have usually a higher surface activity, which becomes evident from the more than additive surface pressure increase. The presence of only small amounts of ionic surfactants can significantly modify the structure of adsorbed proteins. With increasing amounts of ionic surfactants, however, an opposite effect is reached as due to hydrophobic interaction and the complexes become less surface active and can be displaced from the interface due to competitive adsorption. In the presence of non-ionic surfactants the adsorption layer is mainly formed by competitive adsorption between the compounds and the only interaction is of hydrophobic nature. Such complexes are typically less surface active than the pure protein. From a certain surfactant concentration of the interface is covered almost exclusively by the non-ionic surfactant. Mixed layers of proteins and lipids formed by penetration at the water/air or by competitive adsorption at the water/chloroform interface are formed such that at a certain pressure the components start to separate. Using Brewster angle microscopy in penetration experiments of proteins into lipid monolayers this interfacial separation can be visualised. A brief comparison of the protein adsorption at the water/air and water/n-tetradecane shows that the adsorbed amount at the water/oil interface is much stronger and the change in interfacial tension much larger than at the water/air interface. Also some experimental data on the dilational elasticity of proteins at both interfaces measured by a transient relaxation technique are discussed on the basis of the derived thermodynamic model. As a fast developing field of application the use of surface tensiometry and rheometry of mixed protein/surfactant mixed layers is demonstrated as a new tool in the diagnostics of various diseases and for monitoring the progress of therapies.

Adsorption↗

PubMed2004

Pretumor progression: clonal evolution of human stem cell populations.

Multistep carcinogenesis through sequential cycles of mutation and clonal succession is usually described as tumor progression, or the clonal evolution of tumor cell populations. However, many mutations found in cancers are also compatible with normal appearing phenotypes and therefore genetic progression may precede tumor progression. To better characterize such pretumor progression (mutations in the absence of visible phenotypic changes), a quantitative model was developed that postulates most oncogenic cancer mutations first accumulate in normal appearing colon crypt niche stem cells. Each crypt contains multiple stem cells, and random niche stem cell loss with replacement eventually leads to the loss of all stem cell lineages except one. This niche succession or crypt clonal evolution is similar to the clonal succession of tumor progression except it does not require selection or change visible phenotype. Mutations may sequentially accumulate during stem cell clonal evolution either through drift (passenger mutations) or selection. To determine the feasibility of pretumor progression, mutation rates sufficient to recreate the epidemiology of colorectal cancer were estimated. Pretumor progression may completely substitute for visible tumor progression because it is theoretically possible for all cancer mutations to first accumulate in normal appearing colon with normal replication fidelity. Elevated mutation rates or tumorigenesis may be unnecessary for early progression.

Adult↗

PubMed2002

Safe, highly selective use of pulmonary artery catheters in coronary artery bypass grafting: an objective patient selection method.

BACKGROUND: Routine versus selective use of pulmonary artery catheter (PAC) monitoring in coronary artery bypass grafting operations is a topic of significant debate. Accordingly, we retrospectively examined operative outcomes in 2,685 consecutive (1994 to 1998) coronary artery bypass grafting patients in whom PAC use was highly selective. Next, we developed a quantitative model of PAC use in terms of its multivariate predictors as a means of providing an objective criterion for patient PAC use selection. METHODS: Safety of the implemented selective PAC use was assessed by comparisons to contemporaneous coronary artery bypass grafting outcome reported by The Society of Thoracic Surgeons' national data. Continuous relations describing PAC use in terms of continuous univariate predictors were obtained using overlapping-range patient cohorts. Next, independent predictors of PAC use were derived by multivariate regression to best fit the categorical variable PAC (Yes = 1, No = 0). Model estimates were a continuous variable (PAC score) with values between 0 and 1. RESULTS: Planned use of PAC was based on collective consideration of preoperative patient variables, and was not limited to low-risk or preserved ejection fraction patients. Planned and unplanned use of PAC was limited to 176 (planned, 6.6%) and 66 (unplanned, 2.4%) patients, respectively, whereas no PAC was used in 2,443 (91%). Overall patient characteristics and risk factors in this series were comparable to contemporaneous Society of Thoracic Surgeons data, and the incidence of operative deaths was 2.31% (n = 61; observed-to-expected [Society of Thoracic Surgeons risk] mortality = 0.73). Independent predictors of PAC use were ejection fraction, Society of Thoracic Surgeons risk, intraaortic balloon pump, congestive heart failure, reoperative surgery, and New York Heart Association class IV. Expectedly, PAC scores were substantially different for PAC (mean +/- standard deviation, 0.37 +/- 0.20; median, 0.38) and no PAC (0.14 +/- 0.11; median, 0.10) patients (p < 0.001). Area under the receiver operating characteristic curve derived for PAC score was relatively high (area, 0.85). Moreover, the corresponding summed sensitivity (0.68 to 0.91) and specificity (0.85 to 0.62) was maximized at 1.53 for PAC score between 0.15 and 0.31. CONCLUSIONS: Our results indicate that highly selective use of PAC in coronary artery bypass grafting can be accomplished safely, and it need not be limited to patients with preserved ejection fractions or low operative risk. Indeed, coronary artery bypass grafting without PAC may be preferable in the vast majority of patients as it reduces catheter-associated risks and resource utilization without incurring an increased operative risk. Also, pending further prospective confirmation, our analysis suggests that collective consideration of PAC use predictors to derive a PAC score provides an objective criterion to minimize unnecessary use of PAC with an acceptably low probability of error.

Aged↗

PubMed2003

Condensed complexes of cholesterol and phospholipids.

There is overwhelming evidence that lipid bilayer regions of animal cell membranes are in a liquid state. Quantitative models of these bilayer regions must then be models of liquids. These liquids are highly non-ideal. For example, it has been known for more than 75 years that mixtures of cholesterol and certain phospholipids undergo an area contraction or condensation in lipid monolayers at the air-water interface. In the past 3 years, a thermodynamic model of "condensed complexes" has been proposed to account for this non-ideal behavior. Here we give an overview of the model, its relation to other models, and to modern views of the properties of animal cell membranes.

Animals↗

PubMed2000

How yeast cells synchronize their glycolytic oscillations: a perturbation analytic treatment.

Of all the lifeforms that obtain their energy from glycolysis, yeast cells are among the most basic. Under certain conditions the concentrations of the glycolytic intermediates in yeast cells can oscillate. Individual yeast cells in a suspension can synchronize their oscillations to get in phase with each other. Although the glycolytic oscillations originate in the upper part of the glycolytic chain, the signaling agent in this synchronization appears to be acetaldehyde, a membrane-permeating metabolite at the bottom of the anaerobic part of the glycolytic chain. Here we address the issue of how a metabolite remote from the pacemaking origin of the oscillation may nevertheless control the synchronization. We present a quantitative model for glycolytic oscillations and their synchronization in terms of chemical kinetics. We show that, in essence, the common acetaldehyde concentration can be modeled as a small perturbation on the "pacemaker" whose effect on the period of the oscillations of cells in the same suspension is indeed such that a synchronization develops.

Glycolysis↗

PubMed2003

Distinctive modulatory effects of five human auxiliary beta2 subunit splice variants on L-type calcium channel gating.

Sequence analysis of the human genome permitted cloning of five Ca(2+)-channel beta(2) splice variants (beta(2a)-beta(2e)) that differed only in their proximal amino-termini. The functional consequences of such beta(2)-subunit diversity were explored in recombinant L-type channels reconstituted in HEK 293 cells. Beta(2a) and beta(2e) targeted autonomously to the plasma membrane, whereas beta(2b)-beta(2d) localized to the cytosol when expressed in HEK 293 cells. The pattern of modulation of L-type channel voltage-dependent inactivation gating correlated with the subcellular localization of the component beta(2) variant-membrane-bound beta(2a) and beta(2e) subunits conferred slow(er) channel inactivation kinetics and displayed a smaller fraction of channels recovering from inactivation with fast kinetics, compared to beta(2b)-beta(2d) channels. The varying effects of beta(2) subunits on inactivation gating were accounted for by a quantitative model in which L-type channels reversibly distributed between fast and slow forms of voltage-dependent inactivation-membrane-bound beta(2) subunits substantially decreased the steady-state fraction of fast inactivating channels. Finally, the beta(2) variants also had distinctive effects on L-type channel steady-state activation gating, as revealed by differences in the waveforms of tail-activation (G-V) curves, and conferred differing degrees of prepulse facilitation to the channel. Our results predict important physiological consequences arising from subtle changes in Ca(2+)-channel beta(2)-subunit structure due to alternative splicing and emphasize the utility of splice variants in probing structure-function mechanisms.

Adaptation, Physiological↗

PubMed2004

Asymmetry in the F1-ATPase and its implications for the rotational cycle.

ATP synthase uses a rotary mechanism to carry out its cellular function of manufacturing ATP. The central gamma-shaft rotates inside a hexameric cylinder composed of alternating alpha- and beta-subunits. When operating in the hydrolysis direction under high frictional loads and low ATP concentrations, a coordinated mechanochemical cycle in the three catalytic sites of the beta-subunits rotates the gamma-shaft in three 120 degrees steps. At low frictional loads, the 120 degrees steps alternate with three ATP-independent substeps separated by approximately 30 degrees. We present a quantitative model that accounts for these substeps and show that the observed pauses are due to 1), the asymmetry of the F(1) hexamer that produces a propeller-like motion of the power-stroke and 2), the relatively tight binding of ADP to the catalytic sites.

Adenosine Triphosphate↗

PubMed1983

Alamethicin-induced current-voltage curve asymmetry in lipid bilayers.

We have examined the causes of the asymmetry of the current-voltage curve induced by addition of alamethicin to one side of a black lipid membrane. We find that the alamethicin-induced current-voltage (I-V) curve has an inherent asymmetry. If it were possible to confine all alamethicin molecules to one side of the membrane, the I-V curve would exhibit a positive branch (voltage being measured with respect to the side of the membrane trans to the alamethicin addition) of steeper logarithmic slope than the negative branch and at a lower absolute value of potential. This condition is not usually realized, however, because alamethicin can leak through the membrane, so that, except at very high alamethicin concentrations and in certain kinds of membranes, the positive branch of the current-voltage curve has the same logarithmic slope as the negative branch and appears to arise from alamethicin which diffuses from the cis to the trans side of the membrane. We develop simple quantitative models for these two cases.

Alamethicin↗

PubMed1985

Compartmentalization of the submembrane calcium activity during calcium influx and its significance in transmitter release.

Quantitative modeling indicates that, in presynaptic terminals, the intracellular calcium concentration profile during inward calcium current is characterized by discrete peaks of calcium immediately adjacent to the calcium channels. This restriction of intracellular calcium concentration suggests a remarkably well specified intracellular architecture such that calcium, as a second messenger, may regulate particular intracellular domains with a great degree of specificity.

Animals↗

PubMed1995

Three-dimensional reconstruction of fibrin clot networks from stereoscopic intermediate voltage electron microscope images and analysis of branching.

Fibrin polymerizes to produce branching fibers forming a three-dimensional network, which has been difficult to visualize by conventional microscopy. Three-dimensional images of whole clots at high resolution were obtained from stereo-pair intermediate-voltage electron micrographs. Computer software was developed to produce three-dimensional reconstructions of the networks in the form of a pattern of links that connect branching junctions. Network parameters were measured and analyzed to characterize the clots quantitatively. Models in which all links were moved to the origin, while preserving their orientation, allowed visualization of some network parameters and facilitated comparison of networks. Fibrin clots formed in three different conditions were analyzed and compared by these methods. Clots formed in 0.20 M saline buffer consist of fibers of uniform size, and most of the branching junctions consist of three links. Fibrin clots formed in 0.05 M saline buffer are made up of very large diameter fiber bundles with far fewer branching junctions and correspondingly longer links. Clots formed in 0.40 M saline buffer consist of very fine fibers with numerous branching junctions and very short links. In summary, the extent of lateral aggregation is directly related to the distance between branching junctions and inversely related to the total number of branching junctions. These observations must be considered in defining possible mechanisms of fibrin branching.

Biophysical Phenomena↗

PubMed1997

Theoretical considerations on the role of membrane potential in the regulation of endosomal pH.

Na+,K(+)-ATPase has been observed to partially inhibit acidification of early endosomes by increasing membrane potential, whereas chloride channels have been observed to enhance acidification in endosomes and lysosomes. However, little theoretical analysis of the ways in which different pumps and channels may interact has been carried out. We therefore developed quantitative models of endosomal pH regulation based on thermodynamic considerations. We conclude that 1) both size and shape of endosomes will influence steady-state endosomal pH whenever membrane potential due to the pH gradient limits proton pumping, 2) steady-state pH values similar to those observed in early endosomes of living cells can occur in endosomes containing just H(+)-ATPases and Na+,K(+)-ATPases when low endosomal buffering capacities are present, and 3) inclusion of active chloride channels results in predicted pH values well below those observed in vivo. The results support the separation of endocytic compartments into two classes, those (such as early endosomes) whose acidification is limited by attainment of a certain membrane potential, and those (such as lysosomes) whose acidification is limited by the attainment of a certain pH. The theoretical framework and conclusions described are potentially applicable to other membrane-enclosed compartments that are acidified, such as elements of the Golgi apparatus.

Buffers↗

PubMed1999

Correlation of serum triglyceride and its reduction by omega-3 fatty acids with lipid transfer activity and the neutral lipid compositions of high-density and low-density lipoproteins.

Serum triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) concentrations are inversely correlated and mechanistically linked by means of lipid transfer activities. Phospholipid transfer activity (PLTA) moves phospholipids among serum lipoproteins; cholesteryl ester transfer activity (CETA), which exchanges cholesteryl esters (CE) and TG among lipoproteins, is stimulated by nonesterified fatty acids (NEFA). The aims of this study were (a) to develop a quantitative model that correlates the neutral lipid (NL = CE + TG) compositions of HDL and LDL with serum TG concentration; (b) identify the serum lipid determinants of CETA and PLTA, and; (c) identify the effects of serum TG reductions on the neutral lipid compositions of HDL and LDL, serum NEFA concentrations, and on PLTA and CETA. These aims were addressed in 40 hypertriglyceridemic subjects before and after treatment with an 85% concentrate of omega-3 fatty acids (Omacor) and in 16 untreated normolipidemic subjects. In vivo, the NL compositions of LDL and HDL were described by a mathematical model having the form of adsorption isotherms: HDL - (TG/NL) = (0.90 +/- 0.07) serum TG/(7.0 +/- 1.2 mmol/l + serum TG) and LDL - (TG/NL) = (0.65 +/- 0.08) serum TG/(4.9 +/- 1.5 mmol/l + serum TG). Reduction of serum TG was associated with reductions in HDL - (TG/NL), serum NEFA concentration, and serum CETA but not PLTA. These data suggest that both hypertriglyceridemia and the attendant elevated serum CETA but not PLTA are determinants of HDL and LDL composition and structure and that serum TG concentrations are good predictors of the NL compositions of HDL and LDL.

Adolescent↗

PubMed1987

Time-related factors in quantitative risk assessment.

In regulatory or decision-making contexts related to carcinogenic hazards, one would like to know the extra risks associated with various levels, durations, and ages of exposure to a carcinogen. To supply that information, quantitative risk assessments are required that make extrapolations on variables related to dose levels, timing of exposure, and age. Quantitative models that express age-specific mortality rates as functions of the exposure pattern and that allow such extrapolations to be made are presented. The uncertainty inherently associated with those extrapolations is discussed and is found to be exacerbated by small data sets and inadequate data availability. Specific examples are provided that involve asbestos-induced mesothelioma and leukemia caused by benzene exposure.

Actuarial Analysis↗