Effects of ionic strength on the regulation of Na/H exchange and K-Cl cotransport in dog red blood cells.

Dog red cell membranes contain two distinct volume-sensitive transporters: swelling-activated K-Cl cotransport and shrinkage-activated Na/H exchange. Cells were prepared with intracellular salt concentration and weight percentage of cell water (%cw) varied independently by transient permeabilization of the cell membrane to cations. The dependence of transporter-mediated Na and K influxes upon %cw and upon extracellular salt concentration (c(ext)) was measured in cells so prepared. It was found that the critical value of %cw at which transporters are activated, called the set point, is similar for the two transporters, and that the set points for the two transporters decrease similarly with increasing extracellular salt concentration. These findings suggest a common mechanism of regulation of these two transporters. Cellular Na, K, and Cl concentrations were measured as functions of %cw and c(ext). Using these data together with data from the literature for other solute concentrations, empirical expressions were developed to describe the dependence of the intracellular concentrations of all significant small molecule electrolytes, and therefore the intracellular ionic strength, upon %cw and c(ext). A mechanistic model for the dependence of the set point of an individual transporter upon intracellular ionic strength is proposed. According to this model, the set point represents a critical extent of association between the transporter and a postulated soluble regulatory protein, called regulator. Model functions are presented for the calculation of the thermodynamic activity of regulator, and hence extent of regulator-transporter association, as a function of total intracellular protein concentration (or %cw) and ionic strength. The experimentally observed dependence of set point %cw on c(ext) are simulated using these functions and the empirical expressions described above, together with reasonable but not uniquely determined values of model parameters.

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Modelling heavy metal mobilisation in solid waste deposits - a predictive tool for environmental risk assessment

Water Science & Technology ◽

10.2166/wst.1999.0654 ◽

1999 ◽

Vol 39 (10-11) ◽

pp. 193-196

Author(s):

J. Petersen ◽

J. G. Petrie

Keyword(s):

Heavy Metal ◽

Solid Waste ◽

Environmental Risk ◽

Mechanistic Model ◽

Small Sample ◽

Waste Material ◽

Metal Species ◽

Model Parameters ◽

Assessment Methodology ◽

Predictive Tool

The release of heavy metal species from deposits of solid waste materials originating from minerals processing operations poses a serious environmental risk should such species migrate beyond the boundaries of the deposit into the surrounding environment. Legislation increasingly places the liability for wastes with the operators of the process that generates them. The costs for long-term monitoring and clean-up following a potential critical leakage have to be factored in the overall project plan from the outset. Thus assessment of the potential for a particular waste material to generate a harmful leachate is directly relevant for estimating the environmental risk associated with the planned disposal operation. A rigorous mechanistic model is proposed, which allows prediction of the time-dependent generation of a leachate from a solid mineral waste deposit. Model parameters are obtained from a suitably designed laboratory waste assessment methodology on a relatively small sample of the prospective waste material. The parameters are not specific to the laboratory environment in which they were obtained but are valid also for full-scale heap modelling. In this way the model, combined with the assessment methodology, becomes a powerful tool for meaningful assessment of the risks associated with solid waste disposal strategies.

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Modeling Bacterial Regrowth and Trihalomethane Formation in Water Distribution Systems

Water ◽

10.3390/w13040463 ◽

2021 ◽

Vol 13 (4) ◽

pp. 463

Author(s):

Gopinathan R. Abhijith ◽

Leonid Kadinski ◽

Avi Ostfeld

Keyword(s):

Distribution Systems ◽

Water Distribution ◽

Mechanistic Model ◽

Water Distribution Systems ◽

Sensitivity Study ◽

Operating Conditions ◽

Growth Rate Constant ◽

Model Parameters ◽

Bacterial Regrowth ◽

The Impact

The formation of bacterial regrowth and disinfection by-products is ubiquitous in chlorinated water distribution systems (WDSs) operated with organic loads. A generic, easy-to-use mechanistic model describing the fundamental processes governing the interrelationship between chlorine, total organic carbon (TOC), and bacteria to analyze the spatiotemporal water quality variations in WDSs was developed using EPANET-MSX. The representation of multispecies reactions was simplified to minimize the interdependent model parameters. The physicochemical/biological processes that cannot be experimentally determined were neglected. The effects of source water characteristics and water residence time on controlling bacterial regrowth and Trihalomethane (THM) formation in two well-tested systems under chlorinated and non-chlorinated conditions were analyzed by applying the model. The results established that a 100% increase in the free chlorine concentration and a 50% reduction in the TOC at the source effectuated a 5.87 log scale decrement in the bacteriological activity at the expense of a 60% increase in THM formation. The sensitivity study showed the impact of the operating conditions and the network characteristics in determining parameter sensitivities to model outputs. The maximum specific growth rate constant for bulk phase bacteria was found to be the most sensitive parameter to the predicted bacterial regrowth.

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Inverse mechanistic modeling of transdermal drug delivery for fast identification of optimal model parameters

10.1101/2020.12.11.420836 ◽

2020 ◽

Author(s):

Thijs Defraeye ◽

Flora Bahrami ◽

Rene M Rossi

Keyword(s):

Drug Delivery ◽

Inverse Modeling ◽

Transdermal Drug Delivery ◽

Drug Transport ◽

Mechanistic Model ◽

Mechanistic Modeling ◽

Drug Uptake ◽

Added Value ◽

Model Parameters ◽

Transdermal Drug Delivery Systems

Transdermal drug delivery systems are a key technology to administer drugs with a high first-pass effect in a non-invasive and controlled way. Physics-based modeling and simulation are on their way to become a cornerstone in the engineering of these healthcare devices since it provides a unique complementarity to experimental data and insights. Simulations enable to virtually probe the drug transport inside the skin at each point in time and space. However, the tedious experimental or numerical determination of material properties currently forms a bottleneck in the modeling workflow. We show that multiparameter inverse modeling to determine the drug diffusion and partition coefficients is a fast and reliable alternative. We demonstrate this strategy for transdermal delivery of fentanyl. We found that inverse modeling reduced the normalized root mean square deviation of the measured drug uptake flux from 26 to 9%, when compared to the experimental measurement of all skin properties. We found that this improved agreement with experiments was only possible if the diffusion in the reservoir holding the drug was smaller than the experimentally-measured diffusion coefficients suggested. For indirect inverse modeling, which systematically explores the entire parametric space, 30 000 simulations were required. By relying on direct inverse modeling, we reduced the number of simulations to be performed to only 300, so a factor 100 difference. The modeling approach's added value is that it can be calibrated once in-silico for all model parameters simultaneously by solely relying on a single measurement of the drug uptake flux evolution over time. We showed that this calibrated model could accurately be used to simulate transdermal patches with other drug doses. We showed that inverse modeling is a fast way to build up an accurate mechanistic model for drug delivery. This strategy opens the door to clinically-ready therapy that is tailored to patients.

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Surface contraction of dividing newt eggs induced by lowering the external ionic strength or pH, or by trypsinization

Journal of Cell Science ◽

10.1242/jcs.82.1.143 ◽

1986 ◽

Vol 82 (1) ◽

pp. 143-154

Author(s):

T. Kubota

Keyword(s):

Ionic Strength ◽

Conformational Changes ◽

Time Course ◽

Similar Type ◽

Vitelline Membrane ◽

Common Mechanism ◽

Surface Material ◽

Sucrose Medium ◽

Saline Medium ◽

Partial Reversal

As the first cleavage progresses, newt (Cynopus pyrrhogaster) eggs deprived of their vitelline membrane grow to expose the new, unpigmented surface to a saline medium full-strength Steinberg solution). Further exposure of these eggs to sucrose medium resulted in rapid and extensive contraction of the unpigmented surface. In the sucrose medium the contraction continued until the next cleavage, and eventually the eggs divided into many blastomeres. But partial reversal of the contraction was observed when, after brief treatment with sucrose medium, the eggs were returned to saline medium. This and other experiments indicated that the contraction was due to lowering of the extracellular ionic strength. A similar type of contraction was induced by acidification of the saline medium or by trypsinization. The contractions induced by these treatments did not absolutely require the presence of external Ca2+, had a rapid time course, and were restricted to the unpigmented region, suggesting that they had a common mechanism. Acidification of the egg cytoplasm with CO2 did not result in significant contraction. These findings, together with those of others, suggest that contraction of the unpigmented surface induced by these treatments is due to conformational changes of surface material.

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Investigation of copper adsorption to peat using the simple metal sorption model

Water Science & Technology ◽

10.2166/wst.2001.0869 ◽

2001 ◽

Vol 44 (11-12) ◽

pp. 477-483 ◽

Cited By ~ 1

Author(s):

S. Dierks

Keyword(s):

Ionic Strength ◽

Cation Exchange ◽

Proton Exchange ◽

Mass Action ◽

Model Parameters ◽

Copper Binding ◽

Metal Sorption ◽

Power Functions ◽

Simple Metal ◽

Copper Adsorption

The Simple Metal Sorption (SiMS) equilibrium model was used to simulate the proton/cation exchange behavior of peat with dissolved copper. The SiMS model represents proton binding and metal binding as cation exchange for heterogeneous sorbents as a function of pH, salt concentration, total metal concentration and total ligand concentration. The SiMS model uses fewer parameters than other cation exchange models for multidimensional datasets and can be executed on a standard spreadsheet. The cation exchange selectivity coefficient, KMe,app, is represented as KMe,app=KMe{H+}α(LT/MeT)βIphiv. The model is similar to standard surface complexation approaches, with an intrinsic relationship described by mass action laws (KMe=metal equilibrium constant) and variable terms that are expressed as simple power functions of proton concentration, ligand to metal ratio (LT/MeT), and ionic strength (I). The model successfully simulated the proton exchange behavior of acid-washed, Sphagnum peats over a range of 4 to 8 pH units with ionic strength differing by three orders of magnitude (I=0.001 to 0.1). Simulation of copper binding on five peat data sets and the dried biomass of Potamogeton lucens was also successful (0.94<r2<0.99). However, there was no apparent relationship between model parameters and peat characteristics. Incorporation of the SiMS model into a framework for predicting metals removals in wetlands will require more work.

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A computational bio-chemo-mechanical model of in vivo tissue-engineered vascular graft development

Integrative Biology ◽

10.1093/intbio/zyaa004 ◽

2020 ◽

Vol 12 (3) ◽

pp. 47-63

Author(s):

Ramak Khosravi ◽

Abhay B Ramachandra ◽

Jason M Szafron ◽

Daniele E Schiavazzi ◽

Christopher K Breuer ◽

...

Keyword(s):

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Optimal Parameter ◽

Mechanistic Model ◽

Vena Cava ◽

Model Parameters ◽

Identifiability Analysis ◽

Macrophage Activity ◽

Cost Efficient

Abstract Stenosis is the primary complication of current tissue-engineered vascular grafts used in pediatric congenital cardiac surgery. Murine models provide considerable insight into the possible mechanisms underlying this situation, but they are not efficient for identifying optimal changes in scaffold design or therapeutic strategies to prevent narrowing. In contrast, computational modeling promises to enable time- and cost-efficient examinations of factors leading to narrowing. Whereas past models have been limited by their phenomenological basis, we present a new mechanistic model that integrates molecular- and cellular-driven immuno- and mechano-mediated contributions to in vivo neotissue development within implanted polymeric scaffolds. Model parameters are inferred directly from in vivo measurements for an inferior vena cava interposition graft model in the mouse that are augmented by data from the literature. By complementing Bayesian estimation with identifiability analysis and simplex optimization, we found optimal parameter values that match model outputs with experimental targets and quantify variability due to measurement uncertainty. Utility is illustrated by parametrically exploring possible graft narrowing as a function of scaffold pore size, macrophage activity, and the immunomodulatory cytokine transforming growth factor beta 1 (TGF-β1). The model captures salient temporal profiles of infiltrating immune and synthetic cells and associated secretion of cytokines, proteases, and matrix constituents throughout neovessel evolution, and parametric studies suggest that modulating scaffold immunogenicity with early immunomodulatory therapies may reduce graft narrowing without compromising compliance.

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Fluorimetric studies on the dimerization equilibrium of protoporphyrin IX and its haemato derivative

Biochemical Journal ◽

10.1042/bj2090547 ◽

1983 ◽

Vol 209 (2) ◽

pp. 547-552 ◽

Cited By ~ 82

Author(s):

R Margalit ◽

N Shaklai ◽

S Cohen

Keyword(s):

Ionic Strength ◽

Fluorescence Quenching ◽

Fluorescence Intensity ◽

Salt Concentration ◽

Equilibrium Constants ◽

Protoporphyrin Ix ◽

Constant Ionic Strength ◽

Aggregation Process ◽

Buffer Concentration ◽

Common Anion

The aggregations of protoporphyrin IX and haematoporphyrin IX in aqueous solutions were studied by fluorimetric techniques. Porphyrin concentrations were limited to 0.001-0.1 microM and 0.01-1 microM for protoporphyrin and haematoporphyrin respectively, where dimerization is the dominant aggregation process. The dimerization equilibrium constants (at 25 degrees C, neutral pH, 50 mM-Tris/HCl buffer) were determined to be 3×10(7) M and 4×10(5) M for the proto and the haemato derivatives respectively. The fluorescence intensity of a given protoporphyrin solution (within the range indicated above) was markedly decreased by salts in the system, over the salt concentration range 0.1-7 mM at constant ionic strength, in the sequence CaCl2 greater than MgCl2 greater than KCl greater than NaCl. The direction of this effect, fluorescence quenching, suggests that these salts promote an increase in aggregation. The differences in the magnitudes of the effect, among different salt species sharing a common anion, at constant ionic strength, imply that the effect is cation-specific. In contrast, the fluorescence intensity of a given solution of haematoporphyrin (within the range indicated above) was unaffected by these salts, under similar concentrations, nor was it sensitive to the total buffer concentration, or to the type of buffer in the system.

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Regulation of Rho protein binding to membranes by rhoGDI: inhibition of releasing activity by physiological ionic conditions

Biochemistry and Cell Biology ◽

10.1139/o99-004 ◽

1999 ◽

Vol 77 (1) ◽

pp. 59-69 ◽

Cited By ~ 7

Author(s):

Diane Bilodeau ◽

Sylvie Lamy ◽

Richard R Desrosiers ◽

Denis Gingras ◽

Richard Béliveau

Keyword(s):

Ionic Strength ◽

Brush Border ◽

Rat Kidney ◽

Regulatory Protein ◽

Rho Proteins ◽

Glutathione S Transferase ◽

Free System ◽

Brush Border Membranes ◽

A Cell ◽

Membrane Bound

The Rho GDP dissociation inhibitor (GDI) is an ubiquitously expressed regulatory protein involved in the cycling of Rho proteins between membrane-bound and soluble forms. Here, we characterized the Rho solubilization activity of a glutathione S-transferase (GST) - GDI fusion protein in a cell-free system derived from rat kidney. Addition of GST-GDI to kidney brush border membranes resulted in the specific release of Cdc42 and RhoA from the membranes, while RhoB and Ras were not extracted. The release of Cdc42 and RhoA by GST-GDI was dose dependent and saturable with about 50% of both RhoA and Cdc42 extracted. The unextracted Rho proteins were tightly bound to membranes and could not be solubilized by repeated GST-GDI treatment. These results demonstrated that kidney brush border membranes contained two populations of RhoA and Cdc42. Furthermore, the GST-GDI solubilizing activity on membrane-bound Cdc42 and RhoA was abolished at physiological conditions of salt and temperature in all tissues examined. When using bead-immobilized GST-GDI, KCl did not reduced the binding of Rho proteins. However, washing brush border membranes with KCl prior treatment by GST-GDI inhibited the extraction of Rho proteins. Taken together, these results suggest that the binding of GDI to membrane-bound Cdc42 and RhoA occurs easily under physiological ionic strength conditions, but a complementary factor is required to extract these proteins from membranes. These observations suggest that the shuttling activity of GDI upon Rho proteins could be normally downregulated under physiological conditions.Key words: rhoGDI, rho proteins, ionic strength, kidney.

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Capturing variability in pavement performance models from sufficient time-series predictors: a case study of the New Brunswick road network

Canadian Journal of Civil Engineering ◽

10.1139/l10-127 ◽

2011 ◽

Vol 38 (2) ◽

pp. 210-220 ◽

Cited By ~ 7

Author(s):

Luis Esteban Amador-Jiménez ◽

Donath Mrawira

Keyword(s):

New Brunswick ◽

Mechanistic Model ◽

Model Parameters ◽

Traffic Loading ◽

Progression Model ◽

Structural Capacity ◽

Pavement Roughness ◽

Data Points ◽

Rapid Generation

This paper proposes the use of multi-level Bayesian modeling for calibrating mechanistic model parameters from historical data while capturing reliability by estimating a desired confidence interval of the predictions. The model is capable of estimating the parameters from the observed data and expert criteria even in cases of missing data points. This approach allows rapid generation of several deterioration models without the need to partition the data into pavement families. It estimates posterior distributions for model coefficients and predicts values of the response for unobserved levels of the causal factors. A case study from the New Brunswick Department of Transportation is used to calibrate a simplified mechanistic pavement roughness progression model based on 6-year international roughness index (IRI) observations. The model incorporates the effects of pavement structural capacity in terms of deflection basin parameter (AREA) in place of the modified structural number, traffic loading (ESAL) and environmental factors. The results of the model showed that, as expected, chipseal roads have higher as built roughness and deteriorate faster than asphalt roads. Sensitivity analysis of the deterministic (the mean predictions) part of the model showed that in New Brunswick where traffic is relatively low the environment is the most important factor.

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Affinity chromatography of immobilized actin and myosin

Biochemical Journal ◽

10.1042/bj1490365 ◽

1975 ◽

Vol 149 (2) ◽

pp. 365-379 ◽

Cited By ~ 31

Author(s):

R C Bottomley ◽

I P Trayer

Keyword(s):

Ionic Strength ◽

Salt Concentration ◽

Free Solution ◽

Heavy Meromyosin ◽

Chemical Modifications ◽

Low Concentrations ◽

Myosin Subfragment ◽

Myosin Subfragment 1 ◽

One Step ◽

Low Ionic Strength

Actin and myosin were immobilized by coupling them to agarose matrices. Both immobilized G-actin and immobilized myosin retain most of the properties of the proteins in free solution and are reliable over long periods of time. Sepharose-F-actin, under the conditions used in this study, has proved unstable and variable in its properties. Sepharose-G-actin columns were used to bind heavy meromyosin and myosin subfragment 1 specifically and reversibly. The interaction involved is sensitive to variation in ionic strength, such that myosin itself is not retained by the columns at the high salt concentration required for its complete solubilization. Myosin, rendered soluble at low ionic strength by polyalanylation, will interact successfully with the immobilized actin. The latter can distinguish between active and inactive fractions of the proteolytic and polyalanyl myosin derivatives, and was used in the preparation of these molecules. The complexes formed between the myosin derivatives and Sepharose-G-actin can be dissociated by low concentrations of ATP, ADP and pyrophosphate in both the presence and the absence of Mg2+. The G-actin columns were used to evaluate the results of chemical modifications of myosin subfragments on their interactions with actin. F-Actin in free solution is bound specifically and reversibly to columns of insolubilized myosin. Thus, with elution by either ATP or pyrophosphate, actin has been purified in one step from extracts of acetone-dried muscle powder.

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