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PubMed1999

Adsorptive control of water in esterification with immobilized enzymes. Continuous operation in a periodic counter-current reactor.

A periodic counter-current adsorptive-reactor system is developed to carry out continuous esterifications in organic solvents with immobilized enzymes. The system comprises a number of fixed-beds distributed between a reaction-adsorption zone and a regeneration zone and operated in a "merry-go-round" sequence. Water formed in the reaction is adsorbed preventing the formation of a free-water phase and deactivation of the biocatalyst. The adsorbed water is, in turn, recovered by desorption in the regeneration zone. The concept is tested experimentally on a laboratory-scale using, as a model, the esterification of isoamyl alcohol and propionic acid in hexane catalyzed by an immobilized lipase. Pure isoamyl alcohol is used as a regenerant to remove excess water from the biocatalyst. In the periodic steady-state, improvements in ester productivity greater than 50% over that achievable with a conventional fixed-bed reactor are demonstrated experimentally with just two beds in a series arrangement. Use of a water-selective adsorbent in conjunction with the biocatalyst provides further improvements by reducing accumulation of water on the enzyme. A mathematical model is also developed to predict the thermodynamic activity of water along the reactor and describe the dynamic behavior of the system. The model, based on independently developed rate and equilibrium parameters, successfully predicts the experimental behavior and provides an effective tool for scale-up and optimization.

Adsorption↗
PubMed1975

Supramolecular forms of actin from amoebae of Dictyostelium discoideum.

Actin purified from amoebae of Dictyostelium discoideum polymerizes into filaments at 24 degrees upon addition of KCl, as judged by a change in optical density at 232 nm and by electron microscopy. The rate and extent of formation of this supramolecular assembly and the optimal KCl concentrations (0.1 M) for assembly are similar to those of striated muscle actin. The apparent equilibrium constant for the monomer-polymer transition is 1.3 muM for both Dictyostelium and muscle actin. Although assembly of highly purified Dictyostelium actin monomers into individual actin filaments resembles that of muscle actin, Dictyostelium actin but not muscle actin was observed to assemble into two-dimensional nets in 10 mM CaCl2. The Dictyostelium actin also forms filament bundles which are 0.1 mum in diameter and which assemble in the presence of 5 mM MgCl2. These bundles formed from partially purified Dictyostelium actin preparations but not from highly purified preparations, suggesting that their formation may depend on the presence of another component. These actin bundles reconstituted in vitro resemble the actin-containing bundles found in situ by microscopy in many non-muscle cells.

Actins↗
PubMed1996

The metabolic productivity of the cell factory.

It is widely accepted that some performance function has been optimized during the evolution of metabolic pathways. One can study the nature of such a function by analogy with the industrial manufacturing world, in which there have been efforts over recent decades to optimize production chains, and in which it is now accepted that fluxes are not the only important system variables that determine process efficiency, because inventory turnover must also be considered. Inspired by the parallels between living cells and manufacturing factories, we propose that fluxes and transit time may have simultaneously been major targets of natural selection in the optimization of the design, structure and kinetic parameters of metabolic pathways. Accordingly we define the ratio of flux to transit time as a performance index of productivity in metabolic systems: it measures the efficiency with which stocks are administered, and facilitates comparison of a pathway in different steady states or in different tissues or organisms. For a linear chain of two enzymes, at a fixed total equilibrium constant, we have analysed the variation of flux, transit time and productivity index as functions of the equilibrium constants of the two steps. The results show that only the productivity index has a maximum, which represents a good compromise in optimizing flux and transit time. We have extended control analysis to the productivity index and derived the summation theorem that applies to it. For linear chains of different length with maximum productivity index values, the distribution of control coefficients with regard to the three parameters has a characteristic profile independent of the length of the chain. Finally, this control profile changes when other variables are optimized, and we compare the theoretical results with the control profile of the first steps of glycolysis in rat liver.

Animals↗
PubMed1988

Optimal hematologic variables for oxygen transport, including P50, hemoglobin cooperativity, hematocrit, acid-base status, and cardiac function.

The two important blood properties that affect O2 delivery are the O2 equilibrium curve (OEC) and blood viscosity with its subsequent effect on flow (cardiac output). To quantitate these properties blood OEC's were analyzed in terms of the Adair 4-step oxygenation model and the resulting parameters were used to construct a computer nomogram to reproduce the OEC at any combination of effectors that regulate P50 (pH, PCO2, and 2,3-DPG). In this way, the P50 could be changed systematically and the effects on overall O2 transport could be studied. Hematocrit-viscosity-cardiac output relationships were taken from the literature and validated using data from human subjects with various pathological states and high-altitude natives. A model was then developed, using the Bohr integration, to predict the O2 transport function of blood under a variety of conditions including exercise and hypoxia. The results indicate that the optimal hematocrit is about 43-45%, even in hypoxia. The optimal P50, however, depends on the availability of O2: a high P50 is not necessarily beneficial in hypoxia and high cardiac output states. This model and general approach should prove useful in the design of blood substitutes.

2,3-Diphosphoglycerate↗
PubMed1998

Pharmacodynamic aspects of sustained release preparations.

The sustained release (SR) mode of drug administration has certain features that have an important impact on the magnitude of the pharmacologic response: (a) it minimizes fluctuation in blood drug concentrations (i.e. between peak and trough). However, due to the pronounced non-linear relationship between drug concentration and pharmacologic effect (i.e. pharmacodynamics) the impact of this property differs considerably as a function of the shape of the pharmacodynamic profile and the position of the specific range of concentrations on the curve of this profile; (b) it produces a slow input rate which tends to minimize the body's counteraction to the drug's intervening effect on regulated physiological processes; and (c) it provides a continuous mode of drug administration. This important pharmacodynamic characteristic may produce, in certain cases, an opposite clinical effect than that attained by an intermittent (pulsatile) mode of administration of the same drug. For many drugs with non-concentration-dependent pharmacodynamics, the exposure time, rather than the AUC, is the relevant parameter and it can therefore be optimized by SR preparations. The slow input function may minimize hysteresis in cases where the site of action is not in a rapid equilibrium with the blood circulation. The pharmacodynamics of the desired effect(s) and/or adverse effect(s) may also be influenced by the site of administration, especially in cases where the drug is delivered directly to its site of action. These factors demonstrate the important influence of the mode of administration on the pharmacological and clinical outcomes. In addition, they highlight the need to include these pharmacodynamic considerations in all stages from drug development to the optimization of their clinical use.

Journal Article↗
PubMedDate not supplied

Towards understanding the mechanisms of molecular recognition by computer simulations of ligand-protein interactions.

The thermodynamic and kinetic aspects of molecular recognition for the methotrexate (MTX)-dihydrofolate reductase (DHFR) ligand-protein system are investigated by the binding energy landscape approach. The impact of 'hot' and 'cold' errors in ligand mutations on the thermodynamic stability of the native MTX-DHFR complex is analyzed, and relationships between the molecular recognition mechanism and the degree of ligand optimization are discussed. The nature and relative stability of intermediates and thermodynamic phases on the ligand-protein association pathway are studied, providing new insights into connections between protein folding and molecular recognition mechanisms, and cooperativity of ligand-protein binding. The results of kinetic docking simulations are rationalized based on the thermodynamic properties determined from equilibrium simulations and the shape of the underlying binding energy landscape. We show how evolutionary ligand selection for a receptor active site can produce well-optimized ligand-protein systems such as MTX-DHFR complex with the thermodynamically stable native structure and a direct transition mechanism of binding from unbound conformations to the unique native structure.

Animals↗
PubMed1998

Microquantification of cellular and in vitro F-actin by rhodamine phalloidin fluorescence enhancement.

Based on the enhancement of rhodamine phalloidin fluorescence after its binding to actin filaments we have developed a technique to quantify F-actin, drastically (>> 100 times) reducing consumption of the expensive fluorescent dye and sample material in comparison to previous methods. Depolymerization of F-actin is prevented by utilizing short incubation times and stabilization of the filaments by actin-binding proteins or formaldehyde. Equilibrium and kinetic mathematical models relating rhodamine fluorescence with F-actin concentrations were used to predict the optimal assay conditions. The method has been applied to measure relative and absolute F-actin concentrations in cytosolic fractions and stimulus-induced actin polymerization in neutrophils. The cells were lysed with octy1-beta-D-glucopyranoside, which is compatible with the assay due to its high critical micelle concentration. As the assay takes less than 1 h and eliminates all previously required washing or extraction steps, it is faster and much simpler than any other presented up to now for quantification of filamentous actin. Moreover, the method is unique for reliable and easy F-actin measurements in cell-free systems.

Actins↗
PubMed1991

Minimization of intermediate concentrations as a suggested optimality principle for biochemical networks. II. Time hierarchy, enzymatic rate laws, and erythrocyte metabolism.

The multiobjective problem of minimizing all intermediate concentrations is solved for a model of glycolysis, the pentose monophosphate shunt and the glutathione system in human erythrocytes. It turns out that one solution out of four obtained corresponds qualitatively to the real system. Furthermore, it is shown that for any reaction system, the mentioned optimality principle implies distinct time hierarchy in that some reactions are infinitely fast and subsist in quasi-equilibrium. Finally, the relationships to the standard method of deriving enzymatic rate laws are discussed.

Energy Metabolism↗
PubMed1999

Binding affinities of gallotannin analogs with bovine serum albumin: ramifications for polyphenol-protein molecular recognition.

A series of gallotannin analogs were prepared by chemical synthesis, and their affinity for the test-case protein bovine serum albumin was measured by equilibrium dialysis. The structure/activity data obtained suggest that the naturally occurring gallotannins, in fact, do not represent the optimal protein recognition agents amongst polyphenolated templates.

Flavonoids↗
PubMed1980

Quantitative gas chromatographic determination of two oxidized metabolites of the diuretic mefruside in human urine, plasma and red blood cells.

A gas chromatographic method is reported for the quantitative analysis of two metabolites of mefruside, viz., 5-oxo-mefruside (mefruside lactone) and its hydroxy-carboxylic acid analogue in human body fluids. Use was made of extractive methylation as the derivatization technique, and quantitation was achieved, with a suitable internal standard, by means of a nitrogen-sensitive detector. Because the two metabolites are linked chemically through a lactone-open acid equilibrium, interconversion prior to their separation had to be avoided. A pH partitioning study was performed to find optimal separation conditions. The lactone could be extracted quantitatively at pH 7.4, without any trace of co-extracted hydroxy acid. The latter was extracted either at pH 2 directly (in the case of plasma and urine), or after conversion to the lactone at pH 7.4 (in the case of red cells or whole blood). Concentrations down to 25 ng per sample of both compounds could be analysed with a standard deviation of 5%. The two metabolites of mefruside equilibrated instantaneously between red cells and plasma in vitro. At 37 degrees, the red cell/plasma concentration ratio was 20 for the lactone, but only 0.1 for the open acid compound. 5-Oxo-mefruside was able to displace mefruside from its red blood cell binding sites in vitro.

Carboxylic Acids↗
PubMed1993

Characterization of the binding and comparison of the distribution of benzodiazepine receptors labeled with [3H]diazepam and [3H]alprazolam.

The binding characteristics of [3H]diazepam and [3H]alprazolam were obtained by in vitro analysis of sections of rat brain. Dissociation, association, and saturation analyses were performed to optimize the conditions for obtaining selective labeling of benzodiazepine receptors with the two tritiated compounds. Both drugs approached equilibrium rapidly in vitro. Rosenthal analysis (Scatchard plot) of the saturation data indicated a similar finite number of receptors was being occupied by both ligands. Competition studies, using various ligands to inhibit both [3H]diazepam and [3H]alprazolam indicated that these two compounds bind to the tissue sections as typical benzodiazepine drugs and apparently do not overlap onto other subtypes of receptors. These experiments were performed by both binding assay in tissue sections and by light microscopic autoradiography. The major difference between the labeling of the two compounds is represented by the peripheral benzodiazepine sites, which are recognized by [3H]diazepam, but not occupied by [3H]alprazolam (at nanomolar concentrations). This difference was readily apparent in the autoradiograms. Other pharmacokinetic or pharmacodynamic properties must distinguish these two benzodiazepines.

Alprazolam↗
PubMed1986

Structure of viroid replicative intermediates: physico-chemical studies on SP6 transcripts of cloned oligomeric potato spindle tuber viroid.

The structure and structural transitions of transcripts of cloned oligomeric viroid were studied in physico-chemical experiments and stability calculations. Transcripts of (+) and (-) polarity, from unit up to sixfold length, were synthesized from DNA clones of the potato spindle tuber viroid (PSTV) with the SP6 transcription system. Their structural properties were investigated by optical denaturation curves, high performance liquid chromatography (HPLC), electron microscopy, sedimentation-diffusion equilibrium and velocity sedimentation. Secondary structures of the RNAs and theoretical denaturation curves were calculated using an energy optimization program. The secondary structure of lowest free energy for unit length and oligomeric transcripts is a rod-like structure similar to that of the mature circular viroids. When this structure is used as a model for calculations, there is a large degree of agreement between the theoretical and the experimental denaturation curves. At high temperatures, however, (+) strand transcripts exhibited a transition which was more stable than expected from the calculations or than was known from curves of mature viroids. This transition arises from a rearrangement of the central conserved region of viroids to a helical region of 28 stable base pairs either intermolecularly leading to bimolecular complexes, or intramolecularly giving rise to a branched secondary structure. The rearrangement could be detected by electron microscopy, HPLC, and analytical ultracentrifugation. The helical region serves to divide up the oligomeric (+) strand into structural units which may be recognized by cleavage and ligation enzymes which process the oligomeric intermediates to circular mature viroids.

Microscopy, Electron↗
PubMed1986

Measurement of lidocaine free concentration.

Since lidocaine exhibits significant variation in serum protein binding, the availability of a practical method for measuring free lidocaine concentration could contribute to the optimization of individual lidocaine dosage regimens. Fifty serum samples from patients receiving lidocaine were partitioned by ultrafiltration and equilibrium dialysis. The lidocaine concentration in the ultrafiltrate was measured using an enzyme multiplied immunoassay (EMIT) and a gas-liquid chromatographic assay (GLC). The lidocaine concentrations in dialysates and filtered retentates were measured by EMIT. Ultrafiltrate concentrations measured by EMIT correlated well with those measured by GLC (r2 = 0.77), but the EMIT results were approximately 10-20% higher than the GLC measurements (GLC = 0.09 + 0.79 EMIT). At least a portion of this difference could be attributed to minor calibrator differences. The concentrations in dialysate and filtered retentate agreed well (r2 = 0.93; filtered retentate = -0.05 + 1.12 X dialysate). The fraction free values obtained by ultrafiltration were slightly lower than those obtained by equilibrium dialysis (0.301 +/- 0.086 vs. 0.345 +/- 0.137; p less than 0.05). It can be concluded that sample partitioning with ultrafiltration and measurement of free lidocaine concentration by EMIT yields results similar to those obtained by equilibrium dialysis or a GLC assay procedure.

Chromatography, Gas↗
PubMed1976

Interaction of uteroglobin with progesterone, 5alphapregnane-3,20-dione and estrogens.

Uteroglobin was obtained from 5 day pregnant rabbits and purified to homogeneity by Sephadex G 75 and DEAE-cellulose chromatographies. Progesterone binding to uteroglobin was decreased by lyophilization and enhanced by SH-reducing agents. Dithiothreitol was more effective than dithioerythritol, and beta-mercaptoethanol was only active at 25 to 100 mM concentrations. SH-blocking agents (iodoacetate, iodoacetamide, phydroxymercuribenzoate and, dithiobisnitrobenzoic acid) inhibited binding. In the absence of SH-reducing agents only one in every 500 uteroglobin molecules bound the hormone, whereas under optimal conditions (20 mM dithiothreitol) one in every two molecules bound progesterone. There was no significant difference in equilibrium dissociation constants under these two conditions. Uteroglobin had a relatively high affinity for progesterone (KD=4.1 X 10(-7)M) but a threefold higher affinity for 5alpha-pregnane-3,20-dione (KD=1.3 X 10(-7)M). Estradiol was bound but non-specifically with a very low affinity, and its binding was not enhanced by SH-reducing agents. Hormonal specificity of binding to uteroglobin was different from that of binding to rabbit uterine progesterone receptor. Various synthetic progestagens (chlormadinone acetate, norethisterone, R5020) were bound to the latter but not to the former protein. Diethylstilbestrol had some affinity (15% of that of progesterone) for uteroglobin and no affinity for the progesterone receptor. Uteroglobin incubated in the presence or absence of cofactors (NADH and NADPH) with or without dithiothreitol did not metabolize progesterone.

Androgens↗
PubMed1990

A comprehensive model of the dynamic exchange processes during hemodialysis.

The present model for the mathematical description of exchange processes during hemodialysis includes submodels for potassium, sodium, chloride, acetate, acid-base status (with CO2, bicarbonate and H(+)-ions), water distribution, oxygen, ventilation, and the uremic catabolites urea, creatinine, and vitamin B12. For potassium, sodium and urea a 2-compartment model is used consisting of the extra- and the intracellular space. For chloride, creatinine and vitamin B12 a 3-compartment model is necessary. For the description of acetate kinetics a 1-compartment model consisting of the extracellular space is sufficient. For description of the acid-base balance the model includes three submodels for CO2, bicarbonate, and hydrogen ions. All submodels are made of eight compartments, namely the intracellular and the interstitial space as well as six spaces for the blood. The three submodels are coupled to each other by the chemical reaction of CO2 to HCO3- and a H(+)-ion. Besides this reaction the diffusive exchange between the compartments, the convective transport with the blood and the elimination through the dialyzer and the lung for the molecules and ions are considered. Because of the strong buffer capacity of plasma and intracellular proteins, the functional compartments for hydrogen ions are larger than the anatomical spaces. Also the influence of extracellular pH on the electrolyte distribution at the cell membrane has been considered. With this model, which will be adapted to the patient by more than 45 individual parameters, the mass transfer and the course of concentrations during hemodialysis therapy can be reproduced adequately. Further on the values of some unknown parameters, such as the metabolic rate for acetate in the organism, can be estimated by varying the parameters systematically for several runs of the computer simulation until the simulation results are optimally fitted to measured data.

Acid-Base Equilibrium↗
PubMed1980

Pulmonary control systems in exercise.

We reviewed the response and regulation of alveolar ventilation, chest wall mechanics, and alveolar-to-arterial gas exchange to the demands imposed by increases in tissue metabolic rate. The primary mediator of iso-capnic exercise hyperpnea remains a dilemma--with conflicting evidence presented on both sides of a "CO2 flow" humoral hypothesis versus a "neurogenic" non-humoral hypothesis. The increased expiratory flows and tidal volumes at any given level of hyperpnea are achieved at a "minimum" of increased mechanical work exerted on the lung and chest wall, owing to a control system that has multiple levels of nervous integration (from cortex to spinal motor neuron) readily accessible to a wide variety of sensory information concerning the mechanical status of the lung and respiratory muscles. The maintenance of arterial PO2 in the face of a falling CVO2 during exercise was attributed to a precise regulation over factors that limit diffusion equilibrium and intra- and interregional ventilation: perfusion distributions in the lung. Finally, we noted that the near-optimal nature of these responses and their control during exercise had many exceptions in the real world of physical exercise outside of the laboratory.

Carbon Dioxide↗
PubMed1996

[Living better and longer: a holistic approach to health].

Illness can be a signal that a person has exceeded his or her capacity to adapt to a particular situation. To remain healthy, we must learn to manage stress and know how to use energy. The public now has access to various therapeutic models of health care, including medical and psychospiritual approaches. The author discusses the holistic approach as one way of optimizing health. It is an approach that recognizes the innate tendency of the body to re-establish equilibrium when an imbalance has occurred and provides the body with the beneficial conditions necessary to regain strength and increase resistance. The healing process involves redefining one's self, values, behaviors, personal relationships and lifestyle. It is only by establishing harmonious relationships with the physical universe as well as the social and spiritual environments that authentic healing can occur. Because of our capacity to assess and heal ourselves, we have in us the power to change whatever interferes with our well-being and promote attitudes of love, harmony, forgiveness, self-acceptance, responsibility for our actions, while finding a meaning to life and joy in helping others.

Health Promotion↗
PubMed2002

Size and structure of spontaneously forming liposomes in lipid/PEG-lipid mixtures.

The optimal size and structure of spontaneous liposomes formed from lipid/polymer-lipid mixtures was calculated using a molecular mean-field theory. The equilibrium properties of the aggregate are obtained by expanding the free energy of a symmetric planar bilayer up to fourth order in curvature and composition of lipid and polymer. The expansion coefficients are obtained from a molecular theory that explicitly accounts for the conformational degrees of freedom of the hydrophobic tails of the lipid and of the polymer chains. The polar headgroup interactions are treated using the opposing forces model. The onset of stability of the symmetric planar film is obtained from the expansion up to quadratic order. For unstable planar films the equilibrium size and structure of the spherical aggregates is obtained from the second- and fourth-order terms in curvature and composition of lipid and polymer. The driving force for the formation of spontaneous vesicles is the asymmetric distribution of polymers between the inner and outer monolayer. The composition asymmetry between the two monolayers in the aggregates is much larger for the polymer component than for the lipid, and it depends upon the size of the aggregate. The smaller the aggregate, the more asymmetric the distribution of polymer and lipid. The tendency of the polymer chains to be tethered on the outer surface of the aggregate is very strong, and it limits the range of polymer loading for which spherical liposomes are stable. A very small excess of polymer loading causes small spherical micelles to be the optimal aggregates. In these cases spontaneous liposomes can form as metastable aggregates, showing as a local minima in the free energy. Even for metastable aggregates the asymmetric distribution of polymers is very large. The elastic constants of the asymmetric bilayer in the spherical aggregate are found to be the same as those that are calculated from the planar symmetric film. Therefore, the stable structure of the aggregate is not needed to determine its mechanical properties. The range of stable liposomes is very narrow in the range of molecular weights studied, which include the experimental relevant domain of aggregates used in drug delivery. It is found that the stability of the spherical aggregates results from a very fine balance between the tendency of the polymer chains and lipid tails to pack in an asymmetric spherical aggregate and the tendency of the hydrophobic-water interface to keep the area per molecule fixed. The changes in free energy per molecules that are responsible for liposome formation are very small and are very sensitive to detailed molecular properties. The theoretical description of the aggregates requires a theory capable of incorporating these detailed molecular properties. The findings are discussed in the context of vesicle formation and liposome design for drug delivery.

Biophysical Phenomena↗