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PubMed1992

The interplay of temperature and protons in the modulation of oxygen binding by squid blood.

An extensive set of data relating to the binding of oxygen by haemocyanin from the squid Todarodes sagittatus has been collected under various experimental conditions. The results obtained show that, within the range of physiological pH, the concentration of protons affects mainly the high-affinity state of the molecule without significantly affecting the low-affinity state. As far as the effect of temperature is concerned, the data show a characteristic feature which is very similar to that previously described in the case of haemoglobins from Arctic mammals such as reindeer (Rangifer tarandus) and musk ox. (Ovibos moschatus). The shape of the oxygen equilibrium curve shows strong temperature-dependence, since the overall heat of the binding of oxygen to the low-affinity state of the molecule is strongly exothermic and that to the high-affinity state is very close to zero. The results provide an outline of the intramolecular compromise that, through the interplay of temperature and protons, optimizes the loading and unloading of oxygen under the various environmental conditions experienced by this species of squid.

Animals↗
PubMed1998

Cooperation and self-interest: Pareto-inefficiency of Nash equilibria in finite random games.

The relative merits of cooperation and self-interest in an ensemble of strategic interactions can be investigated by using finite random games. In finite random games, finitely many players have finite numbers of actions and independently and identically distributed (iid) random payoffs with continuous distribution functions. In each realization, players are shown the values of all payoffs and then choose their strategies simultaneously. Noncooperative self-interest is modeled by Nash equilibrium (NE). Cooperation is advantageous when a NE is Pareto-inefficient. In ordinal games, the numerical value of the payoff function gives each player's ordinal ranking of payoffs. For a fixed number of players, as the number of actions of any player increases, the conditional probability that a pure strategic profile is not pure Pareto-optimal, given that it is a pure NE, apparently increases, but is bounded above strictly below 1. In games with transferable utility, the numerical payoff values may be averaged across actions (so that mixed NEs are meaningful) and added across players. In simulations of two-player games when both players have small, equal numbers of actions, as the number of actions increases, the probability that a NE (pure and mixed) attains the cooperative maximum declines rapidly; the gain from cooperation relative to the Nash high value decreases; and the gain from cooperation relative to the Nash low value rises dramatically. In the cases studied here, with an increasing number of actions, cooperation is increasingly likely to become advantageous compared with pure self-interest, but self-interest can achieve all that cooperation could achieve in a nonnegligible fraction of cases. These results can be interpreted in terms of cooperation in societies and mutualism in biology.

Journal Article↗
PubMed2006

Ligation of the hairpin ribozyme in cis induced by freezing and dehydration.

Although reducing the temperature slows most chemical reactions, freezing can stimulate some reactions by mechanisms that are only partially understood. Here we show that freezing stimulates the self-ligation (circularization) of linear forms of the hairpin ribozyme (HPR) containing 2',3'-cyclic phosphate and 5'-OH termini. Divalent metal ions (M2+) are not required, but monovalent cations and anions at millimolar concentrations can have various effects on this reaction depending on the specific ion. Under optimal conditions, the observed rate of M2+-independent self-ligation reaches a peak (0.04 min(-1)) at -10 degrees C with a yield of -60% after 1 h. In contrast, no ligation occurs either at above 0 degrees C or in solutions that remain unfrozen when supercooled to subzero temperatures. Under freezing conditions, the cleavage-ligation equilibrium strongly favors ligation. Besides freezing, evaporation of the aqueous solvent as well as the presence of ethanol at levels of 40% or above can also induce M2+-independent HPR ligation at 25 degrees C. We argue that partial RNA dehydration, which is a common feature of freezing, evaporation, and the presence of ethanol, is a key factor supporting HPR ligation activity at both above- and below-freezing temperatures. In the context of the RNA world hypothesis, freezing-induced ligation is an attractive mechanism by which complex RNAs could have evolved under conditions in which RNA was relatively protected against degradation.

Base Sequence↗
PubMed2003

Dynamics of cryoprotectant permeation in porcine heart valve leaflets.

Valve replacement is a common cardiovascular procedure for the treatment of a variety of congenital and acquired defects. Many surgical programs rely on cryopreserved heart valves from regional tissue bank programs to meet clinical demands. Current cryopreservation strategies for heart valves are empirically derived. The aim of this study was to use proton nuclear magnetic resonance spectroscopy (NMR) to monitor changes in cryoprotectant concentration in isolated heart valve leaflets. Porcine aortic valves were locally obtained, freshly isolated, and allowed to equilibrate at various experimental temperatures (22 degrees C, 10 degrees C, 4 degrees C) for 1 h prior to immersion in 1 M Me2SO solution. At defined intervals (0, 0.25, 0.5, 1, 2, 6, and 24 h) the valves were removed from the Me2SO and the leaflets were rapidly dissected and equilibrated in deuterium oxide (D2O). Using previously described techniques the Me2SO concentration in the heart valve leaflets was determined by NMR and the diffusion coefficient was calculated as a function of time and temperature. Heart valve leaflets were fully equilibrated with Me2SO after approximately 2 h of exposure at 22 degrees C while equilibrium was not reached >6 h or more at 10 degrees C and 4 degrees C. These results indicate that that permeation of Me2SO in heart valves is strongly temperature dependent Furthermore, this study provides a quantitative measure of Me2SO permeation and cryoprotectant at equilibration in heart valve leaflets. The clinical applications of these findings may help to optimize the balance between the protective and toxic effects of cryoprotectants and lead to improved methods of preservation of heart valves.

Animals↗
PubMed1992

HLA-DQa allelic frequencies detected with PCR in a variety of human populations.

Polymerase chain reaction (PCR) amplification and oligonucleotide probe hybridization may be used to detect DNA polymorphisms rapidly in large samples. In this study, 475 individuals from thirteen human populations were allelotyped at the human leukocyte antigen (HLA) DQa (DQA1) locus. A 242 or 239 bp fragment was amplified from each individual's DNA. Each of six alleles was detected by hybridization to allele specific oligonucleotide probes (ASOs). Allelic frequencies varied between populations, but the measure of gene frequency variation among populations, the FST value, was relatively low. Most populations had genotypic frequencies in agreement with Hardy-Weinberg equilibrium expectations. Principal component analysis was performed on the populations, and results are presented in graphic form. The heterozygosity at this locus is high in all populations; the average (74%) is close to the theoretical maximum (83%) for a 6 allele system. It is likely that this system is affected by stabilizing selection, which makes it less than optimal for the study of random evolutionary divergence between populations.

Alleles↗
PubMed1988

Diagnostic value of stress radionuclide angiography in coronary artery disease: a comparison of different interpretation criteria.

In order to compare different criteria in the interpretation of stress radionuclide angiography (SRNA) 96 patients with suspected coronary artery disease (CAD) were investigated by both SRNA and coronary arteriography. The result of coronary arteriography was taken as the gold standard for the diagnosis of CAD. Left ventricular ejection fraction (LVEF) was measured at each step of the stress study using the equilibrium radionuclide technique. The diagnostic value of eight interpretation criteria based on the evolution of global LVEF during stress were compared with each other, using the ROC technique. The best diagnostic criterion proved to be the normalized increase of LVEF proposed by Goris. The most commonly used criteria, LVEF increase and LVEF measured at maximal exercise, were not optimal. In the whole population of patients, the best criterion had a sensitivity of 85% for a specificity of 80% and a specificity of 83% for a sensitivity of 80%. In the population, following exclusion of patients with preceding myocardial infarction, the specificity was 74% for a sensitivity of 80% and a sensitivity of 74% for a specificity of 80%. Thus, the choice of interpretation criteria is very important in order to optimize the sensitivity and specificity of this diagnostic test.

Angina Pectoris↗
PubMedDate not supplied

Factors influencing vascular and hepatic enhancement at CT: experimental study on injection protocol using a canine model.

PURPOSE: The purpose of this work was to evaluate the effects of contrast medium injection parameters on aortic, portal vein, and hepatic enhancement at spiral CT and to assess optimal injection protocol for hepatic CT. METHOD: Ten 15 kg dogs underwent single level dynamic CT through the hepatic hilum at 5 s intervals just after the injection of contrast medium for 3 min. With use of different volumes (1, 2, and 3 ml/kg), injection rates (0.5, 1, and 2 ml/s), and concentrations (150, 200, and 300 mg/ml), a total of 270 spiral CT scans were performed. In each scan, time-attenuation curves of aorta, portal vein, and liver were obtained. The degree of maximum contrast enhancement (Imax), time to maximum enhancement (Tmax), and time to equilibrium phase (Teq) for to each injection protocol were analyzed. RESULTS: Alterations in contrast material volume, injection rate, and concentration had significant impact on contrast enhancement of the liver. With increasing volume of contrast medium, Imax, Tmax, and Teq of aorta, portal vein, and liver increased (p < 0.005). With increasing rate of injection, on the other hand, Imax of aorta and liver increased (p < 0.05), but Tmax and Teq decreased (p < 0.005). Change of concentration of contrast medium had a significant effect on Imax of vessels (p < 0.05). CONCLUSION: Maximum contrast enhancement of liver and vessels was influenced mainly by injection volume of contrast medium and the time to peak enhancement by injection rate of contrast medium. Under given amounts of contrast medium, therefore, the strategy of increasing volume by dilution and faster injection might give better Imax values without penalty for the duration of an optimal temporal window (Tmax and Teq).

Animals↗
PubMed2005

Blood lactate removal during recovery at various intensities below the individual anaerobic threshold in triathletes.

AIM: Optimal lactate removal was reported to occur at work-rate between 30% and 70% VO2max. However, it has been recently recommended to quantify exercise intensity not in percentage of VO2max but in relation to validated metabolic reference points such as the individual anaerobic threshold (IAT) and the individual ventilatory threshold (IVT). The purpose of this study was to examine the effect on lactate removal of different recovery work-rates below the IAT defined calculating the difference (DT) between IAT and IVT, then choosing the IVT+50%DT, the IVT and the IVT-50%DT work-rates. METHODS: Eight male triathletes (VO2max 69.7+/-4.7, VO2IAT 52.9+/-4, VO2IVT 41.1+/-4.7 mL x kg(-1) x min(-1)), after a 6-min treadmill run at 75% of difference between IAT and VO2max, performed in a random order the following 30-min recovery treatments: 1) run at IVT(plus;50%DT), 2) at IVT, 3) at IVT(-50%DT), 4) passive. Blood lactate was measured at 1, 3, 6, 9, 12, 15, 20, 25, 30 minutes of recovery. RESULTS: All active recovery work-rates (from 50+/-5% to 67+/-4% VO2max) were within the range previously reported for optimal lactate removal, and significantly more efficient than passive recovery on lactate removal curve (% of accumulated lactate above rest value). However, significant differences (P<0.01) were found among active recovery intensities: the IVT(-50%DT) was the most efficient work-rate from the 9th minute to 30th minute. CONCLUSIONS: In triathletes, the IVT(-50%DT) was the optimal work-rate for lactate removal; moreover none of the studied active work-rate showed further lactate decrease after the 20th minute of recovery.

Acid-Base Equilibrium↗
PubMed2005

Determination of nucleic acids based on shifting the association equilibrium between tetracarboxy aluminum phthalocyanine and poly-lysine.

A new method based on near-infrared (near-IR) fluorescence recovery was presented for the determination of nucleic acids. This method employed a two-reagent system composed of anionic tetracarboxy aluminum phthalocyanine (AlC4Pc) and polycationic poly-lysine. The fluorescence of AlC4Pc, with the maximum excitation and emission wavelengths at 620 and 701 nm, respectively, was quenched by poly-lysine with a proper concentration, but recovered by adding nucleic acids. Under optimal conditions, the recovered fluorescence was in proportional to the concentration of nucleic acids. The linear ranges of the calibration curves were 5-200 ng mL(-1) for both calf thymus DNA (ctDNA) and fish sperm DNA (fsDNA) with the detection limit of 2.6 ng mL(-1) for ctDNA and 2.1 ng mL(-1) for fsDNA. The relative standard deviation (n = 6) was 1.9 and 1.3% for 50 ng mL(-1) ctDNA and fsDNA, respectively. The proposed method was applied to the determination of nucleic acids in synthetic samples with satisfactory results.

Animals↗
PubMedDate not supplied

Accelerated biocatalyst stability testing for process optimization.

The deactivation of protein biocatalysts even at relatively low temperatures is one of the principal drawbacks to their use. To aid in the development of novel biocatalysts, we have derived an equation for both time- and temperature-dependent activity of the biocatalyst based on known concepts such as transition state theory and the Lumry-Eyring model. We then derived an analytical solution for the total turnover number (ttn), under isothermal operation, as a function of the catalytic constant kcat, the unfolding equilibrium constant K, and the intrinsic first-order deactivation rate constant(s) k(d,i). Employing an immobilized glucose isomerase biocatalyst in a CSTR and utilizing a linear temperature ramp beyond the Tm of the enzyme, we demonstrate an accelerated method for extracting the thermodynamic and kinetic constants describing the biocatalyst system. In addition, we demonstrate that the predicted biocatalyst behavior at different temperatures and reaction times is consistent with the experimental observations.

Aldose-Ketose Isomerases↗
PubMed2004

Optimization of effective atom centered potentials for london dispersion forces in density functional theory.

We add an effective atom-centered nonlocal term to the exchange-correlation potential in order to cure the lack of London dispersion forces in standard density functional theory. Calibration of this long-range correction is performed using density functional perturbation theory and an arbitrary reference. Without any prior assignment of types and structures of molecular fragments, our corrected generalized gradient approximation density functional theory calculations yield correct equilibrium geometries and dissociation energies of argon-argon, benzene-benzene, graphite-graphite, and argon-benzene complexes.

Biopolymers↗
PubMed2001

The role of ecotin dimerization in protease inhibition.

Ecotin is a homodimeric protein from Escherichia coli that inhibits many serine proteases of the chymotrypsin fold, often with little effect from the character or extent of enzyme substrate specificity. This pan-specificity of inhibition is believed to derive from formation of a heterotetrameric complex with target proteases involving three types of interface: the dimerization interface, a primary substrate-like interaction, and a smaller secondary interaction between the partner ecotin subunit and the protease. A monomeric ecotin variant (mEcotin) and a single-chain ecotin dimer (scEcotin) were constructed to study the effect of a network of protein interactions on binding affinity and the role of dimerization in broad inhibitor specificity. mEcotin was produced by inserting a beta-turn into the C-terminal arm, which normally exchanges with the other subunit. While the dimerization constant (K(dim)) of wild-type (WT) ecotin was found to be picomolar by subunit exchange experiments using FRET and by association kinetics, mEcotin was monomeric up to 1 mM as judged by gel filtration and analytical centrifugation. A crystal structure of uncomplexed mEcotin to 2.0 A resolution verifies the design, showing a monomeric protein in which the C-terminal arm folds back onto itself to form a beta-barrel structure nearly identical to its dimeric counterpart. The kinetic rate constants and equilibrium dissociation constants for monomeric and dimeric ecotin variants were determined with both trypsin and chymotrypsin. The effect of the secondary binding site on affinity was found to vary inversely with the strength of the interaction at the primary site. This compensatory effect yields a nonadditivity of up to 5 kcal/mol and can be explained in terms of the optimization of binding orientation. Such a mechanism of adaptability allows femtomolar affinities for two proteases with very different specificities.

Bacterial Proteins↗
PubMed1989

Quantitative analysis of histochemical and immunohistochemical reactions in skeletal muscle fibres of Rana and Xenopus.

Intensities of histochemical and immunohistochemical reactions in muscle fibres of Rana and Xenopus have been estimated microphotometrically, and the data from serial sections statically analysed. Quantitative validities of reactions and measurements have also been assessed against independent published evidence. It is concluded that NADH-tetrazolium reductase overestimates tonic-fibre aerobic capacities and the actomyosin ATPase reaction overestimates their contraction speeds. However, it appears that succinate dehydrogenase, despite being a near-equilibrium enzyme of particulate distribution, indicates the relative aerobic capacities of fibres with acceptable accuracy when lightly reacted. Capacities for aerobic and anaerobic metabolism are positively correlated over all types of fibre (r typically approximately 0.6 for 200 fibres), perhaps as an adaptation to environmental hypoxia. Multivariate clusters (indicating fibre types) have been sought, using Ward's method with optimizing procedures (iterative relocation and multivariate-normal modelling). Cluster analysis confirms the subjective identifications of two 'slow/tonic' types in Xenopus (labelled T5 and S4) but of only one (T5) in Rana. Division of the 'fast family' twitch fibres into three types (F1-F3) in both genera, with metabolic capacity related inversely to apparent shortening velocity, is highly supportable by objective criteria. However, statistically significant subdivisions also present themselves. Rana F2 and Xenopus F1 clusters can be bisected according to metabolic capacity; and Xenopus F2 fibres fall into three subtypes reflecting different isomyosin contents. In the different types of twitch fibre, ratios of myofibrillar ATP consumption rate to aerobic capacity increase up to 30-fold with contraction speed, but anaerobic/aerobic ratios do so only 5-fold.

Animals↗
PubMed1982

Nitrogen sparing effects and mechanisms of branched-chain amino acids in the injured rat.

A series of experiments in a rat injury model were designed to elucidate the role and mechanisms of branched-chain amino acids in the post-injury catabolism. Our results suggest that: 1. Nutritional support can maintain nitrogen equilibrium in the early post-operative state. 2. Branched chain amino acids exert a nitrogen sparing effect and thus prevent or minimise post-operative catabolism. 3. Increasing the amount of infused branched chain amino acids results in nitrogen retention. 4. A balanced amino-acid mixture containing 45 per cent branched chain amino acids seems to be optimal for nutritional support in the post-injury state.

Journal Article↗
PubMed1998

Stochastic technology, production organization and costs.

Using a model including patients, physicians, insurers and uncertain diagnostic technology, the optimal cesarean rate is derived from preferences, technology and the incidence rate, when the choice of insured patients is constrained only by technology. Uncertain diagnosis produces unnecessary cesareans and unsafe vaginal births. Technical progress can lead to more cesareans and higher costs. Joint production of goods and bads and collective payments require incentive compatible pricing schemes, different from RBRVS. Equilibrium outcomes of HMOs and free-for-service organizations are identical. However, implementable incentive schemes involve additional costs. Efficiency requires insurers, and not providers, to be liable for malpractice claims.

Adult↗
PubMed2002

DNA shuffling: induced molecular breeding to produce new generation long-lasting vaccines.

The paradigm for classic vaccines has been to mimic natural infection, and their success relies mostly on the induction of neutralizing antibodies followed by long-lasting immunity. The outcome of aggressive chronic infections such as HIV and HCV, the reappearance of fastidious diseases such as tuberculosis and the progression of cancer growth suggest that natural immune responses are definitely insufficient in many cases. A new paradigm is needed to design and develop a new high-efficiency generation of vaccines ideally able to surpass the capabilities of natural immune responses. In vitro evolution is a new, important laboratory method to evolve molecules with desired properties, which appears as an appealing alternative to achieve this goal. In its battle against disease, the vertebrate immune system triggers a series of well-known molecular events in order to produce protective neutralizing antibodies. This natural in vivo response shares remarkable similarities with the in vitro technique known as molecular breeding or "DNA shuffling." This method exploits the recombination between genes to dramatically accelerate the rate at which genes can be evolved under selection pressure in the laboratory, producing optimized high-efficiency mutant proteins. Since new generation vaccines are aimed to overcome natural selection and environmental pressures to fully inactivate rapidly developing pathogen variants, they could be engineered, developed and selected through the application of directed DNA shuffling procedures. This review highlights the potential of the procedure in the complex context of natural immune responses and the equilibrium and interaction existing in nature between hosts and pathogens.

Journal Article↗
PubMed2006

Understanding enzyme action at solid surfaces.

In solid-phase synthesis, there is interest in using enzymes that normally act on dissolved substrates. It is normally observed that rates and yields are substantially reduced when the usual substrates are covalently attached to a solid particle. Recently, there has been some progress in understanding the reasons for this, and hence how to improve behaviour. Diffusion of enzyme molecules into some of the support particles used in solid-phase chemistry is slow or absent. Methods are now available to visualize the sites of reaction, and hence detect this problem, and identify better support materials. Chemical equilibrium positions for reactions at the surface can be substantially altered compared with those in solution, so may unexpectedly limit yields. The shift can also be exploited to carry out, for example, direct synthesis of peptide bonds in an aqueous environment. The rate of enzyme attack depends on how the substrate moiety is attached to the surface, with an optimal 'spacer' length.

Catalysis↗
PubMed2001

Mechanism of activation of ERK2 by dual phosphorylation.

The mitogen-activated protein (MAP) kinases are characterized by their requirement for dual phosphorylation at a conserved threonine and tyrosine residue for catalytic activation. The structural consequences of dual-phosphorylation in the MAP kinase ERK2 (extracellular signal-regulated kinase 2) include active site closure, alignment of key catalytic residues that interact with ATP, and remodeling of the activation loop. In this study, we report the specific effects of dual phosphorylation on the individual catalytic reaction steps in ERK2. Dual phosphorylation leads to an increase in overall catalytic efficiency and turnover rate of approximately 600,000- and 50,000-fold, respectively. Solvent viscosometric studies reveal moderate decreases in the equilibrium dissociation constants (K(d)) for both ATP and myelin basic protein. However, the majority of the overall rate enhancement is due to an increase in the rate of the phosphoryl group transfer step by approximately 60,000-fold. By comparison, the rate of the same step in the ATPase reaction is enhanced only 2000-fold. This suggests that optimizing the position of the invariant residues Lys(52) and Glu(69), which stabilize the phosphates of ATP, accounts for only part of the enhanced rate of phosphoryl group transfer in the kinase reaction. Thus, significant stabilization of the protein phosphoacceptor group must also occur. Our results demonstrate similarities between the activation mechanisms of ERK2 and the cell cycle control enzyme, Cdk2 (cyclin-dependent kinase 2). Rather than dual phosphorylation, however, activation of the latter is controlled by cyclin binding followed by phosphorylation at Thr(160).

Adenosine Triphosphatases↗