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PubMed2004

The keratin cytoskeleton in liver diseases.

The keratin intermediate filament (IF) cytoskeleton of hepatocytes has continuously gained medical relevance over the last two decades. Originally it was mainly recognized as a differentiation marker for diagnostic purposes in pathology. However, keratin IFs were soon identified as major cellular structures to be affected in a variety of chronic liver diseases, such as alcoholic and non-alcoholic steatohepatitis (ASH, NASH), copper toxicosis, and cholestasis. Based on observations in keratin gene knock-out mice, the insight into the functional role of keratins was extended from a mere structural role providing mechanical stability to hepatocytes, to an additional role as target and modulator of toxic stress and apoptosis. The functional relevance of keratins in human diseases has recently been underlined by the identification of mutations in keratin genes in patients with liver cirrhosis.

Biliary Tract↗

PubMed1999

Molecular characterization of the human CRT-1 creatine transporter expressed in Xenopus oocytes.

The protein sequence encoded by a creatine transporter cDNA cloned from a human heart library was identical to that cloned from a human kidney library (Nash et al., Receptors Channels 2, 165-174, 1994), except that at position 285 the former contained an Ala residue and the latter contained a Pro residue. Expression of this human heart cDNA clone in Xenopus laevis oocytes induced a Na+- and Cl--dependent creatine uptake activity that saturated with a Km of approximately 20 microM for creatine. The induced uptake was inhibited by beta-guanidinopropionic acid (IC50 approximately 44.4 microM), 2-amino-1-imidazolidineacetic acid (cyclocreatine; IC50 approximately 369.8 microM), gamma-guanidinobutyric acid (IC50 approximately 697.9 microM), gamma-aminobutyric acid (IC50 approximately 6.47 mM), and amiloride (IC50 approximately 2.46 mM). The inhibitors beta-guanidinopropionic acid, cyclocreatine, and gamma-guanidinobutyric acid also inhibited the uptake activity of the Ala285 to Pro285 (A285P) mutant as effectively as that of the wild type. In contrast, guanidinoethane sulfonic acid, a potent inhibitor of taurine transport, inhibited the uptake activity of the A285P mutant approx. two times more effectively than that of the wild type. The protein kinase C activator phorbol 12-myristate 13-acetate (PMA), but not its inactive analog, 4alpha-phorbol 12, 13-didecanoate, inhibited the creatine uptake, and the inhibitory effect of PMA was both time and concentration dependent. The protein kinase A activator 8-bromo-cyclic AMP, however, had no effect on the creatine uptake. The rate of uptake increased hyperbolically with the increasing concentration of the external Cl- (equilibrium constant KCl- approximately 5 mM) and sigmoidally with the increasing concentration of the external Na+ (equilibrium constant KNa+ approximately 56 mM). Further analyses of the Na+ and Cl- concentration dependence data suggested that at least two Na+ and one Cl- were required to transport one creatine molecule via the creatine transporter.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1994

A fluorimetric assay for hydrogen peroxide, suitable for NAD(P)H-dependent superoxide generating redox systems.

We report a simple and sensitive fluorimetric method for quantitative assay of the production rate of hydrogen peroxide, and indirectly of superoxide, during electron transfer reactions. The assay requires the inclusion of superoxide dismutase, catalase, and 6% methanol in the tested reaction system, to stochiometrically produce formaldehyde per molecule of H2O2 generated. The reaction is terminated by adding 2 vol of Nash reagent and heating at 60 degrees C for 10 min, to convert accumulated formaldehyde to diacetyldihydrolutidine (DDL). The standard curve for formaldehyde, based on the fluorescence of DDL, is highly reproducible and allows measurement of 1 microM amounts in the reaction sample (coefficient of variation < 15%). The excitation and emission wavelengths of DDL at 412 and 505 nm are distant from those of NAD(P)H. Thus, the method can be used in NAD(P)H-dependent enzymatic systems to measure both NAD(P)H oxidation and superoxide production in the same sample. We validated the assay in a mitochondrial P450 system determining the fraction of total electron flow that is channeled to oxy-radical formation. The assay should be useful in the study of this and other superoxide/H2O2 generating systems.

Catalase↗

PubMed1999

Exploring structures in protein folding funnels with free energy functionals: the denatured ensemble.

We discuss the formulation of free energy functionals that describe the formation of structure in partially folded proteins. These free energy functionals take into account the inhomogeneous nature of contact energies, chain entropy and cooperative contributions reflecting the many body character of some folding forces like hydrophobicity, but do not directly account for non-native contacts because they assume the validity of the minimal frustration principle. We show how the free energy functionals can be used to interpret experiments on partially folded proteins that probe the fractional occupancy of specific local structures. In particular, we study the hydrogen protection factors in lysozyme studied in transient experiments by Gladwin and Evans and by Nash and Jonas using equilibrium pressure denaturation and the NMR order parameters measured by Dobson and Kim for the homologous protein alpha-lactalbumin.

Animals↗

PubMed1998

Strategic Play and Adaptive Learning in the Sealed-Bid Bargaining Mechanism.

We report the results of two experiments on bilateral bargaining under the sealed-bid double auction mechanism in environments where theory calls for decidedly strategic play. The observed individual sellers' ask functions and buyers' bid functions, each based on 50 rounds of bargaining, are shown to be in good agreement with the Bayesian-Nash piecewise linear equilibrium solution of Chatterjee & Samuelson (1983). Although the game is played with random matching of traders on each round, both sellers and buyers change their behavior over time. The buyers in particular learn to bid more aggressively. The information sets of the two players are shown to be a major determinant of this result and of the strikingly disparate profits earned by buyer and seller during the experiment. To address the dynamics of this result, we propose a simple adaptive learning model postulating round-to-round changes in the entire bid/ask function which are proportional to the actual gain, if a deal was struck, or the gain that could have been but was not realized, if no agreement was reached on the previous round. Based on results from the experimental psychology literature, this model captures the major features of the mean bid/ask functions and accounts for most of the trial-to-trial variability in the buyers', but not the sellers', decisions. Copyright 1998 Academic Press.

Journal Article↗

PubMed1994

Size effects in Kauffman type evolution for rugged fitness landscapes.

Millions of sites are simulated in an NK fitness model of evolution and coevolution. We find a logarithmic size dependence of the number of hill-climbing iterations needed to reach a local fitness optimum (Nash equilibrium). We also check for chaotic behavior and determine the size of the damage clouds or avalanches. Random noise (simulated annealing) is shown to increase appreciably the fitness.

Algorithms↗

PubMed1997

A general technique for computing evolutionarily stable strategies based on errors in decision-making.

Realistic models of contests between animals will often involve a series of state-dependent decisions by the contestants. Computation of evolutionarily stable strategies for such state-dependent dynamic games are usually based on damped iterations of the best response map. Typically this map is discontinuous so that iterations may not converge and even if they do converge it may not be clear if the limiting strategy is a Nash equilibrium. We present a general computational technique based on errors in decision making that removes these computational difficulties. We show that the computational technique works for a simple example (the Hawk-Dove game) where an analytic solution is known, and prove general results about the technique for more complex games. It is also argued that there is biological justification for inclusion of the types of errors we have introduced.

Animals↗

PubMed1998

War of Attrition with Individual Differences on RHP.

The fact that there always exists various kinds of almost continuous mutations for any animal population implies that players in competitions can never be perfectly symmetric in any sense. To develop a model to fit this reality, we consider war of attrition games in which players have continuously different resource holding potential (RHP). The RHP of each opponent is not known in our settings. Pure ESS functions and Nash equilibria are obtained under sufficiently rotational conditions as unique solutions of certain differential equations among the class of Lebesgue measurable functions. They are normal in that a higher RHP induces a longer attrition time, which implies that a player with greater RHP always wins. This model includes as the limit the conclusions of Maynard Smith (1974, J. theor. Biol. 47, 209-221) and Norman et al. (1977, J. theor. Biol. 65, 571-578), which did not consider individual differences in RHP. Our results suggest that, by changing each player's qualitative differences to continuous quantitative differences, some of the mixed ESS solutions previously found in discrete games may degenerate into pure ESS functions. Moreover, we found that the smaller the individual differences of RHP, the smaller is the mean pay-off of most individuals as well as the total pay-off of the population.Copyright 1998 Academic Press

Journal Article↗

PubMed2000

Increasing Cooperation in Prisoner's Dilemmas by Establishing a Precedent of Efficiency in Coordination Games.

Coordination games have multiple Nash equilibria (i.e., sets of strategies which are best responses to one another). In weak-link coordination games players choose a number 1-7. Their payoff is increasing in the minimum number (or weakest link) and decreasing in the difference between their number and the minimum. Choosing 7 is an efficient equilibrium because it gives everybody a higher payoff than any other coordinated choice. Higher-payoff equilibria are riskier, however, so the game expresses the tradeoff between group efficiency and personal risk present in many social and organizational settings. We tested whether choosing efficiently in a weak-link game increases cooperative play in a subsequent prisoner's dilemma (PD) game. This cross-game transfer resembles the transfer of cooperative norms in small firms (which are more like coordination games than PDs) as firms grow larger and become like PDs. In two experiments, if a group of players share a history of playing the weak-link game efficiently, that efficiency precedent can transfer to a subsequent PD game, improving the level of cooperativeness. The effect of transfer is much larger in magnitude (increasing cooperation from 15-30% to 71%) than the effects of most variables in previous PD studies. However, the transfer effect depends on descriptive similarity of strategies in the two games, since it largely disappears when the strategies are numbered differently in the weak-link game and the PD. Copyright 2000 Academic Press.

Journal Article↗

PubMed1991

The dynamical attainability of ESS in evolutionary games.

In this paper, the attainability of ESS of the evolutionary game among n players under the frequency-independent selection is studied by means of a mathematical model describing the dynamical development and a concept of stability (strongly determined stability). It is assumed that natural selection and small mutations cause the phenotype to change gradually in the direction of fitness increasing. It is shown that (1) the ESS solution is not always evolutionarily attainable in the evolutionary dynamics, (2) in the game where the interaction between two species is completely competitive, the Nash solution is always attainable, and (3) one of two species may attain the state of minimum fitness as a result of evolution. The attainability of ESS is also examined in two game models on the sex ratio of wasps and aphids in light of our criterion of the attainability of ESS.

Animals↗

PubMed1994

Clinical use of the simple 3D-calculation in scoliosis.

In this paper we show the clinical application of a simple method for calculating three-dimensional shape in scoliosis by the use of two tables based on normal standard X-rays in the anteroposterior and lateral projections. The three-dimensional alignment should be considered in both conservative and operative correction. In 57 patients with 87 scoliotic curves we measured the well-known Cobb angle (alpha) and determined the vertebral rotation according to the method of Nash and Moe. We compared this information with the results of the calculated three-dimensional angles of scoliosis (angle beta between the curvature plane and the sagittal plane, angle sigma as the true angle of scoliosis in this curvature plane). In 76 curves (87%) our method was practicable. The true angle sigma is always higher than the projected angle alpha, especially in the clinically relevant range of 20 degrees-40 degrees. Poor correlation is shown between the projected angle alpha and the true angle sigma (r = 0.41 for thoracic curves and r = 0.57 for lumbar curves) and almost no correlation between vertebral rotation and the true angle sigma (r = 0.10 for thoracic curves and r = 0.44 for lumbar curves) and the curvature plane (beta) (r = 0). The three-dimensional shape of scoliosis cannot be estimated by the well-established projected angles and indices and we recommend the use of our simple method for the radiological investigation of scoliotic patients.

Humans↗

PubMed1989

Reducing the radiation dosage in patients with a scoliosis.

A significant number of girls develop an adolescent idiopathic scoliosis and require repeated full-length radiographs of the spine. Since Nash's publication in 1979 [16], there has been considerable concern expressed about protecting them from excessive radiation, and particularly from the development of radiation-induced breast tumours. We present a study which compares the differences in radiation dose using different techniques, specifically, the use of a posteroanterior projection, very fast rare earth screens and progressive wedge-shaped filtration. The use of a posteroanterior projection reduced the sternal exposure by 98.9% and the breast skin exposure by 92%. A combination of all three techniques reduced the sternal exposure by 99.5%. We recommend that these should be used routinely to reduce the radiation hazard to children with an adolescent idiopathic scoliosis.

Adolescent↗

PubMed1996

Darwinian adaptation, population genetics and the streetcar theory of evolution.

This paper investigates the problem of how to conceive a robust theory of phenotypic adaptation in non-trivial models of evolutionary biology. A particular effort is made to develop a foundation of this theory in the context of n-locus population genetics. Therefore, the evolution of phenotypic traits is considered that are coded for by more than one gene. The potential for epistatic gene interactions is not a priori excluded. Furthermore, emphasis is laid on the intricacies of frequency-dependent selection. It is first discussed how strongly the scope for phenotypic adaptation is restricted by the complex nature of 'reproduction mechanics' in sexually reproducing diploid populations. This discussion shows that one can easily lose the traces of Darwinism in n-locus models of population genetics. In order to retrieve these traces, the outline of a new theory is given that I call 'streetcar theory of evolution'. This theory is based on the same models that geneticists have used in order to demonstrate substantial problems with the 'adaptationist programme'. However, these models are now analyzed differently by including thoughts about the evolutionary removal of genetic constraints. This requires consideration of a sufficiently wide range of potential mutant alleles and careful examination of what to consider as a stable state of the evolutionary process. A particular notion of stability is introduced in order to describe population states that are phenotypically stable against the effects of all mutant alleles that are to be expected in the long-run. Surprisingly, a long-term stable state can be characterized at the phenotypic level as a fitness maximum, a Nash equilibrium or an ESS. The paper presents these mathematical results and discusses - at unusual length for a mathematical journal - their fundamental role in our current understanding of evolution.

Animals↗

PubMed1996

Genetic versus phenotypic models of selection: can genetics be neglected in a long-term perspective?

Game theoretical concepts in evolutionary biology have been criticized by populations geneticists, because they neglect such crucial aspects as the mating system or the mode of inheritance. In fact, the dynamics of natural selection does not necessarily lead to a fitness maximum or an ESS if genetic constraints are taken into account. Yet, it may be premature to conclude that game theoretical concepts do not have a dynamical justification. The new paradigm of long-term evolution postulates that genetic constraints, which may be dominant in a short-term perspective, will in the long run disappear in the face of the ongoing influx of mutations. Two basic results (see Hammerstein; this issue) seem to reconcile the dynamical approach of long-term population genetics with the static approach of evolutionary game theory: (1) only populations at local fitness optima (Nash strategies) can be long-term stable; and (2) in monomorphic populations, evolutionary stability is necessary and sufficient to ensure long-term dynamic stability. The present paper has a double purpose. On the one hand, it is demonstrated by fairly general arguments that the scope of the results mentioned above extends to non-linear frequency dependent selection, to multiple loci, and to quite general mating systems. On the other hand, some limitations of the theory of long-term evolution will also be stressed: (1) there is little hope for a game theoretical characterization of stability in polymorphic populations; (2) many interesting systems do not admit long-term stable equilibria; and (3) even if a long-term stable equilibrium exists, it is not at all clear whether and how it is attainable by a series of gene substitution events.

Biological Evolution↗

PubMedDate not supplied

Intervention for gallbladder disease.

Intervention in the gallbladder includes therapy for both acute and chronic gallbladder disease. Although drainage for acute cholecystitis has been described by several investigators, the future seems to be in removal of calculi in symptomatic patients without acute cholecystitis. The technique for acute gallbladder drainage is described in detail using ultrasound guidance with or without fluoroscopy; for symptomatic gallstones, the clinical and technical aspects are described. We also discuss in detail the totally new concept for gallstone removal and the initial patient work using rotational contact lithotripsy with the Kensey-Nash device.

Cholelithiasis↗

PubMed1994

Metabolism of dichloromethane (methylene chloride) to formaldehyde in human erythrocytes: influence of polymorphism of glutathione transferase theta (GST T1-1).

Human hemolysate was incubated in vitro with different concentrations of dichloromethane (methylene chloride). The resulting enzymatically mediated production of formaldehyde was determined by two independent analytical methods (Nash-reaction/colorimetry or HPLC). The formation of formaldehyde from dichloromethane is influenced by the polymorphism of glutathione-S-transferase (GST) Theta, in the same way as the metabolism of methyl bromide, methyl chloride, methyl iodide and ethylene oxide. Three quarters of the population ("conjugators") possess, whereas one quarter ("non-conjugators") lack this enzyme activity in human erythrocytes. The metabolism of dichloromethane in hemolysate in vitro can be described by Michaelis-Menten kinetics; for an individual with high GST T1-1 enzyme activity, the maximum velocity of formaldehyde production was calculated to be approximately 180 pmol/min per mg Hb, the kM being approximately 60 mM dichloromethane. Carcinogenicity of dichloromethane in long-term inhalation exposure of rodents has been attributed to metabolism of the compound via the GST-dependent pathway. Extrapolation of the results to humans for risk assessment should consider the newly discovered polymorphic enzyme activity of GST Theta. Furthermore, the possible existence of a "high-risk" population among humans should be considered in epidemiological research.

Erythrocytes↗

PubMed2006

Evolutionary game dynamics in a Wright-Fisher process.

Evolutionary game dynamics in finite populations can be described by a frequency dependent, stochastic Wright-Fisher process. We consider a symmetric game between two strategies, A and B. There are discrete generations. In each generation, individuals produce offspring proportional to their payoff. The next generation is sampled randomly from this pool of offspring. The total population size is constant. The resulting Markov process has two absorbing states corresponding to homogeneous populations of all A or all B. We quantify frequency dependent selection by comparing the absorption probabilities to the corresponding probabilities under random drift. We derive conditions for selection to favor one strategy or the other by using the concept of total positivity. In the limit of weak selection, we obtain the 1/3 law: if A and B are strict Nash equilibria then selection favors replacement of B by A, if the unstable equilibrium occurs at a frequency of A which is less than 1/3.

Algorithms↗

PubMed2002

Aerial short-range dispersion of volatilized pesticides from an area source.

Owing to legal provisions, pesticides have to be applied in such a way that there is no unacceptable influence on human health and the environment at nearby non-target areas. In order to quantify their concentration over and downwind of agricultural target plots of 0.5-1 ha, covered by winter wheat and winter barely, the pesticides lindane, parathion and pirimicarb were applied. Over these plots the post-application volatilization rates of the pesticides were estimated indirectly from vertical concentration, wind and temperature profile measurements using the aerodynamic gradient technique. Philip's advection model was applied to take non-favourable fetch conditions into account. In addition, at a height of 1.6 m downwind of the area source, measurements of the horizontal concentration profile were made up to a distance of about 250 m at roughly 50-m intervals. The monitoring started immediately after spraying in the morning and continued for about 8-10 h, thus providing a worst-case situation because volatilization, and therefore pesticide concentration in the atmospheric surface layer, is then strongest. The concentration of the airborne pesticides over the downwind non-target area was also calculated by Philip's advection model. By using the Nash-Sutcliffe relative-difference measure between observed and calculated concentrations, a goodness-of-fit of 0.97 was obtained over the downwind non-target area, indicating that the Philip model is well suited for dispersion estimates in the near-field range.

Agriculture↗