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PubMed1996

The effect of perceived challenges and skills on the quality of subjective experience.

This article investigates the effects that perceived challenges and skills in activities have on the quality of everyday life experience. Based on flow theory it was predicted that quality of daily experience would depend on the challenge experienced and skill required in specific situations, as well as on the balance between challenge and skill. The Experience Sampling Method (ESM) was used on a sample of 208 talented adolescents to measure daily variations in four dimensions of experience (concentration, wish to do the activity, involvement, and happiness) in four contexts (in school, with relatives, with friends, and in solitude). The four dimensions of experience were regressed on the predictors challenges, skills, and their absolute difference expressing the balance/imbalance of challenges and skills. Hierarchical linear modeling, explained in detail herein, was conducted on a 1-week sample of experiences. Findings confirm the prediction of flow theory that the balance of challenges and skills has a positive and independent effect on the quality of experience. Yet some differences of parameter estimates were found between dimensions of experience and between social contexts. These heterogeneities call for a further improvement of the flow model.

Adolescent↗

PubMed1995

Structural basis for serpin inhibitor activity.

The mechanism of formation and the structures of serpin-inhibitor complexes are not completely understood, despite detailed knowledge of the structures of a number of cleaved and uncleaved inhibitor, noninhibitor, and latent serpins. It has been proposed from comparison of inhibitor and noninhibitor serpins in the cleaved and uncleaved forms that insertion of strand s4A into preexisting beta-sheet A is a requirement for serpin inhibitor activity. We have investigated the role of this strand in formation of serpin-proteinase complexes and in serpin inhibitor activity through homology modeling of wild type inhibitor, mutant substrate, and latent serpins, and of putative serpin-proteinase complexes. These models explain the high stability of the complexes and provide an understanding of substrate behavior in serpins with point mutations in s4A and of latency in plasminogen activator inhibitor I.

Amino Acid Sequence↗

PubMed1992

Phospholipid domains determine the spatial organization of the Escherichia coli cell cycle: the membrane tectonics model.

Escherichia coli normally divides at its equator between segregated nucleoids. Such division is inhibited during perturbations of chromosome replication (even in the absence of inducible division inhibitors); eventually, division resumes at sites which are not at this equator. Escherichia coli will also divide at its poles to generate minicells following overproduction of the FtsZ or MinE proteins. The mechanisms underlying the division inhibition and the positioning of the division sites are unknown. In the membrane tectonics model, I propose that the formation of phospholipid domains within the cytoplasmic membrane positions division sites. The particular phospholipid composition of a domain attracts particular proteins and determines their activity; conversely, particular proteins change the composition of domains. Principally via such proteins, the interaction of the chromosome with the membrane creates a chromosomal domain. The development of chromosomal domains during replication and nucleoid formation contributes to the formation and positioning of a septal domain between them. During septation (cell division), this septal domain matures into a polar domain. Each domain attracts and activates different enzymes. The septal domain attracts and activates enzymes necessary for septation. Preventing the formation of the septal domain by preventing chromosome replication prevents normal division. Altering the composition of the polar domain may allow septation enzymes to function there and generate minicells. A corollary of the model explains how the formation of an origin domain by the attachment of hemi-methylated origin DNA to the membrane may underlie the creation and migration of structures within the envelope, the periseptal annuli.

Animals↗

PubMed2002

The function of photosystem I. Quantum chemical insight into the role of tryptophan-quinone interactions.

Quantum chemical calculations have provided evidence for the role of tryptophan residues in the electron transfer process of photosystem I (PS-I). The interaction of Trp with quinone acceptors and their radical anions in the A(1) site of PS-I has been modeled by various indole-quinone and indole-semiquinone complexes. MP2 optimizations show that, while neutral quinones and an indole molecule prefer a pi-stacked arrangement, semiquinone radical anions prefer a T-stacked conformation with significant N-H...pi hydrogen bonding interactions. Comparison of density functional calculations of electronic g-tensors with electron paramagnetic resonance data strongly suggests that hydrogen-bonded T-shaped arrangements occur upon reduction of quinone acceptors without an extended side chain (e.g., duroquinone or naphthoquinone), when reconstituted into the phylloquinone-depleted A(1) site of PS-I. In contrast, for the native phylloquinone (vitamin K(1), Q(K)), reorientation of the semiquinone radical anion is prevented by side chain-protein interactions. For a fixed pi-stacked arrangement, the extent of the intermolecular interaction is reduced upon one-electron reduction. This corresponds to a lowering of the redox potential of the P(700)(+)*Q(K)(-)* radical pair, due to interactions of Q(K) with a tryptophan. Together with the comparably weak hydrogen bonding in PS-I, the proposed model explains the very negative redox potential of the A(1) site, needed for forward electron transfer. T-stacking hydrogen bonds to semiquinones may also have to be considered in many other electron transfer processes in living organisms.

Benzoquinones↗

PubMed1980

Protein mobility inside pyruvate dehydrogenase complexes as reflected by laser-pulse fluorometry. A new approach to multi-enzyme catalysis.

The fluorescence decay curves of the flavin in all pyruvate dehydrogenase complexes studied here are consistent with a two-exponential fit. One of the lifetimes calculated is very short, as demonstrated by experiments in which a mode-locked argon-ion laser was used for excitation. In three complexes out of the four which were investigated, about equal weights for the amplitudes of the two lifetimes are found. In the three-component complex from Azotobacter vinelandii this is not the case. No effects of the protein concentration on the lifetimes of the fluorophore were found in the concentration range studied. A small but significant difference in lifetime is observed for the A. vinelandii complexes when coenzyme-free complex is compared with complex to which Mg2+ and thiamin diphosphate are added. The correlation time calculated from the polarized decay of the flavin fluorescence at 11 degrees C is around 40 ns and 50 ns for A. vinelandii complexes and Escherichia coli complexes respectively. This correlation time is of the same order as the rotational correlation time of free lipo-amide dehydrogenase itself, but much shorter than would be expected from the molecular weights of the complexes. Models explaining the two lifetimes are discussed. A catalytic mechanism based on the internal mobility of the lipoamide dehydrogenase inside the multi-enzyme complex is proposed.

Azotobacter↗

PubMed1989

Respiratory mechanics in the normal dog determined by expiratory flow interruption.

We recently proposed an eight-parameter model of the respiratory system to account for its mechanical behavior when flow is interrupted during passive expiration. The model consists of two four-parameter submodels representing the lungs and the chest wall, respectively. The lung submodel consists of an airways resistance together with elements embodying the viscoelastic properties of the lung tissues. The chest wall submodel has similar structure. We estimated the parameters of the model from data obtained in four normal, anesthetized, paralyzed, tracheostomized mongrel dogs. This model explains why lung tissue and chest wall resistances should be markedly frequency dependent at low frequencies and also permits a physiological interpretation of resistance measurements provided by the flow interruption method.

Airway Resistance↗

PubMed1990

Mathematical models of gene amplification with applications to cellular drug resistance and tumorigenicity.

An increased number of copies of specific genes may offer an advantage to cells when they grow in restrictive conditions such as in the presence of toxic drugs, or in a tumor. Three mathematical models of gene amplification and deamplification are proposed to describe the kinetics of unstable phenotypes of cells with amplified genes. The models differ in details but all assume probabilistic mechanisms of increase and decrease in gene copy number per cell (gene amplification/deamplification). Analysis of the models indicates that a stable distribution of numbers of copies of genes per cell, observed experimentally, exists only if the probability of deamplification exceeds the probability of amplification. The models are fitted to published data on the loss of methotrexate resistance in cultured cell lines, due to the loss of amplified dihydrofolate reductase gene. For two mouse cell lines unstably resistant to methotrexate the probabilities of amplification and deamplification of the dihydrofolate reductase gene on double minute chromosomes are estimated to be approximately 2% and 10%, respectively. These probabilities are much higher than widely presumed. The models explain the gradual disappearance of the resistant phenotype when selective pressure is withdrawn, by postulating that the rate of deamplification exceeds the rate of amplification. Thus it is not necessary to invoke a growth advantage of nonresistant cells which has been the standard explanation. For another analogous process, the loss of double minute chromosomes containing the myc oncogene from SEWA tumor cells, the growth advantage model does seem to be superior to the amplification and deamplification model. In a more theoretical section of the paper, it is demonstrated that gene amplification/deamplification can result in reduction to homozygosity, such as is observed in some tumors. Other applications are discussed.

Animals↗

PubMed2005

The physics of filopodial protrusion.

Filopodium, a spike-like actin protrusion at the leading edge of migrating cells, functions as a sensor of the local environment and has a mechanical role in protrusion. We use modeling to examine mechanics and spatial-temporal dynamics of filopodia. We find that >10 actin filaments have to be bundled to overcome the membrane resistance and that the filopodial length is limited by buckling for 10-30 filaments and by G-actin diffusion for >30 filaments. There is an optimal number of bundled filaments, approximately 30, at which the filopodial length can reach a few microns. The model explains characteristic interfilopodial distance of a few microns as a balance of initiation, lateral drift, and merging of the filopodia. The theory suggests that F-actin barbed ends have to be focused and protected from capping (the capping rate has to decrease one order of magnitude) once every hundred seconds per micron of the leading edge to initiate the observed number of filopodia. The model generates testable predictions about how filopodial length, rate of growth, and interfilopodial distance should depend on the number of bundled filaments, membrane resistance, lamellipodial protrusion rate, and G-actin diffusion coefficient.

Actins↗

PubMed1999

Medical and ecological factors in estimating motor outcomes of preschool children.

The twofold purpose of this study was to compare motor function in preschool children born with varying degrees of medical risk and to determine the independent contribution to motor function of three domains of ecological influence. One hundred and eighty-four 4-year-old children and their mothers participated. Three predictor sets, proximal, distal, and child, and four motor outcomes were measured by multiple methods. Children born prematurely scored lower on all dimensions of motor function. Prematurity complications had a different effect on motor function. Hierarchical regression models explained 16-40% of motor score variance. Results are discussed in relation to heterogeneity of prematurity and ecological influences on motor outcomes.

Adult↗

PubMed1989

Phenylthiocarbamide taste sensitivity revisited: complete sorting test supports residual family resemblance.

Phenylthiocarbamide (PTC) taste thresholds were determined in 100 nuclear families using the complete sorting test. Segregation analysis using the mixed model suggested that the variability in PTC thresholds is controlled by a major locus with incomplete dominance as well as by a multifactorial component with significant residual heritability. Such a model explained nearly 96% of the variance, leaving only 4% of the variance in thresholds arising from measurement error and other environmental factors.

Adolescent↗

PubMed2003

A unifying model for functional difference and redundancy of presenilin-1 and -2 in cell apoptosis and differentiation.

Mutations in genes encoding the highly homologous proteins presenilin-1 and -2 (PS1 and PS2) are linked to the early onset of Alzheimer's disease (AD). Here, we report that polyclonal antibodies against Xenopus PSbeta (PS2), but not PSalpha (PS1), suppress the in vitro apoptotic activation of Xenopus egg extracts. To clarify the relationship between structural and functional differences in presenilins, we searched for presenilin homologues in various living sources, and found that presenilins were divided into three distinct groups, named alpha-, beta- and gamma-types, based on the size of the large hydrophilic loop (HL) regions as follows: HLalpha/HLbeta/HLgamma=4:3:6. No such size conservations were found in the N-terminal (NT) hydrophilic regions. Phylogenetic studies revealed that the presenilin genes were duplicated independently in different lineages of phyla/divisions, suggesting that there were functional requirements for and constraints on the generation and conservation of these HL sizes. On the basis of these findings, we propose a model postulating that both PS1 and PS2 can be differentiative or apoptotic when they are proteolytically processed within the HL regions or not, respectively, and PS1 may be more sensitive than PS2 to auto-proteolytic cleavage due to the larger size of the HL region of the former. Furthermore, the model assumes that C-terminal fragments (CTF) stabilized by phosphorylation may inhibit both the activities due to the dominant-negative effect. The model explains not only the functional redundancy but also apparently conflicting observations reported so far for PS1 and PS2.

Animals↗

PubMed2006

Architecture of a polycomb nucleoprotein complex.

Polycomb group (PcG) epigenetic silencing proteins act through cis-acting DNA sequences, named Polycomb response elements (PREs). Within PREs, Pleiohomeotic (PHO) binding sites and juxtaposed Pc binding elements (PBEs) function as an integrated DNA platform for the synergistic binding of PHO and the multisubunit Polycomb core complex (PCC). Here, we analyzed the architecture of the PHO/PCC/PRE nucleoprotein complex. DNase I footprinting revealed extensive contacts between PHO/PCC and the PRE. Scanning force microscopy (SFM) in combination with DNA topological assays suggested that PHO/PCC wraps the PRE DNA around its surface in a constrained negative supercoil. These features are difficult to reconcile with the simultaneous presence of nucleosomes at the PRE. Indeed, chromatin immunoprecipitations (ChIPs) and nuclease mapping demonstrated that PREs are nucleosome depleted in vivo. We discuss the implications of these findings for models explaining PRE function.

Animals↗

PubMed2003

Degradation of the D1 protein of photosystem II under illumination in vivo: two different pathways involving cleavage or intermolecular cross-linking.

The D1 protein of the photosystem II reaction center turns over the most rapidly of all the proteins of the thylakoid membrane under illumination in vivo. In vitro, the D1 protein sustained cleavage in a surface-exposed loop (DE loop) or cross-linking with another reaction center protein, the D2 protein or cytochrome b(559), under illumination. We found that the D1 protein was damaged in essentially the same way in vivo, although the resultant fragments and cross-linked adducts barely accumulated due to digestion by proteases. In vitro studies detected a novel stromal protease(s) that digested the adducts but not the monomeric D1 protein. These observations suggest that, in addition to cleavage, the cross-linking reactions themselves are processes involved in complete degradation of the D1 protein in vivo. Peptide mapping experiments located the cross-linking sites with the D2 protein among residues 226-244, which includes the cross-linking site with cytochrome b(559) [Barbato, R., et al. (1995) J. Biol. Chem. 270, 24032-24037], in the N-terminal part of the DE loop, while N-terminal amino acid sequencing of the fragment located the cleavage site around residue 260 in the C-terminal part of the loop. We propose a model explaining the occurrence of simultaneous cleavage and cross-linking and discuss the mechanisms of complete degradation of the D1 protein in vivo.

Chloroplasts↗

PubMed1996

Anisotropy, fiber curvature, and bath loading effects on activation in thin and thick cardiac tissue preparations: simulations in a three-dimensional bidomain model.

INTRODUCTION: A modeling study is presented to explore the effects of tissue conductivity, fiber orientation, and presence of an adjoining extracellular volume conductor on electrical conduction in cardiac muscle. Simulated results are compared with those of classical in vitro experiments on superfused thin layer preparations and on whole hearts. METHODS AND RESULTS: The tissue is modeled as a three-dimensional bidomain block adjoining an isotropic bath. In the thin layer model, the fibers are assumed parallel. In the thick block model, fiber rotation, curvature, and tipping are incorporated. Results from the thin layer model explain experimental observations that the rate of rise of the entire action potential upstroke is faster and the magnitude of the extracellular potential is smaller across fibers than along fibers in a uniformly propagating front. The simulation identified that this behavior only arises in tissue with unequal anisotropy in the two spaces and adjoining an extracellular bath. Simulated conduction and potential distributions in the thick block model are shown to well approximate experimental maps. The potentials are sensitive to changes in the fiber orientations. A slight 5 degrees tipping of intramural fibers out of the planes parallel to the epicardium and endocardium will lead to an asymmetry of the magnitudes of the positive regions. In addition, the introduction of fiber curvature leads to more realistic isochrone and extracellular potential distributions. The orientation of the central negative region of the extracellular potential is shown to be determined by the average of the fiber direction at the plane of pacing and the plane of recording. CONCLUSIONS: The simulations demonstrate the sensitivity of spread of activation and potential time courses and distributions to the underlying electrical properties in both thick and thin slabs. The bidomain model is shown to be a useful representation of cardiac tissue for interpreting experimental data of activation.

Action Potentials↗

PubMed2002

Biomonitoring of exposure to urban air pollutants: analysis of sister chromatid exchanges and DNA lesions in peripheral lymphocytes of traffic policemen.

In order to elucidate the health effects of occupational exposure to traffic fumes, a few biomarkers of early genetic effect were investigated in Rome traffic policemen. One hundred and ninety healthy subjects engaged in traffic control (133 subjects) or in office work (57 subjects) participated the study. For all subjects, detailed information on smoking habits and other potential confounders were recorded by questionnaires. Average exposure of the study groups to benzene and other aromatic hydrocarbons was evaluated in a parallel exposure survey. All workers were genotyped for the following metabolic polymorphisms: CYP1A1 (m1, m2, and m4 variants), CYP2E1 (PstI and RsaI), NQO1 (Hinf1), GSTM1 and GSTT1 (null variants). In this paper, the results of the analysis of sister chromatid exchanges (SCE) in peripheral lymphocytes, and DNA damage by alkaline (pH 13) comet assay in mononuclear blood cells are reported. No statistically significant difference in the frequency of SCE or high frequency cells (HFC) was observed between traffic wardens and office workers (controls), despite the significantly higher exposure to benzene of the former (average group exposure 9.5 versus 3.8microg/m(3), 7h TWA). Conversely, both SCE per cell and HFC were highly significantly (P<0.001) increased in smokers compared to nonsmokers, showing a significant correlation (P<0.001) with the number of cigarettes per day. Multiple regression analyses of data, with metabolic polymorphisms, smoking habits, alcohol consumption, age, gender, and family history of cancer as independent variables, showed that smoking habits, and possibly the CYP2E1 variant genotypes, were the main factors explaining the variance of both SCE and HFC. Within smokers, an association of borderline significance between the CYP1A1 variant genotypes and increased SCE (P=0.050) and HFC (P=0.090) was found. This effect was mainly observed in light smokers (<15 cigarettes per day). The analysis of DNA damage by comet assay did not highlight any statistically significant difference between the exposed and control workers. Moreover, no significant model explaining tail moment variance was obtained by multiple regression analysis using the independent variables shown above. On the whole, these results indicate that exposure to moderate air pollution levels does not result in a detectable increase of genetic damage in blood cells. This evidence does not rule out any possibility of adverse effects, but strongly suggests that in urban residents life-style related factors, such as tobacco smoking, give the prevailing contribution to individual genotoxic burden.

Adult↗

PubMed2003

Nutrition guidance in Dutch family practice: behavioral determinants of reduction of fat consumption.

BACKGROUND: Studies have shown that the psychosocial determinants attitude, self-efficacy, subjective norm, and health threat are important in predicting intention to change fat consumption. However, the role of habit in relation to these determinants is still largely unknown. OBJECTIVE: We aimed to assess whether and how habit influences intention in relation to attitude, self-efficacy, subjective norm, and health threat. DESIGN: Cross-sectionally, we studied the self-reported psychosocial determinants and intention of 105 (52 intervention, 53 control) patients who participated in a family practice-based tailored nutrition counseling intervention study for lowering cardiovascular risk. Fat intake 15 mo before the assessment of psychosocial determinants was used as a measure of habit. We used logistic regression analyses to develop a model predicting intention to change fat consumption. RESULTS: Our regression model explained 43% of the variance in intention. Patients who perceived higher subjective norm or more social support had a higher intention. Habit was a significant predictor of intention in interaction with self-efficacy and health threat. Attitude, health threat, age, and group membership (ie, whether patients had been in the intervention group or the control group of the intervention study) were also included in the regression model. CONCLUSIONS: The results suggest that habit in addition to subjective norm and the other more frequently investigated psychosocial determinants are important in predicting intention to change fat consumption. To achieve sustainable health improvement through nutrition education programs, these programs should therefore start focusing more on subjective norm and habit.

Attitude to Health↗

PubMed1991

Unequal cell division, growth regulation and colony size of mammalian cells: a mathematical model and analysis of experimental data.

This work describes mathematically the dynamics of expansion of cell populations from the initial division of single cells to colonies of several hundred cells. This stage of population growth is strongly influenced by stochastic (random) elements including, among others, cell death and quiescence. This results in a wide distribution of colony sizes. Experimental observations of the NIH3T3 cell line as well as for the NIH3T3 cell line transformed with the ras oncogene were obtained for this study. They include the number of cells in 4-day-old colonies initiated from single cells and measurements of sizes of sister cells after division, recorded in the 4-day-old colonies. The sister cell sizes were recorded in a way which enabled investigation of their interdependence. We developed a mathematical model which includes cell growth and unequal cell division, with three possible outcomes of each cell division: continued cell growth and division, quiescence, and cell death. The model is successful in reproducing experimental observations. It provides good fits to colony size distributions for both NIH3T3 mouse fibroblast cells and the same cells transformed with the rasEJ human cancer gene. The difference in colony size distributions could be fitted by assuming similar cell lifetimes (12-13 hr) and similar probabilities of cell death (q = 0.15), but using different probabilities of quiescence, r = 0 for the ras oncogene transformed cells and r = 0.1 for the non-transformed cells. The model also reproduces the evolution of distributions of sizes of cells in colonies, from a single founder cell of any specified size to the stable limit distribution after eight to ten cell divisions. Application of the model explains in what way both random events and deterministic control mechanisms strongly influence cell proliferation at early stages in the expansion of colonies.

Animals↗

PubMed1995

Location and properties of pyrophosphate-binding sites in Escherichia coli F1-ATPase.

Binding of pyrophosphate (PPi) to the three catalytic ("C") and three noncatalytic ("NC") nucleotide sites of Escherichia coli F1-ATPase was determined by fluorescence spectroscopy using mutant enzymes with tryptophan inserted specifically in either C sites (beta Y331W) or NC sites (alpha R365W). Fluorescence of the tryptophan is quenched on binding of nucleotide; PPi binding parameters were determined by competition with ATP or adenyl-5'-yl imidodiphosphate. It was found that MgPPi binds to each NC site with Kd = 20 microM. In contrast, even at millimolar concentration, neither MgPPi nor free PPi showed significant binding to C sites. We confirmed that free PPi displaces nucleotide from C sites, but this was shown to be due to complexation of Mg2+ ions rather than to occupancy of the sites. MgPPi bound at NC sites was found not to affect ATP hydrolysis rates. From the data we propose a two-phase model for nucleotide binding at NC sites. In phase one, NC sites recognize the pyrophosphate "end" of the nucleotide, which binds initially with Kd similar to MgPPi; in phase two, a slow conformational change occurs which tightly sequesters adenine nucleotide. Phase two does not occur with guanine nucleotide. This model explains the preference of NC sites for adenine nucleotides. Pi (5 mM) did not bind to either C or NC sites.

Adenine Nucleotides↗