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PubMed2000

Threshold-mediated mechanisms in mutagenesis: implications in the classification and regulation of chemical mutagens.

Chemical mutagens are currently regulated and labelled on the basis of their hazardous properties defined in hazard classification schemes. The strength and type of experimental evidence is used as the only criterion for classification in categories which express different levels of concern for the possibility of adverse effects - notably transmissible genetic alterations - in humans. Differently from the classification of carcinogens, no consideration is given to potency, nor to the mechanism of action. The rationale of such hazard based classification is that the hazardous property of a chemical is an intrinsic feature, which is expressed independently of dosing. Changing of dose level results in a mere change in the probability to observe an adverse effect, but not in its potential occurrence. The lack of theoretical threshold underlying this approach can be envisaged, in principle, for stochastic processes such as DNA damage, which can be triggered by single molecular interactions. On the other hand, indirect mechanisms of genotoxicity, involving multiple interactions with non-DNA targets, are expected to show a threshold. At variance to DNA reactive agents, chemicals acting with threshold-mediated mechanism do change also qualitatively their toxic properties depending on the dose level. Possible problems arising in the application of hazard based schemes for the evaluation of chemicals with threshold-mediated mechanism of action are discussed, using the spindle poisons benzimidazole fungicides as an example.

Dose-Response Relationship, Drug↗

PubMed2000

Effects of chemical contaminants on genetic diversity in natural populations: implications for biomonitoring and ecotoxicology.

The conservation of genetic diversity has emerged as one of the central issues in conservation biology. Although researchers in the areas of evolutionary biology, population management, and conservation biology routinely investigate genetic variability in natural populations, only a handful of studies have addressed the effects of chemical contamination on population genetics. Chemical contamination can cause population reduction by the effects of somatic and heritable mutations, as well as non-genetic modes of toxicity. Stochastic processes in small populations, increased mutation load, and the phenomenon of mutational meltdown are compounding factors that cause reduced fitness and accelerate the process of population extirpation. Although the original damage caused by chemical contaminants is at the molecular level, there are emergent effects at the level of populations, such as the loss of genetic diversity, that are not predictable based solely on knowledge of the mechanism of toxicity of the chemical contaminants. Therefore, the study of evolutionary toxicology, which encompasses the population-genetic effects of environmental contaminants, should be an important focus of ecotoxicology. This paper reviews the issues surrounding the genetic effects of pollution, summarizes the technical approaches that can be used to address these issues, and provides examples of studies that have addressed some of them.

Alleles↗

PubMed2004

Dimeric interaction between the cytoplasmic domains of the Na+/H+ exchanger NHE1 revealed by symmetrical intermolecular cross-linking and selective co-immunoprecipitation.

To investigate the oligomeric structure of Na(+)/H(+) exchanger 1 (NHE1), permeabilized cells and membranes from cells expressing NHE1 variants were treated with the oxidizing agent Cu(2+)/o-phenanthroline or the bifunctional sulfhydryl reagent methanethiosulfonate. These treatments resulted in symmetrical intermolecular cross-linking at intrinsic (Cys(794) and Cys(561)) or 15 exogenous cysteine residues introduced into the distal carboxyl- (C-) terminal cytoplasmic domain (after aa 600) but not at intrinsic Cys(538) because of masking by its tight association with calcineurin B-homologous protein. Cross-linking was abolished in membranes solubilized with sodium dodecyl sulfate, which dissociates oligomeric NHE1, while it was preserved in those treated with Triton X-100. In addition, treatment with cross-linkers did not produce the tetrameric forms of NHE1 mutants with two cysteine residues. Thus, cross-linking presumably occurs between adjacent C-termini of the NHE1 dimer but not by a stochastic process via random collision of NHE1 molecules. The observations suggest that at least the distal C-termini of the NHE1 dimer are flexible or mobile and are thereby capable of easily making contact with each other over the large cytoplasmic portion of the molecule. Furthermore, co-immunoprecipitation experiments showed that the proximal C-termini (aa 503-580) have a strong propensity to interact directly with each other in parallel. Deletion of aa 562-579 resulted in disruption of disulfide cross-linking between the C-termini and markedly reduced the intracellular pH sensitivity of Na(+)/H(+) exchange, suggesting that the dimeric interaction in this region may control the pH-dependent regulation of NHE1.

Animals↗

PubMed1999

Physicochemical aspects of the movement of the rieske iron sulfur protein during quinol oxidation by the bc(1) complex from mitochondria and photosynthetic bacteria.

Crystallographic structures for the mitochondrial ubihydroquinone:cytochrome c oxidoreductase (bc(1) complex) from different sources, and with different inhibitors in cocrystals, have revealed that the extrinsic domain of the iron sulfur subunit is not fixed [Zhang, Z., Huang, L., Shulmeister, V. M., Chi, Y.-I., Kim, K. K., Hung, L.-W., Crofts, A. R., Berry, E. A., and Kim, S.-H. (1998) Nature (London), 392, 677-684], but moves between reaction domains on cytochrome c(1) and cytochrome b subunits. We have suggested that the movement is necessary for quinol oxidation at the Q(o) site of the complex. In this paper, we show that the electron-transfer reactions of the high-potential chain of the complex, including oxidation of the iron sulfur protein by cytochrome c(1) and the reactions by which oxidizing equivalents become available at the Q(o) site, are rapid compared to the rate-determining step. Activation energies of partial reactions that contribute to movement of the iron sulfur protein have been measured and shown to be lower than the high activation barrier associated with quinol oxidation. We conclude that the movement is not the source of the activation barrier. We estimate the occupancies of different positions for the iron sulfur protein from the crystallographic electron densities and discuss the parameters determining the binding of the iron sulfur protein in different configurations. The low activation barrier is consistent with a movement between these locations through a constrained diffusion. Apart from ligation in enzyme-substrate or inhibitor complexes, the binding forces in the native structure are likely to be < = RT, suggesting that the mobile head can explore the reaction interfaces through stochastic processes within the time scale indicated by kinetic measurements.

Animals↗

PubMedDate not supplied

Chemical library subset selection algorithms: a unified derivation using spatial statistics.

If similar compounds have similar activity, rational subset selection becomes superior to random selection in screening for pharmacological lead discovery programs. Traditional approaches to this experimental design problem fall into two classes: (i) a linear or quadratic response function is assumed (ii) some space filling criterion is optimized. The assumptions underlying the first approach are clear but not always defendable; the second approach yields more intuitive designs but lacks a clear theoretical foundation. We model activity in a bioassay as realization of a stochastic process and use the best linear unbiased estimator to construct spatial sampling designs that optimize the integrated mean square prediction error, the maximum mean square prediction error, or the entropy. We argue that our approach constitutes a unifying framework encompassing most proposed techniques as limiting cases and sheds light on their underlying assumptions. In particular, vector quantization is obtained, in dimensions up to eight, in the limiting case of very smooth response surfaces for the integrated mean square error criterion. Closest packing is obtained for very rough surfaces under the integrated mean square error and entropy criteria. We suggest to use either the integrated mean square prediction error or the entropy as optimization criteria rather than approximations thereof and propose a scheme for direct iterative minimization of the integrated mean square prediction error. Finally, we discuss how the quality of chemical descriptors manifests itself and clarify the assumptions underlying the selection of diverse or representative subsets.

Journal Article↗

PubMed2005

The effect of low-temperature dynamics of the dimethylammonium group in [(CH3)2NH2]3Sb2Cl9 on proton spin-lattice relaxation and narrowing of the proton NMR line.

This paper reports the temperature dependence of the relaxation time T1 (55.2 and 90 MHz) and the second moment of the NMR line for protons in a polycrystalline sample of [NH2(CH3)2]3Sb2Cl9 (DMACA). The fundamental aspects of molecular dynamics from quantum tunneling at low temperatures to thermally activated reorientation at elevated temperatures have been studied. The experimentally observed spin-lattice relaxation rate is a consequence of dipolar interactions between the spin pairs inside the methyl group (1/T(1AE) contribution) as well as the spins belonging to neighboring methyl groups and pairs, methyl spin-outer methyl spin (1/T(1EE) contribution). These contributions are considered separately. Two methyl groups in the dimethylammonium (DMA) cations are dynamically inequivalent. The values of the tunnel splitting of separate methyl groups are obtained from the T1 (55.2 MHz) experiment. The tunneling dynamics taking place below the characteristic temperatures 74 and 42 K for separate methyl groups are discussed in terms of the Schrödinger equation. These temperatures point to the one at which thermal energy C(p)T and potential barrier take the same value. It is established that the second moment of the proton NMR line below 74 K up to liquid helium temperature is much lower than the rigid lattice value, which is due to a tunneling stochastic process of the methyl groups.

Antimony↗

PubMed2005

Ultrafast electron dynamics at metal interfaces: intraband relaxation of image state electrons as friction.

Two-photon photoemission of image potential states above monolayers of p-xylene/Ag(111) shows that electrons with different momenta have very different rise and decay rates as a function of parallel momentum. The dynamics are due to energy and momentum loss (intraband relaxation), which we model as a stochastic process isomorphic to the overdamped motion of a harmonic oscillator. The method extracts a friction coefficient from the data which can be explained by electron-electron scattering in a formalism based on the Lindhard dielectric function. One-electron excitations (interband transistions) dominate the dissipation mechanism, with a smaller contribution from collective electronic excitations (plasmons).

Journal Article↗

PubMed1998

Relevance of kinetochore size and microtubule-binding capacity for stable chromosome attachment during mitosis in PtK1 cells.

Chromosomes attach to the mitotic spindle via their kinetochores. The average number of spindle microtubules binding to each kinetochore varies with species, the stage of mitosis, and the length of time that the kinetochore has been attached to the spindle. In this report, we investigate how kinetochore microtubule number varies with kinetochore size and chromosome size in PtK1 cells. From an analysis of serial-section electron micrographs, we determined that the average surface area of metaphase, taxol-treated metaphase, and anaphase kinetochores is 0.16 +/- 0.05 microm2 (N = 181). Surprisingly, kinetochore microtubules are packed more densely on the smaller kinetochores, as seen by a reduction in the average spacing between kinetochore microtubules from 89 nm to 59 nm. Our interpretation of this result is that PtK1 cells require a minimum kinetochore microtubule-binding capacity for survival during repeated rounds of mitotic division. We estimate the lower limit to be 23 kinetochore microtubules and suggest that this capacity is required to ensure stable attachment during the dynamic and highly stochastic process of kinetochore fiber formation. There is a modest but statistically significant increase in kinetochore microtubule number with chromosome size, indicating that chromosome size is a minor determinant of kinetochore microtubule number.

Animals↗

PubMed2002

Adhesion of Staphylococcus aureus to implants with different physicochemical characteristics.

Adhesion of pathogenic Staphylococcus aureus (strain 209) to BT1-0 titanium disks (12 mm in diameter) with different coatings and noncoated was studied in vitro by photocolorimetry. Transparency of bacterial suspension in normal saline was evaluated after 2-h culturing with the implants at 37 degrees C. The decrease of S. aureus content in the suspension due to its adsorption on implants was negligible and increased by 0.9-5.5% in comparison with the control (adhesion to glass). When the specimens were placed into bacterial suspension, the density of staphylococcal adsorption on the surface considerably increased (by 9-53%) in comparison with the control, which attested to active participation of the implants in bacterial adsorption. The degree of bacterial adhesion to the implants decreased in the following order: disk with calcium phosphate ceramic coating-disk with calcium phosphate X-ray amorphous coating-disk without coating-disk with cermet coating. The adhesion of Staphylococcus is a stochastic process depending on the sum of implant characteristics, in particular, on the phase composition of the coating, electric conductivity, and Ca/P ionic ratio. The authors conclude that the formation of antibacterial properties of coating by saturating them with antibiotics or impregnation with metals, specifically silver ion implantation, is justified, because it reduces the postimplantation infection risk.

Adsorption↗

PubMed2003

An RAPD (random amplified polymorphic DNA) analysis of genetic population structure of Balea biplicata (Gastropoda: Clausiliidae) in fragmented floodplain forests of the Elster/Saale riparian system.

Eight German populations of the land snail Balea biplicata (Mollusca: Clausiliidae) were studied using the randomly amplified polymorphic DNA-polymerase chain reaction and morphometrics (principal component and discriminant analysis) to examine population structure and gene flow patterns in a fragmented landscape mosaic along the Elster/Saale riparian system, Germany. A variety of population genetic analyses targeting either more on the geographic scale of gene flow (genetic distances, F statistics, Mantel test) or on local genotypic structure (heterozygosity, linkage disequilibrium, bottleneck probability) showed that (1) the population system in total is governed by high gene flow independent of geographic distance, (2) genetic structure on the narrower sampling scale is mainly determined by stochastic processes due to genetic drift in small isolated and frequently recolonized populations, and (3) the morphometrical variation of the populations was related neither to habitat nor to genetic heterogeneity. The potentials for active and passive dispersal capacity of the snails and possible environmental impacts on their population structure are discussed.

Animals↗

PubMed2003

Quantitative biopharmaceutics classification system: the central role of dose/solubility ratio.

PURPOSE: To develop a quantitative biopharmaceutics drug classification system (QBCS) based on fundamental parameters controlling rate and extent of absorption. METHODS: A simple absorption model that considers transit flow, dissolution, and permeation processes stochastically was used to illustrate the primary importance of dose/solubility ratio and permeability on drug absorption. Simple mean time considerations for dissolution, uptake, and transit were used to identify relationships between the extent of absorption and a drug's dissolution and permeability characteristics. RESULTS: The QBCS developed relies on a (permeability, dose/ solubility ratio) plane with cutoff points 2 x 10(-6)-10(-5) cm/s for the permeability and 0.5-1 (unitless) for the dose/solubility ratio axes. Permeability estimates, P(app) are derived from Caco-2 studies, and a constant intestinal volume content of 250 ml is used to express the dose/solubility ratio as a dimensionless quantity, q. A physiologic range of 250-500 ml was used to account for variability in the intestinal volume. Drugs are classified into the four quadrants of the plane around the cutoff points according to their P(app), q values, establishing four drug categories. i.e., I (P(app) > 10(-5) cm/s, q < or = 0.5), II (P(app) > 10(-5) cm/s, q > 1), III (P(app) < 2 x 10(-6) cm/s. q < or = 0.5), and IV (P(app) < 2 x 10(-6) cm/s, q > 1). A region for borderline drugs (2 x 10(-6) < P(app) < 10(-5) cm/s, 0.5 < q < 1) was defined too. For category I, complete absorption is anticipated, whereas categories II and III exhibit dose/ solubility ratio-limited and permeability-limited absorption, respectively. For category IV, both permeability and dose/solubility ratio are controlling drug absorption. Semiquantitative predictions of the extent of absorption were pointed out on the basis of mean time considerations for dissolution, uptake, and transit in conjunction with drug's dose/solubility ratio and permeability characteristics. A set of 42 drugs were classified into the four categories, and the predictions of intestinal drug absorption were in accord with the experimental observations. CONCLUSIONS: The QBCS provides a basis for compound classification into four explicitly defined drug categories using the fundamental biopharmaceutical properties, permeability, and dose/solubility ratio. Semiquantitative predictions for the extent of absorption are essentially based on these drug properties, which either determine or are strongly related to the in vivo kinetics of drug dissolution and intestinal wall permeation.

Algorithms↗

PubMed2005

Patterns of continuity: a dynamic model for conceptualizing the stability of individual differences in psychological constructs across the life course.

In contemporary psychology there is debate over whether individual differences in psychological constructs are stable over extended periods of time. The authors argue that it is impossible to resolve such debates unless researchers focus on patterns of stability and the developmental mechanisms that may give rise to them. To facilitate this shift in emphasis, they describe a formal model that integrates 3 developmental processes: stochastic-contextual processes, person-environment transactions, and developmental constancies. The theoretical and mathematical analyses indicate that this model makes novel predictions about the way in which test-retest correlations are structured across a wide range of ages and test-retest intervals. The authors illustrate the utility of the model by comparing its predictions against meta-analytic data on Neuroticism. The discussion emphasizes the value of focusing on patterns of continuity, not only as phenomena to be explained but as data capable of clarifying the developmental processes underlying stability and change for a variety of psychological constructs.

Humans↗

PubMed1992

Olfactory cues influence female choice in two lek-breeding antelopes.

Pronounced differences in mating success between males holding territories clustered on traditional mating grounds (leks) are commonly cited as evidence of female choice for male phenotypes, but female ungulates appear to prefer particular territories even when no other individuals are on the lek. Female choice of territories may be influenced by spatial features, but observations suggest that females may also be attracted to successful territories by olfactory cues in the soil. Here we report that transferring the topsoil between successful and unsuccessful territories on leks of two reduncine antelope species caused the numbers of females and matings on the unsuccessful territories to increase tenfold. Females were probably attracted to the soil by smells that had accumulated from heavy use by other females. Because of this attraction, stochastic process may play an important part in generating the variance in mating success between territory holders on leks.

Animals↗

PubMed1979

Relative fitness of genotypes in a population of Rattus norvegicus polymorphic for warfarin resistance.

Resistance to warfarin and an increased vitamin K requirement appear to be pleiotropic effects of the same allele (Rw2). In a natural population containing resistant individuals where the use of warfarin is discouraged the change in the frequency of resistance should reflect the relative fitnesses of the three possible genotypes. A large polymorphic population of rats was extensively poisoned with warfarin and the level of resistance monitored regularly for a period of 18 months after withdrawal of the poison. During this period the proportion of resistant animals in live-capture samples decreased significantly from approximately 80 per cent to 33 per cent. This decline is consistent with a hypothesis of reduced fitness of both Rw2Rw2 and Rw1Rw2 genotypes relative to Rw1Rw1 under natural conditions. The relative fitnesses of these genotypes were calculated using an optimisation method based on least squares analysis. These estimates were: Rw2Rw2 (0.46), Rw1Rw2 (0.77) and Rw1Rw1 (1.00). Homozygous resistant individuals were found in some of the samples, confirming that the Rw2 allele does not act as a recessive lethal, although it must be extremely disadvantageous. Some heterogeneity was observed in the proportion of resistant animals in samples taken from different areas of the farm building complex. This could reflect stochastic processes influencing the Rw2 allele frequency in small peripheral populations.

Animals↗

PubMed1997

Nonrandom partition of mitochondria in heteroplasmic Drosophila.

In order to understand the status of heteroplasmy and its evolution within the Drosophila melanogaster subgroup, cytoplasm microinjections between eggs were performed involving three lineages of Drosophila simulans, carrying the siI, siII or siIII mtDNA type, respectively, and two strains of Drosophila mauritiana carrying the maI or maII mtDNA type. Progeny of eggs from all combinations of injection were analysed. The maII or siI molecules, when provided by the donor, were never detected in the offspring of the hosts, whatever the host's mitochondrial type. Heteroplasmic flies were detected when siII, siIII or maI mitochondria were injected into any of the other cytoplasms. In the majority of cases the percentage of foreign mtDNA increased over generations, leading to a complete replacement of the endogenous mtDNA. In most cases, siII was prevalent. The stochastic processes involved in the evolution of heteroplasmic states are strongly affected by selective values of the different mtDNA types, with a clear hierarchy among them: siII has the most advantage, then siIII and maI, and finally siI and maII. In the siII/maII heteroplasmy case, the loss of maII was more rapid at a high temperature.

Animals↗

PubMed2006

Variability and memory of protein levels in human cells.

Protein expression is a stochastic process that leads to phenotypic variation among cells. The cell-cell distribution of protein levels in microorganisms has been well characterized but little is known about such variability in human cells. Here, we studied the variability of protein levels in human cells, as well as the temporal dynamics of this variability, and addressed whether cells with higher than average protein levels eventually have lower than average levels, and if so, over what timescale does this mixing occur. We measured fluctuations over time in the levels of 20 endogenous proteins in living human cells, tagged by the gene for yellow fluorescent protein at their chromosomal loci. We found variability with a standard deviation that ranged, for different proteins, from about 15% to 30% of the mean. Mixing between high and low levels occurred for all proteins, but the mixing time was longer than two cell generations (more than 40 h) for many proteins. We also tagged pairs of proteins with two colours, and found that the levels of proteins in the same biological pathway were far more correlated than those of proteins in different pathways. The persistent memory for protein levels that we found might underlie individuality in cell behaviour and could set a timescale needed for signals to affect fully every member of a cell population.

Bacterial Proteins↗

PubMed1997

GM-CSF-mobilized peripheral blood CD34+ cells differ from steady-state bone marrow CD34+ cells in adhesion molecule expression.

To determine the effect of growth factor mobilization on the expression of adhesion molecules, we compared CD34+ progenitor cell (PC) populations from steady-state bone marrow (BM) with granulocyte-macrophage colony-stimulating factor (GM-CSF)-mobilized apheresis products (peripheral blood stem cell (PSC)) using flow cytometry. To increase the accuracy of this analysis, CD34+ cells were enriched (MiniMACS) before cytometric analysis. A significantly lower expression of very late antigen-4 (VLA-4), leukocyte function antigen-1 (LFA-1) and LFA-3 were observed on PSC compared to BM CD34+ cells. In addition, significantly lower mean fluorescence intensity (MFI) of VLA-4, VLA-5, intercellular adhesion molecule-1 (ICAM-1), and sialyl Lewisx were observed on PSC as compared to BM CD34+ cells. Significantly higher levels of L-selectin and CD44 expression were observed on PSC as compared to BM CD34+ cells based on frequency and MFI (P < or = 0.05). In addition, the duration of GM-CSF administration or number of prior aphereses had no effect on adhesion molecule expression. These data suggest that decreased expression of adhesion molecules including VLA-4, LFA-1, ICAM-1 and LFA-3 play a role in PC mobilization. Based on these studies, we suggest that PC mobilization occurs as a stochastic process and is associated with the selection of CD34+ cells with low adhesion molecule expression.

Adult↗

PubMed2005

Functional elements residing within satellite DNAs.

Satellite DNAs represent a fast-evolving portion of the eukaryotic genome whose evolution is proposed to be driven by the stochastic process of molecular drive. Recent results indicate that satellite DNAs are subject to certain structural constraints, which are probably related to their interaction with proteins involved in the establishment of specific chromatin structures. The evolutionary persistence and high sequence conservation of some satellites, as well as the presence of stage- or tissue-specific, differentially expressed transcripts in several species, are consistent with the hypothesis that satellite DNA could have a regulatory role in eukaryotic organisms. Although the role of most transcripts is not known, some act as precursors of small interfering RNAs, which are now recognized as having an important role in chromatin modulation and the control of gene expression. Furthermore, some transcripts are involved in the cellular response to stress.

Animals↗