Showing papers in "Basic life sciences in 1994"

Comparison of Various Monte Carlo Track Structure Codes for Energetic Electrons in Gaseous and Liquid Water

Abstract: Cross sections for kurbuc, a Monte Carlo track structure code simulating histories of electrons, molecular interaction by interaction, in the energy range of 10 eV to 10 MeV, have been presented. Comparisons have been made for four independent Monte Carlo track structure codes for energetic electrons in gaseous and liquid water. The comparisons have been made in terms of point kernels for interactions and energy absorbed, and frequencies of energy depositions in cylindrical volumes of sizes similar to biological macromolecules. Comparisons have been made for 100 eV, 300 eV, 500 eV, 1 keV, 10 keV and 100 keV monoenergetic electrons. The four electron codes used in this study are moca8b and kurbuc for water vapour and orec and cpa100 for liquid water. A summary of cross sections used in each code has been presented. The comparisons show similarities and differences in clustering properties of the four codes.

Monte Carlo Track-Structure Calculations for Aqueous Solutions Containing Biomolecules

Abstract: Detailed Monte Carlo calculations provide a powerful tool for understanding mechanisms of radiation damage to biological molecules irradiated in aqueous solution This paper describes the computer codes, OREC and RADLYS, which have been developed for this purpose over a number of years Some results are given for calculations of the irradiation of pure water Comparisons are presented between computations for liquid water and water vapor Detailed calculations of the chemical yields of several products from X-irradiated, oxygen-free glycylglycine solutions have been performed as a function of solute concentration Excellent agreement is obtained between calculated and measured yields The Monte Carlo analysis provides a complete mechanistic picture of pathways to observed radiolytic products This approach, successful with glycylglycine, will be extended to study the irradiation of oligonucleotides in aqueous solution

Track Structure, Chromosome Geometry and Chromosome Aberrations

Abstract: The joint role of radiation track structure and chromosome geometry in determining yields of chromosome aberrations is discussed. Ideally, the geometric models of chromosomes used for analyzing aberration yields should have the same degree of realism as track structure models. However, observed chromosome aberrations are produced by processes on comparatively large scales, e.g., misrepair involving two DSB located on different chromosomes or two DSB separated by millions of base pairs on one chromosome, and quantitative models for chromatin on such large scales have to date almost never been attempted. We survey some recent data on large-scale chromosome geometry, mainly results obtained with fluorescence in situ hybridization (“chromosome painting”) techniques. Using two chromosome models suggested by the data, we interpret the relative yields, at low and high LET, of inter-chromosomal aberrations compared to intra-chromosomal, inter-arm aberrations. The models consider each chromosome confined within its own “chromosome localization sphere,” either as a random cloud of points in one model or as a confined Gaussian polymer in the other. In agreement with other approaches, our results indicate that at any given time during the G 0/G l part of the cell cycle a chromosome is largely confined to a sub-volume comprising less than 10% of the volume of the cell nucleus. The possible significance of the ratio of inter-chromosomal aberrations to intra-chromosomal, inter-arm aberrations as an indicator of previous exposure to high LET radiation is outlined.

Direct ionization of DNA in solution.

Abstract: Most of the energy absorbed in the cell nucleus from a radiation field goes into the aqueous medium that surrounds macromolecules, like DNA, which are critical to the normal function of cells. This part of the energy deposition produces numerous reactive species that can diffuse to DNA sequences and induce chemical changes. The average diffusion distance of the free radicals that mediate this indirect mode of DNA damage is only a few nanometers because the cellular medium contains a high concentration of molecules that rapidly scavenge the radiation-induced species. Under these conditions, direct interaction of the radiation field with DNA can not be neglected as a potential mode of damage induction. Two aspects of the direct effect will be discussed in this paper: (1) screening of the interaction between DNA and charged particles by the dielectric response of the aqueous medium and (2) the impact-parameter dependence of these interactions.

Monte Carlo Approach in Assessing Damage in Higher Order Structures of DNA

Abstract: We have developed a computer monitor of nuclear DNA in the form of chromatin fibre. The fibres are modeled as a ideal solenoid consisting of twenty helical turns with six nucleosomes per turn. The chromatin model, in combination with are Monte Carlo theory of radiation damage induces by charged particles, based on general features of tack structure and stopping power theory, has been used to evaluate the influence of DNA structure on initial damage. An interesting has emerged from our calculations. Our calculated results predict the existence of strong spatial correlations in damage sites associated with the symmetries in the solenoidal model. We have calculated spectra of short fragments of double stranded DNA produced by multiple double strand breaks induced by both high and low LET radiation. The spectra exhibit peaks at multiples of approximately 85 base pairs (the nucleosome periodicity), and approximately 1000 base pairs (solenoid periodicity). Preliminary experiments to investigate the fragment distributions from irradiated DNA, made by B. Rydberg at Lawrence Berkeley Laboratory, confirm the existence of short DNA fragments and are in substantial agreement with the predictions of our theory.

Charged-particle transport in biomolecular media: the third generation.

Abstract: We describe Monte Carlo codes that simulate, event by event, the interaction of energetic electrons with a double-stranded DNA molecule and with the condensed water surrounding it. Both direct and indirect effects are treated explicitly. The cross-sectional input necessary in the transport codes was obtained via quantum-mechanical calculations of the dielectric response function, e(q,ω), of polycytidine. For each inelastic event on DNA we score the energy deposited locally, the position of the event and the moiety that underwent that event. This information provides a detailed picture of the spatial disposition of molecular alterations for DNA exposed to ionizing radiation.

A nucleosome model for the simulation of DNA strand break experiments.

Abstract: Using a set of Monte Carlo simulation models, track structures of 125I Auger electrons generated in liquid water are superimposed on a nucleosome DNA model able to precisely localize energy deposition events on sub-molecular units of the DNA strands. After scoring direct hits taking place during the physical phase (at about 10−15 s) the radiation chemistry of the whole system is simulated between 10−12 and 10−8 s, taking into account all reactions between water radio-chemical species, radicals, sub-molecular units of DNA (Ribose, Adenine, Thymine, Guanine and Cytosine), and scavengers like Tris or Formate ions.

The ERabp gene family: structural and physiological analyses.

Abstract: Auxins are a group of phytohormones that influence a wide range of growth and developmental responses in plants. Effects induced by auxins include a stimulation of cell enlargement and stem growth, cell division, vascular tissue differentiation, initiation of roots on stem cuttings, the development of branch roots and the differentiation of roots in tissue culture (Davies, 1987). Although auxin can inhibit the growth of a primary root at rather low concentrations, probably due to the induction of ethylene production, lateral branch roots and adventitious roots are stimulated by high auxin levels, an effect that has been very useful in horticultural practice for plant propagation by cuttings (see chapter by Blakesley, by Haissig and Davis, and by Howard in this volume).

A computational approach to the relationship between radiation induced double strand breaks and translocations

Abstract: A theoretical framework is presented which provides a quantitative analysis of radiation induced translocations between the ab1 oncogene on CH9q34 and a breakpoint cluster region, bcr, on CH 22q11. Such translocations are associated frequently with chronic myelogenous leukemia. The theory is based on the assumption that incorrect or unfaithful rejoining of initial double strand breaks produced concurrently within the 200 kbp intron region upstream of the second abl exon, and the 16.5 kbp region between bcr exon 2 and exon 6 interact with each other, resulting in a fusion gene. for an x-ray dose of 100 Gy, there is good agreement between the theoretical estimate and the one available experimental result. The theory has been extended to provide dose response curves for these types of translocations. These curves are quadratic at low doses and become linear at high doses.

Computational Biology Opportunity and Challenges for the Future

Abstract: Recent developments in high performance computers and computing methods have opened new avenues for tackling serious, important and challenging problems in biology and medicine. Only a few years back these problems were considered too complex and difficult, if not impossible to solve. An understanding of cross-disciplinary knowledge will be a prerequisite for applications of this enormous computing capability to enhance our understanding of governing principals in biology and medicine. We will show some specific research areas where computational biology can be applied effectively and then provide some ideas on future applications.

Three Statistical Technologies with High Potential in Biological Imaging and Modeling

Abstract: The three technologies that are surveyed here are (1) wavelet approximations, (2) hidden Markov models, and (3) the Markov chain Renaissance. The intention of the article is to provide an introduction to the benefits these technologies offer and to explain as far as possible the sources of their effectiveness. We also hope to suggest some useful relationships between these technologies and issues of importance on the agenda of biological and medical research.