DNA break clustering as a predictor of cell death across various radiation qualities: influence of cell size, cell asymmetry, and beam orientation.

Cosmic radiation, composed of high charge and energy (HZE) particles, causes cellular DNA damage that can result in cell death or mutation that can evolve into cancer. In this work, a cell death model is applied to several cell lines exposed to HZE ions spanning a broad range of linear energy transfer (LET) values. We hypothesize that chromatin movement leads to the clustering of multiple double strand breaks (DSB) within one radiation-induced foci (RIF).

Evaluating biomarkers to model cancer risk post cosmic ray exposure.

Robust predictive models are essential to manage the risk of radiation-induced carcinogenesis. Chronic exposure to cosmic rays in the context of the complex deep space environment may place astronauts at high cancer risk. To estimate this risk, it is critical to understand how radiation-induced cellular stress impacts cell fate decisions and how this in turn alters the risk of carcinogenesis.

Generalized time-dependent model of radiation-induced chromosomal aberrations in normal and repair-deficient human cells.

We have developed a model that can simulate the yield of radiation-induced chromosomal aberrations (CAs) and unrejoined chromosome breaks in normal and repair-deficient cells. The model predicts the kinetics of chromosomal aberration formation after exposure in the G₀/G₁ phase of the cell cycle to either low- or high-LET radiation. A previously formulated model based on a stochastic Monte Carlo approach was updated to consider the time dependence of DNA double-strand break (DSB) repair (proper or improper), and different cell types were assigned different kinetics of DSB repair.

Calculation of the energy deposition in nanovolumes by protons and HZE particles: geometric patterns of initial distributions of DNA repair foci.

The biological effects of high-linear energy transfer (LET) radiation are different from those caused by low-LET radiation due to the difference in the patterns of energy deposition in cells. In this work, we studied the role of the track structure in the spatial distribution of radiation-induced double-strand breaks (DSBs). In the first part, the irradiation of a cubic volume of 12 µm of side by 300 MeV protons (LET ∼0.

Computational model of chromosome aberration yield induced by high- and low-LET radiation exposures.

We present a computational model for calculating the yield of radiation-induced chromosomal aberrations in human cells based on a stochastic Monte Carlo approach and calibrated using the relative frequencies and distributions of chromosomal aberrations reported in the literature. A previously developed DNA-fragmentation model for high- and low-LET radiation called the NASARadiationTrackImage model was enhanced to simulate a stochastic process of the formation of chromosomal aberrations from DNA fragments. The current version of the model gives predictions of the yields and sizes of translocations, dicentrics, rings, and more complex-type aberrations formed in the G(0)/G(1) cell cycle phase during the first cell division after irradiation.

Nuclear interactions in heavy ion transport and event-based risk models.

The physical description of the passage of heavy ions in tissue and shielding materials is of interest in radiobiology, cancer therapy and space exploration, including a human mission to Mars. Galactic cosmic rays (GCRs) consist of a large number of ion types and energies. Energy loss processes occur continuously along the path of heavy ions and are well described by the linear energy transfer (LET), straggling and multiple scattering algorithms.

The analysis of the densely populated patterns of radiation-induced foci by a stochastic, Monte Carlo model of DNA double-strand breaks induction by heavy ions.

Purpose: To resolve the difficulty in counting merged DNA damage foci in high-LET (linear energy transfer) ion-induced patterns.

Materials And Methods: The analysis of patterns of RIF (radiation-induced foci) produced by high-LET Fe and Ti ions were conducted by using a Monte Carlo model that combines the heavy ion track structure with characteristics of the human genome on the level of chromosomes. The foci patterns were also simulated in the maximum projection plane for flat nuclei.

Stochastic properties of radiation-induced DSB: DSB distributions in large scale chromatin loops, the HPRT gene and within the visible volumes of DNA repair foci.

Purpose: We computed probabilities to have multiple double-strand breaks (DSB), which are produced in DNA on a regional scale, and not in close vicinity, in volumes matching the size of DNA damage foci, of a large chromatin loop, and in the physical volume of DNA containing the HPRT (human hypoxanthine phosphoribosyltransferase) locus.

Materials And Methods: The model is based on a Monte Carlo description of DSB formation by heavy ions in the spatial context of the entire human genome contained within the cell nucleus, as well as at the gene sequence level.

Results: We showed that a finite physical volume corresponding to a visible DNA repair focus, believed to be associated with one DSB, can contain multiple DSB due to heavy ion track structure and the DNA supercoiled topography.

Subtraction of background damage in PFGE experiments on DNA fragment-size distributions.

The non-random distribution of DNA breakage in pulsed-field gel electrophoresis (PFGE) experiments poses a problem of proper subtraction of the background damage to obtain a fragment-size distribution due to radiation only. As been pointed out by various authors, a naive bin-to-bin subtraction of the background signal will not result in the right DNA mass distribution histogram, and may even result in negative values. Previous more systematic subtraction methods have been based mainly on random breakage, appropriate for low-LET radiation but problematic for high LET.

A robust procedure for removing background damage in assays of radiation-induced DNA fragment distributions.

The non-random distribution of DNA breakage in PFGE (pulsed-field gel electrophoresis) experiments poses a problem of proper subtraction of the background DNA damage to obtain a fragment-size distribution due to radiation only. A naive bin-to-bin subtraction of the background signal will not result in the right DNA mass distribution histogram. This problem could become more pronounced for high-LET (linear energy transfer) radiation, because the fragment-size distribution manifests a higher frequency of smaller fragments.

Chromatin loops are responsible for higher counts of small DNA fragments induced by high-LET radiation, while chromosomal domains do not affect the fragment sizes.

Purpose: To apply a polymer model of DNA damage induced by high-LET (linear energy transfer) radiation and determine the influence of chromosomal domains and loops on fragment length distribution.

Materials And Methods: The yields of DSB (double-strand breaks) induced by high-LET radiation were calculated using a track structure model along with a polymer model of DNA packed in the cell nucleus. The cell nucleus was constructed to include the chromosomal domains and chromatin loops.

An adjustable-threshold algorithm for the identification of objects in three-dimensional images.

Motivation: To develop a highly accurate, practical and fast automated segmentation algorithm for three-dimensional images containing biological objects. To test the algorithm on images of the Drosophila brain, and identify, count and determine the locations of neurons in the images.

Results: A new adjustable-threshold algorithm was developed to efficiently segment fluorescently labeled objects contained within three-dimensional images obtained from laser scanning confocal microscopy, or two-photon microscopy.