SAMBO-GEOS: On three-dimensional substorm dynamics — A case study for 4 March 1979

For investigations of the isolated magnetospheric substorm the ground-based and satellite geophysical data are discussed. The active phase of the substorm has two parts: an active-convective phase and a classical active phase. The analysed data show that the breakup of the substorm takes place at closed and not very much stretched magnetic field lines.     

Neoplastic cell transformation by high-LET radiation: molecular mechanisms.

Experimental data on molecular mechanisms are essential for understanding the bioeffects of radiation and for developing biophysical models, which can help in determining the shape of dose-response curves at very low doses, e.g., doses less than 1 cGy. Although it has been shown that ionizing radiation can cause neoplastic cell transformation directly, that high-LET heavy ions in general can be more effective than photons in transforming cells, and that the radiogenic cell transformation is a multi-step process [correction of processes], we know very little about the molecular nature of lesions important for cell transformation, the relationship between lethal and transformational damages, and the evolution of initial damages into final chromosomal aberrations which alter the growth control of cells. Using cultured mouse embryo cells (C3H10T1/2) as a model system, we have collected quantitative data on dose-response curves for heavy ions with various charges and energies. An analysis of these quantitative data suggested that two DNA breaks formed within 80 angstroms may cause cell transformation and that two DNA breaks formed within 20 angstroms may be lethal. Through studies with restriction enzymes which produce DNA damages at specific sites, we have found that DNA double strand breaks, including both blunt- and cohesive-ended breaks, can cause cell transformation in vitro. These results indicate that DNA double strand breaks can be important primary lesions for radiogenic cell transformation and that blunt-ended double strand breaks can form lethal as well as transformational damages due to misrepair or incomplete repair in the cell. The RBE-LET relationship is similar for HGPRT gene mutation, chromosomal deletion, and cell transformation, suggesting common lesions may be involved in these radiation effects. The high RBE of high-LET radiation for cell killing and neoplastic cell transformation is most likely related to its effectiveness in producing DNA double strand breaks in mammalian cells. At present the role of oncogenes in radiation cell transformation is unclear.     

Software intensive systems safety analysis

Two important elements in the avionics suite of modern aircraft are: the flight control system (FCS) and the flight management system (FMS). The FCS provides the capability to stabilize and control the aircraft, while the FMS is responsible for flight planning and navigation. A clear trend in the aerospace industry is to place greater reliance on software systems, and many FCS and FMS subsystems are implemented primarily in software. For example, within the FCS is the flight guidance system (FGS) that generates roll and pitch guidance commands. Similarly, within the FMS is the vertical navigation (VNAV) function that acts like a third crew member in the cockpit, ordering mode change requests and resetting target altitude values to enable the aircraft to track the vertical flight plan. We have developed formal, executable models of the requirements for the mode logic of a FGS and for portions of the VNAV functionality. We have also conducted a comprehensive software safety analysis on the FGS mode logic model, and are completing the analysis of the VNAV model. This analysis uses as its starting point several "traditional" safety analysis techniques such as a functional hazard assessment (FHA), a fault tree analysis (FTA), and a failure mode effects analysis (FMEA). However, we are also using formal methods techniques known as model checking and theorem proving to verify the presence of safety properties in the model. This paper summarizes the (now completed) safety analysis that was performed on the FGS model, and highlights the similarities and differences with the (still on-going) safety analysis of the FMS model. In particular, we summarize progress made to date in the use of formal methods to verify the presence of the required safety properties in the models themselves.     

Neoplastic transformation of hamster embryo cells by heavy ions

We have studied the induction of morphological transformation of Syrian hamster embryo cells by low doses of heavy ions with different linear energy transfer (LET), ranging from 13 to 400 keV/μm. Exponentially growing cells were irradiated with ¹²C or ²⁸Si ion beams generated by the Heavy Ion Medical Accelerator in Chiba (HIMAC), inoculated to culture dishes, and transformed colonies were identified when the cells were densely stacked and showed a crisscross pattern. Over the LET range examined, the frequency of transformation induced by the heavy ions increased sharply at very low doses no greater than 5 cGy. The relative biological effectiveness (RBE) of the heavy ions relative to 250 kVp X-rays showed an initial increase with LET, reaching a maximum value of about 7 at 100 keV/μm, and then decreased with the further increase in LET. Thus, we confirmed that high LET heavy ions are significantly more effective than X-rays for the induction of in vitro cell transformation.     

Repair of DNA double-strand breaks and cell killing by charged particles.

It has been suggested that it is not simple double-strand breaks (dsb) but the non-reparable breaks which correlate well with the high biological effectiveness of high LET radiations for cell killing (Kelland et al., 1988; Radford, 1986). We have compared the effects of charged particles on cell death in 3 pairs of cell lines which are normal or defective in the repair of DNA dsbs. For the cell lines SL3-147, M10, and SX10 which are deficient in DNA dsb repair, RBE values were close to unity for cell killing induced by charged particles with linear energy transfer (LET) up to 200 keV/micrometer and were even smaller than unity for the LET region greater than 300 keV/micrometer. The inactivation cross section (ICS) increased with LET for all 3 pairs. The ICS of dsb repair deficient mutants was always larger than that of their parents for all the LET ranges, but with increasing LET the difference in ICS between the mutant and its parent became smaller. Since a small difference in ICS remained at LET of about 300 keV/micrometer, dsb repair may still take place at this high LET, even if its role is apparently small. These results suggest that the DNA repair system does not play a major role in protection against the attack of high LET radiations and that a main muse of cell death is non-reparable dsb which are produced at a higher yield compared with low LET radiations. No correlation was observed between DNA content or nuclear area and ICS.     

Effect of track structure and radioprotectors on the induction of oncogenic transformation in murine fibroblasts by heavy ions

The oncogenic potential of high-energy ⁵⁶Fe particles (1 GeV/nucleon) accelerated with the Alternating Gradient Synchrotron at the Brookhaven National Laboratory was examined utilizing the mouse C3H 10T1/2 cell model. The dose-averaged LET for high-energy ⁵⁶Fe is estimated to be 143 keV/μm with the exposure conditions used in this study. For ⁵⁶Fe ions, the maximum relative biological effectiveness (RBE_max) values for cell survival and oncogenic transformation were 7.71 and 16.5 respectively. Compared to 150 keV/μm ⁴He nuclei, high-energy ⁵⁶Fe nuclei were significantly less effective in cell killing and oncogenic induction. The prostaglandin E₁ analog misoprostol, an effective oncoprotector of C3H 10T1/2 cells exposed to X rays, was evaluated for its potential as a radioprotector of oncogenic transformation with high-energy ⁵⁶Fe. Exposure of cells to misoprostol did not alter ⁵⁶Fe cytotoxicity or the rate of ⁵⁶Fe-induced oncogenic transformation.     

Clinorotation reduces number, but not size, of cartilaginous nodules formed in micromass cultures of mouse limbbud cells.

In previous studies we used a ground based model to investigate the cellular responses to microgravity by exposing micromass cultures of embryonic limb cells to simulated weightlessness on a clinostat. Cultures set up in T-flasks and rotated at 30 rpm showed that clinostatted cultures had less chondrocyte differentiation than stationary or rotation controls, as assessed by number of nodules/culture stained with cartilage specific Alcian blue. In the current study, nodule size and shape of these nodules was assessed by interactive measurement of area, perimeter, circularity, and equivalent diameters, using the Optimas imaging software. Results show no significant difference in any of the measurements, indicating that clinorotation has no effect on expansion of the nodules either by differentiation of cells within the nodule, or by recruitment of cells into the nodule. The reduction in number of nodules without an alteration in size and shape indicates that the effect of simulated microgravity is to reduce the cell interactions required for the initial condensation of cells into a nodule, probably by interference with cell adhesion molecules.     

New evidence for strong non-thermal effects in Tycho’s supernova remnant

For the case of Tycho’s supernova remnant (SNR), we present the relation between the blast wave and contact discontinuity radii calculated within the nonlinear kinetic theory of cosmic ray (CR) acceleration in SNRs. It is demonstrated that these radii are confirmed by recently published Chandra measurements which show that the observed contact discontinuity radius is very close to the shock radius. Therefore a consistent explanation of these observations can be given in terms of efficient CR acceleration which makes the medium more compressible.     

Tissue responses to low protracted doses of high LET radiations or photons: early and late damage relevant to radio-protective countermeasures.

Early and late murine tissue responses to single or fractionated low doses of heavy charged particles, fission-spectrum neutrons or gamma rays are considered. Damage to the hematopoietic system is emphasized, but results on acute lethality, host response to challenge with transplanted leukemia cells and life-shortening are presented. Low dose rates per fraction were used in some neutron experiments. Split-dose lethality studies (LD 50/30) with fission neutrons indicated greater accumulation of injury during a 9 fraction course (over 17 days) than was the case for gamma-radiation. When total doses of 96 or 247 cGy of neutrons or gamma rays were given as a single dose or in 9 fractions, a significant sparing effect on femur CFU-S depression was observed for both radiation qualities during the first 11 days, but there was not an earlier return to normal with dose fractionation. During the 9 fraction sequence, a significant sparing effect of low dose rate on CFU-S depression was observed in both neutron and gamma-irradiated mice. CFU-S content at the end of the fractionation sequence did not correlate with measured LD 50/30. Sustained depression of femur and spleen CFU-S and a significant thrombocytopenia were observed when a total neutron dose of 240 cGy was given in 72 fractions over 24 weeks at low dose rates. The temporal aspects of CFU-S repopulation were different after a single versus fractionated neutron doses. The sustained reduction in the size of the CFU-S population was accompanied by an increase in the fraction in DNA synthesis. The proliferation characteristics and effects of age were different for radial CFU-S population closely associated with bone, compared with the axial population that can be readily aspirated from the femur. In aged irradiated animals, the CFU-S proliferation/redistribution response to typhoid vaccine showed both an age and radiation effect. After high single doses of neutrons or gamma rays, a significant age- and radiation-related deficiency in host defense mechanisms was detected by a shorter mean survival time following challenge with transplantable leukemia cells. Comparison of dose-response curves for life shortening after irradiation with fission-spectrum neutrons or high energy silicon particles indicated high initial slopes for both radiation qualities at low doses, but for higher doses of silicon, the effect per Gy decreased to a value similar to that for gamma rays. The two component life-shortening curve for silicon particles has implications for the potential efficacy of radioprotectants. Recent studies on protection against early and late effects by aminothiols, prostaglandins, and other compounds are discussed.     

Propagation and interaction of interplanetary transient disturbances. Numerical simulations

We study the heliocentric evolution of ICME-like disturbances and their associated transient forward shocks (TFSs) propagating in the interplanetary (IP) medium comparing the solutions of a hydrodynamic (HD) and magnetohydrodynamic (MHD) models using the ZEUS-3D code [Stone, J.M., Norman, M.L., 1992. Zeus-2d: a radiation magnetohydrodynamics code for astrophysical flows in two space dimensions. i – the hydrodynamic algorithms and tests. Astrophysical Journal Supplement Series 80, 753–790]. The simulations show that when a fast ICME and its associated IP shock propagate in the inner heliosphere they have an initial phase of about quasi-constant propagation speed (small deceleration) followed, after a critical distance (deflection point), by an exponential deceleration. By combining white light coronograph and interplanetary scintillation (IPS) measurements of ICMEs propagating within 1 AU [Manoharan, P.K., 2005. Evolution of coronal mass ejections in the inner heliosphere: a study using white-light and scintillation images. Solar Physics 235 (1–2), 345–368], such a critical distance and deceleration has already been inferred observationally. In addition, we also address the interaction between two ICME-like disturbances: a fast ICME 2 overtaking a previously launched slower ICME 1. After interaction, the leading ICME 1 accelerates and the tracking ICME 2 decelerates and both ICMEs tend to arrive at 1 AU having similar speeds. The 2-D HD and MHD models show similar qualitative results for the evolution and interaction of these disturbances in the IP medium.