Cognitive deficits induced by 56Fe radiation exposure.

Exposing rats to particles of high energy and charge (e.g., 56Fe) disrupts neuronal systems and the behaviors mediated by them; these adverse behavioral and neuronal effects are similar to those seen in aged animals. Because cognition declines with age, and our previous study showed that radiation disrupted Morris water maze spatial learning and memory performance, the present study used an 8-arm radial maze (RAM) to further test the cognitive behavioral consequences of radiation exposure. Control rats or rats exposed to whole-body irradiation with 1.0 Gy of 1 GeV/n high-energy 56Fe particles (delivered at the alternating gradient synchrotron at Brookhaven National Laboratory) were tested nine months following exposure. Radiation adversely affected RAM performance, and the changes seen parallel those of aging. Irradiated animals entered baited arms during the first 4 choices significantly less than did controls, produced their first error sooner, and also tended to make more errors as measured by re-entries into non-baited arms. These results show that irradiation with high-energy particles produces age-like decrements in cognitive behavior that may impair the ability of astronauts to perform critical tasks during long-term space travel beyond the magnetosphere.     

Behavioral and neurochemical abnormalities after exposure to low doses of high-energy iron particles.

Exposure of rats to high-energy iron particles (600 MeV/amu) has been found to alter behavior after doses as low as 10 rads. The performance of a task that measures upper body strength was significantly degraded after irradiation. In addition, an impairment in the regulation of dopamine release in the caudate nucleus (a motor center in the brain), lasting at least 6 months, was also found and correlated with the performance deficits. A general indication of behavioral toxicity and an index of nausea and emesis, the conditioned taste aversion, was also evident. The sensitivity to iron particles was 10-600 times greater than to gamma photons. These results suggest that behavioral and neurobiological damage may be a consequence of exposure to low doses of heavy particles and that this possibility should be extensively studied.     

Quantitation of heavy ion damage to the mammalian brain: some preliminary findings.

Histological preparations of brains from rabbits and mice exposed to different doses of various HZE particles or to low-LET photons have been subjected to preliminary quantitation of radiation-induced morphometric changes. Computer assisted measurements of several brain structures and cell types have been made using the KONTRON Automated Interactive Measurement System (IBAS, Carl Zeiss, Inc., Thornwood, N.Y. 10594 U.S.A.). New Zealand white rabbits irradiated at approximately 6 weeks of age were euthanatized 6.5-25 months after exposure to 60Co gamma photons (LET infinity = approximately 0.3 keV/micrometer, 20Ne particles (LET infinity = 35 +/- 3 keV/micrometer), or 40Ar particles (LET infinity = 90 +/- 5 keV/micrometer). Measurements of stained sections of the olfactory bulbs of those animals indicate that the mean size (volume) of olfactory glomeruli is reduced in a dose-dependent (and perhaps an LET-dependent) manner as soon as 6.5 months after irradiation. Differences between mean volumes of additional structures have been noted when histological preparations of control mouse brains were compared with irradiated specimens. Quantitation of intermediate and late changes in nervous (and other) tissues exposed to low- and high-LET radiations will improve our ability to predict late effects in tissues of astronauts and others exposed to the radiation hazards of the space environment.     

High-LET radiation carcinogenesis.

Recent results for neutron radiation-induced tumors are presented to illustrate the complexities of the dose-response curves for high-LET radiation. It is suggested that in order to derive an appropriate model for dose-response curves for the induction of tumors by high-LET radiation it is necessary to take into account dose distribution, cell killing and the susceptibility of the tissue under study. Preliminary results for the induction of Harderian gland tumors in mice exposed to various heavy ion beams are presented. The results suggest that the effectiveness of the heavy ion beams increases with increasing LET. The slopes of the dose-response curves for the different high-LET radiations decrease between 20 and 40 rads and therefore comparisons of the relative effectiveness should be made from data obtained at doses below about 20-30 rads.     

The effects of proton radiation on UHMWPE material properties for space flight and medical applications

Ultra High Molecular Weight Polyethylene (UHMWPE) is a polymer widely used as a radiation shielding material in space flight applications and as a bearing material in total joint replacements. As a long chain hydrocarbon based polymer, UHMWPE’s material properties are influenced by radiation exposure, and prior studies show that gamma irradiation is effective for both medical sterilization and increased wear resistance in total joint replacement applications. However, the effects of space flight radiation types and doses on UHMWPE material properties are poorly understood. In this study, three clinically relevant grades of UHMWPE (GUR 1020, GUR 1050, and GUR 1020 blended with Vitamin E) were proton irradiated and tested for differences in material properties. Each of the three types of UHMWPE was irradiated at nominal doses of 0 Gy (control), 5 Gy, 10 Gy, 20 Gy, and 35 Gy. Following irradiation, uniaxial tensile testing and thermal testing using Differential Scanning Calorimetry (DSC) and Dynamic Mechanical Analysis (DMA) were performed. Results show small but significant changes in several material properties between the control (0 Gy) and 35 Gy samples, indicating that proton irradiation could have a effect on the long term performance of UHMWPE in both medical and space flight applications.     

Large-size space laboratory for biological orbit experiments.

The study of space factors on living systems has great interest and long-term experiments during orbital flight will be important tool for increasing our knowledge. Realization of such experiments is limited by constraints of modern space stations. A new technology of large-size space laboratory for biological experiments has been developed on the basis of polymerization techniques. Using this technique there are no limits of form and size of laboratory for a space station that will permit long term experiments on Earth orbit with plants and animals in sufficient volume for creation of closed self-regulating ecological systems. The technology is based on experiments of the behavior of polymer materials in simulated free space conditions during the reaction of polymerization. The influences of space vacuum, sharp temperature changes and space plasma generated by galactic rays and Sun irradiation on chemical reaction were evaluated in their impact on liquid organic materials in laboratory conditions. The results of our study shows, that the chemical reaction is sensitive to such space factors. But we believe that the technology of polymerization could be used for the creation of space biological laboratories in Earth orbit in the near future.     

CNS-induced deficits of heavy particle irradiation in space: the aging connection.

Our research over the last several years has suggested that young (3 mo) rats exposed to whole-body 56Fe irradiation show neuronal signal transduction alterations and accompanying motor behavioral changes that are similar to those seen in aged (22-24 mo) rats. Since it has been postulated that 1-2% of the composition of cosmic rays contain 56Fe particles of heavy particle irradiation, there may be significant CNS effects on astronauts on long-term space flights which could produce behavioral changes that could be expressed during the mission or at some time after the return. These, when combined with other effects such as weightlessness and exposure to proton irradiations may even supercede mutagenic effects. It is suggested that by determining mechanistic relationships that might exist between aging and irradiation it may be possible to determine the common factor(s) involved in both perturbations and develop procedures to offset their deleterious effects. For example, one method that has been effective is nutritional modification.     

Blood and small intestine cell kinetics under radiation exposures: Mathematical modeling

Mathematical models which describe the dynamics of two vital body systems (hematopoiesis and small intestinal epithelium) in mammals exposed to acute and chronic radiation are developed. These models, based on conventional biological theories, are implemented as systems of nonlinear differential equations. Their variables and constant parameters have clear biological meaning, that provides successful identification and verification of the models in hand. It is shown that the predictions of the models qualitatively and quantitatively agree with the respective experimental data for small laboratory animals (mice, rats) exposed to acute/chronic irradiation in wide ranges of doses and dose rates. The explanation of a number of radiobiological effects, including those of the low-level long-term exposures, is proposed proceeding from the modeling results. All this bears witness to the validity of employment of the developed models, after a proper identification, in investigation and prediction of radiation effects on the hematopoietic and small intestinal epithelium systems in various mammalian species, including humans. In particular, the models can be used for estimating effects of irradiation on astronauts in the long-term space missions, such as Lunar colonies and Mars voyages.     

Comparison of hindlimb unloading and partial weight suspension models for spaceflight-type condition induced effects on white blood cells

Animal models are frequently used to assist in the determination of the long- and short-term effects of space flight. The space environment, including microgravity, can impact many physiological and immunological system parameters. It has been found that ground based models of microgravity produce changes in white blood cell counts, which negatively affects immunologic function. As part of the Center of Acute Radiation Research (CARR), we compared the acute effects on white blood cell parameters induced by the more traditionally used animal model of hindlimb unloading (HU) with a recently developed reduced weightbearing analog known as partial weight suspension (PWS). Female ICR mice were either hindlimb unloaded or placed in the PWS system at 16% quadrupedal weightbearing for 4 h, 1, 2, 7 or 10 days, at which point complete blood counts were obtained. Control animals (jacketed and non-jacketed) were exposed to identical conditions without reduced weightbearing. Results indicate that significant changes in total white blood cell (WBC), neutrophil, lymphocyte, monocyte and eosinophil counts were observed within the first 2 days of exposure to each system. These differences in blood cell counts normalized by day 7 in both systems. The results of these studies indicate that there are some statistically significant changes observed in the blood cell counts for animals exposed to both the PWS and HU simulated microgravity systems.     

The role of gravity in the evolutionary emergence of multicellular complexity: Microgravity effects on arthropod development and aging

While experiments carried out in Space with isolated cells have shown that eucaryotic cells are able to sense and respond to the absence of gravity by modifying their reactions, experiments in which more complex processes have been investigated, such as Biological Systems undergoing development under Microgravity, have been surprisingly unaffected by the space environment. This can be considered a curious result since all organisms are evolutionarily adapted to the current level of the gravity force in our planet and should eventually change if this parameter will vary in a permanent manner. In fact, the small effects of the modifications in gravity on development in short term experiments may be equivalent to the difficulties in detecting the involvement of other basic physical processes such as diffusion-controled auto-organizative reactions in currently developing biological systems. An apparent exception to this lack of effect is experiments where brine shrimp dormant gastrulae directly exposed to the space environment accumulate developmental defects as a consequence of cosmic irradiation. In this article we discuss the idea that at a certain stage during the evolutionary emergence of multicellular organisms the cues laid by generic forces such as gravity were involved in the evolutionary organization of these primitive organisms. As evolution proceed, these early mechanisms may have been obscured and/or made redundant by the appearance of new internal, environment-independent biological regulatory mechanisms. On the other hand, behavioral responses that may be important, for example, in setting the life-spans of organisms may still be more readily susceptible to manipulation by external cues as experiments carried out by our group in Space and on the ground with Drosophila melanogaster indicate.     

Protection by WR-2721 and WR-151327 against late effects of gamma rays and neutrons.

Two thiophosphoroate compounds WR-2721 and WR-151327 were assessed for their ability to modify the deleterious effects (life shortening and carcinogenesis) of fission-spectrum neutrons (kerma-weighted mean energy of 0.85 MeV) or gamma rays on B6CF1 hybrid mice. Male and female mice, 200 of each sex per experimental group, were irradiated individually at 110 days of age. Radioprotectors (400 mg/kg of WR-2721 or 580 mg/kg of WR-151327) were administered intraperitoneally 30 min prior to irradiation. Neutron doses were 10 cGy or 40 cGy and gamma ray doses were 206 cGy or 417 cGy. Animals were housed five to a cage; cage locations in the holding rooms were randomized by computer. Animals were checked daily and all deceased animals were necropsied. WR-2721 afforded protection against both neutron- and gamma-ray-induced carcinogenesis and subsequent life shortening. Cumulative survival curves for unirradiated mice of either sex were unaffectecd by protectors. WR-2721 protected irradiated groups against life shortening by approximately 10 cGy of neutrons or 100 cGy of gamma rays. WR-151327 was as effective as WR-2721 against neutron irradiation.     

Late cataractogenesis in primates and lagomorphs after exposure to particulate radiations.

Rhesus monkeys that were exposed in 1969, at the age of approximately 2 years, to low doses of "mixed-energy" protons (10- and 110-MeV) are exhibiting progressive (degenerative) lenticular changes. We have conducted regular examinations of this group of monkeys for cataractogenic development since 1987, i.e., 18 years after irradiation, and the animals began to show enhanced degrees of lenticular opacification two years later. The lenses of age-matched controls (median lifespan in captivity approximately 24 years) continue to exhibit much lower levels of opacification (senile cataracts). Trends in the new data are consistent with the cataractogenic patterns observed for other groups of monkeys that were exposed at similar ages in 1964 and 1965 to protons of different energies, and which we began to monitor only 20-21 years later. Therefore, the new information from the mixed-energy group of monkeys provides insight into the development of late cataractogenic sequelae in the other groups of animals during the 2-3 years before we began to measure them. Comparisons are also made here among recent results from the different groups of primates and from New Zealand white (NZW) rabbits that were exposed when young to 56Fe ions and monitored continuously thereafter. This is done because analogous expression of radiation-induced degenerative cataractogenesis also occurs late in the lifespan of the lagomorphs (control median lifespan in captivity approximately 5-7 years), but in this case the cataractogenic profile has been documented through most of the post-irradiation lifespan.     

The influence of dose, dose-rate and particle fragmentation on cataract induction by energetic iron ions.

Because activities in space necessarily involve chronic exposure to a heterogeneous charged particle radiation field it is important to assess the influence of dose-rate and the possible modulating role of heavy particle fragmentation on biological systems. Using the well-studied cataract model, mice were exposed to plateau 600 MeV/amu 56Fe ions either as acute or fractionated exposures at total doses of 5 - 504 cGy. Additional groups of mice received 20, 360 and 504 cGy behind 50 mm of polyethylene, which simulates body shielding. The reference radiation consisted of 60Co gamma radiation. The animals were examined by slit lamp biomicroscopy over their three year life spans. In accordance with our previous observations with heavy particles, the cataractogenic potential of the 600 MeV/amu 56Fe ions was greater than for low-LET radiation and increased with decreasing dose relative to gamma-rays. Fractionation of a given dose of 56Fe ions did not reduce the cataractogenicity of the radiation compared to the acute regimen. Fragmentation of the beam in the polyethylene did not alter the cataractotoxicity of the ions, either when administered singly or in fractions.     

The effects of proton exposure on neurochemistry and behavior.

Future space missions will involve long-term travel beyond the magnetic field of the Earth, where astronauts will be exposed to radiation hazards such as those that arise from galactic cosmic rays. Galactic cosmic rays are composed of protons, alpha particles, and particles of high energy and charge (HZE particles). Research by our group has shown that exposure to HZE particles, primarily 600 MeV/n and 1 GeV/n 56Fe, can produce significant alterations in brain neurochemistry and behavior. However, given that protons can make up a significant portion of the radiation spectrum, it is important to study their effects on neural functioning and on related performance. Therefore, these studies examined the effects of exposure to proton irradiation on neurochemical and behavioral endpoints, including dopaminergic functioning, amphetamine-induced conditioned taste aversion learning, and spatial learning and memory as measured by the Morris water maze. Male Sprague-Dawley rats received a dose of 0, 1.5, 3.0 or 4.0 Gy of 250 MeV protons at Loma Linda University and were tested in the different behavioral tests at various times following exposure. Results showed that there was no effect of proton irradiation at any dose on any of the endpoints measured. Therefore, there is a contrast between the insignificant effects of high dose proton exposure and the dramatic effectiveness of low dose (<0.1 Gy) exposures to 56Fe particles on both neurochemical and behavioral endpoints.     

Comparative study of spermatogonial survival after x-ray exposure, high LET (HZE) irradiation or spaceflight.

Spermatogonial cell loss has been observed in rats flown on Space Lab 3, Cosmos 1887, Cosmos 2044 and in mice following irradiation with X-ray or with high energy (HZE) particle beams. Spermatogonial loss is determined by cell counting in maturation stage 6 seminiferous [correction of seminferous] tubules. With the exception of Iron, laboratory irradiation experiments (with mice) revealed a similar pattern of spermatogonial loss proportional to the radiation dose at levels less than 0.1 Gy. Helium and Argon irradiation resulted in a 5% loss of spermatogonia after only 0.01 Gy exposure. However, significant spermatogonial loss (45%) occured at this radiation level with Iron particle beams. The loss of spermatogonia during each space flight was less than 10% when compared to control (non-flight) animals. This loss, although small, was significant. Although radiation may be a contributing factor in the loss of spermatogonia during space flight, exposure levels, as determined by dosimetry, were not significant to account for the total cell loss observed.     

Cataractogenesis from high-LET radiation and the Casarett model.

Space radiations, especially heavy ions, constitute significant hazards to astronauts. These hazards will increase as space missions lengthen. Moreover, the dangers to astronauts will be enhanced by the persistence, or even the progression, of biological damage throughout their subsequent life spans. To assist in the assessment of risks to astronauts, we are investigating the long-term effects of heavy ions on specific animal tissues. In one study, the eyes of rabbits of various ages were exposed to a single dose of Bragg plateau 20Ne ions (LET infinity approximately equals 30 keV/micrometer). The development of cataracts has shown a pronounced age-related response during the first year after irradiation, and will be followed for two more years. In other studies, mice were exposed to single or fractionated doses of 12C ions (4-cm spread-out Bragg peak; dose-averaged LET infinity = 70-80 keV/micrometer) or 60Co gamma-photons (LET infinity = 0.3 keV/micrometer). Measurements of the frequency of posterior lens opacification have shown that the tissue sparing observed with dose fractionation of gamma-photons was absent when 12C-ion doses were fractionated. Development of posterior lens cataracts was also followed for long periods (up to 21 months) in mice exposed to single doses of Bragg plateau HZE particles (40Ar, 20Ne and 12C ions: LET infinity approximately equals 100, 30 and 10 keV/micrometer, respectively) or 225 kVp X-rays. Based on average cataract levels at the different observation times, the RBE's (RBE = relative biological effectiveness) for the ions were circa 5, 3 and 1-2, respectively, over the range of doses used (0.05-0.9 Gy). Investigations of cataractogenesis are useful for exploring the model of radiation damage proposed by Casarett and by Rubin and Casarett with a tissue not connected directly to the vasculature.     

Survival of irradiated mice treated with WR-151327, synthetic trehalose dicorynomycolate, or ofloxacin.

Spaceflight personnel need treatment options that would enhance survival from radiation and would not disrupt task performance. Doses of prophylactic or therapeutic agents known to induce significant short-term (30-day) survival with minimal behavioral (locomotor) changes were used for 180-day survival studies. In protection studies, groups of mice were treated with the phosphorothioate WR-151327 (200 mg/kg, 25% of the LD(10)) or the immunomodulator, synthetic trehalose dicorynomycolate (S-TDCM; 8 mg/kg), before lethal irradiation with reactor-generated fission neutrons and gamma-rays (n/gamma=1) or 60Co gamma-rays. In therapy studies, groups of mice received either S-TDCM, the antimicrobial ofloxacin, or S-TDCM plus ofloxacin after irradiation. For WR-151327 treated-mice, survival at 180 days for n/gamma=1 and gamma-irradiated mice was 90% and 92%, respectively; for S-TDCM (protection), 57% and 78%, respectively; for S-TDCM (therapy), 20% and 25%, respectively; for ofloxacin, 38% and 5%, respectively; for S-TDCM combined with ofloxacin, 30% and 30%, respectively; and for saline, 8% and 5%, respectively. Ofloxacin or combined ofloxacin and S-TDCM increased survival from the gram-negative bacterial sepsis that predominated in n/gamma=1 irradiated mice. The efficacies of the treatments depended on radiation quality, treatment agent and its mode of use, and microflora of the host.     

Protective effects of melatonin against C beam irradiation-induced oxidative stress and DNA injury in the mouse brain

The purpose of this experiment was to estimate the protective effects of melatonin against radiation-induced brain damages in mice induced by heavy ion beams. Kun-Ming mice were randomly divided into five groups: normal control group, irradiation control group, and three different doses of melatonin (5, 10, and 20 mg/kg, i.p.) treated groups. Apart from the normal control group, the other four groups were exposed to whole-body 4.0 Gy carbon ion beam irradiation (approximately 0.5 Gy/min) after i.p. administration of normal saline or melatonin 1 h before irradiation. The oxidative redox status of brain tissue was assessed by measurement of malondiadehyde (MDA) levels, total superoxide dismutase (T-SOD), cytosolic superoxide dismutase (Cu/ZnSOD, SOD1) and mitochondrial superoxide dismutase (MnSOD, SOD2) activities at 8 h after irradiation. DNA damages were determined using the Comet assay and apoptosis and cell cycle distribution were detected by flow cytometric analyses. A dramatic dose-dependent decrease in MDA levels, tail moment, rates of tailing cells, and apoptosis, and a dose-dependent increase in T-SOD and SOD2 activities, in brain tissues in the melatonin-treated groups were detected compared with the irradiation only group. Furthermore, flow cytometric analysis demonstrated that the percentage of brain cells in the G0/G1 phase decreased significantly, while those in the S and G2/M stage increased dramatically, with mice pretreated with melatonin compared to the irradiation control group. These data indicate that melatonin has protective effects against irradiation-induced brain injury, and that its underlying protective mechanisms may relate to modulation of oxidative stress induced by heavy ionirradiation.     

基于PXI总线的无人机飞控自动检测系统设计与实现

针对某型无人机飞行自动控制系统的老式检测设备在长期使用过程中出现的问题,设计研制了一套基于PXI总线的自动检测系统,满足了无人机飞控系统自动测试的需要,提高了测试效率。     

Signs of Müller cell gliotic response found in the retina of newts exposed to real and simulated microgravity

The effects of real and simulated microgravity on the eye tissue regeneration of newts were investigated. For the first time changes in Müller glial cells in the retina of eyes regenerating after retinal detachment were detected in newts exposed to clinorotation. The cells divided, were hypertrophied, and their processes were thickened. Such changes suggested reactive gliosis and were more significant in animals exposed to rotation when compared with desk-top controls. Later experiments onboard the Russian biosatellite Bion-11 showed similar changes in the retinas that were regenerating in a two-week spaceflight. In the Bion-11 animals, GFAP, the major structural protein of retinal macroglial cells, was found to be upregulated. In a more recent experiment onboard Foton-M3 (2007), GFAP expression in retinas of space-flown, ground control (kept at 1 g), and basal control (sacrificed on launch day) newts was quantified, using microscopy, immunohistochemistry, and digital image analysis. A low level of immunoreactivity was observed in basal controls. In contrast, retinas of space-flown animals showed greater GFAP immunoreactivity associated with both an increased cell number and a higher thickness of intermediate filaments. This, in turn, was accompanied by up-regulation of stress protein (HSP90) and growth factor (FGF2) expressions. It can be postulated that such a response of Müller cells was to mitigate the retinal stress in newts exposed to microgravity. Taken together, the data suggest that the retinal population of macroglial cells could be sensitive to gravity changes and that in space it can react by enhancing its neuroprotective function.