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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 73 records · Page 4
All sourcesNASA NTRSDOE OSTI
NASA NTRS1972

Factors modifying the response of large animals to low-intensity radiation exposure

In assessing the biological response to space radiation, two of the most important modifying factors are dose protraction and dose distribution to the body. Studies are reported in which sheep and swine were used to compare the hematology and lethality response resulting from radiation exposure encountered in a variety of forms, including acute (high dose-rate), chronic (low dose-rate), combinations of acute and chronic, and whether received as a continuous or as fractionated exposure. While sheep and swine are basically similar in response to acute radiation, their sensitivity to chronic irradiation is markedly different. Sheep remain relatively sensitive as the radiation exposure is protracted while swine are more resistant and capable of surviving extremely large doses of chronic irradiation. This response to chronic irradiation correlated well with changes in radiosensitivity and recovery following an acute, sublethal exposure.

Page, N. P.↗
DOE OSTI2024

Characterization of Histophilus somni sialic acid uptake mutant (Δ nanP -Δ nanU ) using a mouse septicemia and mortality model

Histophilus somni is an important pathogen of the bovine respiratory disease complex, yet the mechanisms underlying its virulence remain poorly understood. It is known that H. somni can incorporate sialic acid into lipooligosaccharide (LOS), and sialylated H. somni is more resistant to phagocytosis and complement-mediated killing by serum compared to non-sialylated bacteria in vitro. However, the virulence of non-sialylated H. somni has not been evaluated in vivo using an animal model. In this study, we investigated the contribution of sialic acid to virulence by constructing an H. somni sialic acid uptake mutant (ΔnanP-ΔnanU) and comparing the parent and mutant strains in a mouse septicemia and mortality model. Intraperitoneal challenge of mice with wildtype H. somni (1 × 10 8 colony forming units/mouse, CFU) was lethal to all animals. Mice challenged with three different doses (1, 2, or 5 × 108 CFU/mouse) of an H. somni ΔnanP-ΔnanU sialic acid uptake mutant exhibited survival rates of 90 %, 60 %, and 0 % respectively. High-performance anion exchange chromatography analyses revealed that LOS prepared from both parent and the ΔnanP-ΔnanU mutant strains of H. somni were sialylated. These findings suggest the presence of de novo sialic acid synthesis pathway, although the genes associated with de novo sialic acid synthesis (neuB and neuC) were not identified by genomic analysis. The lower attenuation in mice is most likely attributed to the sialylated LOS of H. somni nanPU mutant.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Combatting melioidosis with chemical synthetic lethality

Burkholderia thailandensishas emerged as a nonpathogenic surrogate forBurkholderia pseudomallei, the causative agent of melioidosis, and an important Gram-negative model bacterium for studying the biosynthesis and regulation of secondary metabolism. We recently reported that subinhibitory concentrations of trimethoprim induce vast changes in both the primary and secondary metabolome ofB. thailandensis. In the current work, we show that the folate biosynthetic enzyme FolE2 is permissive under standard growth conditions but essential forB. thailandensisin the presence of subinhibitory doses of trimethoprim. Reasoning that FolE2 may serve as an attractive drug target, we screened for and identified ten inhibitors, including dehydrocostus lactone (DHL), parthenolide, and β-lapachone, all of which are innocuous individually but form a chemical-synthetic lethal combination with subinhibitory doses of trimethoprim. We show that DHL is a mechanism-based inhibitor of FolE2 and capture the structure of the covalently inhibited enzyme using X-ray crystallography. In vitro, the combination of subinhibitory trimethoprim and DHL is more potent than Bactrim, the current standard of care against melioidosis. Moreover, unlike Bactrim, this combination does not affect the growth of most commensal and beneficial gut bacteria tested, thereby providing a degree of specificity againstB. pseudomallei. Our work provides a path for identifying antimicrobial drug targets and for utilizing binary combinations of molecules that form a toxic cocktail based on metabolic idiosyncrasies of specific pathogens.

Science & Technology - Other Topics↗
DOE OSTI2018

Long-term effects of ionizing radiation after the Chernobyl accident: Possible contribution of historic dose

Highlights: • Paper considers the role of delayed non-targeted effects (DNTE) in environmental radiation protection (ERP). • Comparison of the DNTE dose response relationship (DRR) in Chernobyl birds 9–11 generations after accident. • Dose reconstruction suggests the pattern of DNTE induced by the historical dose is similar datasets. • Conclude the historic dose contribution is important to consider. The impact of the Chernobyl NPP accident on the environment is documented to be greater than expected, with higher mutation rates than expected at the current, chronic low dose rate. In this paper we suggest that the historic acute exposure and resulting non-targeted effects (NTE) such as delayed mutations and genomic instability could account at least in part for currently measured mutation rates and provide an initial test of this concept. Data from Møller and Mousseau on the phenotypic mutation rates of Chernobyl birds 9–11 generations post the Chernobyl accident were used and the reconstructed dose response for mutations was compared with delayed reproductive death dose responses (as a measure of genomic instability) in cell cultures exposed to a similar range of doses. The dose to birds present during the Chernobyl NPP accident was reconstructed through the external pathway due to Cs-137 with an estimate of the uncertainty associated with such reconstruction. The percentage of Chernobyl birds several generations after the accident without mutations followed the general shape of the clonogenic survival percentage of the progeny of irradiated cells, and it plateaued at low doses. This is the expected result if NTE of radiation are involved. We suggest therefore, that NTE induced by the historic dose may play a role in generating mutations in progeny many generations following the initial disaster.

54 ENVIRONMENTAL SCIENCES↗
NASA NTRS2007

Anti-radiation vaccine: Immunologically-based Prophylaxis of Acute Toxic Radiation Syndromes Associated with Long-term Space Flight

Protecting crew from ionizing radiation is a key life sciences problem for long-duration space missions. The three major sources/types of radiation are found in space: galactic cosmic rays, trapped Van Allen belt radiation, and solar particle events. All present varying degrees of hazard to crews; however, exposure to high doses of any of these types of radiation ultimately induce both acute and long-term biological effects. High doses of space radiation can lead to the development of toxicity associated with the acute radiation syndrome (ARS) which could have significant mission impact, and even render the crew incapable of performing flight duties. The creation of efficient radiation protection technologies is considered an important target in space radiobiology, immunology, biochemistry and pharmacology. Two major mechanisms of cellular, organelle, and molecular destruction as a result of radiation exposure have been identified: 1) damage induced directly by incident radiation on the macromolecules they encounter and 2) radiolysis of water and generation of secondary free radicals and reactive oxygen species (ROS), which induce chemical bond breakage, molecular substitutions, and damage to biological molecules and membranes. Free-radical scavengers and antioxidants, which neutralize the damaging activities of ROS, are effective in reducing the impact of small to moderate doses of radiation. In the case of high doses of radiation, antioxidants alone may be inadequate as a radioprotective therapy. However, it remains a valuable component of a more holistic strategy of prophylaxis and therapy. High doses of radiation directly damage biological molecules and modify chemical bond, resulting in the main pathological processes that drive the development of acute radiation syndromes (ARS). Which of two types of radiation-induced cellular lethality that ultimately develops, apoptosis or necrosis, depends on the spectrum of incident radiation, dose, dose rate, and functional conditions of impacted cells/organisms. The administration of an experimental anti-radiation vaccine may provide an immunologically based, adjunct method of prevention or prophylaxis against clinical ARS. The administration of experimental anti-radiation serum (ARS) and the use of the blood dialysis methods, such as immune plasma-sorption, may assist in the clearance of radiation-specific toxins and may enhance established strategies for the mitigation of the biological effects leading to ARS, and should be evaluated for use on exploration-class space missions.

Popov, Dmitri↗
NASA NTRS2017

Predicting Cell Death and Mutation Frequency for a Wide Spectrum of LET by Assuming DNA Break Clustering Inside Repair Domains

The high relative biological effectiveness (RBE) of high charged and energy (HZE) particles for cell death, DNA mutations and cancer remain based on experimental data. In this work, we propose that the existence of DNA repair domains is sufficient to predict both cell death and mutation frequencies for any LET by only taking into account experimental data from low-LET, offering one mechanism for RBE across LET. We hypothesize that whenever multiple DNA double-strand breaks (DSBs) are generated within the same DNA repair domain, DSBs are actively regrouped for more efficient repair [1]. This hypothesis has been supported by the low-LET sublinear dose response observed at doses greater than ~1Gy for 53BP1 radiation-induced foci (RIF) reflecting increasing DSB/RIF with dose [2]. Previously, we modeled radiation-induced cell death of human breast cells by first inferring the size of these domains from the dose dependence of low-LET RIF, and by associating a lethality factor to the number of pairs of DSBs in each RIF [1]. In this work, we first integrate the new NASA computer models RITCARD (Relativistic Ion Tracks, Chromosome Aberrations, Repair, and Damage) [3] and BDSTracks (Biological Damage by Stochastic Tracks) for a more accurate microdosimetry and a better model of the nuclear organization to predict the location of DSBs. A large array of particles and energy are simulated, covering more than three orders of magnitude for LET (~1-1000 keV/µm). Next, we extend our previous model to predict mutation frequencies by assuming that clustered DSBs increase mutation probability, which is formalized by the mutation frequency being linearly dependent on both the number of DSBs and the number of pairs of DSBs inside individual RIF. Linear coefficients are estimated so that simulations predict accurately mutation frequencies observed in Chinese hamster cells exposed to low-LET. Keeping these coefficients unchanged, we then predict mutation frequencies induced by HZE by simulating DSBs and obtain RBEs for mutations and cell death following the expected experimental bell shape for LET dependence. We also observe an orientation effect that needs to be confirmed, showing different RBE depending on the angle of the HZE beam hitting the main axis of the cell.

Plante, Ianik↗
DOE OSTI2024

Comparison of Routes of Administration, Frequency, and Duration of Favipiravir Treatment in Mouse and Guinea Pig Models of Ebola Virus Disease

Favipiravir is a ribonucleoside analogue that has been explored as a therapeutic for the treatment of Ebola Virus Disease (EVD). Promising data from rodent models has informed nonhuman primate trials, as well as evaluation in patients during the 2013–2016 West African EVD outbreak of favipiravir treatment. However, mixed results from these studies hindered regulatory approval of favipiravir for the indication of EVD. This study examined the influence of route of administration, duration of treatment, and treatment schedule of favipiravir in immune competent mouse and guinea pig models using rodent-adapted Zaire ebolavirus (EBOV). A dose of 300 mg/kg/day of favipiravir with an 8-day treatment was found to be fully effective at preventing lethal EVD-like disease in BALB/c mice regardless of route of administration (oral, intraperitoneal, or subcutaneous) or whether it was provided as a once-daily dose or a twice-daily split dose. Preclinical data generated in guinea pigs demonstrates that an 8-day treatment of 300 mg/kg/day of favipiravir reduces mortality following EBOV challenge regardless of route of treatment or duration of treatments for 8, 11, or 15 days. This work supports the future translational development of favipiravir as an EVD therapeutic.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Selective Shielding Bone Marrow: An Approach to Create Personal Protective Equipment for Gamma Radiation

Many casualties of the Hiroshima and Nagasaki atomic bombs, and many of the firefighters who first responded to the Chernobyl nuclear power plant accident, became ill with acute radiation syndrome (ARS). Most of the people who do not recover from ARS will die within a few weeks to a few months after exposure, with the primary cause of death being the destruction of the body's bone marrow (BM). This is exemplified by the Chernobyl firefighters, the majority of whom received whole body doses between 0.8 and 10 Gy, and the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) final report on the disaster concluded that the underlying cause of death of all 28 firefighters who succumbed to ARS was from bone marrow failure. BM is comprised of hematopoietic stem cells (HSCs) which are responsible for the constant renewal of blood cells. Due to their high rate of proliferation, HSCs are especially vulnerable to ionizing radiation, but are endowed with remarkable regenerative potential. Owing to their central role in blood production, lethal irradiation of HSCs leads to death from severe anemia, infection and internal bleeding. This relationship between high doses of radiation and HSC apoptosis has led to the use of HSC transplantation as a life-saving intervention in cases of acute exposure. This is demonstrable in medical practice, where thousands of individuals have undergone supra-lethal Total Body Irradiation (TBI) for purposes of cancer therapy, and were rescued by well-matched BM transplantation. Indeed, life-threatening damage may be reversed by BM transplantation in individuals receiving doses of radiation of up to 10 Gy. At doses > 10 Gy, damage to gastrointestinal (GI) tissue may become a limiting factor in survival. Remarkably, in the common procedure of BM transplantation, the number of HSCs extracted from a single active BM site containing less than 5% of the donor's BM tissue is sufficient to support the complete reconstitution of the HSC compartment in a lethally irradiated recipient. This capacity of BM to expand and replenish is due to the high regenerative potential of the HSCs it harbors. In contrast to mature blood cells, which are dispersed throughout the body, HSCs are confined to the bones, allowing for effective targeted shielding. This has been confirmed in several animal models, where sparing the HSC-rich area of a subject receiving otherwise full-body irradiation is sufficient to support hematopoietic functions and allow survival. Approximately 48% of the human body's active BM is contained within the lumbar vertebrae and the pelvic region. This high concentration of BM makes the pelvic region an ideal area to shield for preventing the serious hematopoietic effects of radiation exposure. Stem-cell rich tissues like active BM are also more sensitive to the stochastic effects (i.e. cancer) of radiation exposure. The high amount of BM in the pelvic region, combined with the presence of the sensitive gastrointestinal system and female gonads in this same area of the body allows for the possibility of significantly reducing stochastic effects of radiation by limiting radiation exposure to this vital area. Thus, shielding this region holds great promise for both acute and protracted exposures. Thus, a specialized radiation shielding device for the protection of active BM concentrations is presented here. This belt-like selective shielding device focuses on the protection of BM that is present in the pelvis and hip bones, protecting the medullary volume from which BM is commonly extracted for transplantation (i.e. the iliac bones) while allowing relatively unhindered movement of the wearer. In order to optimize the use of shielding materials towards the protection of active BM, the shielding uniquely brings into account the natural shielding properties of human tissue, with thickness being inversely related to the thickness and radiation attenuation of the underlying tissue at each point surrounding the area being protected. The findings resulting from both experimental and simulation testing of this selective shielding device are presented here.

61 RADIATION PROTECTION AND DOSIMETRY↗
DOE OSTI2024

Optimization of a Lethal, Combat-Relevant Model of Sterile Inflammation in Mice for Drug Candidate Screening

ABSTRACT Introduction Extensive trauma, commonly seen in wounded military Service Members, often leads to a severe sterile inflammation termed systemic inflammatory response syndrome (SIRS), which can progress to multiple organ dysfunction syndrome (MODS) and death. MODS is a serious threat to wounded Service Members, historically causing 10% of all deaths in trauma admissions at a forward deployed combat hospital. The importance of this problem will be exacerbated in large-scale combat operations, in which evacuation will be delayed and care of complex injuries at lower echelons of care may be prolonged. The main goal of this study was to optimize an existing mouse model of lethal SIRS/MODS as a therapeutic screening platform for the evaluation of immunomodulatory drugs. Materials and Methods Male C57BL/6 mice were euthanized, and the bones and muscles were collected and blended into a paste termed tissue–bone matrix (TBX). The TBX at 12.5%–20% relative to body weight of each recipient mouse was implanted into subcutaneous pouches created on the dorsum of anesthetized animals. Mice were observed for clinical scores for up to 48 hours postimplantation and euthanized at the preset point of moribundity. To test effects of anesthetics on TBX-induced mortality, animals received isoflurane or ketamine/xylazine (K/X). In a separate set of studies, mice received TBX followed by intraperitoneal injection with 20 mg/kg or 40 mg/kg Eritoran or a placebo carrier. All Eritoran studies were performed in a blinded fashion. Results We observed that K/X anesthesia significantly increased the lethality of the implanted TBX in comparison to inhaled anesthetics. Although all the mice anesthetized with isoflurane and implanted with 12.5% TBX survived for 24 hours, 60% of mice anesthetized with K/X were moribund by 24 hours postimplantation. To mimic more closely the timing of lethal SIRS/MODS following polytrauma in human patients, we extended observation to 48 hours. We performed TBX dose–response studies and found that as low as 15%, 17.5%, and 20% TBX caused moribundity/mortality in 50%, 80%, and 100% mice, respectively, over a 48-hour time period. With 17.5% TBX, we tested if moribundity/mortality could be rescued by anti-inflammatory drug Eritoran, a toll-like receptor 4 antagonist. Neither 20 mg/kg nor 40 mg/kg doses of Eritoran were found to be effective in this model. Conclusions We optimized a TBX mouse model of SIRS/MODS for the purpose of evaluating novel therapeutic interventions to prevent trauma-related pathophysiologies in wounded Service Members. Negative effects of K/X on lethality of TBX should be further evaluated, particularly in the light of widespread use of ketamine in treatment of pain. By mimicking muscle crush, bone fracture, and necrosis, the TBX model has pleiotropic effects on physiology and immunology that make it uniquely valuable as a screening tool for the evaluation of novel therapeutics against trauma-induced SIRS/MODS.

General & Internal Medicine↗
DOE OSTI2019

An integrated experimental-computational approach for predicting virulence in New Zealand white rabbits and humans following inhalation exposure to Bacillus anthracis spores

Inhalation of Bacillus anthracis spores can lead to an anthrax infection that can be fatal. Previously published mathematical models have extrapolated kinetic rates associated with bacterial growth in New Zealand White (NZW) rabbits to humans, but to date, actual measurements of the underlying processes associated with anthrax virulence between species have not been conducted. To address this knowledge gap, we have quantified species-specific rate constants associated with germination, proliferation, and immune cell inactivation of B. anthracis Sterne using an in vitro test platform that includes primary lung epithelial and immune cells. The generated data was then used to develop a physiologically based biokinetic model (PBBK) which quantitatively compares bacterial growth and mean time to death under lethal conditions in rabbits and humans. Simulations based upon our in vitro data and previously published in vivo data from rabbits indicate that disease progression is likely to be faster in humans than in NZW rabbits under comparable total deposited dose conditions. With the computational framework established, PBBK parameters can now be refined using experimental data for lethal B. anthracis strains (e.g. Ames) under identical conditions in future studies. The PBBK model can also be linked to existing aerosol dosimetry models that account for species-specific differences in aerosol deposition patterns to further improve the human health risk assessment of inhalation anthrax.

3-D tissue culture, B. anthracis Sterne, biothreat↗
DOE OSTI2022

Molecular basis for antiviral activity of two pediatric neutralizing antibodies targeting SARS-CoV-2 Spike RBD

Neutralizing antibodies (NAbs) hold great promise for clinical interventions against SARS-CoV-2 variants of concern (VOCs). Understanding NAb epitopedependent antiviral mechanisms is crucial for developing vaccines and therapeutics against VOCs. Here we characterized two potent NAbs, EH3 and EH8, isolated from an unvaccinated pediatric patient with exceptional plasma neutralization activity. EH3 and EH8 cross-neutralize the early VOCsandmediatestrong Fc-dependent effector activity in vitro. Structural analyses of EH3 and EH8 in complex with the receptor-binding domain (RBD) revealed the molecular determinantsoftheepitope-drivenprotectionandVOCevasion.WhileEH3represents the prevalent IGHV3-53 NAb whose epitope substantially overlaps with the ACE2 binding site, EH8 recognizes a narrow epitope exposed in both RBD-up and RBD-down conformations. When tested in vivo, a single-dose prophylactic administration of EH3 fully protected stringent K18-hACE2 micefrom lethal challenge with Delta VOC. Our study demonstrates that protective NAbs responses converge in pediatric and adult SARS-CoV-2 patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Characterizing responses to gamma radiation by a highly clonogenic fish brain endothelial cell line

Purpose: The clonogenic property and radiobiological responses of a fish brain endothelial cell line, eelB, derived from the American eel were studied. Methods: Clonogenic assays were performed to determine the plating efficiency of the eelB cells and to evaluate the clonogenic survival fractions after direct irradiation to low-dose low-LET gamma radiation or receiving irradiated cell conditioned medium in the bystander effect experiments. Result: eelB had the second highest plating efficiency ever reported to date for fish cell lines. Large eelB macroscopic colonies could be formed in a short period of time and were easy to identify and count. Unlike with other fish clonogenic cell lines, which had a relatively slow proliferation profile, clonogenic assays with the eelB cells could be completed as early as 12 days in culture. After direct irradiation with gamma rays at low doses ranging from 0.1 Gy to 5 Gy, the dose-clonogenic survival curve of the eelB cell line showed a linear trend and did not develop a shoulder region. A classical radio-adaptive response was not induced with the clonogenic survival endpoint when the priming dose (0.1 or 0.5 Gy) was delivered 6 h before the challenge dose (3 or 5 Gy). However, a radio-adaptive response was observed in progeny cells that survived 5 Gy and developed lethal mutations. eelB appeared to lack the ability to produce damaging radiation-induced bystander signals on both eelB and HaCaT recipient cells. Conclusion: eelB cell line could be a very useful cell model in the study of radiation impacts on the aquatic health. - Highlights: • The fish endothelial cell line eelB showed exceptional clonogenic properties. • eelB decreased clonogenic survival upon an increase in gamma dose (0.1-5 Gy). • eelB did not develop a classical radio-adaptive response (RAR). • eelB progenies surviving 5 Gy developed lethal mutations and a RAR-like response. • eelB appeared to lack the ability to produce radiation-induced bystander effects.

54 ENVIRONMENTAL SCIENCES↗
NASA NTRS2000

Clustered DNA damages induced in isolated DNA and in human cells by low doses of ionizing radiation

Clustered DNA damages-two or more closely spaced damages (strand breaks, abasic sites, or oxidized bases) on opposing strands-are suspects as critical lesions producing lethal and mutagenic effects of ionizing radiation. However, as a result of the lack of methods for measuring damage clusters induced by ionizing radiation in genomic DNA, neither the frequencies of their production by physiological doses of radiation, nor their repairability, nor their biological effects are known. On the basis of methods that we developed for quantitating damages in large DNAs, we have devised and validated a way of measuring ionizing radiation-induced clustered lesions in genomic DNA, including DNA from human cells. DNA is treated with an endonuclease that induces a single-strand cleavage at an oxidized base or abasic site. If there are two closely spaced damages on opposing strands, such cleavage will reduce the size of the DNA on a nondenaturing gel. We show that ionizing radiation does induce clustered DNA damages containing abasic sites, oxidized purines, or oxidized pyrimidines. Further, the frequency of each of these cluster classes is comparable to that of frank double-strand breaks; among all complex damages induced by ionizing radiation, double-strand breaks are only about 20%, with other clustered damage constituting some 80%. We also show that even low doses (0.1-1 Gy) of high linear energy transfer ionizing radiation induce clustered damages in human cells.

NASA Discipline Radiation Health↗
DOE OSTI2019

The efficacy of poly-ICLC against Ebola-Zaire virus (EBOV) infection in mice and cynomolgus monkeys

The potential protection of poly-ICLC (Hiltonol®) a double stranded RNA (dsRNA) against EBOV infection was assessed with prophylactic and therapeutic administration to wild type and TLR3-negative mice, and in non-human primates (NHPs) by measuring EBOL serum titers, survival extension, and serum liver and kidney function markers. Various doses of aqueous and liposomal poly-ICLC monotherapy provided robust protection in otherwise lethal murine EBOV challenge models, when treatment is started on the day 0 or one day after virus challenge. There was no advantage of liposomal vs. the aqueous poly-ICLC form. Protection appeared to be independent of TLR-3. NHPs treated with poly-ICLC and challenged with EBOV survived longer but eventually succumbed to Ebola infection. Nevertheless, the liver and kidney serum markers were markedly reduced in the infected and treated NHPs. Finally, in the two longest surviving poly-ICLC- treated NHPs, the day 10 serum EBOV titer was reduced 2.1 and 30 fold respectively.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Radiation-Induced Myocardial Fibrosis in Long-Term Esophageal Cancer Survivors

Radiation-induced cardiac toxicity is a potential lethal complication. The aim of this study was to assess whether there is a dose-dependent relationship between radiation dose and myocardial fibrosis in patients who received neoadjuvant chemoradiation (nCRT) for esophageal cancer (EC).

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2022

ASFV Gene A151R Is Involved in the Process of Virulence in Domestic Swine

African swine fever virus (ASFV) is the etiological agent of a swine pandemic affecting a large geographical area extending from Central Europe to Asia. The viral disease was also recently identified in the Dominican Republic and Haiti. ASFV is a structurally complex virus with a large dsDNA genome that encodes for more than 150 genes. Most of these genes have not been experimentally characterized. One of these genes, A151R, encodes for a nonstructural protein and has been reported to be required for the replication of a Vero-cell-adapted ASFV strain. Here, we evaluated the role of the A151R gene in the context of the highly virulent field isolate Georgia 2010 (ASFV-G) during virus replication in swine macrophage cell cultures and during experimental infection in swine. We show that the recombinant virus ASFV-G-ΔA151R, harboring a deletion of the A151R gene, replicated in swine macrophage cultures as efficiently as the parental virus ASFV-G, indicating that the A151R gene is not required for ASFV replication in swine macrophages. Interestingly, experimental infection of domestic pigs demonstrated that ASFV-G-ΔA151R had a decreased replication rate and produced a drastic reduction in virus virulence. Animals were intramuscularly inoculated with 102 HAD50 of ASFV-G-ΔA151R and compared with pigs receiving a similar dose of virulent ASFV-G. All ASFV-G-infected pigs developed an acute lethal form of the disease, while those inoculated with ASFV-G-ΔA151R remained healthy during the 28-day observational period, with the exception of only one showing a protracted, but fatal, form of the disease. All ASFV-G-ΔA151R surviving animals presented protracted viremias with lower virus titers than those detected in ASFV-G-infected animals. In addition, three out of the four animals surviving the infection with ASFV-G-ΔA151R were protected against the challenge with the virulent parental virus ASFV-G. This is the first report indicating that the ASFV A151R gene is involved in virus virulence in domestic swine, suggesting that its deletion may be used to increase the safety profile of currently experimental vaccines.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2003

Radiation-induced genomic instability: radiation quality and dose response

Genomic instability is a term used to describe a phenomenon that results in the accumulation of multiple changes required to convert a stable genome of a normal cell to an unstable genome characteristic of a tumor. There has been considerable recent debate concerning the importance of genomic instability in human cancer and its temporal occurrence in the carcinogenic process. Radiation is capable of inducing genomic instability in mammalian cells and instability is thought to be the driving force responsible for radiation carcinogenesis. Genomic instability is characterized by a large collection of diverse endpoints that include large-scale chromosomal rearrangements and aberrations, amplification of genetic material, aneuploidy, micronucleus formation, microsatellite instability, and gene mutation. The capacity of radiation to induce genomic instability depends to a large extent on radiation quality or linear energy transfer (LET) and dose. There appears to be a low dose threshold effect with low LET, beyond which no additional genomic instability is induced. Low doses of both high and low LET radiation are capable of inducing this phenomenon. This report reviews data concerning dose rate effects of high and low LET radiation and their capacity to induce genomic instability assayed by chromosomal aberrations, delayed lethal mutations, micronuclei and apoptosis.

Review↗