Strain background determines lymphoma incidence in Atm knockout mice

About 10% to 30% of patients with ataxia-telangiectasia (A-T) develop leukemias or lymphomas. There is considerable interpatient variation in the age of onset and leukemia/lymphoma type. The incomplete penetrance and variable age of onset may be attributable to several factors. These include competing mortality from other A-T-associated pathologies, particularly neurodegeneration and interstitial lung disease, and allele-specific effects of ataxia-telangiectasia mutated (ATM) gene mutations. There is also limited evidence from clinical observations and studies using Atm knockout mice that modifier genes may account for some variation in leukemia/lymphoma susceptibility. We have introgressed the Atm knockout allele (Atm) onto several inbred murine strains and observed differences in thymic lymphoma incidence and latency between Atm mice on the different strain backgrounds and between their F1 hybrids. The lymphomas that arose in these mice had a pattern of sequence gains and losses that were similar to those previously described by others. These results provide further evidence for the existence of modifier genes controlling lymphomagenesis in individuals carrying defective copies of Atm, at least in mice, and the characterized Atm- congenic strain set provides a resource with which to identify these genes. In addition, we found that fewer than expected Atm pups were weaned on two strain backgrounds and that there was no correlation between body weight of young Atm mice and lymphoma incidence or latency

Persistence of Gamma-H2AX Foci in Irradiated Bronchial Cells Correlates with Susceptibility to Radiation Associated Lung Cancer in Mice

The risk of developing radiation-induced lung cancer differs between different strains of mice, but the underlying cause of the strain differences is unknown. Strains of mice also differ in their ability to efficiently repair DNA double strand breaks resulting from radiation exposure. We phenotyped mouse strains from the CcS/Dem recombinant congenic strain set for their efficacy in repairing DNA double strand breaks during protracted radiation exposures. We monitored persistent gamma-H2AX radiation induced foci (RIF) 24 hours after exposure to chronic gamma-rays as a surrogate marker for repair deficiency in bronchial epithelial cells for 17 of the CcS/Dem strains and the BALB/cHeN founder strain. We observed a very strong correlation R2 = 79.18%, P < 0.001) between the level of persistent RIF and radiogenic lung cancer percent incidence measured in the same strains. Interestingly, spontaneous levels of foci in non-irradiated strains also showed good correlation with lung cancer incidence (R2=32.74%, P =0.013). These results suggest that genetic differences in DNA repair capacity largely account for differing susceptibilities to radiation-induced lung cancer among CcS/Dem mouse strains and that high levels of spontaneous DNA damage is also a relatively good marker of cancer predisposition. In a smaller pilot study, we found that the repair capacity measured in peripheral blood leucocytes also correlated well with radiogenic lung cancer susceptibility, raising the possibility that such phenotyping assay could be used to detect radiogenic lung cancer susceptibility in humans

New Concerns for Neurocognitive Function during Deep Space Exposures to Chronic, Low Dose-Rate, Neutron Radiation.

As NASA prepares for a mission to Mars, concerns regarding the health risks associated with deep space radiation exposure have emerged. Until now, the impacts of such exposures have only been studied in animals after acute exposures, using dose rates ∼1.5×105 higher than those actually encountered in space. Using a new, low dose-rate neutron irradiation facility, we have uncovered that realistic, low dose-rate exposures produce serious neurocognitive complications associated with impaired neurotransmission. Chronic (6 month) low-dose (18 cGy) and dose rate (1 mGy/d) exposures of mice to a mixed field of neutrons and photons result in diminished hippocampal neuronal excitability and disrupted hippocampal and cortical long-term potentiation. Furthermore, mice displayed severe impairments in learning and memory, and the emergence of distress behaviors. Behavioral analyses showed an alarming increase in risk associated with these realistic simulations, revealing for the first time, some unexpected potential problems associated with deep space travel on all levels of neurological function

Space Radiation Alters Genotype–Phenotype Correlations in Fear Learning and Memory Tests

Behavioral and cognitive traits have a genetic component even though contributions from individual genes and genomic loci are in many cases modest. Changes in the environment can alter genotype–phenotype relationships. Space travel, which includes exposure to ionizing radiation, constitutes environmental challenges and is expected to induce not only dramatic behavioral and cognitive changes but also has the potential to induce physical DNA damage. In this study, we utilized a genetically heterogeneous mouse model, dense genotype data, and shifting environmental challenges, including ionizing radiation exposure, to explore and quantify the size and stability of the genetic component of fear learning and memory-related measures. Exposure to ionizing radiation and other external stressors altered the genotype–phenotype correlations, although different behavioral and cognitive measures were affected to different extents. Utilizing an integrative genomic approach, we identified pathways and functional ontology categories associated with these behavioral and cognitive measures

D6.6 Final report on the METIS 5G system concept and technology roadmap

This deliverable presents the METIS 5G system concept which was developed to fulfil the requirements of the beyond-2020 connected information society and to extend today’s wireless communication systems to include new usage scenarios. The METIS 5G system concept consists of three generic 5G services and four main enablers. The three generic 5G services are Extreme Mobile BroadBand (xMBB), Massive Machine- Type Communications (mMTC), and Ultra-reliable Machine-Type Communication (uMTC). The four main enablers are Lean System Control Plane (LSCP), Dynamic RAN, Localized Contents and Traffic Flows, and Spectrum Toolbox. An overview of the METIS 5G architecture is given, as well as spectrum requirements and considerations. System-level evaluation of the METIS 5G system concept has been conducted, and we conclude that the METIS technical objectives are met. A technology roadmap outlining further 5G development, including a timeline and recommended future work is given.Popovski, P.; Mange, G.; Gozalvez -Serrano, D.; Rosowski, T.; Zimmermann, G.; Agyapong, P.; Fallgren, M.... (2014). D6.6 Final report on the METIS 5G system concept and technology roadmap. http://hdl.handle.net/10251/7676

D6.3 Intermediate system evaluation results

The overall purpose of METIS is to develop a 5G system concept that fulfil s the requirements of the beyond-2020 connected information society and to extend today’s wireless communication systems for new usage cases. First, in this deliverable an updated view on the overall METIS 5G system concept is presented. Thereafter, simulation results for the most promising technology components supporting the METIS 5G system concept are reported. Finally, s imulation results are presented for one relevant aspect of each Horizontal Topic: Direct Device - to - Device Communication, Massive Machine Communication, Moving Networks, Ultra - Dense Networks, and Ultra - Reliable Communication.Popovski, P.; Mange, G.; Fertl, P.; Gozálvez - Serrano, D.; Droste, H.; Bayer, N.; Roos, A.... (2014). D6.3 Intermediate system evaluation results. http://hdl.handle.net/10251/7676