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

Cosmic radiation, which is composed of high charged and energy (HZE) particles, is responsible for cell death and mutation, which may be involved in cancer induction. Mutations are consequences of mis-repaired DNA breaks especially double-strand breaks (DSBs) that induce inter- and intra-chromosomal rearrangements (translocations, deletions, inversion). In this study, a computer simulation model is used to investigate the clustering of DSBs in repair domains, previously evidenced by our group in human breast cells [1]. This model is calibrated with experimental data measuring persistent 53BP1 radiation-induced foci (RIF) and is used to explain the high relative biological effectiveness (RBE) of HZE for both cell death and DNA mutation frequencies. We first validate our DSB cluster model using a new track structure model deployed on a simple geometrical configuration for repair domains in the nucleus; then we extend the scope from cell death to mutation induction. This work suggests that mechanism based on DSB repair process can explain several biological effects induced by HZE particles on different type of living cell

Simulation of the Formation of DNA Double Strand Breaks and Chromosome Aberrations in Irradiated Cells

The formation of DNA double-strand breaks (DSBs) and chromosome aberrations is an important consequence of ionizing radiation. To simulate DNA double-strand breaks and the formation of chromosome aberrations, we have recently merged the codes RITRACKS (Relativistic Ion Tracks) and NASARTI (NASA Radiation Track Image). The program RITRACKS is a stochastic code developed to simulate detailed event-by-event radiation track structure: [1] This code is used to calculate the dose in voxels of 20 nm, in a volume containing simulated chromosomes, [2] The number of tracks in the volume is calculated for each simulation by sampling a Poisson distribution, with the distribution parameter obtained from the irradiation dose, ion type and energy. The program NASARTI generates the chromosomes present in a cell nucleus by random walks of 20 nm, corresponding to the size of the dose voxels, [3] The generated chromosomes are located within domains which may intertwine, and [4] Each segment of the random walks corresponds to approx. 2,000 DNA base pairs. NASARTI uses pre-calculated dose at each voxel to calculate the probability of DNA damage at each random walk segment. Using the location of double-strand breaks, possible rejoining between damaged segments is evaluated. This yields various types of chromosomes aberrations, including deletions, inversions, exchanges, etc. By performing the calculations using various types of radiations, it will be possible to obtain relative biological effectiveness (RBE) values for several types of chromosome aberrations

Recent Developments in the Code RITRACKS (Relativistic Ion Tracks)

The code RITRACKS (Relativistic Ion Tracks) was developed to simulate detailed stochastic radiation track structures of ions of different types and energies. Many new capabilities were added to the code during the recent years. Several options were added to specify the times at which the tracks appear in the irradiated volume, allowing the simulation of dose-rate effects. The code has been used to simulate energy deposition in several targets: spherical, ellipsoidal and cylindrical. More recently, density changes as well as a spherical shell were implemented for spherical targets, in order to simulate energy deposition in walled tissue equivalent proportional counters. RITRACKS is used as a part of the new program BDSTracks (Biological Damage by Stochastic Tracks) to simulate several types of chromosome aberrations in various irradiation conditions. The simulation of damage to various DNA structures (linear and chromatin fiber) by direct and indirect effects has been improved and is ongoing. Many improvements were also made to the graphic user interface (GUI), including the addition of several labels allowing changes of units. A new GUI has been added to display the electron ejection vectors. The parallel calculation capabilities, notably the pre- and post-simulation processing on Windows and Linux machines have been reviewed to make them more portable between different systems. The calculation part is currently maintained in an Atlassian Stash repository for code tracking and possibly future collaboration

DNA Repair Domain Modeling Can Predict Cell Death and Mutation Frequency for Wide Range Spectrum of Radiation

Exploration missions to Mars and other destinations raise many questions about the health of astronauts. The continuous exposure of astronauts to galactic cosmic rays is one of the main concerns for long-term missions. Cosmic ionizing radiations are composed of different ions of various charges and energies notably, highly charged energy (HZE) particles. The HZE particles have been shown to be more carcinogenic than low-LET radiation, suggesting the severity of chromosomal aberrations induced by HZE particles is one possible explanation. However, most mathematical models predicting cell death and mutation frequency are based on directly fitting various HZE dose response and are in essence empirical approaches. In this work, we assume a simple biological mechanism to model DNA repair and use it to simultaneously explain the low- and high-LET response using the exact same fitting parameters. Our work shows that the geometrical position of DNA repair along tracks of heavy ions are sufficient to explain why high-LET particles can induce more death and mutations. Our model is based on assuming DNA double strand breaks (DSBs) are repaired within repair domain, and that any DSBs located within the same repair domain cluster into one repair unit, facilitating chromosomal rearrangements and increasing the probability of cell death. We introduced this model in 2014 using simplified microdosimetry profiles to predict cell death. In this work, we collaborated with NASA Johnson Space Center to generate more accurate microdosimetry profiles derived by Monte Carlo techniques, taking into account track structure of HZE particles and simulating DSBs in realistic cell geometry. We simulated 224 data points (D, A, Z, E) with the BDSTRACKS model, leading to a large coverage of LET from ~10 to 2,400 keV/m. This model was used to generate theoretical RBE for various particles and energies for both cell death and mutation frequencies. The RBE LET dependence is in agreement with experimental data known in human and murine cells. It suggests that cell shape and its orientation with respect to the HZE particle beam can modify the biological response to radiation. Such discovery will be tested experimentally and, if proven accurate, will be another strong supporting evidence for DNA repair domains and their critical role in interpreting cosmic radiation sensitivity

Toward food sovereignty for coastal communities of eastern Québec : co-designing a website to support consumption of edible resources from the St. Lawrence River, Estuary, and Gulf

Background. Despite the abundance and proximity of edible marine resources, coastal communities along the St. Lawrence in Eastern Québec rarely consume these resources. Within a community-based food sovereignty project, Manger notre Saint-Laurent (‘‘Sustenance from our St. Lawrence''), members of participating communities (3 nonIndigenous, 1 Indigenous) identified a need for a web-based decision tool to help make informed consumption choices. Methods. We thus aimed to co-design a prototype website that facilitates informed choices about consuming local edible marine resources based on seasonal and regional availability, food safety, nutrition, and sustainability, with community members, regional stakeholders, and experts in user experience design and web development. We conducted 48 interviews with a variety of people over 3 iterative cycles, assessing the prototype's ease of use with a validated measure, the System Usability Scale. Results. Community members, regional stakeholders, and other experts identified problematic elements in initial versions of the website (e.g., confusing symbols). We resolved issues and added features people identified as useful. Usability scores reached ‘‘best imaginable'' for both the second and the third versions and did not differ significantly between sociodemographic groups. The final prototype includes a tool to explore each species and index cards to regroup accurate evidence relevant to each species. Conclusions. Engaging co-designers with different sociodemographic characteristics brought together a variety of perspectives. Several components would not have been included without co-designers' input; other components were greatly improved thanks to their feedback. Co-design approaches in research and intervention development are preferable to foster the inclusion of a variety of people. Once the prototype is programmed and available online, we hope to evaluate the website to determine its effects on food choices

Oceans and human health : navigating changes on Canada’s coasts

Ocean conditions can affect human health in a variety of ways that are often overlooked and unappreciated. Oceans adjacent to Canada are affected by many anthropogenic stressors, with implications for human health and well-being. Climate change further escalates these pressures and can expose coastal populations to unique health hazards and distressing conditions. However, current research efforts, education or training curriculums, and policies in Canada critically lack explicit consideration of these ocean–public health linkages. The objective of this paper is to present multiple disciplinary perspectives from academics and health practitioners to inform the development of future directions for research, capacity development, and policy and practice at the interface of oceans and human health in Canada. We synthesize major ocean and human health linkages in Canada, and identify climate-sensitive drivers of change, drawing attention to unique considerations in Canada. To support effective, sustained, and equitable collaborations at the nexus of oceans and human health, we recommend the need for progress in three critical areas: (i) holistic worldviews and perspectives, (ii) capacity development, and (iii) structural supports. Canada can play a key role in supporting the global community in addressing the health challenges of climate and ocean changes

A novel isolator-based system promotes viability of human embryos during laboratory processing

In vitro fertilisation (IVF) and related technologies are arguably the most challenging of all cell culture applications. The starting material is a single cell from which one aims to produce an embryo capable of establishing a pregnancy eventually leading to a live birth. Laboratory processing during IVF treatment requires open manipulations of gametes and embryos, which typically involves exposure to ambient conditions. To reduce the risk of cellular stress, we have developed a totally enclosed system of interlinked isolator-based workstations designed to maintain oocytes and embryos in a physiological environment throughout the IVF process. Comparison of clinical and laboratory data before and after the introduction of the new system revealed that significantly more embryos developed to the blastocyst stage in the enclosed isolator-based system compared with conventional open-fronted laminar flow hoods. Moreover, blastocysts produced in the isolator-based system contained significantly more cells and their development was accelerated. Consistent with this, the introduction of the enclosed system was accompanied by a significant increase in the clinical pregnancy rate and in the proportion of embryos implanting following transfer to the uterus. The data indicate that protection from ambient conditions promotes improved development of human embryos. Importantly, we found that it was entirely feasible to conduct all IVF-related procedures in the isolator-based workstations

2011 Report of NSF Workshop Series on Scientific Software Security Innovation Institute

Over the period of 2010-2011, a series of two workshops were held in response to NSF Dear Colleague Letter NSF 10-050 calling for exploratory workshops to consider requirements for Scientific Software Innovation Institutes (S2I2s). The specific topic of the workshop series was the potential benefits of a security-focused software institute that would serve the entire NSF research and development community. The first workshop was held on August 6th, 2010 in Arlington, VA and represented an initial exploration of the topic. The second workshop was held on October 26th, 2011 in Chicago, IL and its goals were to 1) Extend our understanding of relevant needs of MREFC and large NSF Projects, 2) refine outcome from first workshop with broader community input, and 3) vet concepts for a trusted cyberinfrastructure institute. Towards those goals, the participants other 2011workshop included greater representation from MREFC and large NSF projects, and, for the most part, did not overlap with the participants from the 2010 workshop. A highlight of the second workshop was, at the invitation of the organizers, a presentation by Scott Koranda of the LIGO project on the history of LIGO’s identity management activities and how those could have benefited from a security institute. A key analysis he presented is that, by his estimation, LIGO could have saved 2 senior FTE-years of effort by following suitable expert guidance had it existed. The overarching finding from the workshops is that security is a critical crosscutting issue for the NSF software infrastructure and recommended a security focused activity to address this issue broadly, for example a security software institute (S2I2) under the SI2 program. Additionally, the 2010 workshop participants agreed to 15 key additional findings, which the 2011 workshop confirmed, with some refinement as discussed in this report.NSF Grant # 1043843Ope