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2017 Summer. ; Includes bibliographical references. ; Mammals, and in particular humans, are masterful at overcoming and adapting to extreme environments. Whether astronauts in low earth orbit aboard the International Space Station (ISS) or U.S. military veterans exposed to nuclear fallout from atomic weapons testing, humans can persist through a wide range of physical, psychological, and environmental stressors. The overall goal of the studies presented here was to evaluate the biological influences of extreme environments not commonly experienced by the general population. Whether spaceflight or exposure to nuclear fallout, results improve our understanding of short- and long-term effects of low gravity environments, exposure to ionizing radiation (IR) of mixed qualities, as well as low dose and low dose effects of IR. We explored these scenarios by evaluating biomarkers of stress, specifically telomere length dynamics, and biomarkers of DNA damage, specifically transmissible structural rearrangements. Telomeres are not only regarded as valuable biomarkers of aging and age-related degenerative pathologies like cardiovascular disease and cancer, and so are reflective of overall health status, they also serve as "hallmarks" of radiosensitivity. Stable chromosomal structural rearrangements (translocations and inversions) persist with time and so provide informative signatures of IR exposure as well. During the 1950's United States military personnel and weathermen, collectively known as the atomic veterans, were unintentionally exposed to nuclear fallout during atomic bomb testing following WWII. Here, directional Genomic Hybridization (dGH) for high-resolution detection of IR-induced chromosomal inversions and translocations was assessed as a more sensitive, quantitative retrospective biodosimetry approach. The influence of IR exposure on telomere length dynamics was also evaluated to determine the long-term influence of such exposures. Our results illustrate that even for nuclear events that occurred six decades in the past, evidence of exposure is still present. We find that although translocations and inversions are reliable biodosimeters independently, a combined approach provides a more sensitive measurement of past radiation exposure. We also report, for the first time, the influence of age and smoking on background inversion frequencies. Furthermore, telomere length was inversely related to IR dose, suggesting that a single acute exposure to nuclear fallout may lead to persistent long-term effects on overall health. Telomere length dynamics and structural rearrangements were also monitored longitudinally in monozygotic twin and unrelated astronauts. NASA astronauts are a unique group of individuals who experience an extreme environment that the human body is not adapted for. Little is known about the biological health effects of a low gravity environment with increased IR exposure including galactic cosmic rays (GCRs), solar particle events, and secondary neutrons. Not only do astronauts have shorter telomeres than age-/gender-matched controls at baseline (pre-flight), but a transient increase in telomere length during space flight was also observed. Results suggest this unexpected finding may be due to an upregulation of telomerase, the enzyme responsible for maintaining telomere length. Moreover, telomerase activity also increased post-flight in both twins, Scott and Mark Kelly. Although not spaceflight specific, this is the first report of telomerase upregulation in humans due to a psychologically traumatic event. A dose dependent increase in inversions, and to a lesser extent, translocations, as a consequence of IR exposure on the ISS was also seen in Scott Kelly. Collectively, the studies presented here demonstrate a profound influence of extreme environments, particularly those involving low dose IR, on human biological responses. Telomere length dynamics and chromosome aberration frequencies (e.g. translocations and inversions) provide insight into the long-term health effects and implications of spaceflight and exposure to nuclear events.

It has now been over 60 years since U.S. nuclear testing was conducted in the Pacific islands and Nevada, exposing military personnel to varying levels of ionizing radiation. Actual doses are not well-established, as film badges in the 1950s had many limitations. We sought a means of independently assessing dose for comparison with historical film badge records and dose reconstruction conducted in parallel. For the purpose of quantitative retrospective biodosimetry, peripheral blood samples from 12 exposed veterans and 12 age-matched (>80 years) veteran controls were collected and evaluated for radiation-induced chromosome damage utilizing directional genomic hybridization (dGH), a cytogenomics-based methodology that facilitates simultaneous detection of translocations and inversions. Standard calibration curves were constructed from six male volunteers in their mid-20s to reflect the age range of the veterans at time of exposure. Doses were estimated for each veteran using translocation and inversion rates independently; however, combining them by a weighted-average generally improved the accuracy of dose estimations. Various confounding factors were also evaluated for potential effects on chromosome aberration frequencies. Perhaps not surprisingly, smoking and age-associated increases in background frequencies of inversions were observed. Telomere length was also measured, and inverse relationships with both age and combined weighted dose estimates were observed. Interestingly, smokers in the non-exposed control veteran cohort displayed similar telomere lengths as those in the never-smoker exposed veteran group, suggesting that chronic smoking had as much effect on telomere length as a single exposure to radioactive fallout. Taken together, we find that our approach of combined chromosome aberration-based retrospective biodosimetry provided reliable dose estimation capability, particularly on a group average basis, for exposures above statistical detection limits.

Vietnam is at a crossroads. It can grow as an export platform for GVCs, specializing in low value-added assembly functions with industrialization occurring in enclaves with little connection to the broader economy or society; or it can leverage the current wave of growth, enabled and accelerated by its successful participation in GVCs, to diversify and move up the chain into higher value-added functions. Success will require Vietnam's policymakers to view the processes of development differently, and to take new realities of the global economy more fully into account. The purpose of this volume is to support Vietnam's path to economic prosperity by identifying policies and targeted interventions that will drive development through leveraging GVC participation that take major shifts in trade policy and rapid technological advances in ICT into account. The volume is based on a compilation of studies completed by World Bank staff and external consultants in 2015 supporting the "Enabling Economic Modernization and Private Sector Development" chapter of the Vietnam 2035 report. The objective of these studies was to diagnose Vietnam's current participation in GVCs, visualize where Vietnam could be by 2035 in the context of a changing global environment, and identify the policy actions needed to get there. The studies also supported topics related more broadly to export competitiveness, including firm-level productivity, services, and connectivity. It then identifies targeted strategies and policy interventions that will help overcome challenges, minimize risks, and maximize opportunities. Readers will gain a strong understanding of Vietnam's current and potential engagement with GVCs--and will learn about strategic GVC policy tools that can help developing countries achieve economic prosperity in the context of compressed development. --