Predicting Cell Death and Mutation Frequency for a Wide Spectrum of LET and Across Cell Lines from DNA Double Strand Break Clustering Inside Repair Domains
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One of the fundamental questions about Venus is whether it ever had a habitable period in its distant past. If it did have such a period how did Venus get from a temperate state to its present day hot-house? Recent studies have demonstrated that increasing solar luminosity through time is an unlikely pathway for Venus even if that is one way for Earth to end up in a runaway greenhouse state. Large Igneous Provinces (LIPs; like that of the Siberian Traps) have been responsible for the End Permian mass extinction and other dramatic climate change events throughout Earth’s history. We investigate the hypothesis that overlapping Large Igneous Provinces could have driven Venus from a temperate to a runaway greenhouse state. We look at the LIP record in Earth history and the probability for overlapping LIP events as a proxy.
The idea of a habitable Venus epoch has gained traction in recent years via 1-D and 3-D General Circulation Modeling (GCM) efforts [1,2,3]. Although recent work has supported an alternative permanent hot and dry scenario [4]. However, the habitable scenario presents us with a conundrum - how does a terrestrial planet transform from temperate to hot-house? For decades it was proposed that the gradual brightening of the sun was the probable cause [5]. Yet 4 billion years ago Venus was receiving nearly 1.4 times the insolation that Earth receives today, and many studies have put Earth at the inner boundary of the habitable zone today [6]. The newer 3-D GCM efforts have demonstrated that if Venus had an early habitable period, that the cloud-albedo feedback responsible for maintaining temperate surface conditions [7] could still be in operation today. From this perspective increasing insolation through time cannot be an answer to the transition from habitable to hot-house. We propose that the 'Great Climate Transition' (GCT) was trigged by simultaneous large igneous provinces (LIPs) akin to those like the Siberian Traps responsible for the End Permian [8]. We have taken the most up to date LIP database for Earth [9] and characterized their distribution through time as random or nearly random. Next we initiate a large suite of Monte Carlo simulations based on this record and generate the likelihood for simultaneous, or environmentally overlapping events in this hypothetical setup. We find the probability of such events to be quite high, a probable cause for Venus' GCT, and a possible harbinger of things to come for Earth.
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Aviation awards a special name—airmanship—for the quality of being highly competent in foundational piloting skills, which seem to comprise primarily judgment, decision making, stick-and-rudder skills, and a bit of intuition. The term, which has a mystical quality, has historically resisted analysis; airmanship is acquired solely through experience. The graying of the Boomers and the extreme turbulence of the last few years in commercial aviation have led to a significant loss of those pilots who started out in simpler, round-dial airplanes and made a tortured transition to glass. Those pilots were comfortable disengaging the autopilot at any time, and more importantly, they continued to stay mentally engaged with flight and systems management even as automation continued to encroach on traditional pilot roles. As an industry, we need to prepare for the loss of these pilots by understanding the elements of airmanship and finding a way to replace the competency. The goal is to eliminate “airmanship” by understanding it...by demystifying it. Human factors/cognitive engineering offers tools and methods to develop a system interface that supports skilled performance from the human/technology team. In this presentation, I will talk about my efforts to understand the elements of skilled performance so that they can be trained, or supported by the interface in a seamless manner Specific topics will include the limits of SOP, monitoring for flight path management, alerting non-normals, and autoflight/mode confusion.
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Over the past 50 years, the discovery and initial investigation of subglacial lakes in Antarctica have highlighted the paleoglaciological information that may be recorded in sediments at their beds. In December 2018, we accessed Mercer Subglacial Lake, West Antarctica, and recovered the first in situ subglacial lake-sediment record—120 mm of finely laminated mud. We combined geophysical observations, image analysis, and quantitative stratigraphy techniques to estimate long-term mean lake sedimentation rates (SRs) between 0.49 ± 0.12 mm a –1 and 2.3 ± 0.2 mm a –1 , with a most likely SR of 0.68 ± 0.08 mm a –1 . These estimates suggest that this lake formed between 53 and 260 a before core recovery (BCR), with a most likely age of 180 ± 20 a BCR—coincident with the stagnation of the nearby Kamb Ice Stream. Our work demonstrates that interconnected subglacial lake systems are fundamentally linked to larger-scale ice dynamics and highlights that subglacial sediment archives contain powerful, century-scale records of ice history and provide a modern process-based analogue for interpreting paleo–subglacial lake facies.
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We conducted a historical cohort study of mortality among 195 astronauts who were exposed to space and medical sources of radiation between 1959 and 1991. Cumulative occupational and medical radiation exposures were obtained from the astronaut radiation exposure history data base. Causes of death were obtained from obligatory death certificates and autopsy reports that were on file in the medical records. A total of 18 deaths occurred during the 32-year follow-up period for which the all-cause standardized mortality ratio (SMR) was 142 (95 percent confidence interval 84 225). There was one cancer death in the buccal cavity and pharynegeal ICD-9 rubric whose occurrence was significantly beyond expectation. Mortality for coronary disease was 59 percent lower than expected (2 deaths; SMR = 41; 95 percent confidence limit 5 147). The crude death rate for 10 occupationally related accidents was 400 deaths per 100,000 person-years, which is an order of magnitude greater than accidental death rates in mining industries. The SMR of 1027 for fatal accidents was significantly beyond expectation (14 deaths; 95 percent confidence limit 561 1723) and was similar to SMRs for accidents among aerial pesticide applications. The 10-year cumulative risk of occupational fatalities based on the exponential, Weibull, Gompertz, and linear-exponential distributions was 10 percent. Mortality from motor vehicle accidents was slightly higher than expected but was not significant (1 death; SMR = 145; 95 percent confidence limit 2 808). Radiation exposures from medical procedures accounted for a majority of cumulative dose when compared with space radiation exposures. The results of the study do not confirm the impression that astronauts are at increased risk of cancer, but this does not obviate the need for further study. Overall, it was found that astronauts are at a health disadvantage as a result of catastrophic accidents.
Programmed cell death (PCD) in filamentous fungi prevents cytoplasmic mixing following fusion between conspecific genetically distinct individuals (allorecognition) and serves as a defense mechanism against mycoparasitism, genome exploitation, and deleterious cytoplasmic elements (i.e., senescence plasmids). Recently, we identified regulator of cell death-1 ( rcd-1 ), a gene controlling PCD in germinated asexual spores in the filamentous fungus Neurospora crassa . rcd-1 alleles are highly polymorphic and fall into two haplogroups in N. crassa populations. Coexpression of alleles from the two haplogroups, rcd-1–1 and rcd-1–2 , is necessary and sufficient to trigger a cell death reaction. Here, we investigated the molecular bases of rcd-1 -dependent cell death. Based on in silico analyses, we found that RCD-1 is a remote homolog of the N-terminal pore-forming domain of gasdermin, the executioner protein of a highly inflammatory cell death reaction termed pyroptosis, which plays a key role in mammalian innate immunity. We show that RCD-1 localizes to the cell periphery and that cellular localization of RCD-1 was correlated with conserved positively charged residues on predicted amphipathic α-helices, as shown for murine gasdermin-D. Similar to gasdermin, RCD-1 binds acidic phospholipids in vitro, notably, cardiolipin and phosphatidylserine, and interacts with liposomes containing such lipids. The RCD-1 incompatibility system was reconstituted in human 293T cells, where coexpression of incompatible rcd-1–1/rcd-1–2 alleles triggered pyroptotic-like cell death. Oligomers of RCD-1 were associated with the cell death reaction, further supporting the evolutionary relationship between gasdermin and rcd-1 . This report documents an ancient transkingdom relationship of cell death execution modules involved in organismal defense.
Background To determine if construction and trades workers formerly employed at US Department of Energy (DOE) nuclear weapons sites are at significant risk for occupational diseases, we studied the mortality experience of participants in the Building Trades National Medical Screening Program (BTMed). Methods The cohort included 26,922 participants enrolled between 1998 and 2021 and 8367 deaths. Standardized mortality ratios were calculated based on US death rates. Cox models compared construction workers (n = 22,747; 7487 deaths) to two nonconstruction subpopulations: administrative, scientific and security workers (n = 1894; 330 deaths), and all other nonconstruction workers (n = 2218; 550 deaths). Results Mortality was elevated for all causes, all cancers, cancers of the trachea, bronchus, lung, kidneys, and lymphatic and hematopoietic system, mesothelioma, chronic obstructive pulmonary disease (COPD), asbestosis, transportation injuries, and other injuries, particularly accidental poisonings. There were 167 deaths from coronavirus disease 2019 (COVID-19), which was lower than expected using US death rates. Overall cause-specific mortality was significantly higher among construction workers than for internal comparison groups. Conclusions Construction workers employed at DOE sites have a significantly increased risk for occupational illnesses. Apart from COVID-19 deaths, this update: (1) found that mortality among construction workers is significantly elevated compared to the US population and significantly higher than in the internal comparison populations, and (2) confirmed excess risk for these workers for first employment after 1990. Cancer mortality risks are similar to the cancers identified for DOE compensation from radiation exposures. In conclusion, the high lung cancer risk supports the value of early lung cancer detection. Continued medical surveillance is important.