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All sourcesNASA NTRSDOE OSTI
DOE OSTI2023

Cancer survival in the United States 2007–2016: Results from the National Program of Cancer Registries

Background Cancer survival has improved for the most common cancers. However, less improvement and lower survival has been observed in some groups perhaps due to differential access to cancer care including prevention, screening, diagnosis, and treatment. Methods To further understand contemporary relative cancer survival (one- and five- year), we used survival data from CDC’s National Program of Cancer Registries (NPCR) for cancers diagnosed during 2007–2016. We examined overall relative cancer survival by sex, race and ethnicity, age, and county-level metropolitan and non-metropolitan status. Relative cancer survival by metropolitan and non-metropolitan status was further examined by sex, race and ethnicity, age, and cancer type. Results Among persons with cancer diagnosed during 2007–2016 the overall one-year and five-year relative survival was 80.6% and 67.4%, respectively. One-year relative survival for persons living in metropolitan counties was 81.1% and 77.8% among persons living in non-metropolitan counties. We found that persons who lived in non-metropolitan counties had lower survival than those who lived in metropolitan counties, and this difference persisted across sex, race and ethnicity, age, and most cancer types. Conclusion Further examination of the differences in cancer survival by cancer type or other characteristics might be helpful for identifying potential interventions, such as programs that target screening and early detection or strategies to improve access to high quality cancer treatment and follow-up care, that could improve long-term outcomes. Impact This analysis provided a high-level overview of contemporary cancer survival in the United States.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

A Spatially Explicit Individual-Based Modeling Approach to Evaluate the Cumulative Effects of Wind Energy Development on the Greater Sage-Grouse: Sensitivity Analysis and Validation of Key Parameters

To address the need for an approach to evaluate cumulative ecological impacts of wind energy development, particularly those on critical wildlife habitats and species, the authors developed a proof-of-concept, landscape-based, spatially explicit individual-based modeling (IBM) framework for populations of the greater sage-grouse (Centrocercus urophasianus) in Albany County, Wyoming, based on published and other available information on the life history of the species. This sage-grouse IBM estimates the spatial and temporal movements of sage-grouse based on modeled effects of habitat characteristics and developments on sage-grouse condition, survivorship, and reproduction. After completing the initial version of the model, we conducted a series of sensitivity analyses of key model parameters and validation of lek occurrences and spatial distributions to better understand performance of the model relative to observed values of important life history characteristics. The parameter sensitivity analysis was conducted as a series of one-factor-at-a-time tests in which the values of selected parameters were individually varied to evaluate the corresponding effects on model output. We examined the model’s response to changes in parameter values to gain insight into the overall robustness of the model, identify key driver parameters, and initiate qualitative validation. Five functions selected for sensitivity analyses were (1) the rate of change in body condition in relationship to habitat suitability index (HSI) of occupied habitat (condition change rate), (2) the effect of competition between individuals with overlapping home ranges expressed as a percentage reduction in HSI (competition factor), (3) value of condition at which survivorship probability is equal to zero (zero survivorship condition), (4) the relationship between female body condition and clutch size, and (5) the relationship between female body condition and nest success. We varied the parameter values to be tested for the sensitivity analysis around the original value used in the model (i.e., tested values were higher and lower than the model’s original value) to examine the effect of this variation on the predicted output of the model. Model outputs evaluated in the sensitivity analysis included (1) predicted age-class distribution (as measured by the percentage of immature individuals within the population); (2) predicted sex ratio; (3) predicted age-sex class distribution (percent of population in each of six age-sex classes, i.e., male and female juveniles, yearlings, and adults); (4) lifespan; (5) population size; and (6) spatial distribution. Of the five parameters analyzed, condition change rate, survivorship, clutch size, and nest success did not substantially affect any of the evaluated model outputs. For the predicted age-class distribution, the percentage of immature individuals predicted by the model for these four parameters ranged from 61.9% to 65.0%, which was reasonable with respect to the reference values of 51.4 to 57.8% in published studies. The ratio of females to males ranged from 1.09 to 1.14, which was comparable to the reference values of 1.2 to 3.0 presented in an existing study. The predicted mean lifespan ranged from 1.62 to 1.74 years, which appears to be reasonable with respect to the reference values of 0.9 to 1.1 years for sharp-tail grouse and greater prairie chickens presented by published studies. The predicted population size ranged from 1,877 to 3,140. This prediction would be reasonable with respect to our estimate of 5,000 yearlings and adults, which was based on the USFWS estimate for the state of Wyoming scaled to the number of leks in the county. The predicted spatial distribution was not substantially affected by the parameter values examined. In our sensitivity analyses, the only tested parameter that had a noticeable effect on model output was competition factor. Over the range of values tested for this parameter, predicted population size exhibited the largest range (from 1,833 to 4,737) of all parameters tested. As the competition factor increased, the predicted population size decreased. This reflects the effect competition had on the number of individuals that could co occur in high-quality habitat patches. Despite this apparently significant effect, the range of values appears to be reasonable with respect to our estimate of 5,000 yearlings and adults, which was based on the USFWS estimate for the state of Wyoming scaled to the number of leks in the county.

17 WIND ENERGY↗
DOE OSTI2020

Measuring Intelligence with the Sandia Matrices: Psychometric Review and Recommendations for Free Raven-Like Item Sets

The Sandia Matrices are a free alternative to the Raven’s Progressive Matrices (RPMs). This study offers a psychometric review of Sandia Matrices items focused on two of the most commonly investigated issues regarding the RPMs: (a) dimensionality and (b) sex differences. Model-data fit of three alternative factor structures are compared using confirmatory multidimensional item response theory (IRT) analyses, and measurement equivalence analyses are conducted to evaluate potential sex bias. Although results are somewhat inconclusive regarding factor structure, results do not show evidence of bias or mean differences by sex. Finally, although the Sandia Matrices software can generate infinite items, editing and validating items may be infeasible for many researchers. Further, to aide implementation of the Sandia Matrices, we provide scoring materials for two brief static tests and a computer adaptive test. Implications and suggestions for future research using the Sandia Matrices are discussed.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

The 300 Marines: characterizing the US Marines with perfect scores on their physical and combat fitness tests

Few US Marines earn perfect 300 scores on both their Physical Fitness Test (PFT) and Combat Fitness Test (CFT). The number 300 invokes the legendary 300 Spartans that fought at the Battle of Thermopylae, which inspired high physical fitness capabilities for elite ground forces ever since. Purpose: Determine distinguishing characteristics of the “300 Marines” (perfect PFT and CFT scores) that may provide insights into the physical and physiological requirements associated with this capability. These tests have been refined over time to reflect physical capabilities associated with Marine Corps basic rifleman performance. Materials and methods: Data were analyzed from US Marines, including 497 women (age, 29 ± 7 years; height 1.63 ± 0.07 m; body mass, 67.4 ± 8.4 kg) and 1,224 men (30 ± 8 years; 1.77 ± 0.07 m; 86.1 ± 11.1 kg). Marines were grouped by whether they earned perfect 300 scores on both the PFT and CFT (300 Marines) or not. We analyzed group differences in individual fitness test events and body composition (dual-energy x-ray absorptiometry). Results: Only 2.5% (n = 43) of this sample earned perfect PFT and CFT scores (n = 21 women; n = 22 men). Compared to sex-matched peers, 300 Marines performed more pull-ups, with faster three-mile run, maneuver-under-fire, and movement-to-contact times (each p < 0.001); 300 Marines of both sexes had lower fat mass, body mass index, and percent body fat (each p < 0.001). The lower percent body fat was explained by greater lean mass (p = 0.041) but similar body mass (p = 0.085) in women, whereas men had similar lean mass (p = 0.618), but lower total body mass (p = 0.025). Conclusion: Marines earning perfect PFT and CFT scores are most distinguished from their peers by their maneuverability, suggesting speed and agility capabilities. While both sexes had considerably lower percent body fat than their peers, 300 Marine women were relatively more muscular while men were lighter.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

The relationship between urinary selenium levels and risk of gestational diabetes mellitus: A nested case–control study

Background Selenium (Se) is an essential trace element for the human body. Serum Se and urinary Se are also biomarkers to assess Se exposure status. However, studies focusing on the association between urinary Se and the risk of gestational diabetes mellitus (GDM) are rare. Objective To investigate the association between urinary Se and the risk of GDM. Methods A nested case–control study based on a prospective birth cohort in Wuhan, China, which focuses on the effects of prenatal environmental factors exposure on pregnant women and children’s health was conducted. Two hundred and twenty-six cases and 452 controls were included. Maternal urine samples were collected before GDM diagnosis, and the urinary Se levels were determined. We assessed the association of urinary Se with GDM by conditional logistic regression with maternal urinary Se level as a categorical variable, and estimated the association between Se and glucose levels by multiple linear regression. The potential modifier roles of maternal age and fetal sex have also been assessed. Results Lower urinary level of Se was significantly associated with a higher risk of GDM (OR = 2.35 for the tertile 1, 95% CI:1.36-4.06; adjusted OR = 1.79 for the tertile 2, 95%CI:1.09-2.95; p for trend = 0.01). Fetal sex had an interaction with Se in the association with GDM. The association was more pronounced among pregnant women with female fetuses than with male fetuses. Discussion Our study suggested a significant negative association between urinary Se and the risk of GDM, and this association may vary depending on the fetal sex.

Liu, Yuanxia↗
DOE OSTI2023

Recognizability of Demographically Altered Computerized Facial Approximations in an Automated Facial Recognition Context for Potential Application in Unidentified Persons Data Repositories

This study examined the recognizability of demographically altered facial approximations for potential utility in unidentified persons tracking systems. Five computer-generated approximations were generated for each of 26 African male participants using the following demographic parameters: (i) African male (true demographics), (ii) African female, (iii) Caucasian male, (iv) Asian male, and (v) Hispanic male. Overall, 62% of the true demographic facial approximations for the 26 African male participants examined were matched to a corresponding life photo within the top 50 images of a candidate list generated from an automated blind search of an optimally standardized gallery of 6159 photographs. When the African male participants were processed as African females, the identification rate was 50%. In contrast, less congruent identification rates were observed when the African male participants were processed as Caucasian (42%), Asian (35%), and Hispanic (27%) males. The observed results suggest that approximations generated using the opposite sex may be operationally informative if sex is unknown. The performance of approximations generated using alternative ancestry assignments, however, was less congruent with the performance of the true demographic approximation (African male) and may not yield as operationally constructive data as sex-altered approximations.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Loss of Mitochondrial Tusc2/Fus1 Triggers a Brain Pro-Inflammatory Microenvironment and Early Spatial Memory Impairment

Brain pathological changes impair cognition early in disease etiology. There is an urgent need to understand aging-linked mechanisms of early memory loss to develop therapeutic strategies and prevent the development of cognitive impairment. Tusc2 is a mitochondrial-resident protein regulating Ca 2+ fluxes to and from mitochondria impacting overall health. We previously reported that Tusc2 –/– female mice develop chronic inflammation and age prematurely, causing age- and sex-dependent spatial memory deficits at 5 months old. Therefore, we investigated Tusc2-dependent mechanisms of memory impairment in 4-month-old mice, comparing changes in resident and brain-infiltrating immune cells. Interestingly, Tusc2 –/– female mice demonstrated a pro-inflammatory increase in astrocytes, expression of IFN-γ in CD4 + T cells and Granzyme-B in CD8 + T cells. We also found fewer FOXP3 + T-regulatory cells and Ly49G + NK and Ly49G + NKT cells in female Tusc2 –/– brains, suggesting a dampened anti-inflammatory response. Moreover, Tusc2 –/– hippocampi exhibited Tusc2- and sex-specific protein changes associated with brain plasticity, including mTOR activation, and Calbindin and CamKII dysregulation affecting intracellular Ca2 + dynamics. Overall, the data suggest that dysregulation of Ca 2+ -dependent processes and a heightened pro-inflammatory brain microenvironment in Tusc2 –/– mice could underlie cognitive impairment. Thus, strategies to modulate the mitochondrial Tusc2- and Ca 2+ - signaling pathways in the brain should be explored to improve cognitive health.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

DIFFERENTIAL CANID PREDATION OF TRANSLOCATED JUVENILE DESERT TORTOISES AND CHEMICAL SIGNATURE DIFFERENCES BETWEEN FEMALE AND MALE ADULT AND JUVENILE DESERT TORTOISES

Differential predation was observed in a population of 59 translocated juvenile Desert Tortoises (Gopherus agassizii) of known sex during a juvenile translocation survival study between September 2012 and November 2017. The main source of mortality (77%; 24 of 31 deaths) was attributed to Coyote (Canis latrans) and Kit Fox (Vulpes macrotis) predation. Predation was skewed with 71% (n = 17) female mortality versus 29% (n = 7) male mortality. We tested the hypothesis that juvenile females smell different than males which leads to increased canid predation. We also explored differences in chemical signatures of resident adult female and male Desert Tortoises. We collected oral, cloacal and chin/forelimb swabs from translocated juvenile and resident adult female and male tortoises during fall 2015 and fall 2017 and analyzed them using headspace gas chromatography/mass spectrometry to determine potential differences in the chemical signatures among the four groups. Standardized chromatographic peak responses were subjected to repeated analyses of variance (ANOVA). For development of artificial scents, mean responses were calculated for each juvenile tortoise from standardized responses representing all collections (i.e., oral, cloacal, and chin/forelimb swabs) and grand means were determined for males and females. Repeated measures ANOVAs clearly demonstrated that the collections of volatiles differed according to age and/or sex depending on the body location of collection. Among the plausibly endogenous volatiles that differed by age, many of them are alcohols. Two field trials using captive Coyotes and one field trial partially within the translocation area were conducted to test if Coyotes showed a preference for female or bias against male synthesized scent. No consistent preference or bias was shown, suggesting that no innate preference for female odor was evident.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Assessment of Demographic, Genetic, and Imaging Variables Associated With Brain Resilience and Cognitive Resilience to Pathological Tau in Patients With Alzheimer Disease

Importance: Better understanding is needed of the degree to which individuals tolerate Alzheimer disease (AD)-like pathological tau with respect to brain structure (brain resilience) and cognition (cognitive resilience). Objective: To examine the demographic (age, sex, and educational level), genetic (APOE-ε4 status), and neuroimaging (white matter hyperintensities and cortical thickness) factors associated with interindividual differences in brain and cognitive resilience to tau positron emission tomography (PET) load and to changes in global cognition over time. Design, setting, an participants: In this cross-sectional, longitudinal study, tau PET was performed from June 1, 2014, to November 30, 2017, and global cognition monitored for a mean [SD] interval of 2.0 [1.8] years at 3 dementia centers in South Korea, Sweden, and the United States. The study included amyloid-β-positive participants with mild cognitive impairment or AD dementia. Data analysis was performed from October 26, 2018, to December 11, 2019. Exposures: Standard dementia screening, cognitive testing, brain magnetic resonance imaging, amyloid-β PET and cerebrospinal fluid analysis, and flortaucipir (tau) labeled with fluor-18 (18F) PET. Main outcomes and measures: Separate linear regression models were performed between whole cortex [18F]flortaucipir uptake and cortical thickness, and standardized residuals were used to obtain a measure of brain resilience. The same procedure was performed for whole cortex [18F]flortaucipir uptake vs Mini-Mental State Examination (MMSE) as a measure of cognitive resilience. Bivariate and multivariable linear regression models were conducted with age, sex, educational level, APOE-ε4 status, white matter hyperintensity volumes, and cortical thickness as independent variables and brain and cognitive resilience measures as dependent variables. Linear mixed models were performed to examine whether changes in MMSE scores over time differed as a function of a combined brain and cognitive resilience variable. Results: A total of 260 participants (145 [55.8%] female; mean [SD] age, 69.2 [9.5] years; mean [SD] MMSE score, 21.9 [5.5]) were included in the study. In multivariable models, women (standardized β = -0.15, P = .02) and young patients (standardized β = -0.20, P = .006) had greater brain resilience to pathological tau. Higher educational level (standardized β = 0.23, P < .001) and global cortical thickness (standardized β = 0.23, P < .001) were associated with greater cognitive resilience to pathological tau. Linear mixed models indicated a significant interaction of brain resilience × cognitive resilience × time on MMSE (β [SE] = -0.235 [0.111], P = .03), with steepest slopes for individuals with both low brain and cognitive resilience. Conclusions and relevance: Results of this study suggest that women and young patients with AD have relative preservation of brain structure when exposed to neocortical pathological tau. Interindividual differences in resilience to pathological tau may be important to disease progression because participants with both low brain and cognitive resilience had the most rapid cognitive decline over time.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Raccoon densities across four land cover types in the southeastern United States

Raccoons (Procyon lotor) are the primary reservoir for rabies virus in eastern North America. Management of rabies in raccoons is achieved primarily with the use of oral rabies vaccination (ORV) and effective ORV bait densities are determined in part by the densities of raccoons. Decisions regarding ORV bait densities, however, are limited by an incomplete understanding of raccoon densities across the spectrum of landscapes they occupy. We carried out a mark-recapture study of raccoons on the Savannah River Site in South Carolina, USA, from 2017–2019, to develop sex- and landscape-specific raccoon density estimates across 4 rural land cover types in the southeastern United States: bottomland hardwood, riparian forest, isolated wetland, and upland pine (Pinus spp.). We captured 404 unique raccoons 773 times over the 3-year trapping period. Estimated densities were 5.44 ± 0.37 (SE) animals/km 2 in bottomland hardwood forest, 2.62 ± 0.32 animals/km 2 in riparian forest, 2.19 ± 0.29 animals/km 2 in isolated wetlands, and 2.14 ± 0.23 animals/km 2 in upland pine. Densities were significantly higher in bottomland hardwood than all other land cover types, whereas densities among the remaining cover types were similar. These patterns are likely the result of landscape fragmentation and configuration, with riparian forests typically embedded in a matrix of less suitable cover types, leading to low densities despite presumably high resource availability. There were higher densities of males than females in every cover type except upland pine, where the sex ratio was balanced. Densities on our site were low compared to other rural areas, which likely results from the lack of human influence in terms of agriculture or development. The financial cost of baiting for ORV distribution may be reduced by considering the comparatively low densities of raccoons in these rural landscapes in the southeastern United States.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Development and cross‐validation of a circumference‐based predictive equation to estimate body fat in an active population

Abstract Objective The U.S. Army uses sex‐specific circumference‐based prediction equations to estimate percent body fat (%BF) to evaluate adherence to body composition standards. The equations are periodically evaluated to ensure that they continue to accurately assess %BF in a diverse population. The objective of this study was to develop and validate alternative field expedient equations that may improve upon the current Army Regulation (AR) body fat (%BF) equations. Methods Body size and composition were evaluated in a representatively sampled cohort of 1904 active‐duty Soldiers (1261 Males, 643 Females), using dual‐energy X‐ray absorptiometry (%BF DXA ), and circumferences obtained with 3D imaging and manual measurements. Sex stratified linear prediction equations for %BF were constructed using internal cross validation with %BF DXA as the criterion measure. Prediction equations were evaluated for accuracy and precision using root mean squared error, bias, and intraclass correlations. Equations were externally validated in a convenient sample of 1073 Soldiers. Results Three new equations were developed using one to three circumference sites. The predictive values of waist, abdomen, hip circumference, weight and height were evaluated. Changing from a 3‐site model to a 1‐site model had minimal impact on measurements of model accuracy and performance. Male‐specific equations demonstrated larger gains in accuracy, whereas female‐specific equations resulted in minor improvements in accuracy compared to existing AR equations. Equations performed similarly in the second external validation cohort. Conclusions The equations developed improved upon the current AR equation while demonstrating robust and consistent results within an external population. The 1‐site waist circumference‐based equation utilized the abdominal measurement, which aligns with associated obesity related health outcomes. This could be used to identify individuals at risk for negative health outcomes for earlier intervention.

Taylor, Kathryn M.↗
DOE OSTI2022

Chromosome aberrations among atomic-bomb survivors exposed in utero: updated analysis accounting for revised radiation doses and smoking

A previous study of peripheral blood lymphocyte translocations around age 40 among atomic-bomb survivors exposed in utero revealed no overall association with radiation dose—despite a clear association between translocations and dose among their mothers—but the data suggested an increase at doses below 100 mGy with a definite peak. That analysis of the in utero-exposed survivors did not adjust for their subsequent smoking behavior, an established cause of chromosomal aberrations, or their subsequent exposures to medical irradiation, a potential mediator. In addition, atomic-bomb survivor radiation dose estimates have subsequently been updated and refined. We therefore re-estimated the dose response using the latest DS02R1 dose estimates and adjusting for smoking as well as for city and proximal–distal location at the time of exposure to the atomic bomb. Sex of the survivor, mother’s age around the time of conception, and approximate trimester of gestation at the time of exposure were also considered as explanatory variables and modifiers. Precision of the estimated dose response was slightly lower due to greater variability near zero in the updated dose estimates, but there was little change in evidence of a low-dose increase and still no suggestion of an overall increase across the entire dose range. Adjustment for smoking behavior led to a decline in background number of translocations (the dose–response intercept), but smoking did not interact with dose overall (across the entire dose range). Adjustment for medical irradiation did not alter the association between dose and translocation frequency. Sex, mother’s age, and trimester were not associated with number of translocations, nor did they interact with dose overall. Interactions with dose in the low-dose range could not be evaluated because of numerical instability.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Differential DNA methylation and metabolite profiling of Atlantic killifish (Fundulus heteroclitus) from the New Bedford Harbor Superfund site

Atlantic killifish (Fundulus heteroclitus) is a valuable model in evolutionary toxicology to study how the interactions between genetic and environmental factors serve the adaptive ability of organisms to resist chemical pollution. Killifish populations inhabiting environmental toxicant-contaminated New Bedford Harbor (NBH) show phenotypes tolerant to polychlorinated biphenyls (PCBs) and differences at the transcriptional and genomic levels. However, limited research has explored epigenetic alterations and metabolic effects in NBH killifish. To identify the involvement of epigenetic and metabolic regulation in the adaptive response of killifish, we investigated tissue- and sex-specific differences in global DNA methylation and metabolomic profiles of NBH killifish populations, compared to sensitive populations from a non-polluted site, Scorton Creek (SC). The results revealed that liver-specific global DNA hypomethylation and differential metabolites were evident in fish from NBH compared with those from SC. The sex-specific differences were not greater than the tissue-specific differences. We demonstrated liver-specific enriched metabolic pathways (e.g., amino acid metabolic pathways converged into the urea cycle and glutathione metabolism), suggesting possible crosstalk between differential metabolites and DNA hypomethylation in the livers of NBH killifish. Additional investigation of methylated gene regions is necessary to understand the functional role of DNA hypomethylation in the regulation of enzyme-encoding genes associated with metabolic processes and physiological changes in NBH populations.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2026

Endurance exercise elicits temporal and sexual dimorphic multi-omics remodeling of liver metabolism revealed by MoTrPAC

The mechanisms by which exercise modulate liver metabolism, a central regulator of systemic metabolism, are poorly understood. Leveraging data from MoTrPAC, we analyzed liver adaptations across 1, 2, 4, and 8 weeks of exercise in male and female rats using multi-omic approaches. Female livers displayed a progressive increase in oxidative phosphorylation (OXPHOS) complexes (at the protein level), while male livers showed an increase in acetylation of OXPHOS, TCA cycle, and fatty acid oxidation enzymes. Exercise also enhanced liver cholesterol and bile acid synthesis, reducing liver lipid metabolites in males after 8 weeks of exercise. Male rats had higher fecal cholesterol and cholic acid levels, indicating a sex-specific mechanism of lipid excretion with exercise. Moreover, 8 weeks of training reduced markers related to hepatic stellate cell activation and fibrosis in both sexes. This study highlights the sexual dimorphic and temporal molecular signatures by which exercise modulates liver metabolism to provide hepatoprotective effects.

Kelty, Taylor↗
DOE OSTI2025

Risk of Mortality in Family Members of Men Seeking Fertility Assessment

Objective: To assess mortality in family members of men seeking fertility assessment. Subfertility serves as a biomarker for overall somatic health, and poor semen quality is associated with increased risk of hospitalization and mortality from chronic conditions. However, it is unclear if these risks extend to family members of men with low sperm count. Design: Retrospective cohort study. Subjects: Family members, up to third-degree relatives, of men in the Subfertility, Health and Assisted Reproduction and the Environment cohort who underwent a semen analysis as part of a fertility assessment 1996–2017. Relatives of men with a recorded total sperm count who lived in Utah for ≥1 year 1904–2017 were included in the analysis (N = 22,280 families). Exposure: Individuals were classified by family membership. Families were classified as relatives of azoospermic (0M), oligozoospermic (<39M), or normozoospermic (≥39M) men. The average total sperm count of the proband (male relative) with fertility assessment was also included as a continuous exposure measure. Main Outcome Measures: The main outcomes were all-cause and cause-specific mortality risk by sex, age, and degree of relation: first-, second-, and third-degree. Cox proportional hazard models were used to test the association between fertility classification and mortality, controlling for sex, race/ethnicity, and birth year. Results: A total of 666,437 relatives of men with fertility assessment (N deaths = 183,974) were included in the analysis. Relative to normozoospermia families, all-cause mortality risk increased in oligozoospermia families (hazard ratio [HR] oligozoospermia , 1.03; 95% confidence interval [CI], 1.01–1.05). Close relatives, first- (HR oligozoospermia , 1.17; 95% CI, 1.07–1.28) and second-degree relatives (HR azoospermia , 1.11; 95% CI, 1.04–1.20; HR oligozoospermia , 1.05; 95% CI,1.01–1.09), of azoospermic and oligozoospermic men had the highest all-cause and cause-specific mortality risk, including death attributed to cardiovascular disease or congenital birth conditions. Conclusion: Our results suggest that familial all-cause and cause-specific mortality risk differ by fertility phenotype. Families of azoospermic and oligozoospermic men showed significantly increased risk, particularly for close relatives. This study provides further evidence that shared genetic and/or environmental factors could influence both fertility and somatic health.

Male fertility↗
DOE OSTI2021

Sixty days of head-down tilt bed rest with or without artificial gravity do not affect the neuromuscular secretome

Highlights: • Long-term bed rest with/without artificial gravity does not affect the neuromuscular secretome. • Serum concentrations of markers of muscle wasting are not affected by bed rest/artificial gravity. • C-terminal Agrin Fragment serum concentrations are not affected by bed rest/artificial gravity. • Human centrifugation during bed rest does not have a negative impact on the neuromuscular secretome. Artificial gravity is a potential countermeasure to attenuate effects of weightlessness during long-term spaceflight, including losses of muscle mass and function, possibly to some extent attributable to disturbed neuromuscular interaction. The 60-day AGBRESA bed-rest study was conducted with 24 participants (16 men, 8 women; 33 ± 9 years; 175 ± 9 cm; 74 ± 10 kg; 8 control group, 8 continuous (cAG) and 8 intermittent (iAG) centrifugation) to assess the impact of bed rest with or without daily 30-min continuous/intermittent centrifugation with 1G at the centre of mass. Fasting blood samples were collected before and on day 6, 20, 40 and 57 during 6° head-down tilt bed rest. Concentrations of circulating markers of muscle wasting (GDF-8/myostatin; slow skeletal muscle troponin T; prostaglandin E2), neurotrophic factors (BDNF; GDNF) and C-terminal Agrin Fragment (CAF) were determined by ELISAs. Creatine kinase activity was assessed by colorimetric enzyme assay. Repeated-measures ANOVAs were conducted with TIME as within-subject, and INTERVENTION and SEX as between-subject factors. The analyses revealed no significant effect of bed rest or sex on any of the parameters. Continuous or intermittent artificial gravity is a safe intervention that does not have a negative impact of the neuromuscular secretome.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Fine-scale contemporary recombination variation and its fitness consequences in adaptively diverging stickleback fish

Despite deep evolutionary conservation, recombination rates vary greatly across the genome and among individuals, sexes and populations. Yet the impact of this variation on adaptively diverging populations is not well understood. Here we characterized fine-scale recombination landscapes in an adaptively divergent pair of marine and freshwater populations of threespine stickleback from River Tyne, Scotland. Through whole-genome sequencing of large nuclear families, we identified the genomic locations of almost 50,000 crossovers and built recombination maps for marine, freshwater and hybrid individuals at a resolution of 3.8 kb. We used these maps to quantify the factors driving variation in recombination rates. We found strong heterochiasmy between sexes but also differences in recombination rates among ecotypes. Hybrids showed evidence of significant recombination suppression in overall map length and in individual loci. Recombination rates were lower not only within individual marine–freshwater-adaptive loci, but also between loci on the same chromosome, suggesting selection on linked gene ‘cassettes’. Through temporal sampling along a natural hybrid zone, we found that recombinants showed traits associated with reduced fitness. Our results support predictions that divergence in cis-acting recombination modifiers, whose functions are disrupted in hybrids, may play an important role in maintaining differences among adaptively diverging populations.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Short term treatment with a cocktail of rapamycin, acarbose and phenylbutyrate delays aging phenotypes in mice

Pharmaceutical intervention of aging requires targeting multiple pathways, thus there is rationale to test combinations of drugs targeting different but overlapping processes. In order to determine if combining drugs shown to extend lifespan and healthy aging in mice would have greater impact than any individual drug, a cocktail diet containing 14 ppm rapamycin, 1000 ppm acarbose, and 1000 ppm phenylbutyrate was fed to 20-month-old C57BL/6 and HET3 4-way cross mice of both sexes for three months. Mice treated with the cocktail showed a sex and strain-dependent phenotype consistent with healthy aging including decreased body fat, improved cognition, increased strength and endurance, and decreased age-related pathology compared to mice treated with individual drugs or control. The severity of age-related lesions in heart, lungs, liver, and kidney was consistently decreased in mice treated with the cocktail compared to mice treated with individual drugs or control, suggesting an interactive advantage of the three drugs. This study shows that a combination of three drugs, each previously shown to enhance lifespan and health span in mice, is able to delay aging phenotypes in middle-aged mice more effectively than any individual drug in the cocktail over a 3-month treatment period.

60 APPLIED LIFE SCIENCES↗