Search NASA⌕ Search

SEARCH · Search NASA

Results for “Sex”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 253 records · Page 14
All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

Metabolomic and transcriptomic remodeling of bone marrow myeloid cells in response to maternal obesity

Maternal obesity puts the offspring at high risk of developing obesity and cardiometabolic diseases in adulthood. Here, we utilized a mouse model of maternal high-fat diet (HFD)-induced obesity that recapitulates metabolic perturbations seen in humans. We show increased adiposity in the offspring of HFD-fed mothers (Off-HFD) when compared with the offspring of regular diet-fed mothers (Off-RD). We have previously reported significant immune perturbations in the bone marrow of newly weaned Off-HFD. Here, we hypothesized that lipid metabolism is altered in the bone marrow of Off-HFD versus Off-RD. To test this hypothesis, we investigated the lipidomic profile of bone marrow cells collected from 3-week-old Off-RD and Off-HFD. Diacylglycerols (DAGs), triacylglycerols (TAGs), sphingolipids, and phospholipids were remarkably different between the groups, independent of fetal sex. Levels of cholesteryl esters were significantly decreased in Off-HFD, suggesting reduced delivery of cholesterol. These were accompanied by age-dependent progression of mitochondrial dysfunction in bone marrow cells. We subsequently isolated CD11b+ myeloid cells from 3-wk-old mice and conducted metabolomic, lipidomic, and transcriptomic analyses. The lipidomic profiles of myeloid cells were similar to those of bone marrow cells and included increases in DAGs and decreased TAGs. Transcriptomics revealed altered expression of genes related to immune pathways, including macrophage alternative activation, B-cell receptors, and transforming growth factor-β signaling. All told, this study revealed lipidomic, metabolomic, and gene expression abnormalities in bone marrow cells broadly, and in bone marrow myeloid cells particularly, in the newly weaned offspring of mothers with obesity, which might at least partially explain the progression of metabolic and cardiovascular diseases in their adulthood.

RNA sequencing↗
DOE OSTI2021

Quantile-Dependent Expressivity of Serum Uric Acid Concentrations

“Quantile-dependent expressivity” occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g., serum uric acid) is high or low relative to its distribution. Analyses were performed to test whether serum uric acid heritability is quantile-specific and whether this could explain some reported gene-environment interactions. Methods. Serum uric acid concentrations were analyzed from 2151 sibships and 12,068 offspring-parent pairs from the Framingham Heart Study. Quantile-specific heritability from offspring-parent regression slopes (β OP , h 2 = 2β OP /(1 + r spouse )) and full-sib regression slopes (β FS ,h 2 = {(1 + 8r spouse β FS ) 0.5 - 1}/(2r spouse ) was robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples. Results. Quantile-specific h 2 (±SE) increased with increasing percentiles of the offspring’s sex- and age-adjusted uric acid distribution when estimated from β OP (P trend = 0.001): 0.34 ± 0.03 at the 10th, 0.36 ± 0.03 at the 25th, 0.41 ± 0.03 at the 50th, 0.46 ± 0.04 at the 75th, and 0.49 ± 0.05 at the 90th percentile and when estimated from β FS (P trend = 0.006). This is consistent with the larger genetic effect size of (1) the SLC2A9 rs11722228 polymorphism in gout patients vs. controls, (2) the ABCG2 rs2231142 polymorphism in men vs. women, (3) the SLC2A9 rs13113918 polymorphism in obese patients prior to bariatric surgery vs. two-year postsurgery following 29 kg weight loss, (4) the ABCG2 rs6855911 polymorphism in obese vs. nonobese women, and (5) the LRP2 rs2544390 polymorphism in heavier drinkers vs. abstainers. Quantile-dependent expressivity may also explain the larger genetic effect size of an SLC2A9/PKD2/ABCG2 haplotype for high vs. low intakes of alcohol, chicken, or processed meats. Conclusions. Heritability of serum uric acid concentrations is quantile-specific.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Familial Associations of Prevalence and Cause-Specific Mortality for Thoracic Aortic Disease and Bicuspid Aortic Valve in a Large-Population Database

Thoracic aortic disease and bicuspid aortic valve (BAV) likely have a heritable component, but large population-based studies are lacking. This study characterizes familial associations of thoracic aortic disease and BAV, as well as cardiovascular and aortic-specific mortality, among relatives of these individuals in a large-population database. In this observational case-control study of the Utah Population Database, we identified probands with a diagnosis of BAV, thoracic aortic aneurysm, or thoracic aortic dissection. Age- and sex-matched controls (10:1 ratio) were identified for each proband. First-degree relatives, second-degree relatives, and first cousins of probands and controls were identified through linked genealogical information. Cox proportional hazard models were used to quantify the familial associations for each diagnosis. We used a competing-risk model to determine the risk of cardiovascular-specific and aortic-specific mortality for relatives of probands. The study population included 3,812,588 unique individuals. Familial hazard risk of a concordant diagnosis was elevated in the following populations compared with controls: first-degree relatives of patients with BAV (hazard ratio [HR], 6.88 [95% CI, 5.62–8.43]); first-degree relatives of patients with thoracic aortic aneurysm (HR, 5.09 [95% CI, 3.80–6.82]); and first-degree relatives of patients with thoracic aortic dissection (HR, 4.15 [95% CI, 3.25–5.31]). In addition, the risk of aortic dissection was higher in first-degree relatives of patients with BAV (HR, 3.63 [95% CI, 2.68–4.91]) and in first-degree relatives of patients with thoracic aneurysm (HR, 3.89 [95% CI, 2.93–5.18]) compared with controls. Dissection risk was highest in first-degree relatives of patients who carried a diagnosis of both BAV and aneurysm (HR, 6.13 [95% CI, 2.82–13.33]). First-degree relatives of patients with BAV, thoracic aneurysm, or aortic dissection had a higher risk of aortic-specific mortality (HR, 2.83 [95% CI, 2.44–3.29]) compared with controls. Our results indicate that BAV and thoracic aortic disease carry a significant familial association for concordant disease and aortic dissection. The pattern of familiality is consistent with a genetic cause of disease. Furthermore, we observed higher risk of aortic-specific mortality in relatives of individuals with these diagnoses. In conclusion, this study provides supportive evidence for screening in relatives of patients with BAV, thoracic aneurysm, or dissection.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Predicting Postoperative Injury and Military Discharge Status After Knee Surgery in the US Army

Background: Researchers have assessed postoperative injury or disability predictors in the military setting but typically focused on 1 type of surgical procedure at a time, used relatively small sample sizes, or investigated mixed cohorts with civilian populations. Purpose: To identify the relationship between baseline variables and injury incidence or military discharge status in US Army soldiers after knee surgery. Study Design: Case-control study; Level of evidence, 3. Methods: Data were obtained from a repository containing personnel, performance, and medical records for all active-duty US Army soldiers. Multivariate logistic regressions were used to estimate the effects of numerous variables on postoperative injury or on medical discharge. Variable selection and model validation were conducted using the k-fold method. Results: A total of 7567 soldiers underwent knee surgery between 2017 and 2019. Meniscal procedures were the most common type of surgery (39%), and approximately 71% of the cohort had a postoperative injury. Significant predictors for sustaining a postoperative injury included having a previous nonknee injury (odds ratio [OR], 1.5), female sex (OR, 1.3), and Black race (OR, 1.2). Within 4 years after surgery, 17% of soldiers were discharged from the military because of knee-related disability. Significant predictors for discharge from duty included enlisted rank (OR, 2.3), recent fitness test failure (OR, 1.9), number of previous knee surgeries (OR, 1.7), and having a previous nonknee injury (OR, 1.6). Conclusion: After knee surgery, nearly three-fourths of the soldiers in this cohort sustained a postoperative injury and almost one-fifth of soldiers were medically discharged from the military within 4 years. This study identified variables that indicate statistically increased risk for these postoperative outcomes and highlighted potentially modifiable factors.

Orthopedics↗
DOE OSTI2023

Smoothing Lexis diagrams using kernel functions: A contemporary approach

Lexis diagrams are rectangular arrays of event rates indexed by age and period. Analysis of Lexis diagrams is a cornerstone of cancer surveillance research. Typically, population-based descriptive studies analyze multiple Lexis diagrams defined by sex, tumor characteristics, race/ethnicity, geographic region, etc. Inevitably the amount of information per Lexis diminishes with increasing stratification. Several methods have been proposed to smooth observed Lexis diagrams up front to clarify salient patterns and improve summary estimates of averages, gradients, and trends. In this article, we develop a novel bivariate kernel-based smoother that incorporates two key innovations. First, for any given kernel, we calculate its singular values decomposition, and select an optimal truncation point—the number of leading singular vectors to retain—based on the bias-corrected Akaike information criterion. Second, we model-average over a panel of candidate kernels with diverse shapes and bandwidths. The truncated model averaging approach is fast, automatic, has excellent performance, and provides a variance-covariance matrix that takes model selection into account. We present an in-depth case study (invasive estrogen receptor-negative breast cancer incidence among non-Hispanic white women in the United States) and simulate operating characteristics for 20 representative cancers. The truncated model averaging approach consistently outperforms any fixed kernel. Our results support the routine use of the truncated model averaging approach in descriptive studies of cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Chromosome-level genome assemblies and genetic maps reveal heterochiasmy and macrosynteny in endangered Atlantic Acropora

Abstract Background Over their evolutionary history, corals have adapted to sea level rise and increasing ocean temperatures, however, it is unclear how quickly they may respond to rapid change. Genome structure and genetic diversity contained within may highlight their adaptive potential. Results We present chromosome-scale genome assemblies and linkage maps of the critically endangered Atlantic acroporids,Acropora palmataandA. cervicornis. Both assemblies and linkage maps were resolved into 14 chromosomes with their gene content and colinearity. Repeats and chromosome arrangements were largely preserved between the species. The family Acroporidae and the genusAcroporaexhibited many phylogenetically significant gene family expansions. Macrosynteny decreased with phylogenetic distance. Nevertheless, scleractinians shared six of the 21 cnidarian ancestral linkage groups as well as numerous fission and fusion events compared to other distantly related cnidarians. Genetic linkage maps were constructed from oneA. palmatafamily and 16A. cervicornisfamilies using a genotyping array. The consensus maps span 1,013.42 cM and 927.36 cM forA. palmataandA. cervicornis, respectively. Both species exhibited high genome-wide recombination rates (3.04 to 3.53 cM/Mb) and pronounced sex-based differences, known as heterochiasmy, with 2 to 2.5X higher recombination rates estimated in the female maps. Conclusions Together, the chromosome-scale assemblies and genetic maps we present here are the first detailed look at the genomic landscapes of the critically endangered Atlantic acroporids. These data sets revealed that adaptive capacity of Atlantic acroporids is not limited by their recombination rates. The sister species maintain macrosynteny with few genes with high sequence divergence that may act as reproductive barriers between them. In the AtlanticAcropora, hybridization between the two sister species yields an F1 hybrid with limited fertility despite the high levels of macrosynteny and gene colinearity of their genomes. Together, these resources now enable genome-wide association studies and discovery of quantitative trait loci, two tools that can aid in the conservation of these species.

Biotechnology & Applied Microbiology↗
DOE OSTI2020

The gut mycobiota of rural and urban individuals is shaped by geography

Understanding the structure and drivers of gut microbiota remains a major ecological endeavour. Recent studies have shown that several factors including diet, lifestyle and geography may substantially shape the human gut microbiota. However, most of these studies have focused on the more abundant bacterial component and comparatively less is known regarding fungi in the human gut. This knowledge deficit is especially true for rural and urban African populations. Therefore, we assessed the structure and drivers of rural and urban gut mycobiota. Results Our participants (n=100) were balanced by geography and sex. The mycobiota of these geographically separated cohorts was characterized using amplicon analysis of the Internal Transcribed Spacer (ITS) gene. We further assessed biomarker species specific to rural and urban cohorts. In addition to phyla which have been shown to be ubiquitous constituents of gut microbiota, Pichia were key constituents of the mycobiota. We found that several factors including geographic location and lifestyle factors such as the smoking status were major drivers of gut mycobiota. Linear discriminant and the linear discriminant analysis effect size analysis revealed several distinct urban and rural biomarkers. Conclusions Together, our analysis reveals distinct community structure in urban and rural South African individuals. Geography and lifestyle related factors were shown to be key drivers of rural and urban gut microbiota.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

The 6-minute walk test predicts mortality in a pulmonary nontuberculous mycobacteria-predominant bronchiectasis cohort

Background: Bronchiectasis is a chronic lung condition frequently associated with nontuberculous mycobacteria pulmonary (NTM) disease. Persons with these conditions are at increased risk of mortality. Patient reported outcome (PRO) instruments and the 6-minute walk test (6MWT) have been shown to predict mortality for several lung conditions, but these measures have not been fully evaluated for bronchiectasis and NTM. Methods: We conducted a retrospective cohort study among adult patients enrolled in a natural history study of bronchiectasis at the National Heart, Lung, and Blood Institute. Electronic medical records were queried for demographic, clinical, microbiologic, radiographic, and PRO instrument data: St. George’s Respiratory Questionnaire (SGRQ), Medical Research Council Dyspnea Scale, and the Pulmonary Symptom Severity Score (PSSS). The study baseline date was defined as the patient’s first visit after January 1st, 2015 with a SGRQ or 6MWT completed. Follow-up was defined as the interval between the study baseline visit and date of death or December 31st, 2019. Sex-stratified Cox proportional-hazards regression was conducted to identify predictors of mortality. Separate models were run for each PRO and 6MWT measure, controlling for age, body mass index (BMI), fibrocavitary disease status, and M. abscessus infection. Results: In multivariable Cox proportional-hazards regression models, the PSSS-severity (aHR 1.29, 95% CI 1.04–1.59), the 6MWT total distance walked (aHR 0.938, 95% CI 0.896–0.981) and distance saturation product (aHR 0.930, 95% CI 0.887–0.974) independently predicted mortality. In addition, BMI was significantly predictive of mortality in all models. Conclusions: The 6MWT and a PRO instrument capturing symptom severity are independently predictive of mortality in our cohort of bronchiectasis patients.

6-minute walk test↗
DOE OSTI2023

NREM sleep as a novel protective cognitive reserve factor in the face of Alzheimer's disease pathology

Alzheimer’s disease (AD) pathology impairs cognitive function. Yet some individuals with high amounts of AD pathology suffer marked memory impairment, while others with the same degree of pathology burden show little impairment. Why is this? One proposed explanation is cognitive reserve i.e., factors that confer resilience against, or compensation for the effects of AD pathology. Deep NREM slow wave sleep (SWS) is recognized to enhance functions of learning and memory in healthy older adults. However, that the quality of NREM SWS (NREM slow wave activity, SWA) represents a novel cognitive reserve factor in older adults with AD pathology, thereby providing compensation against memory dysfunction otherwise caused by high AD pathology burden, remains unknown. Here, we tested this hypothesis in cognitively normal older adults (N = 62) by combining 11 C-PiB (Pittsburgh compound B) positron emission tomography (PET) scanning for the quantification of β-amyloid (Aβ) with sleep electroencephalography (EEG) recordings to quantify NREM SWA and a hippocampal-dependent face-name learning task. We demonstrated that NREM SWA significantly moderates the effect of Aβ status on memory function. Specifically, NREM SWA selectively supported superior memory function in individuals suffering high Aβ burden, i.e., those most in need of cognitive reserve (B = 2.694, p = 0.019). In contrast, those without significant Aβ pathological burden, and thus without the same need for cognitive reserve, did not similarly benefit from the presence of NREM SWA (B = -0.115, p = 0.876). This interaction between NREM SWA and Aβ status predicting memory function was significant after correcting for age, sex, Body Mass Index, gray matter atrophy, and previously identified cognitive reserve factors, such as education and physical activity (p = 0.042). These findings indicate that NREM SWA is a novel cognitive reserve factor providing resilience against the memory impairment otherwise caused by high AD pathology burden. Furthermore, this cognitive reserve function of NREM SWA remained significant when accounting both for covariates, and factors previously linked to resilience, suggesting that sleep might be an independent cognitive reserve resource. Beyond such mechanistic insights are potential therapeutic implications. Unlike many other cognitive reserve factors (e.g., years of education, prior job complexity), sleep is a modifiable factor. As such, it represents an intervention possibility that may aid the preservation of cognitive function in the face of AD pathology, both present moment and longitudinally.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Multi-modal characterisation of early-stage, subclinical cardiac deterioration in patients with type 2 diabetes

Abstract Background Type 2 diabetes mellitus (T2DM) is a major risk factor for heart failure with preserved ejection fraction and cardiac arrhythmias. Precursors of these complications, such as diabetic cardiomyopathy, remain incompletely understood and underdiagnosed. Detection of early signs of cardiac deterioration in T2DM patients is critical for prevention. Our goal is to quantify T2DM-driven abnormalities in ECG and cardiac imaging biomarkers leading to cardiovascular disease. Methods We quantified ECG and cardiac magnetic resonance imaging biomarkers in two matched cohorts of 1781 UK Biobank participants, with and without T2DM, and no diagnosed cardiovascular disease at the time of assessment. We performed a pair-matched cross-sectional study to compare cardiac biomarkers in both cohorts, and examined the association between T2DM and these biomarkers. We built multivariate multiple linear regression models sequentially adjusted for socio-demographic, lifestyle, and clinical covariates. Results Participants with T2DM had a higher resting heart rate (66 vs. 61 beats per minute,p < 0.001), longer QTc interval (424 vs. 420ms,p < 0.001), reduced T wave amplitude (0.33 vs. 0.37mV,p < 0.001), lower stroke volume (72 vs. 78ml,p < 0.001) and thicker left ventricular wall (6.1 vs. 5.9mm,p < 0.001) despite a decreased Sokolow-Lyon index (19.1 vs. 20.2mm,p < 0.001). T2DM was independently associated with higher heart rate (beta = 3.11, 95% CI = [2.11,4.10],p < 0.001), lower stroke volume (beta = −4.11, 95% CI = [−6.03, −2.19],p < 0.001) and higher left ventricular wall thickness (beta = 0.133, 95% CI = [0.081,0.186],p < 0.001). Trends were consistent in subgroups of different sex, age and body mass index. Fewer significant differences were observed in participants of non-white ethnic background. QRS duration and Sokolow-Lyon index showed a positive association with the development of cardiovascular disease in cohorts with and without T2DM, respectively. A higher left ventricular mass and wall thickness were associated with cardiovascular outcomes in both groups. Conclusion T2DM prior to cardiovascular disease was linked with a higher heart rate, QTc prolongation, T wave amplitude reduction, as well as lower stroke volume and increased left ventricular wall thickness. Increased QRS duration and left ventricular wall thickness and mass were most strongly associated with future cardiovascular disease. Although subclinical, these changes may indicate the presence of autonomic dysfunction and diabetic cardiomyopathy. Graphical Abstract

Cardiovascular System & Cardiology↗
DOE OSTI2023

Wildfire smoke exposure and early childhood respiratory health: a study of prescription claims data

Abstract Wildfire smoke is associated with short-term respiratory outcomes including asthma exacerbation in children. As investigations into developmental wildfire smoke exposure on children’s longer-term respiratory health are sparse, we investigated associations between developmental wildfire smoke exposure and first use of respiratory medications. Prescription claims from IBM MarketScan Commercial Claims and Encounters database were linked with wildfire smoke plume data from NASA satellites based on Metropolitan Statistical Area (MSA). A retrospective cohort of live infants (2010–2016) born into MSAs in six western states (U.S.A.), having prescription insurance, and whose birthdate was estimable from claims data was constructed ( N = 184,703); of these, gestational age was estimated for 113,154 infants. The residential MSA, gestational age, and birthdate were used to estimate average weekly smoke exposure days ( smoke-day ) for each developmental period: three trimesters, and two sequential 12-week periods post-birth. Medications treating respiratory tract inflammation were classified using active ingredient and mode of administration into three categories:: 'upper respiratory', 'lower respiratory', 'systemic anti-inflammatory'. To evaluate associations between wildfire smoke exposure and medication usage, Cox models associating smoke-days with first observed prescription of each medication category were adjusted for infant sex, birth-season, and birthyear with a random intercept for MSA. Smoke exposure during postnatal periods was associated with earlier first use of upper respiratory medications (1–12 weeks: hazard ratio (HR) = 1.094 per 1-day increase in average weekly smoke-day, 95%CI: (1.005,1.191); 13–24 weeks: HR = 1.108, 95%CI: (1.016,1.209)). Protective associations were observed during gestational windows for both lower respiratory and systemic anti-inflammatory medications; it is possible that these associations may be a consequence of live-birth bias. These findings suggest wildfire smoke exposure during early postnatal developmental periods impact subsequent early life respiratory health.

Dhingra, Radhika↗
DOE OSTI2023

Prescribed fires, smoke exposure, and hospital utilization among heart failure patients

Abstract Background Prescribed fires often have ecological benefits, but their environmental health risks have been infrequently studied. We investigated associations between residing near a prescribed fire, wildfire smoke exposure, and heart failure (HF) patients’ hospital utilization. Methods We used electronic health records from January 2014 to December 2016 in a North Carolina hospital-based cohort to determine HF diagnoses, primary residence, and hospital utilization. Using a cross-sectional study design, we associated the prescribed fire occurrences within 1, 2, and 5 km of the patients’ primary residence with the number of hospital visits and 7- and 30-day readmissions. To compare prescribed fire associations with those observed for wildfire smoke, we also associated zip code-level smoke density data designed to capture wildfire smoke emissions with hospital utilization amongst HF patients. Quasi-Poisson regression models were used for the number of hospital visits, while zero-inflated Poisson regression models were used for readmissions. All models were adjusted for age, sex, race, and neighborhood socioeconomic status and included an offset for follow-up time. The results are the percent change and the 95% confidence interval (CI). Results Associations between prescribed fire occurrences and hospital visits were generally null, with the few associations observed being with prescribed fires within 5 and 2 km of the primary residence in the negative direction but not the more restrictive 1 km radius. However, exposure to medium or heavy smoke (primarily from wildfires) at the zip code level was associated with both 7-day (8.5% increase; 95% CI = 1.5%, 16.0%) and 30-day readmissions (5.4%; 95% CI = 2.3%, 8.5%), and to a lesser degree, hospital visits (1.5%; 95% CI: 0.0%, 3.0%) matching previous studies. Conclusions Area-level smoke exposure driven by wildfires is positively associated with hospital utilization but not proximity to prescribed fires.

Raab, Henry↗
DOE OSTI2024

Relationship Between Radiation Dose and Markers of Insulin Resistance and Inflammation in Atomic Bomb Survivors

Abstract Context In recent studies of childhood cancer survivors, diabetes has been considered a late effect associated with high therapeutic doses of radiation therapy. Our recent study of atomic bomb (A-bomb) survivors also suggested an association between radiation dose and diabetes incidence, with exposure city and age at exposure as radiation dose effect modifiers. Insulin resistance mediated by systemic inflammation and abnormal body composition has been suggested as a possible primary mechanism for the incidence of diabetes after total body irradiation; however, no studies have examined low to moderate radiation exposure (<4 Gy) and insulin resistance in A-bomb survivors. Objective To examine the association between radiation dose and markers of inflammation and insulin resistance. Methods This study investigated 3152 survivors who underwent a health examination between 2008 and 2012 and who were younger than 15 years at exposure. Multivariate linear regression analyses were used to evaluate the radiation effects on levels of markers of inflammation and insulin resistance. Results Radiation dose was significantly and positively associated with levels of C-reactive protein, triglycerides, homeostasis model assessment of β-cell function (HOMA-β), and HOMA of insulin resistance (HOMA-IR) after adjustment for relevant covariates including sex, city, and age at exposure. Adiponectin and high-density lipoprotein cholesterol levels were also associated significantly and negatively with radiation dose. However, city was not a dose modifier of the radiation response on these markers of inflammation and insulin resistance. Conclusion Insulin resistance might be a possible factor in radiation-related diabetes incidence in A-bomb survivors.

Endocrinology & Metabolism↗
DOE OSTI2024

RNA Splicing Events in Circulation Distinguish Individuals With and Without New-onset Type 1 Diabetes

Context: Alterations in RNA splicing may influence protein isoform diversity that contributes to or reflects the pathophysiology of certain diseases. Whereas specific RNA splicing events in pancreatic islets have been investigated in models of inflammation in vitro, how RNA splicing in the circulation correlates with or is reflective of type 1 diabetes (T1D) disease pathophysiology in humans remains unexplored. Objective: To use machine learning to investigate if alternative RNA splicing events differ between individuals with and without new-onset T1D and to determine if these splicing events provide insight into T1D pathophysiology. Methods: RNA deep sequencing was performed on whole blood samples from 2 independent cohorts: a training cohort consisting of 12 individuals with new-onset T1D and 12 age- and sex-matched nondiabetic controls and a validation cohort of the same size and demographics. Machine learning analysis was used to identify specific isoforms that could distinguish individuals with T1D from controls. Results: Distinct patterns of RNA splicing differentiated participants with T1D from unaffected controls. Notably, certain splicing events, particularly involving retained introns, showed significant association with T1D. Machine learning analysis using these splicing events as features from the training cohort demonstrated high accuracy in distinguishing between T1D subjects and controls in the validation cohort. Gene Ontology pathway enrichment analysis of the retained intron category showed evidence for a systemic viral response in T1D subjects. Conclusion: Alternative RNA splicing events in whole blood are significantly enriched in individuals with new-onset T1D and can effectively distinguish these individuals from unaffected controls. Further, our findings also suggest that RNA splicing profiles offer the potential to provide insights into disease pathogenesis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Stepwise recombination suppression around the mating-type locus in an ascomycete fungus with self-fertile spores

Recombination is often suppressed at sex-determining loci in plants and animals, and at self-incompatibility or mating-type loci in plants and fungi. In fungal ascomycetes, recombination suppression around the mating-type locus is associated with pseudo-homothallism, i.e. the production of self-fertile dikaryotic sexual spores carrying the two opposite mating types. This has been well studied in two species complexes from different families of Sordariales: Podospora anserina and Neurospora tetrasperma. However, it is unclear whether this intriguing association holds in other species. We show here that Schizothecium tetrasporum, a fungus from a third family in the order Sordariales, also produces mostly self-fertile dikaryotic spores carrying the two opposite mating types. This was due to a high frequency of second meiotic division segregation at the mating-type locus, indicating the occurrence of a single and systematic crossing-over event between the mating-type locus and the centromere, as in P. anserina. The mating-type locus has the typical Sordariales organization, plus a MAT1-1-1 pseudogene in the MAT1-2 haplotype. High-quality genome assemblies of opposite mating types and segregation analyses revealed a suppression of recombination in a region of 1.47 Mb around the mating-type locus. We detected three evolutionary strata, indicating a stepwise extension of recombination suppression. The three strata displayed no rearrangement or transposable element accumulation but gene losses and gene disruptions were present, and precisely at the strata margins. Our findings indicate a convergent evolution of self-fertile dikaryotic sexual spores across multiple ascomycete fungi. The particular pattern of meiotic segregation at the mating-type locus was associated with recombination suppression around this locus, that had extended stepwise. This association between pseudo-homothallism and recombination suppression across lineages and the presence of gene disruption at the strata limits are consistent with a recently proposed mechanism of sheltering deleterious alleles to explain stepwise recombination suppression.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Genome-wide association study identifies four pan-ancestry loci for suicidal ideation in the Million Veteran Program

Suicidal ideation (SI) often precedes and predicts suicide attempt and death, is the most common suicidal phenotype and is over-represented in veterans. The genetic architecture of SI in the absence of suicide attempt (SA) is unknown, yet believed to have distinct and overlapping risk with other suicidal behaviors. We performed the first GWAS of SI without SA in the Million Veteran Program (MVP), identifying 99,814 SI cases from electronic health records without a history of SA or suicide death (SD) and 512,567 controls without SI, SA or SD. GWAS was performed separately in the four largest ancestry groups, controlling for sex, age and genetic substructure. Ancestry-specific results were combined via meta-analysis to identify pan-ancestry loci. Four genome-wide significant (GWS) loci were identified in the pan-ancestry meta-analysis with loci on chromosomes 6 and 9 associated with suicide attempt in an independent sample. Pan-ancestry gene-based analysis identified GWS associations with DRD2, DCC, FBXL19, BCL7C, CTF1, ANNK1, and EXD3. Gene-set analysis implicated synaptic and startle response pathways (q’s<0.05). European ancestry (EA) analysis identified GWS loci on chromosomes 6 and 9, as well as GWS gene associations in EXD3, DRD2, and DCC. No other ancestry-specific GWS results were identified, underscoring the need to increase representation of diverse individuals. The genetic correlation of SI and SA within MVP was high (r G = 0.87; p = 1.09e-50), as well as with post-traumatic stress disorder (PTSD; r G = 0.78; p = 1.98e-95) and major depressive disorder (MDD; r G = 0.78; p = 8.33e-83). Conditional analysis on PTSD and MDD attenuated most pan-ancestry and EA GWS signals for SI without SA to nominal significance, with the exception of EXD3 which remained GWS. Our novel findings support a polygenic and complex architecture for SI without SA which is largely shared with SA and overlaps with psychiatric conditions frequently comorbid with suicidal behaviors.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Quantile-dependent expressivity of postprandial lipemia

“Quantile-dependent expressivity” describes an effect of the genotype that depends upon the level of the phenotype (e.g., whether a subject’s triglycerides are high or low relative to its population distribution). Prior analyses suggest that the effect of a genetic risk score (GRS) on fasting plasma triglyceride levels increases with the percentile of the triglyceride distribution. Postprandial lipemia is well suited for testing quantile-dependent expressivity because it exposes each individual’s genotype to substantial increases in their plasma triglyceride concentrations. Ninety-seven published papers were identified that plotted mean triglyceride response vs. time and genotype, which were converted into quantitative data. Separately, for each published graph, standard least-squares regression analysis was used to compare the genotype differences at time t (dependent variable) to average triglyceride concentrations at time t (independent variable) to assess whether the genetic effect size increased in association with higher triglyceride concentrations and whether the phenomenon could explain purported genetic interactions with sex, diet, disease, BMI, and drugs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Predicting drug-metagenome interactions: Variation in the microbial β-glucuronidase level in the human gut metagenomes

Characterizing the gut microbiota in terms of their capacity to interfere with drug metabolism is necessary to achieve drug efficacy and safety. Although examples of drug-microbiome interactions are well-documented, little has been reported about a computational pipeline for systematically identifying and characterizing bacterial enzymes that process particular classes of drugs. The goal of our study is to develop a computational approach that compiles drugs whose metabolism may be influenced by a particular class of microbial enzymes and that quantifies the variability in the collective level of those enzymes among individuals. The present paper describes this approach, with microbial β-glucuronidases as an example, which break down drug-glucuronide conjugates and reactivate the drugs or their metabolites. We identified 100 medications that may be metabolized by β-glucuronidases from the gut microbiome. These medications included morphine, estrogen, ibuprofen, midazolam, and their structural analogues. The analysis of metagenomic data available through the Sequence Read Archive (SRA) showed that the level of β-glucuronidase in the gut metagenomes was higher in males than in females, which provides a potential explanation for the sex-based differences in efficacy and toxicity for several drugs, reported in previous studies. Our analysis also showed that infant gut metagenomes at birth and 12 months of age have higher levels of β-glucuronidase than the metagenomes of their mothers and the implication of this observed variability was discussed in the context of breastfeeding as well as infant hyperbilirubinemia. Overall, despite important limitations discussed in this paper, our analysis provided useful insights on the role of the human gut metagenome in the variability in drug response among individuals. Importantly, this approach exploits drug and metagenome data available in public databases as well as open-source cheminformatics and bioinformatics tools to predict drug-metagenome interactions.

59 BASIC BIOLOGICAL SCIENCES↗