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All sourcesNASA NTRSDOE OSTI
DOE OSTI2026

Discovering the Most Severe K-Point Failure Based on Reinforcement Learning: Preprint

Smart devices are essential to ensure the stability of the power grid and resilience to intermittent energy production. However, smart devices can also be the target of cyber adversaries that may exploit false data injection attacks (FDIAs) to induce unstable grid conditions. A practical consideration of FDIA mitigation approaches is addressed here: given a finite available budget, for which smart device should cyber-threat mitigation be deployed first? In this work, this question is answered by identifying the so-called most-sensitive devices, i.e., the devices that, if compromised, can let an adversary induce the most serious grid instabilities. The method proposed utilizes an adversarial reinforcement learning (RL) framework to identify the k-mostsensitive smart devices (here, smart inverters). The adversarial agent can tamper with the compromised inverters' active and reactive operating power setup points, with the goal of maximizing voltage deviations. Numerical results show that the proposed RL method finds the optimal attack scenarios for 1-point failure and the near-optimal solution for the 2-point case. Additionally, the proposed RL method achieves an 8.8 speed-up ratio in running time compared to the brute force method for the 2-point case.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2024

Describing patterns of familial cancer risk in subfertile men using population pedigree data

STUDY QUESTION Can we simultaneously assess risk for multiple cancers to identify familial multicancer patterns in families of azoospermic and severely oligozoospermic men? SUMMARY ANSWER Here, distinct familial cancer patterns were observed in the azoospermia and severe oligozoospermia cohorts, suggesting heterogeneity in familial cancer risk by both type of subfertility and within subfertility type. WHAT IS KNOWN ALREADY Subfertile men and their relatives show increased risk for certain cancers including testicular, thyroid, and pediatric. STUDY DESIGN, SIZE, DURATION A retrospective cohort of subfertile men (N = 786) was identified and matched to fertile population controls (N = 5674). Family members out to third-degree relatives were identified for both subfertile men and fertile population controls (N = 337 754). The study period was 1966–2017. Individuals were censored at death or loss to follow-up, loss to follow-up occurred if they left Utah during the study period. PARTICIPANTS/MATERIALS, SETTING, METHODS Azoospermic (0 × 10 6 /mL) and severely oligozoospermic (<1.5 × 10 6 /mL) men were identified in the Subfertility Health and Assisted Reproduction and the Environment cohort (SHARE). Subfertile men were age- and sex-matched 5:1 to fertile population controls and family members out to third-degree relatives were identified using the Utah Population Database (UPDB). Cancer diagnoses were identified through the Utah Cancer Registry. Families containing ≥10 members with ≥1 year of follow-up 1966–2017 were included (azoospermic: N = 426 families, 21 361 individuals; oligozoospermic: N = 360 families, 18 818 individuals). Unsupervised clustering based on standardized incidence ratios for 34 cancer phenotypes in the families was used to identify familial multicancer patterns; azoospermia and severe oligospermia families were assessed separately. MAIN RESULTS AND THE ROLE OF CHANCE Compared to control families, significant increases in cancer risks were observed in the azoospermia cohort for five cancer types: bone and joint cancers hazard ratio (HR) = 2.56 (95% CI = 1.48–4.42), soft tissue cancers HR = 1.56 (95% CI = 1.01–2.39), uterine cancers HR = 1.27 (95% CI = 1.03–1.56), Hodgkin lymphomas HR = 1.60 (95% CI = 1.07–2.39), and thyroid cancer HR = 1.54 (95% CI = 1.21–1.97). Among severe oligozoospermia families, increased risk was seen for three cancer types: colon cancer HR = 1.16 (95% CI = 1.01–1.32), bone and joint cancers HR = 2.43 (95% CI = 1.30–4.54), and testis cancer HR = 2.34 (95% CI = 1.60–3.42) along with a significant decrease in esophageal cancer risk HR = 0.39 (95% CI = 0.16–0.97). Thirteen clusters of familial multicancer patterns were identified in families of azoospermic men, 66% of families in the azoospermia cohort showed population-level cancer risks, however, the remaining 12 clusters showed elevated risk for 2-7 cancer types. Several of the clusters with elevated cancer risks also showed increased odds of cancer diagnoses at young ages with six clusters showing increased odds of adolescent and young adult (AYA) diagnosis [odds ratio (OR) = 1.96–2.88] and two clusters showing increased odds of pediatric cancer diagnosis (OR = 3.64–12.63). Within the severe oligozoospermia cohort, 12 distinct familial multicancer clusters were identified. All 12 clusters showed elevated risk for 1–3 cancer types. An increase in odds of cancer diagnoses at young ages was also seen in five of the severe oligozoospermia familial multicancer clusters, three clusters showed increased odds of AYA diagnosis (OR = 2.19–2.78) with an additional two clusters showing increased odds of a pediatric diagnosis (OR = 3.84–9.32). LIMITATIONS, REASONS FOR CAUTION Although this study has many strengths, including population data for family structure, cancer diagnoses and subfertility, there are limitations. First, semen measures are not available for the sample of fertile men. Second, there is no information on medical comorbidities or lifestyle risk factors such as smoking status, BMI, or environmental exposures. Third, all of the subfertile men included in this study were seen at a fertility clinic for evaluation. These men were therefore a subset of the overall population experiencing fertility problems and likely represent those with the socioeconomic means for evaluation by a physician. WIDER IMPLICATIONS OF THE FINDINGS This analysis leveraged unique population-level data resources, SHARE and the UPDB, to describe novel multicancer clusters among the families of azoospermic and severely oligozoospermic men. Distinct overall multicancer risk and familial multicancer patterns were observed in the azoospermia and severe oligozoospermia cohorts, suggesting heterogeneity in cancer risk by type of subfertility and within subfertility type. Describing families with similar cancer risk patterns provides a new avenue to increase homogeneity for focused gene discovery and environmental risk factor studies. Such discoveries will lead to more accurate risk predictions and improved counseling for patients and their families. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by GEMS: Genomic approach to connecting Elevated germline Mutation rates with male infertility and Somatic health (Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): R01 HD106112). The authors have no conflicts of interest relevant to this work.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Low Peripheral Blood Counts and Elevated Proinflammatory Cytokines Signal a Poor CD19 Chimeric Antigen Receptor T-cell Response in Acute Lymphoblastic Leukemia

CD19 chimeric antigen receptor T-cell (CAR-T) therapy has significantly improved outcomes for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). However, approximately 20% of patients fail to achieve a complete remission (CR), and some develop severe, life-threatening toxicities. Understanding the biological mechanisms underlying both dysfunctional responses and severe toxicity is essential for optimizing patient management and improving therapeutic efficacy. This study aimed to (1) characterize cytokine profiles associated with dysfunctional responses and severe toxicity following CAR-T infusion, (2) examine the timing and trajectory of cytokine changes in relation to treatment outcomes, and evaluate potential strategies for mitigating toxicity and treatment failure. We conducted a comprehensive analysis of serum cytokine profiles in 86 adult and pediatric patients undergoing autologous CD19 CAR-T therapy for B-ALL. Patients were categorized into three groups: (1) Dysfunctional response—Patients who failed to achieve a minimal residual disease-negative CR (MRD-CR) by Day 63 or who experienced recurrence of CD19+ disease in the setting ongoing CAR-T cell detection before Day 63. (2) Functional response with severe cytokine release syndrome (CRS) and/or neurotoxicity (NTX)—Patients with best response of MRD-CR by Day 63 who experienced grade 3 or higher CRS or NTX. (3) Functional response without severe CRS or NTX—Patients with best response of MRD-CR by Day 63 who did not experience grade =3 CRS or NTX. Cytokine levels were measured during the first-week postinfusion and correlated with treatment efficacy, toxicity outcomes, complete blood counts, and CAR-T expansion dynamics. This analysis aimed to better understand how cytokine profiles relate to patient outcomes and immune responses in CAR-T therapy. Patients with dysfunctional response exhibited decreased neutrophils, platelets, and levels of granulocytic cytokines (suggestive of low bone marrow reserve) alongside elevated pro-inflammatory cytokines by Day 1. Functional response with severe toxicity patients showed a progressive rise in proinflammatory cytokines, reaching similar levels to dysfunctional response patients by Day 7. We observed that high cytokines at both the Day 1 and Day 7 time points were associated with poor survival. These findings remained significant when adjusting for high disease burden, a known predictor of severe inflammatory toxicity and lack of response. Early post-CAR-T infusion inflammation is associated with both dysfunctional response and severe toxicity—even after adjusting for disease burden. This suggests that inflammation, in addition to disease burden, plays a role in determining patient outcome. Therefore, strategies aimed at reducing the pro-inflammatory state prior to or early after CAR-T cell infusion may improve outcomes for R/R B-ALL patients.

Serum cytokines↗
DOE OSTI2022

Quantitative Resistance Loci to Southern Rust Mapped in a Temperate Maize Diversity Panel

Southern rust is a severe foliar disease of maize (Zea mays) resulting from infection with the obligate biotrophic fungus Puccinia polysora. This disease reduces photosynthetic productivity, which in turn reduces yields, with the greatest yield losses (up to 50%) associated with earlier onset infections. P. polysora urediniospores overwinter only in tropical and subtropical regions but cause outbreaks when environmental conditions favor initial infection. Increased temperatures and humidity during the growing season combined with an increased frequency of moderate winters are likely to increase the frequency of severe southern rust outbreaks in the U.S. Corn Belt. In summer 2020, a severe outbreak of southern rust was observed in eastern Nebraska, United States. We scored a replicated maize association panel planted in Lincoln, NE for disease severity and found that disease incidence and severity showed significant variation among maize genotypes. Genome-wide association studies identified four loci associated with significant quantitative variation in disease severity. These loci were associated with candidate genes with plausible links to quantitative disease resistance. A transcriptome-wide association study identified additional genes associated with disease severity. Together, these results indicate that substantial diversity in resistance to southern rust exists among current temperate-adapted maize germplasm, including several candidate loci that may explain the observed variation in resistance to southern rust. [Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY 4.0 International license .

Plant Sciences↗
DOE OSTI2023

Carbon stored in live ponderosa pines in the Sierra Nevada will not return to pre-drought (2012) levels during the 21st century due to bark beetle outbreaks

Outbreaks of several bark beetle species can develop rapidly in response to drought and may result in large transfers of carbon (C) stored in live trees to C stored in dead trees (10s of Tg C yr -1 in the western U.S. alone), which over time will be released back to the atmosphere. The western pine beetle (WPB) outbreak incited by the 2012–2015 mega-drought in the Sierra Nevada, California, U.S., could portend more frequent and/or severe bark beetle outbreaks as the temperature warms and drought frequency and intensity increase in the future. However, changes in the frequency and/or severity (resultant levels of host tree mortality) of beetle outbreaks are difficult to predict as outbreaks are complex with non-linear and eruptive processes primarily driven by interactions among beetle populations, the demography of hosts and other tree species, and climate and weather. Using an insect phenology and tree defense model, we projected the future likelihood of WPB outbreaks in the Sierra Nevada with climate drivers from different Earth System Models. Our goal was to understand how host (ponderosa pine, PIPO) recovery and future warming and drought affect the frequency and severity of WPB outbreaks and their C consequences. Our projections suggested that by 2100 the C stored in live PIPO (mean: 1.98 kg C m -2 , 95% CI: 1.74–2.21 kg C m -2 ) will not return to levels that occurred before the 2012–2015 drought (2012: ~2.30 kg C m –2 ) due to future WPB outbreaks. However, differences in climate models indicate a wide range of possible WPB outbreak frequencies and severities. Our results suggest that total plot basal area is the most significant factor in the mortality rate of PIPO by WPB in any given year, followed by drought severity and temperature. High levels of host basal area, higher temperature, and extreme drought all contribute to the frequency and severity of future WPB outbreaks. While PIPO basal area may decline under increased drought and warming, limiting high-stand basal area (>60 m 2 ha -1 ) may reduce the severity of future WPB outbreaks in the Sierra Nevada.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2022

Notable impact of wildfires in the western United States on weather hazards in the central United States

Increased wildfire events constitute a significant threat to life and property in the United States. Wildfire impact on severe storms and weather hazards is another pathway that threatens society, and our understanding of which is very limited. Here, we use unique modeling developments to explore the effects of wildfires in the western US (mainly California and Oregon) on precipitation and hail in the central US. We find that the western US wildfires notably increase the occurrences of heavy precipitation rates by 38% and significant severe hail (≥2 in.) by 34% in the central United States. Both heat and aerosols from wildfires play an important role. By enhancing surface high pressure and increasing westerly and southwesterly winds, wildfires in the western United States produce ( 1 ) stronger moisture and aerosol transport to the central United States and ( 2 ) larger wind shear and storm-relative helicity in the central United States. Both the meteorological environment more conducive to severe convective storms and increased aerosols contribute to the enhancements of heavy precipitation rates and large hail. Moreover, the local wildfires in the central US also enhance the severity of storms, but their impact is notably smaller than the impact of remote wildfires in California and Oregon because of the lessened severity of the local wildfires. As wildfires are projected to be more frequent and severe in a warmer climate, the influence of wildfires on severe weather in downwind regions may become increasingly important.

54 ENVIRONMENTAL SCIENCES↗