Results for “extreme biophysics”

DOE OSTI2025

Extreme hydroclimates amplify the biophysical effects of advanced green-up in temperate China

Vegetation phenology modulates climate by altering energy and water exchange between the land and atmosphere. However, how extreme hydroclimatic conditions modify these phenology-climate feedbacks is still poorly understood. Here, in this study, we used a land–atmosphere-coupled Weather Research and Forecasting model to explore the impacts of advanced green-up on air temperature under different hydroclimate conditions across temperate China and to Mechanistic analysis elucidate the underlying biophysical mechanisms. By imposing a 14-day earlier green-up in line with recent satellite observations, we found that under mean climate conditions, an earlier leaf-out induces immediate surface cooling of 0.14 °C during green-up and a lagging 0.02 °C warming during senescence averaged for temperate China. Extremely humid conditions amplify the cooling effects to 0.18 °C during green-up, extending this cooling into the senescence period. Conversely, under extremely arid conditions, earlier green-up cools air temperature by 0.09 °C, and amplified senescence warming to 0.16 °C. Mechanism analysis revealed that evapotranspiration-dominated non-radiative processes drive immediate cooling during green-up while radiation and circulation process dominates the delayed but opposite warming/cooling effects during senescence in extremely arid/humid hydroclimates. Given the projected continuation of warming trends and increased frequency of extreme climatic events, it is imperative to incorporate the biophysical effects of vegetation phenology into local climate adaptation strategies.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2022

Inline small-angle X-ray scattering-coupled chromatography under extreme hydrostatic pressure

As continuing discoveries highlight the surprising abundance and resilience of deep ocean and subsurface microbial life, the effects of extreme hydrostatic pressure on biological structure and function have attracted renewed interest. Biological small-angle X-ray scattering (BioSAXS) is a widely used method of obtaining structural information from biomolecules in solution under a wide range of solution conditions. Due to its ability to reduce radiation damage, remove aggregates, and separate monodisperse components from complex mixtures, size-exclusion chromatography-coupled SAXS (SEC-SAXS) is now the dominant form of BioSAXS at many synchrotron beamlines. While BioSAXS can currently be performed with some difficulty under pressure with non-flowing samples, it has not been clear how, or even if, continuously flowing SEC-SAXS, with its fragile media-packed columns, might work in an extreme high-pressure environment. Here we show, for the first time, that reproducible chromatographic separations coupled directly to high-pressure BioSAXS can be achieved at pressures up to at least 100 MPa and that pressure-induced changes in folding and oligomeric state and other properties can be observed. Further, the apparatus described here functions at a range of temperatures (0°C–50°C), expanding opportunities for understanding biomolecular rules of life in deep ocean and subsurface environments.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Trunk muscle forces and spinal loads while walking in persons with lower limb amputation: Influences of chronic low back pain

Persons with lower limb amputation (LLA) are at high risk for developing chronic low back pain (LBP), often with biomechanical factors considered as likely contributors. Here, trunk and pelvis kinematics, muscle forces, and resultant spinal loads were characterized in persons with LLA, with and without chronic LBP. Thirty-five persons with unilateral LLA – 19 with chronic LBP (“LLA-cLBP”), 16 without LBP (“LLA-nLBP”) – and 15 (uninjured) persons without LBP (“CTR-nLBP”) walked overground (1.3 m/s) while thorax and pelvis kinematics were tracked (and ranges of motion [ROM] computed), and used as inputs for a non-linear finite element model of the spine to estimate global and local muscle forces, and resultant spinal loads. In the frontal and transverse planes, thorax ROM were up to 66.6% smaller in LLA-nLBP versus LLA-cLBP (P < 0.001) and CTR-nLBP (P < 0.001). In the sagittal plane, pelvis ROM was 50.4% smaller in LLA-nLBP versus LLA-cLBP (P = 0.014). LLA-cLBP exhibited 45.5% and 34.2% greater peak local and global muscle forces, respectively, versus CTR-nLBP (P < 0.011). Up to 48.1% greater spinal loads were observed in LLA-cLBP versus CTR-nLBP (P < 0.013); peak compression and local muscle forces were respectively 20.2% and 41.0% larger in LLA-nLBP versus CTR-nLBP (P < 0.005). Despite differences in trunk and pelvis kinematics between LLA-cLBP and LLA-nLBP, trunk muscle forces and spinal loads were similar (P > 0.101) between these groups. Similar loading parameters regardless of LBP presence, while highly dependent on trunk muscle activation strategies, may mitigate further accumulation of mechanical fatigue. Finally, it remains important to understand the temporality of loading with respect to LBP onset following LLA.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2024

Future increase in compound soil drought-heat extremes exacerbated by vegetation greening

Compound soil drought and heat extremes are expected to occur more frequently with global warming, causing wide-ranging socio-ecological repercussions. Vegetation modulates air temperature and soil moisture through biophysical processes, thereby influencing the occurrence of such extremes. Global vegetation cover is broadly expected to increase under climate change, but it remains unclear whether vegetation greening will alleviate or aggravate future increases in compound soil drought-heat events. Here, using a suite of state-of-the-art model simulations, we show that the projected vegetation greening will increase the frequency of global compound soil drought-heat events, equivalent to 12-21% of the total increment at the end of 21st century. This increase is predominantly driven by reduced albedo and enhanced transpiration associated with increased leaf area. Although greening-induced transpiration enhancement has counteracting cooling and drying effects, the excessive water loss in the early growing season can lead to later soil moisture deficits, amplifying compound soil drought-heat extremes during the subsequent warm season. These changes are most pronounced in northern high latitudes and are dominated by the warming effect of CO 2 . Our study highlights the necessity of integrating vegetation biophysical effects into mitigation and adaptation strategies for addressing compound climate risks.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2026

Roadmap for the future of extreme wildfire events

Background Extreme wildfire events (EWEs) represent a growing threat globally, posing substantial risks to ecosystems, human communities, and infrastructure. Despite increased recognition of their ecological, social, and economic significance, current definitions of EWEs vary widely, reflecting disciplinary biases and regional contexts. This article emerges from an interdisciplinary workshop convened to reassess and refine the definition of EWEs, examine their impacts across ecological and social dimensions, and identify critical knowledge gaps impeding our understanding of these infrequent but important events. Results Our synthesis highlights significant limitations with existing definitions, particularly their reliance on subjective thresholds and their emphasis on extreme fire behavior alone. EWEs encompass a spectrum of complex, multi-dimensional phenomena that extend beyond immediate biophysical characteristics to include cumulative social, economic, and ecological impacts. These impacts often manifest over extended timeframes and include hazardous environmental contamination, severe geomorphic disturbances, ecosystem transformations, and unintended consequences of post-fire management actions. Current wildfire modeling frameworks inadequately capture these compounding factors, particularly the interactions among social systems, ecological conditions, and extreme fire behavior. To overcome these issues, we advocate for an interdisciplinary and context-sensitive approach to defining and studying EWEs. This revised definition emphasizes wildfires exhibiting anomalies in fire behavior, ecological outcomes, or social impacts relative to historically observed baselines, accommodating variability across different geographic regions and ecological settings. Conclusions Adopting an interdisciplinary framework that integrates biophysical and social sciences will enhance the predictive capability of wildfire models and improve resilience planning and response strategies. Filling identified knowledge gaps—such as limited high-quality empirical fire behavior data and insufficient integration of social dynamics into modeling—will better prepare communities and ecosystems to cope with and adapt to EWEs. This inclusive approach underscores the necessity for collaboration across disciplines and sectors, essential to managing extreme wildfires in an era of increasing climatic and ecological uncertainty.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2022

Urbanization Impact on Regional Climate and Extreme Weather: Current Understanding, Uncertainties, and Future Research Directions

Abstract Urban environments lie at the confluence of social, cultural, and economic activities and have unique biophysical characteristics due to continued infrastructure development that generally replaces natural landscapes with built-up structures. The vast majority of studies on urban perturbation of local weather and climate have been centered on the urban heat island (UHI) effect, referring to the higher temperature in cities compared to their natural surroundings. Besides the UHI effect and heat waves, urbanization also impacts atmospheric moisture, wind, boundary layer structure, cloud formation, dispersion of air pollutants, precipitation, and storms. In this review article, we first introduce the datasets and methods used in studying urban areas and their impacts through both observation and modeling and then summarize the scientific insights on the impact of urbanization on various aspects of regional climate and extreme weather based on more than 500 studies. We also highlight the major research gaps and challenges in our understanding of the impacts of urbanization and provide our perspective and recommendations for future research priorities and directions.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2021

Empirical estimation of weather-driven yield shocks using biophysical characteristics for U.S. rainfed and irrigated maize, soybeans, and winter wheat

Agricultural yields are highly susceptible to changes in weather system patterns, including both annual and sub-annual changes in temperature and precipitation. Understanding the impacts of future changes in meteorological variables on crop yields have been widely studied in both empirical and process-based models. This work presents a structural econometric approach that combines historical weather data with information about the biophysical growth cycles of maize, winter wheat, and soy to predict the year-to-year yield responses for rainfed crops. Modeled soil moisture and temperature are taken as key predictors, which allows testing the fitted rainfed model’s ability to predict irrigated yields by assuming irrigation produces the numerically optimal level of soil moisture. This approach is grounded in known biophysical processes, which improves confidence in the model predictions. It produces estimates of interannual variability in yields, which enable study of the effects of extreme events on agricultural productivity. Finally, it enables prediction of the potential impacts of changing weather patterns on irrigated crops in areas that are currently primarily rainfed. We present the results of the empirical model, fitted with rainfed data; out-of-sample validation on irrigated crops; and projections of yield shocks under multiple future climate scenarios. Under a bias-corrected GFDL RCP8.5 scenario, this approach predicts average yield change, relative to 2006-2020 average yields, across U.S. counties in the 2040-2060 period of -16.9% and -13.4% for rainfed and irrigated maize, of -19.1% and -18.4% for rainfed and irrigated soy, and of -4.0% and -2.0% for rainfed and irrigated winter wheat. And in the 2070-2090 period of -30.3% and -28.8 % for rainfed and irrigated maize, of -33.1% and -32.8% for rainfed and irrigated soy, and of -6.5% and -5.2%for rainfed and irrigated winter wheat.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2025

Conformational Dynamics and Catalytic Backups in a Hyper-thermostable Engineered Archaeal Protein Tyrosine Phosphatase

Protein tyrosine phosphatases (PTPs) are a family of enzymes that play important roles in regulating cellular signaling pathways. The activity of these enzymes is regulated by the motion of a catalytic loop that places a critical conserved aspartic acid side chain into the active site for acid–base catalysis upon loop closure. These enzymes also have a conserved phosphate-binding loop that is typically highly rigid and forms a well-defined anion-binding nest. The intimate links between loop dynamics and chemistry in these enzymes make PTPs an excellent model system for understanding the role of loop dynamics in protein function and evolution. In this context, archaeal PTPs, which have often evolved in extremophilic organisms, are highly understudied, despite their unusual biophysical properties. We present here an engineered chimeric PTP (ShufPTP) generated by shuffling the amino acid sequence of five extant hyperthermophilic archaeal PTPs. Despite ShufPTP’s high sequence similarity to its natural counterparts, it presents a suite of unique properties, including high flexibility of the phosphate binding P-loop, facile oxidation of the active-site cysteine, mechanistic promiscuity, and, most notably, hyperthermostability, with a denaturation temperature likely >130 °C (>8 °C higher than the highest recorded growth temperature of any archaeal strain). Our combined structural, biochemical, biophysical, and computational analysis provides insight both into how small steps in evolutionary space can radically modulate the biophysical properties of an enzyme and showcases the tremendous potential of archaeal enzymes for biotechnology, to generate novel enzymes capable of operating under extreme conditions.

archaea↗

DOE OSTI2023

Widespread spring phenology effects on drought recovery of Northern Hemisphere ecosystems

The time required for an ecosystem to recover from severe drought is a key component of ecological resilience. The phenology effects on drought recovery are, however, poorly understood. These effects centre on how phenology variations impact biophysical feedbacks, vegetation growth and, ultimately, recovery itself. Using multiple remotely sensed datasets, we found that more than half of ecosystems in mid- and high-latitudinal Northern Hemisphere failed to recover from extreme droughts within a single growing season. Earlier spring phenology in the drought year slowed drought recovery when extreme droughts occurred in mid-growing season. Delayed spring phenology in the subsequent year slowed drought recovery for all vegetation types (with importance of spring phenology ranging from 46% to 58%). The phenology effects on drought recovery were comparable to or larger than other well-known postdrought climatic factors. These results strongly suggest that the interactions between vegetation phenology and drought must be incorporated into Earth system models to accurately quantify ecosystem resilience.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2023

Local, regional, and global adaptations to a compound pandemic-weather stress event

Global food security can be threatened by short-term extreme events that negatively impact food production, food purchasing power, and agricultural economic activity. At the same time, environmental pollutants like greenhouse gases (GHGs) can be reduced due to the same short-term extreme stressors. Stress events include pandemics like COVID-19 and widespread droughts like those experienced in 2015. Here we consider the question: what if COVID-19 had co-occurred with a 2015-like drought year? Using a coupled biophysical-economic modeling framework, we evaluate how this compound stress would alter both agricultural sector GHG emissions and change the number of undernourished people worldwide. We further consider three interdependent adaptation options: local water use for crop production, regional shifts in cropland area, and global trade of agricultural products. We find that GHG emissions decline due to reduced economic activity in the agricultural sector, but this is paired with large increases in undernourished populations in developing nations. Local and regional adaptations that make use of natural resources enable global-scale reductions in impacted populations via increased global trade.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2026

A tale of two extremes: Temperature sensitivity of carbon loss from cool and hot soils

Soils represent the largest terrestrial carbon (C) pool, and the flux of carbon dioxide (CO 2 ) from soils to the atmosphere is ~ 6-10 times more than anthropogenic emissions. Understanding responses of soil CO 2 emissions to warming is crucial for evaluating feedback to ongoing environmental changes. The relationship between microbial respiration and temperature is typically modeled using a Q 10 function. Generally, observations of the apparent Q 10 of soil respiration are higher for cold vs. warm ecosystems, reflecting expected biophysical controls of Arrhenius kinetics. However, results from two field warming experiments in the tropics contradict this expectation, both observing extraordinarily high soil respiration responses to in situ warming. Our overall objective for the proposed work is to reduce uncertainty in temperature sensitivity of soil C loss by systematically synthesizing underlying mechanisms related to soil C turnover and stabilization. We are evaluating the temperature sensitivity of soil respiration in ecosystems across temperature extremes (e.g., arctic/boreal and tropical systems) by integrating data collected from field warming experiments with machine learning and biogeochemical models.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2023

Wildfire Risk Evaluation Framework for Grid Operations and Planning

The United States (US) environmental protection agency's (EPA's) climate change indicators for wildfires show a long-term trend of increased annual wildfire activity, larger wildfire size, and more variable dynamics in wildfire behavior. This has caused more frequent preemptive public safety power shutoff (PSPS) events in the regions with recognized high wildfire risk. These preemptive power shutoffs attempt to prevent the ignition of a wildfire but it nonetheless renders the transmission line non-operational, which often sheds load of downstream communities. As wildfires and PSPS events become more frequent, it is crucial to find the communities most at risk of load shedding. To that end, this paper proposes the wildfire risk evaluation of the system (WiRES) framework, which is a performance-based framework that translates extreme weather-related and PSPS event probabilities into a cumulative probability of a non-operational transmission line. This study also provides a geospatial visualization tool that breaks down the entire western electrical coordinating council (WECC) region into 50 km grid cells which can be used to 1) filter out transmission lines with higher than a threshold outage probability, and 2) graphically discover the affected regions and their biophysical and socioeconomic metrics. %such as the social vulnerability index, population density, gross domestic product, etc. Lastly, an impact assessment study is conducted which connects the results of the proposed framework to python and powerworld-based contingency analysis to highlight the applicability of the framework.

Wildfire, Resilience, Extreme Events, Grid Reslien↗

DOE OSTI2022

Social-ecological interactions in a disaster context: Puerto Rican farmer households’ food security after Hurricane Maria

Islands are uniquely vulnerable to extreme weather events and food insecurity, and have additional response challenges due to their limited landmasses and economies, isolation, colonial legacies, and high dependence of food imports. Domestic farmers have a key role in producing food for island communities like Puerto Rico, which can safeguard food security when food importation may be challenging. Nevertheless, in the context of disaster, farmers themselves may be vulnerable to food insecurity and unable to contribute to domestic markets. This paper examines Puerto Rican farmers households’ food security in the aftermath of 2017’s Hurricane Maria using a social-ecological lens. Survey data from 405 farmers gathered eight months after Maria, coupled with biophysical data from the hurricane’s impacts (winds, rains, and landslides), were analyzed. Overall, 69% of farmers experienced at least one month of food insecurity in the aftermath of Hurricane Maria, and 38% reported persistent food insecurity (three months or more). A multinomial logistic regression suggests that biophysical impacts, but especially social factors, such as age and constraint access to external sources of support, are linked with persistent food insecurity. This suggests that the biophysical impacts of the hurricane interact with existing infrastructure and social resources to affect farmer vulnerability and the food environment in different ways. Thus, strengthening adaptive capacity in multiple domains can help farmers and vulnerable populations better navigate the disruptions faced during disasters to alleviate food insecurity.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2023

2023 SAGE-Camp Report

The 7 th Summer Physics Camp for Young Women was successfully held in person in 2023 from June 5 th to 16 th at the New Mexico School for the Arts in Santa Fe, NM at Hilo Intermediate School in Hawaii. This year’s camp was dedicated to the topic of Energy Security and was made possible thanks to the strong collaboration of Los Alamos, Sandia and Hawaii teams and the logistical and financial support of Los Alamos and Sandia National Laboratories, New Mexico Consortium, SAGE- Moore Foundation, LANL Foundation, ACS, IEE, APS four corners, N3B, Hawaii Museum of Science and Technology, New Mexico School for the Arts (NMSA) and Tech Source. The camp mobilized more than 120 volunteers who made the camp a success. The camp is free of charge to the students and included free lunch and snacks for the busy brains to have plenty of energy, also included all materials needed for the hands-on activities (like drone building, crystal structure, solar panels, wind turbine fabrication, soldering, coding etc) and also a stipend for students who attended for the full two weeks and for two educators and two student mentors in NM. The camp offered 32 high school students from New Mexico and 8 from Hawaii a unique opportunity to explore science topics and meet a broad range of role model professionals across STEM fields including astrophysics, cybersecurity, Energy fields, space science, engineering, biophysics, environmental science, robotics, computer science, nuclear engineering, radiological science, physics and chemistry. With nearly 120 volunteers who came mainly from Los Alamos National Laboratory (66%) and Sandia national laboratories (18%), two funded educators from NM, Dr. Weldon Beauchamp and Dr. Ellee Cook, and two educators from Hilo, Dr. Pascale Creek Pinner and LeAnn Ragasa, the camp was educationally sound and extremely varied. The collaboration with school educators is critical for the goal of this camp to not only impact students' lives but also improve STEM education in NM and Hawaii. The ultimate goal of the camp is to increase higher education aspirations of students, empower them to consider careers in STEM and learn more about the opportunities available to them in our local colleges and DOE National Laboratories. In addition, the camp also hired 2 past students as student mentors, Megan Odom and Elisea Jackson, who currently attend NMSA and were students at the camp in 2022 when it was virtual. The in-person camp which aims at empowering under-represented minorities in STEM in our community received more than 52 applications this year from all over NM and 8 applications from Hawaii. Our selection criteria are based on diversity, equity and inclusion, and students for whom the camp can be a life-changing opportunity are given a chance to attend the camp. During COVID, the camp was held virtually and gave the opportunity to students from remote areas in NM and Hawaii to attend from their homes. This year, fantastic families supported students everyday even when home was in remote areas in NM like Lea county, Sandoval county, Bernalillo or Mora county. The organizers hope next year they can offer a residential option for students from remote areas.

99 GENERAL AND MISCELLANEOUS↗

DOE OSTI2024

SEC ‐ SAXS / MC Ensemble Structural Studies of the Microtubule Binding Protein Cdt1 Show Monomeric, Folded‐Over Conformations

ABSTRACT Cdt1 is a mixed folded protein critical for DNA replication licensing and it also has a “moonlighting” role at the kinetochore via direct binding to microtubules and the Ndc80 complex. However, it is unknown how the structure and conformations of Cdt1 could allow it to participate in these multiple, unique sets of protein complexes. While robust methods exist to study entirely folded or unfolded proteins, structure–function studies of combined, mixed folded/disordered proteins remain challenging. In this work, we employ orthogonal biophysical and computational techniques to provide structural characterization of mitosis‐competent human Cdt1. Thermal stability analyses shows that both folded winged helix domains1 are unstable. CD and NMR show that the N‐terminal and linker regions are intrinsically disordered. DLS shows that Cdt1 is monomeric and polydisperse, while SEC‐MALS confirms that it is monomeric at high concentrations, but without any apparent inter‐molecular self‐association. SEC‐SAXS enabled computational modeling of the protein structures. Using the program SASSIE, we performed rigid body Monte Carlo simulations to generate a conformational ensemble of structures. We observe that neither fully extended nor extremely compact Cdt1 conformations are consistent with SAXS. The best‐fit models have the N‐terminal and linker disordered regions extended into the solution and the two folded domains close to each other in apparent “folded over” conformations. We hypothesize the best‐fit Cdt1 conformations could be consistent with a function as a scaffold protein that may be sterically blocked without binding partners. Our study also provides a template for combining experimental and computational techniques to study mixed‐folded proteins.

Cell Biology↗

DOE OSTI2022

A mutagenic analysis of NahE, a hydratase-aldolase in the naphthalene degradative pathway

NahE is a hydratase-aldolase that converts o-substituted trans-benzylidenepyruvates (H, OH, or CO 2 - ) to benzaldehyde, salicylaldehyde, or 2-carboxybenzaldehyde, respectively, and pyruvate. The enzyme is in a bacterial degradative pathway for naphthalene, which is a toxic and persistent environmental contaminant. Sequence, crystallographic, and mutagenic analysis identified the enzyme as a member of the N-acetylneuraminate lyase (NAL) subgroup in the aldolase superfamily. As such, it has a conserved lysine (Lys183) and tyrosine (Tyr155), for Schiff base formation, as well as a GXXGE motif for binding of the pyruvoyl carboxylate group. A crystal structure of the selenomethionine derivative of NahE shows these active site elements along with nearby residues that might be involved in the mechanism and/or specificity. Mutations of five active site amino acids (Thr65, Trp128, Tyr155, Asn157, and Asn281) were constructed and kinetic parameters measured in order to assess the effect(s) on catalysis. Here, the results show that the two Trp128 mutants (Phe and Tyr) have the least effect on catalysis, whereas amino acids with bulky side chains at Thr65 (Val) and Asn281 (Leu) have the greatest effect. Changing Tyr155 to Phe and Asn157 to Ala also hinders catalysis, and the effects fall in between these extremes. These observations are put into a structural context using a crystal structure of the Schiff base of the reaction intermediate. Trapping experiments with substrate, Na(CN)BH 3 , and wild type enzyme and selected mutants mostly paralleled the kinetic analysis, and identified two salicylaldehyde-modified lysines: the active site lysine (Lys183) and one outside the active site (Lys279). The latter could be responsible for the observed inhibition of NahE by salicylaldehyde. Together, the results provide new insights into the NahE-catalyzed reaction.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2024

National User Resource for Biological Accelerator Mass Spectrometry

The National User Resource for Biological Accelerator Mass Spectrometry (User Resource) will provide isotopic analysis (primarily radiocarbon or 14C) by accelerator mass spectrometry (AMS) for NIH- funded researchers across the United States and will be the only User Resource of its type in the United States. The User Resource will provide measurement capability and expertise to a research community that requires highly sensitive, quantitative isotope analyses. Since commissioning a new accelerator mass spectrometer in June 2014, we have measured over 4000 samples a year for collaborators and service users. The User Resource will enable us to continue to meet these research needs, as well as provide for new users whose research programs would benefit from AMS as a measurement tool. The User Resource’s forte will be ultra-high sensitivity quantitation of radiocarbon and selected other radioisotopes for research studies where isotopes are required. Radioisotope labeling studies have been and will continue to be an important tool for addressing many complex biomedical science problems. AMS is a specialized and unique type of mass spectrometry that provides absolute quantitation of radiocarbon and other relevant radioisotopes with extreme sensitivity, having limits of detection in real samples on the order of a few attomol/mg of sample at measurement precisions of ~3%. It is the only instrumental method capable of quantifying radioisotope-labeled agents routinely in real-world samples with such precision and sensitivity. The sensitivity of AMS allows for the quantification of radiolabeled metabolites in extremely complex matrices of cells and organisms at very low concentrations and in small samples. AMS allows studies to be conducted without perturbing metabolism leading to more relevant quantification of metabolic rates and pathways. In addition, it enables quantification of pharmacokinetic and metabolic properties of toxicants at environmentally relevant concentrations in model systems as well as the ability to quantify pharmacokinetics and other molecular endpoints directly in humans. Such quantitative assessments can 1) improve risk assessment for toxicants, 2) address safety and efficacy considerations for therapeutic entities, 3) deepen understanding of xenobiotic and intermediary metabolism, 4) help understand the interactions between critical molecular pathways, and 5) improve efforts to model and predict various metabolic and biological states. These capabilities have been applied in a number of areas including research in carcinogenesis, toxicology, nutrition, pharmacology/drug development and basic biological science. As a NIGMS National Resource the National User Resource for Biological Accelerator Mass Spectrometry will help NIH funded scientists achieve a deeper understanding of the etiology of human health concerns by (1) enabling the quantification of pharmacokinetics and other molecular endpoints directly in humans; (2) offering the ability to conduct quantitative studies using biologics such as proteins or lipids, and thereby reducing the amount of radioisotope usage in biomedical labs; and (3) enabling more relevant studies of metabolic pathways in health and disease through the use of much lower, more biologically-relevant, concentrations of metabolic substrates in cells and intact organisms. Such studies support NIGMS’s basic biomedical research areas that contribute to the understanding of fundamental cellular and physiological principles and enable research supported by the Biophysics, Biomedical Technology, and Computational Biosciences (BBCB); Genetics and Molecular, Cellular, and Developmental Biology (GMCDB); Pharmacology, Physiology, Biological Chemistry (PPBC) and Training, Workforce Development, and Diversity (TWD) Divisions.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

DOE OSTI2025

National User Resource for Biological Accelerator Mass Spectrometry (Final Report)

The National User Resource for Biological Accelerator Mass Spectrometry (User Resource) will provide isotopic analysis (primarily radiocarbon or 14C) by accelerator mass spectrometry (AMS) for NIH- funded researchers across the United States and will be the only User Resource of its type in the United States. The User Resource will provide measurement capability and expertise to a research community that requires highly sensitive, quantitative isotope analyses. Since commissioning a new accelerator mass spectrometer in June 2014, we have measured over 4000 samples a year for collaborators and service users. The User Resource will enable us to continue to meet these research needs, as well as provide for new users whose research programs would benefit from AMS as a measurement tool. The User Resource’s forte will be ultra-high sensitivity quantitation of radiocarbon and selected other radioisotopes for research studies where isotopes are required. Radioisotope labeling studies have been and will continue to be an important tool for addressing many complex biomedical science problems. AMS is a specialized and unique type of mass spectrometry that provides absolute quantitation of radiocarbon and other relevant radioisotopes with extreme sensitivity, having limits of detection in real samples on the order of a few attomol/mg of sample at measurement precisions of ~3%. It is the only instrumental method capable of quantifying radioisotope-labeled agents routinely in real-world samples with such precision and sensitivity. The sensitivity of AMS allows for the quantification of radiolabeled metabolites in extremely complex matrices of cells and organisms at very low concentrations and in small samples. AMS allows studies to be conducted without perturbing metabolism leading to more relevant quantification of metabolic rates and pathways. In addition, it enables quantification of pharmacokinetic and metabolic properties of toxicants at environmentally relevant concentrations in model systems as well as the ability to quantify pharmacokinetics and other molecular endpoints directly in humans. Such quantitative assessments can 1) improve risk assessment for toxicants, 2) address safety and efficacy considerations for therapeutic entities, 3) deepen understanding of xenobiotic and intermediary metabolism, 4) help understand the interactions between critical molecular pathways, and 5) improve efforts to model and predict various metabolic and biological states. These capabilities have been applied in a number of areas including research in carcinogenesis, toxicology, nutrition, pharmacology/drug development and basic biological science. As a NIGMS National Resource the National User Resource for Biological Accelerator Mass Spectrometry will help NIH funded scientists achieve a deeper understanding of the etiology of human health concerns by (1) enabling the quantification of pharmacokinetics and other molecular endpoints directly in humans; (2) offering the ability to conduct quantitative studies using biologics such as proteins or lipids, and thereby reducing the amount of radioisotope usage in biomedical labs; and (3) enabling more relevant studies of metabolic pathways in health and disease through the use of much lower, more biologically-relevant, concentrations of metabolic substrates in cells and intact organisms. Such studies support NIGMS’s basic biomedical research areas that contribute to the understanding of fundamental cellular and physiological principles and enable research supported by the Biophysics, Biomedical Technology, and Computational Biosciences (BBCB); Genetics and Molecular, Cellular, and Developmental Biology (GMCDB); Pharmacology, Physiology, Biological Chemistry (PPBC) and Training, Workforce Development, and Diversity (TWD) Divisions. Over the next five years, our goals are to: 1. Improve the efficiency of operation for AMS measurements through installation of new interfaces to our AMS systems, technical modifications to improve gas accepting ion source efficiency and upgrading our data analysis software for improved ease of use and data reporting. 2. Increase the accessibility and visibility of ultra-sensitive 14C measurements for the biomedical research community by training of new investigators and expanding our national user base. 3. Provide high throughput, ultra-sensitive 14C analysis for the NIGMS and NIH user community.

47 OTHER INSTRUMENTATION↗