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At least 271 records · Page 15
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Investigating the Influence of River Geomorphology on Human Presence Using Night Light Data: A Case Study in the Indus Basin

Human settlements have historically thrived near rivers due to enhanced navigation and trade, and the availability of water supply and resources. The use of night light data, representing economic activities, provides a novel approach to studying the interactions between human activity and rivers over time. Here, we use the Defense Meteorological Satellite Program (DMSP) stable night light data from 2000 to 2013 as a proxy for human presence and activities to quantify the statistical relationships between night light presence and intensity in the Indus Basin, Asia. We test how these data are affected by proximity to trunk channels and by channel type (single/multi-thread) in the study area. We find that night light presence is enhanced by 26% within a 0 to 5 km proximity range of the Indus River and its tributaries, relative to the basin as a whole. We interpret this to represent increased human presence and activity within this zone. However, the mean intensity is lower near the river and higher away from the river, signifying denser settlements, such as towns and cities, which are preferentially located away from the Indus and its tributaries. Moreover, the enhancement of lit pixels signifying human presence and activities is increased by 18% near single-thread sections of the Indus River, compared to segments of the Indus displaying multi-thread morphologies. We suggest that this is due to the enhanced stability of single-threaded channels, relative to mobile multi-threaded channel reaches. This study demonstrates how night lights are an important tool in studying the relationship between human presence and river dynamics in large catchments such as the Indus, and we suggest that these data will have an important role in assessing differential flood spatial and social vulnerability at a regional scale.

Environmental Sciences & Ecology↗
DOE OSTI2020

Human XPG nuclease structure, assembly, and activities with insights for neurodegeneration and cancer from pathogenic mutations

Xeroderma pigmentosum group G (XPG) protein is both a functional partner in multiple DNA damage responses (DDR) and a pathway coordinator and structure-specific endonuclease in nucleotide excision repair (NER). Different mutations in the XPG gene ERCC5 lead to either of two distinct human diseases: Cancer-prone xeroderma pigmentosum (XP-G) or the fatal neurodevelopmental disorder Cockayne syndrome (XP-G/CS). To address the enigmatic structural mechanism for these differing disease phenotypes and for XPG’s role in multiple DDRs, here we determined the crystal structure of human XPG catalytic domain (XPGcat), revealing XPG-specific features for its activities and regulation. Furthermore, XPG DNA binding elements conserved with FEN1 superfamily members enable insights on DNA interactions. Notably, all but one of the known pathogenic point mutations map to XPGcat, and both XP-G and XP-G/CS mutations destabilize XPG and reduce its cellular protein levels. Mapping the distinct mutation classes provides structure-based predictions for disease phenotypes: Residues mutated in XP-G are positioned to reduce local stability and NER activity, whereas residues mutated in XP-G/CS have implied long-range structural defects that would likely disrupt stability of the whole protein, and thus interfere with its functional interactions. Combined data from crystallography, biochemistry, small angle X-ray scattering, and electron microscopy unveil an XPG homodimer that binds, unstacks, and sculpts duplex DNA at internal unpaired regions (bubbles) into strongly bent structures, and suggest how XPG complexes may bind both NER bubble junctions and replication forks. Collective results support XPG scaffolding and DNA sculpting functions in multiple DDR processes to maintain genome stability.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Stochastic parametric skeletal dosimetry model for humans: General approach and application to active marrow exposure from bone-seeking beta-particle emitters

The objective of this study is to develop a skeleton model for assessing active marrow dose from bone-seeking beta-emitting radionuclides. This article explains the modeling methodology which accounts for individual variability of the macro- and microstructure of bone tissue. Bone sites with active hematopoiesis are assessed by dividing them into small segments described by simple geometric shapes. Spongiosa, which fills the segments, is modeled as an isotropic three-dimensional grid (framework) of rod-like trabeculae that “run through” the bone marrow. Randomized multiple framework deformations are simulated by changing the positions of the grid nodes and the thickness of the rods. Model grid parameters are selected in accordance with the parameters of spongiosa microstructures taken from the published papers. Stochastic modeling of radiation transport in heterogeneous media simulating the distribution of bone tissue and marrow in each of the segments is performed by Monte Carlo methods. Model output for the human femur at different ages is provided as an example. The uncertainty of dosimetric characteristics associated with individual variability of bone structure was evaluated. An advantage of this methodology for the calculation of doses absorbed in the marrow from bone-seeking radionuclides is that it does not require additional studies of autopsy material. The biokinetic model results will be used in the future to calculate individual doses to members of a cohort exposed to 89,90 Sr from liquid radioactive waste discharged to the Techa River by the Mayak Production Association in 1949–1956. Further study of these unique cohorts provides an opportunity to gain more in-depth knowledge about the effects of chronic radiation on the hematopoietic system. In addition, the proposed model can be used to assess the doses to active marrow under any other scenarios of 90 Sr and 89 Sr intake to humans.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Glucocorticoids activate Yes-associated protein in human vocal fold fibroblasts

Fibrosis of the vocal folds poses a substantive clinical challenge potentially underlying the rapid proliferation of direct steroid injections into the upper airway. The variable clinical response to glucocorticoids (GCs) in the vocal folds is likely related to diversity inherent to GCs and patient-specific, and upstream, cell-specific responses to GCs. Broadly, we hypothesize the disparity in clinical outcomes are due to undesirable effects of GCs on resident fibroblasts. Transcriptome analysis identified significant GC-mediated modulation of Hippo signaling, a known regulator of fibrotic gene expression. Subsequent analysis confirmed GC-mediated YAP activation, a transcriptional co-factor in the Hippo signaling pathway. YAP inhibition attenuated ACTA2 expression in GC-treated human vocal fold fibroblasts. Nuclear localization and phosphorylation at Ser211, however, was not affected by YAP inhibition, suggesting nuclear translocation of YAP is indirectly driven by GR. RNA-seq analysis confirmed the influence of GCs on Wnt signaling, and canonical Wnt signaling target genes were upregulated by GCs. These data implicate YAP and its downstream targets as putative mediators of a pro-fibrotic response to GCs. Therapeutic YAP inhibition may ultimately be clinically relevant and warrants further consideration.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

SARS-CoV-2 Diverges from Other Betacoronaviruses in Only Partially Activating the IRE1α/XBP1 Endoplasmic Reticulum Stress Pathway in Human Lung-Derived Cells

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed over 6 million individuals worldwide and continues to spread in countries where vaccines are not yet widely available or its citizens are hesitant to become vaccinated. Therefore, it is critical to unravel the molecular mechanisms that allow SARS-CoV-2 and other coronaviruses to infect and overtake the host machinery of human cells. Coronavirus replication triggers endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR), a key host cell pathway widely believed to be essential for viral replication. We examined the master UPR sensor IRE1α kinase/RNase and its downstream transcription factor effector XBP1s, which is processed through an IRE1α-mediated mRNA splicing event, in human lung-derived cells infected with betacoronaviruses. We found that human respiratory coronavirus OC43 (HCoV-OC43), Middle East respiratory syndrome coronavirus (MERS-CoV), and murine coronavirus (MHV) all induce ER stress and strongly trigger the kinase and RNase activities of IRE1α as well as XBP1 splicing. In contrast, SARS-CoV-2 only partially activates IRE1α through autophosphorylation, but its RNase activity fails to splice XBP1. Moreover, while IRE1α was dispensable for replication in human cells for all coronaviruses tested, it was required for maximal expression of genes associated with several key cellular functions, including the interferon signaling pathway, during SARS-CoV-2 infection. Our data suggest that SARS-CoV-2 actively inhibits the RNase of autophosphorylated IRE1α, perhaps as a strategy to eliminate detection by the host immune system.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines

Molecular-glue degraders are small molecules that induce a specific interaction between an E3 ligase and a target protein, resulting in the target proteolysis. The discovery of molecular glue degraders currently relies mostly on screening approaches. Here, we describe screening of a library of cereblon (CRBN) ligands against a panel of patient-derived cancer cell lines, leading to the discovery of SJ7095, a potent degrader of CK1α, IKZF1 and IKZF3 proteins. Through a structure-informed exploration of structure activity relationship (SAR) around this small molecule we develop SJ3149, a selective and potent degrader of CK1α protein in vitro and in vivo. The structure of SJ3149 co-crystalized in complex with CK1α + CRBN + DDB1 provides a rationale for the improved degradation properties of this compound. In a panel of 115 cancer cell lines SJ3149 displays a broad antiproliferative activity profile, which shows statistically significant correlation with MDM2 inhibitor Nutlin-3a. These findings suggest potential utility of selective CK1α degraders for treatment of hematological cancers and solid tumors.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

A Design of Activity-Based Mobility Intervention

Human mobility influences our society and vice versa. During the COVID-19 pandemic, non-pharmaceutical intervention that alters activity-based mobility such as work-from-home greatly impacted human mobility patterns. Many studies on developing mitigation strategies have employed or implemented their own mobility intervention within their model assumption. For fair evaluation between intervention strategies across models, it is significant to set up compatible experimental environments. However, it is difficult to apply the identical intervention to different kinds of models and compare their effectiveness because each model might have different assumptions, capabilities, and implementations. Even if one can apply intervention to heterogeneous models, it may produce undesirable artifacts due to difference of models and integration with intervention. Therefore, minimizing undesirable artifacts and facilitating intervention experiments across heterogeneous models are substantial. Taking this into account, this paper investigates a design of activity-based mobility intervention (ABMI). We define ABMI together with related concepts and develop an extensible data model and schema of ABMI based on the 5W1H method that can be used in different models. As a case study, we apply the ABMI model to a micro-simulation to demonstrate the usability of the proposed model. We expect that standardized ABMI and interfaces may help to streamline development and experiments of intervention strategies across heterogeneous models.

Kim, Joon-Seok↗
DOE OSTI2021

Oestrogen regulates SOX9 bioavailability by rapidly activating ERK1/2 and stabilising microtubules in a human testis-derived cell line

Highlights: • Brief oestrogen treatment causes the cytoplasmic retention of the testis factor SOX9. • The cytoplasmic retention of SOX9 by oestrogen is associated with the rapid stabilisation of microtubules. • ERK1/2 is required for the stabilisation of microtubules by activated oestrogen receptors. • Oestrogen can act on both a non-genomic and genomic level to impact gonad somatic cell fate. Nuclear SOX9 is essential for Sertoli cell differentiation and the development of a testis. Exposure of Sertoli cells to exogenous oestrogen causes cytoplasmic retention of SOX9, inhibiting testis development and promoting ovarian development. The cytoplasmic localisation of SOX9 requires a stabilised microtubule network and a key MAPK complex, ERK1/2, is responsive to oestrogen and known to affect the microtubule network. We hypothesised that oestrogen could stabilise microtubules through the activation of ERK1/2 to promote the cytoplasmic retention of SOX9. Treatment of human testis-derived NT2/D1 cells for 30 min with oestrogen rapidly activated ERK1/2, stabilised the microtubule network and increased cytoplasmic localisation of SOX9. The effects of oestrogen on SOX9 and tubulin were blocked by the ERK1/2 inhibitor U0126, demonstrating that ERK1/2 mediates the stabilisation of microtubules and cytoplasmic retention of SOX9 by oestrogen. Together, these data revealed a previously unknown mechanism for oestrogen in impacting MAPK signalling to block SOX9 bioavailability and the differentiation of Sertoli cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Spatial variability in Arctic–boreal fire regimes influenced by environmental and human factors

Abstract Wildfire activity in Arctic and boreal regions is rapidly increasing, with severe consequences for climate and human health. Regional long-term variations in fire frequency and intensity characterize fire regimes. The spatial variability in Arctic–boreal fire regimes and their environmental and anthropogenic drivers, however, remain poorly understood. Here we present a fire tracking system to map the sub-daily evolution of all circumpolar Arctic–boreal fires between 2012 and 2023 using 375 m Visible Infrared Imaging Radiometer Suite active fire detections and the resulting dataset of the ignition time, location, size, duration, spread and intensity of individual fires. We use this dataset to classify the Arctic–boreal biomes into seven distinct ‘pyroregions’ with unique climatic and geographic environments. We find that these pyroregions exhibit varying responses to environmental drivers, with boreal North America, eastern Siberia and northern tundra regions showing the highest sensitivity to climate and lightning density. In addition, anthropogenic factors play an important role in influencing fire number and size, interacting with other factors. Understanding the spatial variability of fire regimes and its interconnected drivers in the Arctic–boreal domain is important for improving future predictions of fire activity and identifying areas at risk for extreme events.

Geology↗
DOE OSTI2022

Attribution of 2020 hurricane season extreme rainfall to human-induced climate change

Abstract The 2020 North Atlantic hurricane season was one of the most active on record, causing heavy rains, strong storm surges, and high winds. Human activities continue to increase the amount of greenhouse gases in the atmosphere, resulting in an increase of more than 1 °C in the global average surface temperature in 2020 compared to 1850. This increase in temperature led to increases in sea surface temperature in the North Atlantic basin of 0.4–0.9 °C during the 2020 hurricane season. Here we show that human-induced climate change increased the extreme 3-hourly storm rainfall rates and extreme 3-day accumulated rainfall amounts during the full 2020 hurricane season for observed storms that are at least tropical storm strength (>18 m/s) by 10 and 5%, respectively. When focusing on hurricane strength storms (>33 m/s), extreme 3-hourly rainfall rates and extreme 3-day accumulated rainfall amounts increase by 11 and 8%, respectively.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2024

Graph-Based Modeling for the Detection and Tracking of Sarin-Surrogate-Induced Neurotoxicity Using a Human-Relevant, In-Vitro Brain Model

Organophosphorus (OP) nerve agents are a chemical threat to the United States, to the civilian population (e.g., pesticides) and historically weaponized (e.g., sarin) as chemical warfare agents. The unprecedented, accelerated process from “bench-to-bedside” during the SARSCov2 pandemic has made it clear that technology and tools need to be readily available for immediate response. Advances in human organ tissue mimetic systems are a promising technology to evaluate the human-relevant response in vitro for basic and applied research and drug screening. In particular, current brain microphysiological systems (MPS) have the capability to monitor and detect changes in engineered human neural circuit activity. However, current data analytics approaches for these systems lack the granularity to functionally detect and distinguish the different mechanisms that occur in the brain following neurotoxicity, injury, and disease. The goal of this project was to advance the computational analytical capabilities of the brain MPS to detect functional changes in neural circuit structure at different stages of Sarin surrogate-induced neurotoxicity. We developed graph-based models to (1) identify the composition of the neural circuit structure; (2) detect and monitor how this structure changes following sarin-induced neurotoxicity; and (3) evaluate the analytical pipeline using known/promising oxime reactivators. Through experiments on the bMPS where in vitro neuronal cultures were exposed to a sarin surrogate, we demonstrated the capabilities of our computational pipeline to identify different responses in the functional networks of brain cells exposed to low and high concentrations of the nerve agent. We identified a biphasic response of human neural network activity following exposure to a sarin-surrogate that had not been reported in the literature before. The graph-based models and software developed in this project can be used for future studies that leverage the brain MPS technology, such as treatment efficacy assessment.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

A dynamic Bayesian optimized active recommender system for curiosity-driven partially Human-in-the-loop automated experiments

Optimization of experimental materials synthesis and characterization through active learning methods has been growing over the last decade, with examples ranging from measurements of diffraction on combinatorial alloys at synchrotrons, to searches through chemical space with automated synthesis robots for perovskites. In virtually all cases, the target property of interest for optimization is defined a priori with the ability to shift the trajectory of the optimization based on human-identified findings during the experiment is lacking. Thus, to highlight the best of both human operators and AI-driven experiments, here we present the development of a human–AI collaborated experimental workflow, via a Bayesian optimized active recommender system (BOARS), to shape targets on the fly with human real-time feedback. Here, the human guidance overpowers AI at early iteration when prior knowledge (uncertainty) is minimal (higher), while the AI overpowers the human during later iterations to accelerate the process with the human-assessed goal. We showcase examples of this framework applied to pre-acquired piezoresponse force spectroscopy of a ferroelectric thin film, and in real-time on an atomic force microscope, with human assessment to find symmetric hysteresis loops. It is found that such features appear more affected by subsurface defects than the local domain structure. This work shows the utility of human–AI approaches for curiosity driven exploration of systems across experimental domains.

36 MATERIALS SCIENCE↗
DOE OSTI2026

Activation dynamics of a water-soluble human mu-opioid receptor

The mu-opioid receptor (MOR), a class A G protein-coupled receptor mediates opioid analgesia and remains a central target for pain therapeutics. While crystal structures of MOR exist, they provide limited insight into the receptor’s dynamic conformational landscape underlying function. Here, we engineered a thermostable water-soluble MOR variant (wsMOR) that retains native-like ligand-binding and activation dynamics. This variant enables high-yield production and detailed solution-phase structural studies that are challenging with membrane-embedded MOR, providing a valuable tool for studying receptor activation and aqueous-phase drug screening. Using a combined computational and experimental approach, we performed long-timescale all-atom molecular dynamics simulations together with neutron scattering and single-molecule FRET, revealing a structurally stable receptor with a diverse ensemble of conformations at different temporal resolutions. In the ligand-free state, wsMOR displayed high conformational flexibility, which decreased upon agonist binding, particularly in transmembrane helix 6, a hallmark of G protein-coupled receptor activation. Positive allosteric modulation and G protein binding further stabilized active-like states. These findings highlight wsMOR’s conformational plasticity across picosecond to millisecond timescales and provide a foundation for structure-guided development of next-generation opioid ligands with improved efficacy and safety.

E, Agyemang [University of Tennessee Knoxville]↗