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At least 955 records · Page 53
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Birth of protein folds and functions in the virome

The rapid evolution of viruses generates proteins that are essential for infectivity and replication but with unknown functions, due to extreme sequence divergence. Here, using a database of 67,715 newly predicted protein structures from 4,463 eukaryotic viral species, we found that 62% of viral proteins are structurally distinct and lack homologues in the AlphaFold database. Among the remaining 38% of viral proteins, many have non-viral structural analogues that revealed surprising similarities between human pathogens and their eukaryotic hosts. Structural comparisons suggested putative functions for up to 25% of unannotated viral proteins, including those with roles in the evasion of innate immunity. In particular, RNA ligase T-like phosphodiesterases were found to resemble phage-encoded proteins that hydrolyse the host immune-activating cyclic dinucleotides 3',3'- and 2',3'-cyclic GMP-AMP (cGAMP). Experimental analysis showed that RNA ligase T homologues encoded by avian poxviruses similarly hydrolyse cGAMP, showing that RNA ligase T-mediated targeting of cGAMP is an evolutionarily conserved mechanism of immune evasion that is present in both bacteriophage and eukaryotic viruses. Together, the viral protein structural database and analyses presented here afford new opportunities to identify mechanisms of virus–host interactions that are common across the virome.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Opportunities in AI/ML for the Rubin LSST Dark Energy Science Collaboration

The Vera C. Rubin Observatory's Legacy Survey of Space and Time (LSST) will produce unprecedented volumes of heterogeneous astronomical data (images, catalogs, and alerts) that challenge traditional analysis pipelines. The LSST Dark Energy Science Collaboration (DESC) aims to derive robust constraints on dark energy and dark matter from these data, requiring methods that are statistically powerful, scalable, and operationally reliable. Artificial intelligence and machine learning (AI/ML) are already embedded across DESC science workflows, from photometric redshifts and transient classification to weak lensing inference and cosmological simulations. Yet their utility for precision cosmology hinges on trustworthy uncertainty quantification, robustness to covariate shift and model misspecification, and reproducible integration within scientific pipelines. This white paper surveys the current landscape of AI/ML across DESC's primary cosmological probes and cross-cutting analyses, revealing that the same core methodologies and fundamental challenges recur across disparate science cases. Since progress on these cross-cutting challenges would benefit multiple probes simultaneously, we identify key methodological research priorities, including Bayesian inference at scale, physics-informed methods, validation frameworks, and active learning for discovery. With an eye on emerging techniques, we also explore the potential of the latest foundation model methodologies and LLM-driven agentic AI systems to reshape DESC workflows, provided their deployment is coupled with rigorous evaluation and governance. Finally, we discuss critical software, computing, data infrastructure, and human capital requirements for the successful deployment of these new methodologies, and consider associated risks and opportunities for broader coordination with external actors.

Aubourg, Eric [APC, Paris] (ORCID:000000025592023X↗
DOE OSTI2020

Update to the Performance Assessment for the Savannah River Site Saltstone Disposal Facility - 20124

In 2019, Savannah River Remediation developed a revision to the performance assessment (PA) on behalf of the U.S. Department of Energy (DOE) Savannah River Operations Office (SR) for the near-surface disposal of low-level waste at the Savannah River Site (SRS) Saltstone Disposal Facility (SDF). Soluble waste from SRS Tank Farms undergoes salt processing to remove cesium and other high activity constituents. The low-activity decontaminated salt solution (DSS) is then immobilized by mixing it into a cementitious waste form known as saltstone. After mixing, the saltstone is poured into leak-tight concrete vaults, known as saltstone disposal units (SDUs), where the waste form cures. By the time of facility closure, the SDF is expected to consist of 15 SDUs with a combined capacity of 1.06 E+09 L (280 Mgal) of cured saltstone. The facility operates under a Disposal Authorization Statement (DAS) from DOE and a permit from the South Carolina Department of Health and Environmental Control (SCDHEC). Since the start of operations in 1990, the SDF has received almost 6.7 E+07 L (18 Mgal) of DSS, resulting in the safe disposal of 2.7 E+16 Bq (7.3 E+05 Ci) of activity. Due to the radioactive decay of short-lived contaminants, the total remaining activity in the disposed waste is estimated to be approximately 1.4 E+16 Bq (3.9 E+05 Ci), as of September 2018. The Disposal Authorization Statement requires a demonstration that the system of engineered and natural features of the disposal facility will limit releases from the facility and be protective of human health and the environment for at least the next 1,000 years. The long-term performance of the facility was evaluated under the requirements of the DoE's Radioactive Waste Management Manual (US DOE Manual 435.1-1). Simulations were performed to demonstrate that the disposal facility would meet performance objectives specified in the manual. The evaluation was based on numerical models that simulate the releases of contaminants from the saltstone waste form. Contaminants were transported through groundwater and air pathways to points of assessment to evaluate compliance. In addition, the potential consequences of an inadvertent human intrusion (IHI) were also evaluated. In accordance with the guidance and recommendations in US DoE's technical standard for DAS, deterministic and probabilistic analyses were performed to demonstrate the SDF system, which includes the engineered cover system, the SDUs, the waste form, and the natural features of the site, provides a reasonable expectation that saltstone disposal will meet performance objectives. Post-closure doses to future members of the public (MOP) were evaluated; dose estimates from the air pathway were well below the 1.0 E-04 Sv/yr (10 mrem/yr) performance objective within 1,000 years, and the calculated doses to the MOP from all exposure pathways, including the groundwater and air pathways, were well below the 2.5 E-04 Sv/yr (25 mrem/yr) performance objective within 1,000 years. Doses following an assumed intrusion event within the facility boundaries were well below the IHI performance objectives, where the acute IHI dose was below the acute IHI dose performance objective of 5.0 E-03 Sv (500 mrem) and the chronic IHI dose was below the chronic IHI dose performance objective of 1.0 E-03 Sv/yr (100 mrem/yr) within 1,000 years. (author)

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗
DOE OSTI2020

Issue Resolution During the Development of the Performance Assessment for the Savannah River Site Saltstone Disposal Facility - 20125

In 2019, Savannah River Remediation developed a revision to the performance assessment (PA) on behalf of the U.S. Department of Energy (DOE) Savannah River Operations Office (SR) for the near-surface disposal of low-level waste at the Savannah River Site (SRS) Saltstone Disposal Facility (SDF). Soluble waste from SRS Tank Farms undergoes salt processing to remove cesium and other high-activity constituents. The low-activity decontaminated salt solution (DSS) is then immobilized by mixing it into a cementitious waste form known as saltstone. After mixing, the saltstone is poured into leak-tight concrete vaults, known as saltstone disposal units (SDUs), where the waste form cures. By the time of facility closure, the SDF is expected to consist of 15 SDUs with a combined capacity of 1.06 E+09 L (280 Mgal) of cured saltstone. The facility operates under a Disposal Authorization Statement from DOE and a permit from the South Carolina Department of Health and Environmental Control (SCDHEC). Since the start of operations in 1990, the SDF has received almost 6.7 E+07 L (18 Mgal) of DSS, resulting in the safe disposal of 2.7 E+16 Bq (7.3 E+05 Ci) of activity. Due to the radioactive decay of short-lived contaminants, the total remaining activity in the disposed waste is estimated to be approximately 1.4 E+16 Bq (3.9 E+05 Ci), as of September 2018. The Disposal Authorization Statement requires a demonstration that the system of engineered and natural features of the disposal facility will limit releases from the facility and be protective of human health and the environment for at least the next 1,000 years. The long-term performance of the facility was evaluated under the requirements of the DoE's Radioactive Waste Management Manual (US DOE Manual 435.1-1). Simulations were performed to demonstrate that the disposal facility would meet performance objectives specified in the manual. The evaluation was based on numerical models that simulate the releases of contaminants from the saltstone waste form. Contaminants were transported through groundwater and air pathways to points of assessment to evaluate compliance (i.e., 100 m from the SDUs). In addition, the potential consequences of an inadvertent human intrusion (IHI) were also evaluated. A number of issues were overcome during the development of these simulations. These issues were identified as part of internal technical reviews. Simulations are developed by people and people make mistakes, so the internal technical review process is a vital step in PA development. Specific examples of resolved issues include a unit-conversion error, an inappropriate definition for a model boundary condition, a model time-stepping issue, and an error in the calculation for the buildup of contaminants in soil. Actions taken to address these issues resulted in an improved product with a better supported technical basis and more defensible results. The identification and correction of these issues are discussed. By understanding these issues, model developers and technical reviewers working on PAs in the future may avoid repeating these types of mistakes. Transparency with respect to these mistakes builds trust between waste management sites, regulators, and stakeholders. (authors)

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗
DOE OSTI2021

Activation of the CaR-CSE/H2S pathway confers cardioprotection against ischemia-reperfusion injury

Ischemia-reperfusion (I/R) injury is a multifactorial process triggered when an organ is subjected to transiently reduced blood supply. The result is a cascade of pathological complications and organ damage due to the production of reactive oxygen species following reperfusion. The present study aims to evaluate the role of activated calcium-sensing receptor (CaR)-cystathionine γ-lyase (CSE)/hydrogen sulfide (H2S) pathway in I/R injury. Firstly, an I/R rat model with CSE knockout was constructed. Transthoracic echocardiography, TTC and HE staining were performed to determine the cardiac function of rats following I/R Injury, followed by TUNEL staining observation on apoptosis. Besides, with the attempt to better elucidate how CaR-CSE/H2S affects I/R, in-vitro culture of human coronary artery endothelial cells (HCAECs) was conducted with gadolinium chloride (GdCl3, a CaR agonist), H{sub 2}O{sub 2}, siRNA against CSE (siCSE), or W7 (a CaM inhibitor). The interaction between CSE and CaM was subsequently detected. Plasma oxidative stress indexes, H2S and CSE, and apoptosis-related proteins were all analyzed following cell apoptosis. We found that H2S elevation led to the improvement whereas CSE knockdown decreased cardiac function in rats with I/R injury. Moreover, oxidative stress injury in I/R rats with CSE knockout was aggravated, while the increased expression of H2S and CSE in the aortic tissues resulted in alleviated the oxidative stress injury. Moreover, increased H2S and CSE levels were found to inhibit cell apoptotic ability in the aortic tissues after I/R injury, thus attenuating oxidative stress injury, accompanied by inhibited expression of apoptosis-related proteins. In HCAECs following oxidative stress treatment, siCSE and CaM inhibitor were observed to reverse the protection of CaR agonist. Coimmunoprecipitation assay revealed the interaction between CSE and CaM. Taken together, all above-mentioned data provides evidence that activation of the CaR-CSE/H2S pathway may confer a potent protective effect in cardiac I/R injury.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Characterization of two distinct neutrophil serine protease–binding modes within a Staphylococcus aureus innate immune evasion protein family

Extracellular adherence protein domain (EAPs) proteins are a class of innate immune evasion proteins secreted by the human pathogen Staphylococcus aureus. EAPs are potent and selective inhibitors of cathepsin-G (CG) and neutrophil elastase (NE), which are the two most abundant neutrophil serine proteases (NSPs). Previous work from our group has shown that the prototypical EAP, EapH1, relies on plasticity within a single inhibitory site to block the activities of CG and NE. However, whether other EAPs follow similar structure–function relationships is unclear. To address this question, we studied the inhibitory properties of the first (Eap1) and second (Eap2) domains of the modular extracellular adherence protein of S. aureus and determined their structures when bound to CG and NE, respectively. We observed that both Eap1 and Eap2 displayed time-dependent inhibition of CG (on the order of 10 -9 M) and of NE (on the order of 10 -10 M). We also found that whereas the structures of Eap1 and Eap2 bound to CG showed an overall inhibitory mode like that seen previously for EapH1, the structures of Eap1 and Eap2 bound to NE revealed a new inhibitory mode involving a distal region of the EAP domain. Using site-directed mutagenesis of Eap1 and Eap2, along with enzyme assays, we confirmed the roles of interfacial residues in NSP inhibition. Taken together, our work demonstrates that EAPs can form structurally divergent complexes with two closely related serine proteases and further suggests that certain EAPs may be capable of inhibiting two NSPs simultaneously.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

Overcoming significant challenges in extracting off-stoichiometric thermodynamics using the compound energy formalism through complementary use of experimental and first principles data: A case study of Ba 1-x Sr x FeO 3-δ

The compound energy formalism (CEF) is a powerful framework to describe the thermodynamics of metal oxides as a function of off-stoichiometry, temperature, and composition. The thermodynamic properties are crucial materials design attributes in metal oxide-based oxygen-exchange chemical processes. Despite the richness of information an accurate CEF model provides, a method to determine a unique and accurate fit for oxygen exchange materials remains elusive. This contribution details a method for fitting the CEF model that overcomes the current fitting challenges through three innovations: 1) the combination of density functional theory calculations with experimental data decorrelates excess terms and delineates the enthalpic/entropic contributions to the Gibbs free energy; 2) a systematic determination of the important CEF model terms, removing thermodynamic predetermining human intervention; 3) a self-consistent solution of the starting oxygen offstoichiometry (δ 0 ) of thermogravimetric measurements. Thus, our method enables the reliable extraction of off-stoichiometric metal oxide thermodynamic properties and facilitates rapid materials compositional screening, and reliable process design of systems dependent on off-stoichiometric redox-active metal oxides. We apply this method to a Ba x Sr 1-x FeO 3-δ test case. We find by systematically examining the performance of the CEF model fit with and without each innovation that all three innovations are necessary for an accurate fit. We determined that reduction enthalpy is higher and more sensitive to off-stoichiometry when the Sr fraction is large (139.5 and 185.3 kJ/mol O 2 for SrFeO 3 at δ = 0 and δ = 0.5, respectively vs. nearly constant 83 kJ/mol O 2 for BaFeO 3 ). However, the reduction entropy is mostly insensitive to Sr fraction, but highly dependent on δ suggesting larger contributions in the non-configurational entropy parameters.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

A unique class of Zn 2+ -binding serine-based PBPs underlies cephalosporin resistance and sporogenesis in Clostridioides difficile

Treatment with β-lactam antibiotics, particularly cephalosporins, is a major risk factor for Clostridioides difficile infection. These broad-spectrum antibiotics irreversibly inhibit penicillin-binding proteins (PBPs), which are serine-based enzymes that assemble the bacterial cell wall. However, C. difficile has four different PBPs (PBP1-3 and SpoVD) with various roles in growth and spore formation, and their specific links to β-lactam resistance in this pathogen are underexplored. Here, we show that PBP2 (known to be essential for vegetative growth) is the primary bactericidal target for β-lactams in C. difficile. PBP2 is insensitive to cephalosporin inhibition, and this appears to be the main basis for cephalosporin resistance in this organism. We determine crystal structures of C. difficile PBP2, alone and in complex with β-lactams, revealing unique features including ligand-induced conformational changes and an active site Zn 2+ -binding motif that influences β-lactam binding and protein stability. The Zn 2+ -binding motif is also present in C. difficile PBP3 and SpoVD (which are known to be essential for sporulation), as well as in other bacterial taxa including species living in extreme environments and the human gut. We speculate that this thiol-containing motif and its cognate Zn 2+ might function as a redox sensor to regulate cell wall synthesis for survival in adverse or anaerobic environments.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress

Fis1-mediated mitochondrial localization of Drp1 and excessive mitochondrial fission occur in human pathologies associated with oxidative stress. However, it is not known how Fis1 detects oxidative stress and what structural changes in Fis1 enable mitochondrial recruitment of Drp1. We find that conformational change involving α1 helix in Fis1 exposes its only cysteine, Cys41. In the presence of oxidative stress, the exposed Cys41 in activated Fis1 forms a disulfide bridge and the Fis1 covalent homodimers cause increased mitochondrial fission through increased Drp1 recruitment to mitochondria. Our discovery of a small molecule, SP11, that binds only to activated Fis1 by engaging Cys41, and data from genetically engineered cell lines lacking Cys41 strongly suggest a role of Fis1 homodimerization in Drp1 recruitment to mitochondria and excessive mitochondrial fission. The structure of activated Fis1-SP11 complex further confirms these insights related to Cys41 being the sensor for oxidative stress. Importantly, SP11 preserves mitochondrial integrity and function in cells during oxidative stress and thus may serve as a candidate molecule for the development of treatment for diseases with underlying Fis1-mediated mitochondrial fragmentation and dysfunction.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

California wildfire spread derived using VIIRS satellite observations and an object-based tracking system

Changing wildfire regimes in the western US and other fire-prone regions pose considerable risks to human health and ecosystem function. However, our understanding of wildfire behavior is still limited by a lack of data products that systematically quantify fire spread, behavior and impacts. Here we develop a novel object-based system for tracking the progression of individual fires using 375 m Visible Infrared Imaging Radiometer Suite active fire detections. At each half-daily time step, fire pixels are clustered according to their spatial proximity, and are either appended to an existing active fire object or are assigned to a new object. This automatic system allows us to update the attributes of each fire event, delineate the fire perimeter, and identify the active fire front shortly after satellite data acquisition. Using this system, we mapped the history of California fires during 2012–2020. Our approach and data stream may be useful for calibration and evaluation of fire spread models, estimation of near-real-time wildfire emissions, and as means for prescribing initial conditions in fire forecast models.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2020

Artificial Intelligence for Digital Security and Protections

Proper functioning of nuclear power plants relies on a mix of well-regulated human and machine-driven workflows. This regulation supports nuclear safety through a series of processes and many of the tasks that support these processes have a repetitive nature that make artificial intelligence (AI) informed by machine learning (ML) a potential aid in a variety of tasks. AI is being evaluated for activities that include inspections, fuel processing, monitoring, and other activities. The introduction of any new technology presents a potential new attack vector. In the case of AI/ML, there are many attacks that have already been discovered and over time the attacks can be expected to follow the growth pattern observed in cyber security. While future planning is necessary, current efforts need to be established now to predict the threat emergence over the next year 10 years and mitigate potential threats. Based on these observations, AI/ML will need to become trustworthy, which corresponds to techniques and procedures that emphasize AI explainability along with resilience techniques to data, algorithms, models, and systems. This kind of system robustness is the foundation for defenses against AI/ML-specific attacks. Attempting to look forward and take a broad view of capabilities provides input to research roadmaps and the ability to distill vulnerabilities into specific use cases may provide greater assistance in understanding the technology benefits while introducing new risks. The impact of current and future AI in three areas—capabilities, challenges, and recovery strategies—represents an initial attempt at balancing both.

45 MILITARY TECHNOLOGY, WEAPONRY, AND NATIONAL DEF↗
DOE OSTI2026

Free Energy and Flexibility Analysis of Autoinhibited Human BRAF

The RAF serine/threonine protein kinases function as direct effectors of RAS in the intracellular transmission of extracellular growth signals, and they are key targets for drug discovery, given the high incidence of oncogenic mutations in RAF and other components of this signaling pathway. In its inactive state, RAF is held in an autoinhibited conformation in the cytosol through a combination of intramolecular interactions and binding to a regulatory 14−3−3 protein dimer. Activation of RAF is initiated by its interaction with membrane-localized GTP-bound RAS, which induces conformational changes that release RAF from its autoinhibited state. However, the molecular mechanisms governing RAF activation remain incomplete, largely due to the challenges in experimentally capturing the intermediate conformational states in this process. To address this gap, we developed a comprehensive all-atom model of BRAF based on existing cryo-EM structures. Using this model, we performed extensive molecular dynamics simulations to evaluate the stability and free energy landscape of autoinhibited BRAF in solution. Our analysis reveals conformational flexibility within the autoinhibited complex, suggesting that this dynamic behavior may play a role in facilitating BRAF activation upon engagement with the membrane-bound RAS.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

Los Alamos National Laboratory Hazardous Waste Facility Permit Community Relations Plan

The requirements of the Hazardous Waste Facility Permit are fulfilled through execution of LANL's fourth strategic goal: “Enabling mission delivery through next-generation facility, infrastructure, and operational excellence.” With input from our stakeholders, we will continue to fulfill those requirements and to improve our waste operations. In 2015, the Laboratory purpose statement focused waste management efforts by directing delivery of mission success through operational effectiveness and scientific excellence. This Plan advances that purpose through community involvement. In the process of achieving our national security mission, Los Alamos National Laboratory generates some hazardous and mixed waste. Hazardous waste is solid waste that is dangerous or potentially harmful to human health or the environment. Hazardous wastes can be liquids, solids, gases, or sludges. They can be discarded as commercial products, such as cleaning fluids or pesticides, or as the byproducts of operations. Specific substances are listed in 40 Code of Federal Regulations (CFR), Part 261: 40 CFR Part 261. Hazardous waste management activities are regulated by the U. S. Environmental Protection Agency and the New Mexico Environment Department (NMED) pursuant to New Mexico Hazardous Waste Act (HWA; Chapter 74, Article 4 NMSA 1978) and regulations under the Act. In 1989, NMED issued the Hazardous Waste Facility Permit (EPA ID Number NM0890010515-1) that established standards for the Laboratory to manage, store, and treat hazardous wastes on-site and to undertake the closure, post closure care, and cleanup as necessary, of permitted waste management units. On November 30, 2010, NMED renewed the Hazardous Waste Facility Permit (the Permit). In June 2020 the Permittees submitted a permit renewal application to the NMED for their review and approval. The Hazardous Waste Facility Permit Community Relations Plan (CRP) describes the scope of public involvement in the activities of the Permit. The CRP is specifically designed to facilitate the community outreach, engagement, and relations activities concerning the Laboratory’s Hazardous Waste Facility Permit and coordinates with but does not include public involvement for other Laboratory programs, initiatives, or environmental activities.

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗
DOE OSTI2026

EV Load Forecasting Guide: A Report by the Energy Systems Integration Group’s EV Load Forecasting Task Force

Forecasting electricity usage is a foundational planning activity for utilities, underpinning billions of dollars in grid investments that ensure system reliability. Historically, forecasting relied on trends in economic and population growth; however, transportation electrification presents a new and complex planning challenge. Unlike conventional loads, electric vehicle (EV) charging has relatively limited usage history. In addition, charging is driven by complex human behaviors, is mobile, and at the same time can concentrate geographically in ways that, without proper planning, can quickly overwhelm local distribution systems.

Giraldez, Julieta [Electric Power Engineers, Austi↗
DOE OSTI2023

Analysis of Tasks in Autonomous Systems Using the EMRALD Dynamic Risk Assessment Tool

An autonomous system refers to the system that has the power and ability for self-governance in the performance of system functions. Autonomous systems have been actively pursued in a variety of domains such as automotive, aviation, maritime, medicine, and nuclear fields. As an unmanned concept employing the highest automation level, the autonomous system basically performs most of the work in normal operations or emergency situations. However, despite advances in technology, many researchers have noted these systems still require human actions. The nature of human actions on autonomous systems is different than the human actions that are considered in existing systems. Nevertheless, only a few studies have been conducted on 1) characterizing the different types of errors and risks associated with human actions interacting with autonomous systems and 2) how to evaluate human actions in the autonomous operations. As a starting point, this study aims to investigate differences of tasks in autonomous operation compared to those in existing nuclear power plant operation using the Event Modeling Risk Assessment Using Linked Diagram (EMRALD) software. In this paper, insights aspect of human error and time are derived out and discussed based on the output of the EMRALD models.

99 GENERAL AND MISCELLANEOUS↗
DOE OSTI2020

A 3.4-Å cryo-electron microscopy structure of the human coronavirus spike trimer computationally derived from vitrified NL63 virus particles

Human coronavirus NL63 (HCoV-NL63) is an enveloped pathogen of the family Coronaviridae that spreads worldwide and causes up to 10% of all annual respiratory diseases. HCoV-NL63 is typically associated with mild upper respiratory symptoms in children, elderly and immunocompromised individuals. It has also been shown to cause severe lower respiratory illness. NL63 shares ACE2 as a receptor for viral entry with SARS-CoV-1 and SARS-CoV-2. Here we present the in situ structure of HCoV-NL63 spike (S) trimer at 3.4-Å resolution by single-particle cryo-EM imaging of vitrified virions without chemical fixative. It is structurally homologous to that obtained previously from the biochemically purified ectodomain of HCoV-NL63 S trimer, which displays a 3-fold symmetric trimer in a single conformation. In addition to previously proposed and observed glycosylation sites, our map shows density at other sites, as well as different glycan structures. The domain arrangement within a protomer is strikingly different from that of the SARS-CoV-2 S and may explain their different requirements for activating binding to the receptor. Overall, this structure provides the basis for future studies of spike proteins with receptors, antibodies, or drugs, in the native state of the coronavirus particles.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Ultra-low binder content 3D printed calcium phosphate graphene scaffolds as resorbable, osteoinductive matrices that support bone formation in vivo

Bone regenerative engineering could replace autografts; however, no synthetic material fulfills all design criteria. Nanocarbons incorporated into three-dimensional printed (3DP) matrices can improve properties, but incorporation is constrained to low wt%. Further, unmodified nanocarbons have limited osteogenic potential. Functionalization to calcium phosphate graphene (CaPG) imparts osteoinductivity and osteoconductivity, but loading into matrices remained limited. This work presents ultra-high content (90%), 3DP-CaPG matrices. 3DP-CaPG matrices are highly porous (95%), moderately stiff (3 MPa), and mechanically robust. In vitro, they are cytocompatible and induce osteogenic differentiation of human mesenchymal stem cells (hMSCs), indicated by alkaline phosphatase, mineralization, and COL1α1 expression. In vivo, bone regeneration was studied using a transgenic fluorescent-reporter mouse non-union calvarial defect model. 3DP-CaPG stimulates cellular ingrowth, retains donor cells, and induces osteogenic differentiation. Histology shows TRAP staining around struts, suggesting potential osteoclast activity. Apparent resorption of 3DP-CaPG was observed and presented no toxicity. 3DP-CaPG represents an advancement towards a synthetic bone regeneration matrix.

60 APPLIED LIFE SCIENCES↗