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666 records · Page 37
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

What Clinical Trials Can Teach Us About the Development of More Resilient AI for Cybersecurity

Policy-mandated, rigorously administered scientific testing is needed to provide transparency into the efficacy of artificial intelligence-–based (AI-based) cyber defense tools for consumers and to prioritize future research and development. In this work, we propose a model that is informed by our experience, urged forward by massive-scale cyberattacks, and inspired by parallel developments in the biomedical field and the unprecedentedly fast development of new vaccines to combat global pathogens.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2021

Learning from the Pandemic: the Future of Meetings in HEP and Beyond

The COVID-19 pandemic has by-and-large prevented in-person meetings since March 2020. While the increasing deployment of effective vaccines around the world is a very positive development, the timeline and pathway to "normality" is uncertain and the "new normal" we will settle into is anyone's guess. Particle physics, like many other scientific fields, has more than a year of experience in holding virtual meetings, workshops, and conferences. A great deal of experimentation and innovation to explore how to execute these meetings effectively has occurred. Therefore, it is an appropriate time to take stock of what we as a community learned from running virtual meetings and discuss possible strategies for the future. Continuing to develop effective strategies for meetings with a virtual component is likely to be important for reducing the carbon footprint of our research activities, while also enabling greater diversity and inclusion for participation. This report summarizes a virtual two-day workshop on Virtual Meetings held May 5-6, 2021 which brought together experts from both inside and outside of high-energy physics to share their experiences and practices with organizing and executing virtual workshops, and to develop possible strategies for future meetings as we begin to emerge from the COVID-19 pandemic. This report outlines some of the practices and tools that have worked well which we hope will serve as a valuable resource for future virtual meeting organizers in all scientific fields.

Neubauer, Mark S.↗
DOE OSTI2021

Cyberbiosecurity and Public Health in the Age of COVID-19

Cyberbiosecurity, the aspect of biosecurity involving the digital representation of biological data, had already been emerging as a matter of public concern even prior to the onset of the COVID-19 pandemic. Key issues of concern include, among others, the privacy of patient data, the security of public health databases, the integrity of diagnostic test data, the integrity of public biological databases, the security implications of automated laboratory systems and the security of proprietary biological engineering advances. With the onset of the COVID-19 pandemic, and the importance of digital resources in combatting it, concern about the potential for cyber attacks by state-based or non-state actors has been elevated. To illuminate the challenges, we focus on the cyber vulnerabilities that need to be addressed in public health activities such as disease surveillance and outbreak management. In particular, we examine cyber issues raised by the accelerated pace of development for COVID mitigations, treatments, and vaccines.

cybersecurity, biosecurity↗
DOE OSTI2022

Antiviral Strategies Against SARS-CoV-2: A Systems Biology Approach

The unprecedented scientific achievements in combating the COVID-19 pandemic reflect a global response informed by unprecedented access to data. We now have the ability to rapidly generate a diversity of information on an emerging pathogen and, by using high-performance computing and a systems biology approach, we can mine this wealth of information to understand the complexities of viral pathogenesis and contagion like never before. These efforts will aid in the development of vaccines, antiviral medications, and inform policymakers and clinicians. Here we detail computational protocols developed as SARS-CoV-2 began to spread across the globe. They include pathogen detection, comparative structural proteomics, evolutionary adaptation analysis via network and artificial intelligence methodologies, and multiomic integration. These protocols constitute a core framework on which to build a systems-level infrastructure that can be quickly brought to bear on future pathogens before they evolve into pandemic proportions.

Teixeira Prates, Erica↗
DOE OSTI2022

Chimeric OspA genes, proteins and methods of use thereof

The invention relates to the development of chimeric OspA molecules for use in a new Lyme vaccine. More specifically, the chimeric OspA molecules comprise the proximal portion from one OspA serotype, together with the distal portion from another OspA serotype, while retaining antigenic properties of both of the parent polypeptides. The chimeric OspA molecules are delivered alone or in combination to provide protection against a variety of Borrelia genospecies. The invention also provides methods for administering the chimeric OspA molecules to a subject in the prevention and treatment of Lyme disease or borreliosis.

Crowe, Brian A.↗
DOE OSTI2023

Biomineralization

The hierarchically structured biominerals with excellent functions are produced by the regulation of organisms via biomineralization. The organic matrix and molecules regulate the inorganic mineralization to fabricate the delicate structural materials with the optimized properties. Inspired by natural biomineralization process, may biomimetic tactics have been developed for applications for materials and biomedicines, such as collagen re-mineralization, tooth and bone repairs. Biomineralization always highlights the control of inorganic materials by using organisms; reversely, the mineralized materials can also regulate or improve the living organisms. By conferring materials on to organism, the rationally designed organism-material hybrids can be created artificially, which are featured by their improved or new functions such as cell protection, bioenergy production, vaccine modification and cell treatment. Such a combination follows a materials-based biological modification, which would contribute a more comprehensive view of biomineralization as well as a new window for biological inorganic chemistry.

Biomineralization↗
DOE OSTI2023

A structural blueprint for interleukin-21 signal modulation

Interleukin-21 (IL-21) plays a critical role in generating immunological memory by promoting the germinal center reaction, yet clinical use of IL-21 remains challenging because of its pleiotropy and association with autoimmune disease. To better understand the structural basis of IL-21 signaling, we determine the structure of the IL-21-IL-21R-γc ternary signaling complex by X-ray crystallography and a structure of a dimer of trimeric complexes using cryo-electron microscopy. Guided by the structure, we design analogs of IL-21 by introducing substitutions to the IL-21-γc interface. These IL-21 analogs act as partial agonists that modulate downstream activation of pS6, pSTAT3, and pSTAT1. These analogs exhibit differential activity on T and B cell subsets and modulate antibody production in human tonsil organoids. These results clarify the structural basis of IL-21 signaling and offer a potential strategy for tunable manipulation of humoral immunity.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Structures of drug-specific monoclonal antibodies bound to opioids and nicotine reveal a common mode of binding

Opioid-related fatal overdoses have reached epidemic proportions. Because existing treatments for opioid use disorders offer limited long-term protection, accelerating the development of newer approaches is critical. Monoclonal antibodies (mAbs) are an emerging treatment strategy that targets and sequesters selected opioids in the bloodstream, reducing drug distribution across the blood-brain barrier, thus preventing or reversing opioid toxicity. We previously identified a series of murine mAbs with high affinity and selectivity for oxycodone, morphine, fentanyl, and nicotine. To determine their binding mechanism, we used X-ray crystallography to solve the structures of mAbs bound to their respective targets, to 2.2 Å resolution or higher. Structural analysis showed a critical convergent hydrogen bonding mode that is dependent on a glutamic acid residue in the mAbs’ heavy chain and a tertiary amine of the ligand. Further, characterizing drug-mAb complexes represents a significant step toward rational antibody engineering and future manufacturing activities to support clinical evaluation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

The COVID-19 High-Performance Computing Consortium

In March of 2020, recognizing the potential of High Performance Computing (HPC) to accelerate understanding and the pace of scientific discovery in the fight to stop COVID-19, the HPC community assembled the largest collection of worldwide HPC resources to enable COVID-19 researchers worldwide to advance their critical efforts. Amazingly, the COVID-19 HPC Consortium was formed within one week through the joint effort of the Office of Science and Technology Policy (OSTP), the U.S. Department of Energy (DOE), the National Science Foundation (NSF), and IBM to create a unique public–private partnership between government, industry, and academic leaders. This article is the Consortium's story–how the Consortium was created, its founding members, what it provides, how it works, and its accomplishments. We will reflect on the lessons learned from the creation and operation of the Consortium and describe how the features of the Consortium could be sustained as a National Strategic Computing Reserve to ensure the nation is prepared for future crises.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2021

Neutralizing Antibodies Induced by First-Generation gp41-Stabilized HIV-1 Envelope Trimers and Nanoparticles

Self-assembling protein nanoparticles (NPs) presenting BG505 envelope (Env) trimers can elicit tier 2 HIV-1-neutralizing antibody (NAb) responses more effectively than soluble trimers. In the present study, monoclonal NAbs were isolated from previously immunized mice and rabbits for structural and functional analyses, which revealed that potent mouse NAbs recognize the C3/V4 region and small NP-elicited rabbit NAbs primarily target known glycan holes on BG505 Env.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

A Germline-Targeting Chimpanzee SIV Envelope Glycoprotein Elicits a New Class of V2-Apex Directed Cross-Neutralizing Antibodies

HIV-1 and its SIV precursors share a broadly neutralizing antibody (bNAb) epitope in variable loop 2 (V2) at the envelope glycoprotein (Env) trimer apex. Here, we tested the immunogenicity of germ line-targeting versions of a chimpanzee SIV (SIVcpz) Env in human V2-apex bNAb heavy-chain precursor-expressing knock-in mice and as chimeric simian-chimpanzee immunodeficiency viruses (SCIVs) in rhesus macaques (RMs). Trimer immunization of knock-in mice induced V2-directed NAbs, indicating activation of V2-apex bNAb precursor-expressing mouse B cells. SCIV infection of RMs elicited high-titer viremia, potent autologous tier 2 neutralizing antibodies, and rapid sequence escape in the canonical V2-apex epitope. Six of seven animals also developed low-titer heterologous plasma breadth that mapped to the V2-apex. Antibody cloning from two of these animals identified multiple expanded lineages with long heavy chain third complementarity determining regions that cross-neutralized as many as 7 of 19 primary HIV-1 strains, but with low potency. Negative stain electron microscopy (NSEM) of members of the two most cross-reactive lineages confirmed V2 targeting but identified an angle of approach distinct from prototypical V2-apex bNAbs, with antibody binding either requiring or inducing an occluded-open trimer. Probing with conformation-sensitive, nonneutralizing antibodies revealed that SCIV-expressed, but not wild-type SIVcpz Envs, as well as a subset of primary HIV-1 Envs, preferentially adopted a more open trimeric state. These results reveal the existence of a cryptic V2 epitope that is exposed in occluded-open SIVcpz and HIV-1 Env trimers and elicits cross-neutralizing responses of limited breadth and potency.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Neutralization profiles of HIV-1 viruses from the VRC01 Antibody Mediated Prevention (AMP) trials

The VRC01 Antibody Mediated Prevention (AMP) efficacy trials conducted between 2016 and 2020 showed for the first time that passively administered broadly neutralizing antibodies (bnAbs) could prevent HIV-1 acquisition against bnAb-sensitive viruses. HIV-1 viruses isolated from AMP participants who acquired infection during the study in the sub-Saharan African (HVTN 703/HPTN 081) and the Americas/European (HVTN 704/HPTN 085) trials represent a panel of currently circulating strains of HIV-1 and offer a unique opportunity to investigate the sensitivity of the virus to broadly neutralizing antibodies (bnAbs) being considered for clinical development. Pseudoviruses were constructed using envelope sequences from 218 individuals. The majority of viruses identified were clade B and C; with clades A, D, F and G and recombinants AC and BF detected at lower frequencies. We tested eight bnAbs in clinical development (VRC01, VRC07-523LS, 3BNC117, CAP256.25, PGDM1400, PGT121, 10–1074 and 10E8v4) for neutralization against all AMP placebo viruses (n = 76). Compared to older clade C viruses (1998–2010), the HVTN703/HPTN081 clade C viruses showed increased resistance to VRC07-523LS and CAP256.25. At a concentration of 1μg/ml (IC80), predictive modeling identified the triple combination of V3/V2-glycan/CD4bs-targeting bnAbs (10-1074/PGDM1400/VRC07-523LS) as the best against clade C viruses and a combination of MPER/V3/CD4bs-targeting bnAbs (10E8v4/10-1074/VRC07-523LS) as the best against clade B viruses, due to low coverage of V2-glycan directed bnAbs against clade B viruses. Overall, the AMP placebo viruses represent a valuable resource for defining the sensitivity of contemporaneous circulating viral strains to bnAbs and highlight the need to update reference panels regularly. Our data also suggests that combining bnAbs in passive immunization trials would improve coverage of global viruses.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

“Thought I’d Share First” and Other Conspiracy Theory Tweets from the COVID-19 Infodemic: Exploratory Study

Background: The COVID-19 outbreak has left many people isolated within their homes; these people are turning to social media for news and social connection, which leaves them vulnerable to believing and sharing misinformation. Health-related misinformation threatens adherence to public health messaging, and monitoring its spread on social media is critical to understanding the evolution of ideas that have potentially negative public health impacts. Objective: The aim of this study is to use Twitter data to explore methods to characterize and classify four COVID-19 conspiracy theories and to provide context for each of these conspiracy theories through the first 5 months of the pandemic. Methods: We began with a corpus of COVID-19 tweets (approximately 120 million) spanning late January to early May 2020. We first filtered tweets using regular expressions (n=1.8 million) and used random forest classification models to identify tweets related to four conspiracy theories. Our classified data sets were then used in downstream sentiment analysis and dynamic topic modeling to characterize the linguistic features of COVID-19 conspiracy theories as they evolve over time. Results: Analysis using model-labeled data was beneficial for increasing the proportion of data matching misinformation indicators. Random forest classifier metrics varied across the four conspiracy theories considered (F1 scores between 0.347 and 0.857); this performance increased as the given conspiracy theory was more narrowly defined. We showed that misinformation tweets demonstrate more negative sentiment when compared to non-misinformation tweets and that theories evolve over time, incorporating details from unrelated conspiracy theories as well as real-world events. Conclusions: Although we focus here on health-related misinformation, this combination of approaches is not specific to public health and is valuable for characterizing misinformation in general, which is an important first step in creating targeted messaging to counteract its spread. Initial messaging should aim to preempt generalized misinformation before it becomes widespread, while later messaging will

5g↗
DOE OSTI2024

Simple Scattering: Lipid nanoparticle structural data repository

Lipid nanoparticles (LNPs) are being intensively researched and developed to leverage their ability to safely and effectively deliver therapeutics. To achieve optimal therapeutic delivery, a comprehensive understanding of the relationship between formulation, structure, and efficacy is critical. However, the vast chemical space involved in the production of LNPs and the resulting structural complexity make the structure to function relationship challenging to assess and predict. New components and formulation procedures, which provide new opportunities for the use of LNPs, would be best identified and optimized using high-throughput characterization methods. Recently, a high-throughput workflow, consisting of automated mixing, small-angle X-ray scattering (SAXS), and cellular assays, demonstrated a link between formulation, internal structure, and efficacy for a library of LNPs. As SAXS data can be rapidly collected, the stage is set for the collection of thousands of SAXS profiles from a myriad of LNP formulations. In addition, correlated LNP small-angle neutron scattering (SANS) datasets, where components are systematically deuterated for additional contrast inside, provide complementary structural information. The centralization of SAXS and SANS datasets from LNPs, with appropriate, standardized metadata describing formulation parameters, into a data repository will provide valuable guidance for the formulation of LNPs with desired properties. To this end, we introduce Simple Scattering, an easy-to-use, open data repository for storing and sharing groups of correlated scattering profiles obtained from LNP screening experiments. Here, we discuss the current state of the repository, including limitations and upcoming changes, and our vision towards future usage in developing our collective knowledge base of LNPs.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1995

Immune responses in humans after 60 days of confinement

A confinement experiment in a normobaric diving chamber was undertaken to better understand the effect of confinement and isolation on human psychology and physiology. Pre- and postconfinement blood samples were obtained from four test subjects and control donors to analyze immune responses. No modification in the levels of CD2+, CD3+, CD4+, CD8+, CD19+, and CD56+ cells was observed after confinement. Mitogen-induced T-lymphocyte proliferation and interleukin-2 receptor expression were not altered significantly. Whole blood interferon-alpha and gamma-induction and plasma cortisol levels were also unchanged, as was natural killer cell activity. These data suggest that in humans, no specific components of the immune response are affected by a 2-month isolation and confinement of a small group.

NASA Discipline Number 18-10↗