Search NASA⌕ Search

SEARCH · Search NASA

Results for “Infectious diseases”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 127 records · Page 7
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

AI-based language models powering drug discovery and development

The discovery and development of new medicines is expensive, time-consuming, and often inefficient, with many failures along the way. Powered by artificial intelligence (AI), language models (LMs) have changed the landscape of natural language processing (NLP), offering possibilities to transform treatment development more effectively. Here, we summarize advances in AI-powered LMs and their potential to aid drug discovery and development. We highlight opportunities for AI-powered LMs in target identification, clinical design, regulatory decision-making, and pharmacovigilance. We specifically emphasize the potential role of AI-powered LMs for developing new treatments for Coronavirus 2019 (COVID-19) strategies, including drug repurposing, which can be extrapolated to other infectious diseases that have the potential to cause pandemics. Finally, we set out the remaining challenges and propose possible solutions for improvement.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Different chemical scaffolds bind to L-phe site in Mycobacterium tuberculosis Phe-tRNA synthetase

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mt), is one of the deadliest infectious diseases. The rise of multidrug-resistant strains represents a major public health threat, requiring new therapeutic options. Bacterial aminoacyl-tRNA synthetases (aaRS) have been shown to be highly promising drug targets, including for TB treatment. These enzymes play an essential role in translating the DNA gene code into protein sequence by attaching specific amino acid to their cognate tRNAs. They have multiple binding sites that can be targeted for inhibitor discovery: amino acid binding pocket, ATP binding pocket, tRNA binding site and an editing domain. Recently we reported several high-resolution structures of M. tuberculosis phenylalanyl-tRNA synthetase (MtPheRS) complexed with tRNA Phe and either L-Phe or a nonhydrolyzable phenylalanine adenylate analog. Here, in this study, using Nucleic Magnetic Resonance (NMR) and Surface Plasmon Resonance (SPR) we identified fragments that bind to MtPheRS and we determined crystal structures of their complexes with MtPheRS/tRNA Phe . All the binders interact with the L-Phe amino acid binding site. The analysis of interactions of the new compounds combined with adenylate analog structure provides insights for the rational design of antituberculosis drugs. The 3 ' arm of the tRNA Phe in all the structures was disordered with exception of one complex with D-735 compound. In this structure the 3' CCA end of the acceptor stem is observed in the editing domain of MtPheRS providing insights regarding the post-transfer editing activity of class II aaRS.

Gade, Priyanka [Univ. of Chicago, IL (United State↗
DOE OSTI2022

Enabling machine learning-ready HPC ensembles with Merlin

With the growing complexity of computational and experimental facilities, many scientific researchers are turning to machine learning (ML) techniques to analyze large scale ensemble data. With complexities such as multi-component workflows, heterogeneous machine architectures, parallel file systems, and batch scheduling, care must be taken to facilitate this analysis in a high performance computing (HPC) environment. Here, we present Merlin, a workflow framework to enable large ML-friendly ensembles of scientific HPC simulations. By augmenting traditional HPC with distributed compute technologies, Merlin aims to lower the barrier for scientific subject matter experts to incorporate ML into their analysis. As a producer–consumer workflow model, Merlin enables multi-machine, cross-batch job, dynamically allocated yet persistent workflows capable of utilizing surge-compute resources. Key features of Merlin are a flexible HPC-centric interface, low per-task overhead, multi-tiered fault recovery, and a hierarchical sampling algorithm that allows for $\mathscr{O}$(N) task execution and $\mathscr{O}$(N ln N) task queuing to ensembles of millions of tasks. In addition to Merlin’s design, we test the algorithm’s performance in an HPC center and demonstrate the ability to enqueue 40 million simulations in 100 s, with a 30 millisecond per-task overhead that is independent of ensemble size. Finally, we describe some example applications that Merlin has enabled on leadership-class HPC resources, such as the ML-augmented optimization of nuclear fusion experiments and the calibration of infectious disease models to study the progression of and possible mitigation strategies for COVID-19.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2024

Lignin - A green material for antibacterial application — A review

Lignin's antibacterial properties have become increasingly relevant due to the rise of microbial infectious diseases and antibiotic resistance. Lignin is capable of interacting electrostatically with bacteria and contains polyphenols that cause damage to their cell walls. These features make lignin a desirable material to exhibit antibacterial behavior. Therefore, lignin in antibacterial applications offers a novel approach to address the growing need for sustainable and effective antibacterial materials. Recent research has explored the incorporation of lignin in various biomedical applications, such as wound dressings, implants, and drug delivery systems, highlighting their potential as a sustainable alternative to synthetic antibacterial agents. Furthermore, the development of lignin-based nanomaterials with enhanced antimicrobial activity is an active area of research that holds great promise for the future. Here, in this review, we have provided a summary of how lignin can be incorporated into different forms, such as composite and non-composite synthesis of antibacterial agents and their performances. The challenges and future considerations are also discussed in this review article.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Structural basis of heme scavenging by the ChtA and HtaA hemophores in Corynebacterium diphtheriae

Corynebacterium diphtheriae causes diphtheria, a potentially fatal infectious disease that damages tissues in the upper respiratory tract. In order to proliferate, this pathogen acquires the essential nutrient iron from heme (iron-protoporphyrin IX) primarily found in human hemoglobin (Hb). C. diphtheriae secretes ChtA and HtaA hemophore proteins that bind ferric heme (hemin) via conserved region (CR) domains. Here, we demonstrate that their CR domains scavenge hemin after it is spontaneously released from Hb, and define the structural basis of hemin binding to ChtA and the N-terminal CR domain from HtaA by determining X-ray crystal structures of their protein-hemin complexes. Resonance Raman and electron paramagnetic resonance experiments demonstrate that the CR domains from ChtA and HtaA engage in pentacoordinate hemin binding through a conserved iron-tyrosyl linkage, though variations in their hemin pockets alter the way they stabilize the axial tyrosine and mask hemin’s metal. The importance of these interactions is probed using isothermal titration calorimetry experiments, which represent the first quantitative assessment of CR-hemin affinity and reveal that ChtA binds hemin via an enthalpically driven process. Hemin partitioning experiments using native mass spectrometry demonstrate that the cohort of CR domains within C. diphtheriae ’s hemin-uptake system have dissociation constants for hemin between 0.8 and 22 nM, raising the possibility that affinity differences contribute to the directional flow of hemin into the cell. Collectively, the results of this work provide insight into how C. diphtheriae and other pathogenic and commensal corynebacterium species utilize CR domains to scavenge iron rich hemin from their environment.

Corynebacterium diphtheriae↗
DOE OSTI2022

Structure-Based Prototyping of Allosteric Inhibitors of Human Uridine/Cytidine Kinase 2 (UCK2)

Pyrimidine nucleotide biosynthesis in humans is a promising chemotherapeutic target for infectious diseases caused by RNA viruses. Because mammalian cells derive pyrimidine ribonucleotides through a combination of de novo biosynthesis and salvage, combined inhibition of dihydroorotate dehydrogenase (DHODH; the first committed step in de novo pyrimidine nucleotide biosynthesis) and uridine/cytidine kinase 2 (UCK2; the first step in salvage of exogenous nucleosides) strongly attenuates viral replication in infected cells. However, while several pharmacologically promising inhibitors of human DHODH are known, to date there are no reports of medicinally viable leads against UCK2. Here we use structure-based drug prototyping to identify two classes of promising leads that non-competitively inhibit UCK2 activity. In the process we have identified a hitherto unknown allosteric site at the inter-subunit interface of this homotetrameric enzyme. By reducing the kcat of human UCK2 without altering its KM, these new inhibitors have the potential to enable systematic dialing of the fractional inhibition of pyrimidine salvage to achieve the desired antiviral effect with minimal host toxicity.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Zirconium-Based Metal–Organic Frameworks as Reusable Antibacterial Peroxide Carriers for Protective Textiles

Countries around the world have sought efficient protective coverings, including masks, gowns, and fabrics, for air purification to protect people against infectious diseases. However, the demand for significant quantities of disposable protective textiles poses a global challenge, especially when the production of protective gear is suspended due to COVID-19 outbreaks in factories and along supply lines. Therefore, the development of reusable, self-decontaminating protective masks and coverings loaded with disinfectants, such as antibacterial peroxide species, presents an attractive strategy to fight against bacteria risks. In this work, we incorporated persulfate ions, which serve as stable active peroxide precursors, into two porous zirconium-based metal–organic frameworks (Zr-MOFs), enabling these materials to act as regenerable reservoirs for the slow release of biocidal hydrogen peroxide upon hydrolysis by contact with humid air. Single-crystal X-ray diffraction studies reveal the two different coordination motifs for the persulfate ions, which can either bridge between two adjacent nodes or coordinate to a single node depending on both the node connectivity and the distances between open metal sites. The active peroxide precursors within the porous Zr-MOF carriers are stable during storage and easily regenerated once consumed. Importantly, these persulfate-loaded Zr-MOFs can be integrated onto textiles using a facile aqueous in-situ growth procedure, and these composites demonstrate potent and reusable biocidal activity against both Gram-negative bacteria and Gram-positive bacteria. Altogether, this approach presents a viable strategy to develop robust protective textiles capable of rapidly deactivating pathogens.

36 MATERIALS SCIENCE↗
DOE OSTI2024

Targeting Mycobacterium tuberculosis Persistence through Inhibition of the Trehalose Catalytic Shift

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the leading cause of death worldwide by infectious disease. Treatment of Mtb infection requires a six-month course of multiple antibiotics, an extremely challenging regimen necessitated by Mtb’s ability to form drug-tolerant persister cells. Mtb persister formation is dependent on the trehalose catalytic shift, a stress-responsive metabolic remodeling mechanism in which the disaccharide trehalose is liberated from cell surface glycolipids and repurposed as an internal carbon source to meet energy and redox demands. Here, using a biofilm-persister model, metabolomics, and cryo-electron microscopy (EM), we found that azidodeoxy- and aminodeoxy-d-trehalose analogues block the Mtb trehalose catalytic shift through inhibition of trehalose synthase TreS (Rv0126), which catalyzes the isomerization of trehalose to maltose. Out of a focused eight-member compound panel constructed by chemoenzymatic synthesis, the natural product 2-trehalosamine exhibited the highest potency and significantly potentiated first- and second-line TB drugs in broth culture and macrophage infection assays. We also report the first structure of TreS bound to a substrate analogue inhibitor, obtained via cryo-EM, which revealed conformational changes likely essential for catalysis and inhibitor binding that can potentially be exploited for future therapeutic development. Our results demonstrate that inhibition of the trehalose catalytic shift is a viable strategy to target Mtb persisters and advance trehalose analogues as tools and potential adjunctive therapeutics for investigating and targeting mycobacterial persistence.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Standardized Residue Numbering and Secondary Structure Nomenclature in the Class D β-Lactamases

Over 1370 class D β-lactamases are currently known, and they pose a serious threat to the effective treatment of many infectious diseases, particularly in some pathogenic bacteria where evolving carbapenemase activity has been reported. Detailed understanding of their molecular biology, enzymology, and structural biology are critically important, but the lack of a standardized residue numbering scheme and inconsistent secondary structure annotation has made comparative analyses sometimes difficult and cumbersome. Compounding this, in the post-AlphaFold world where we currently find ourselves, an extraordinary wealth of detailed structural information on these enzymes is literally at our fingertips; therefore it is vitally important that a standard numbering system is in place to facilitate the accurate and straightforward analysis of their structures. In conclusion, here we present a residue numbering and secondary structure scheme for the class D enzymes based on the sequence and structure of OXA-48 and apply it to test targets to demonstrate the ease with which it can be used.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Developing Scenario‐Based Strategies for Health, Climate, and Environmental Preparedness: The One Health, One Earth Approach

Climate change amplifies many threats to human health. Despite advances in understanding climate change dynamics and impacts, there remains a critical gap in translating scientific knowledge into equitable, and community-driven health interventions. The inaugural One Earth, One Health workshop sought to explore this gap through human-centered design exercises involving interdisciplinary researchers from climate and Earth sciences, engineering, epidemiology, microbiology, and environmental health. Although participants did not co-develop solutions with affected communities, they used stakeholder role-playing to guide ideation and lay groundwork for actionable plans. Through these methods, participants identified community needs and proposed prototype solutions to alleviate health threats exacerbated by global environmental change. Prototypes were organized around infectious diseases, extreme weather, and air quality, as illustrative themes rather than an exhaustive set of risks. Key solutions included strategies for anticipatory systems and early warning (e.g., integrating environmental signals with health data), inclusive communication and infrastructure needs for responding to extreme weather events, and integrated platforms visualizing air quality trends to support tailored, context-aware guidance beyond one-size-fits-all alerts. The workshop highlighted opportunities such as leveraging machine learning, Earth observation, and real-time surveillance to protect communities, but also noted barriers including data quality, technological redundancy, privacy, and governance challenges. Additionally, participants emphasized the need for interdisciplinary teams capable of collaborating across sectors, breaking down silos and addressing gaps in training and education. Overall, the workshop illustrates how process-driven, human-centered approaches can help surface user needs and generate testable prototype concepts, while underscoring the importance of direct community partnership for implementation.

Abadi, Azar M. [University of Alabama, Birmingham,↗
DOE OSTI2021

Multivalency transforms SARS-CoV-2 antibodies into ultrapotent neutralizers

SARS-CoV-2, the virus responsible for COVID-19, has caused a global pandemic. Antibodies can be powerful biotherapeutics to fight viral infections. Here, we use the human apoferritin protomer as a modular subunit to drive oligomerization of antibody fragments and transform antibodies targeting SARS-CoV-2 into exceptionally potent neutralizers. Using this platform, half-maximal inhibitory concentration (IC 50 ) values as low as 9 × 10 - 14 M are achieved as a result of up to 10,000-fold potency enhancements compared to corresponding IgGs. Combination of three different antibody specificities and the fragment crystallizable (Fc) domain on a single multivalent molecule conferred the ability to overcome viral sequence variability together with outstanding potency and IgG-like bioavailability. The MULTi-specific, multi-Affinity antiBODY (Multabody or MB) platform thus uniquely leverages binding avidity together with multi-specificity to deliver ultrapotent and broad neutralizers against SARS-CoV-2. The modularity of the platform also makes it relevant for rapid evaluation against other infectious diseases of global health importance. Neutralizing antibodies are a promising therapeutic for SARS-CoV-2.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Structural analysis of mycobacterial homoserine transacetylases central to methionine biosynthesis reveals druggable active site

Mycobacterium tuberculosis is the cause of the world’s most deadly infectious disease. Efforts are underway to target the methionine biosynthesis pathway, as it is not part of the host metabolism. The homoserine transacetylase MetX converts L-homoserine to O-acetyl-L-homoserine at the committed step of this pathway. In order to facilitate structure-based drug design, we determined the high-resolution crystal structures of three MetX proteins, including M. tuberculosis (MtMetX), Mycolicibacterium abscessus (MaMetX), and Mycolicibacterium hassiacum (MhMetX). A comparison of homoserine transacetylases from other bacterial and fungal species reveals a high degree of structural conservation amongst the enzymes. Utilizing homologous structures with bound cofactors, we analyzed the potential ligandability of MetX. The deep active-site tunnel surrounding the catalytic serine yielded many consensus clusters during mapping, suggesting that MtMetX is highly druggable.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2021

A multi-scale pipeline linking drug transcriptomics with pharmacokinetics predicts in vivo interactions of tuberculosis drugs

Tuberculosis (TB) is the deadliest infectious disease worldwide. The design of new treatments for TB is hindered by the large number of candidate drugs, drug combinations, dosing choices, and complex pharmaco-kinetics/dynamics (PK/PD). Here we study the interplay of these factors in designing combination therapies by linking a machine-learning model, INDIGO-MTB, which predicts in vitro drug interactions using drug transcriptomics, with a multi-scale model of drug PK/PD and pathogen-immune interactions called GranSim. We calculate an in vivo drug interaction score (iDIS) from dynamics of drug diffusion, spatial distribution, and activity within lesions against various pathogen sub-populations. The iDIS of drug regimens evaluated against non-replicating bacteria significantly correlates with efficacy metrics from clinical trials. Our approach identifies mechanisms that can amplify synergistic or mitigate antagonistic drug interactions in vivo by modulating the relative distribution of drugs. Our mechanistic framework enables efficient evaluation of in vivo drug interactions and optimization of combination therapies.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

405 nm light microbicidal efficacy on Treponema pallidum spiked in ex vivo human platelets

Abstract Pathogen reduction technologies using chemicals and or UV light have been demonstrated to improve the safety of ex vivo platelets from infectious diseases. However, UV light exposure also may affect the treated products, depending on wavelength and exposure. Alternatively, visible spectra 405 nm violet-blue light has broad-spectrum microbicidal activity. Here we tested the effect of 405 nm light onTreponema pallidum, the bacterium that causes syphilis. We contaminated platelets stored in plasma with two treponemal concentrations (low and high titers) and treated an aliquot with 270 J/cm 2 dose (irradiance = 15 mW/cm 2 ) of 405 nm light while another aliquot remained untreated. Next, we inoculated intradermally an aliquot of both samples into rabbits. Rabbits inoculated with untreated samples developed syphilis while animals inoculated with light-treated samples did not. Thus, inactivation was demonstrated to the limit of detection of the bioassay. We estimated > 2 log 10 and > 4 log 10 reduction in the low and high dose studies, respectively. These results provide proof-of-concept that 405 nm light is effective in reducing syphilis risk in ex vivo platelets.

Science & Technology - Other Topics↗
DOE OSTI2021

Direct numerical simulation of turbulent dispersion of evaporative aerosol clouds produced by an intense expiratory event

Airborne particles are a major route for transmission of COVID-19 and many other infectious diseases. When a person talks, sings, coughs, or sneezes, nasal and throat secretions are spewed into the air. After a short initial fragmentation stage, the expelled material is mostly composed of spherical particles of different sizes. While the dynamics of the largest droplets are dominated by gravitational effects, the smaller aerosol particles, mostly transported by means of hydrodynamic drag, form clouds that can remain afloat for long times. In subsaturated air environments, the dependence of pathogen-laden particle dispersion on their size is complicated due to evaporation of the aqueous fraction. Particle dynamics can significantly change when ambient conditions favor rapid evaporation rates that result in a transition from buoyancyto-drag dominated dispersion regimes. To investigate the effect of particle size and evaporation on pathogen-laden cloud evolution, a direct numerical simulation of a mild cough was coupled with an evaporative Lagrangian particle advection model. The results suggest that while the dispersion of cough particles in the tails of the size distribution are unlikely to be disrupted by evaporative effects, preferential aerosol diameters (30-40 μm) may exhibit significant increases in the residence time and horizontal range under typical ambient conditions. Using estimations of the viral concentration in the spewed fluid and the number of ejected particles in a typical respiratory event, we obtained a map of viral load per volume of air at the end of the cough and the number of virus copies per inhalation in the emitter vicinity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

The antibiotic sorangicin A inhibits promoter DNA unwinding in a Mycobacterium tuberculosis rifampicin-resistant RNA polymerase

Rifampicin (Rif) is a first-line therapeutic used to treat the infectious disease tuberculosis (TB), which is caused by the pathogen Mycobacterium tuberculosis (Mtb). The emergence of Rif-resistant (Rif R ) Mtb presents a need for new antibiotics. Rif targets the enzyme RNA polymerase (RNAP). Sorangicin A (Sor) is an unrelated inhibitor that binds in the Rif-binding pocket of RNAP. Sor inhibits a subset of Rif R RNAPs, including the most prevalent clinical Rif R RNAP substitution found in Mtb infected patients (S456>L of the β subunit). In this paper, we present structural and biochemical data demonstrating that Sor inhibits the wild-type Mtb RNAP by a similar mechanism as Rif: by preventing the translocation of very short RNAs. By contrast, Sor inhibits the RifR S456L enzyme at an earlier step, preventing the transition of a partially unwound promoter DNA intermediate to the fully opened DNA and blocking the template-strand DNA from reaching the active site in the RNAP catalytic center. By defining template-strand blocking as a mechanism for inhibition, we provide a mechanistic drug target in RNAP. Our finding that Sor inhibits the wild-type and mutant RNAPs through different mechanisms prompts future considerations for designing antibiotics against resistant targets. Also, we show that Sor has a better pharmacokinetic profile than Rif, making it a suitable starting molecule to design drugs to be used for the treatment of TB patients with comorbidities who require multiple medications.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Effects of ionising radiation exposure in offspring and next generations: dosimetric aspects and uncertainties

The impact of the exposure to ionizing radiation in the offspring and next generation has been investigated in the last decades and currently is the subject of study of the ICRP Task Group 121. Studying the effects of radiation exposure in pre-conceptional and post-conceptional phases can be a challenge since potential effects to the fetus vary depending on the stage of fetal development. Epidemiology and radiobiology studies are the two sources of information one can use to correlate the radiation dose to the human body and tissues and the resulting effects. For a proper evaluation of the outcomes of such studies, and a correct appraisal of the exposure/dose-effect relationship, (i) reliable dosimetry, (ii) accurate reporting, and (iii) reproducibility of results are required. Although variables related to dose, including for instance source of radiation, geometry of irradiation, dose rate etc., are usually known, especially in radiobiology studies, often important details of the irradiation are not reported. In conclusion, based on standards developed by the National Cancer Institute (NCI), the National Institute of Allergy and Infectious Disease (NIAID) and the National Institute of Standards and Technology (NIST), a review of the scientific studies used by the UNSCEAR to estimate the risk of hereditary effects, and by the ICRP in its current recommendations, was conducted to evaluate the way dosimetry was reported. Dosimetry and the related uncertainties were not adequately described in the vast majority of those studies. This does not necessarily mean that they do not provide relevant information, however it prevents from a thorough verification and reproduction of their findings. In order to guarantee the reliability and robustness of the process of revision of the estimates of risk and detriment it is therefore considered mandatory to include a careful check of the new relevant literature with regard to the criteria on the completeness and reproducibility of the dosimetric information.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗
DOE OSTI2021

A Case Study on Pathogen Transport, Deposition, Evaporation and Transmission: Linking High-Fidelity Computational Fluid Dynamics Simulations to Probability of Infection

A high-fidelity, low-Mach computational fluid dynamics simulation tool that includes evaporating droplets and variable-density turbulent flow coupling is well-suited to ascertain transmission probability and supports risk mitigation methods development for airborne infectious diseases such as COVID-19. A multi-physics large-eddy simulation-based paradigm is used to explore droplet and aerosol pathogen transport from a synthetic cough emanating from a kneeling humanoid. For an outdoor configuration that mimics the recent open-space social distance strategy of San Francisco, maximum primary droplet deposition distances are shown to approach 8.1 m in a moderate wind configuration with the aerosol plume transported in excess of 15 m. In quiescent conditions, the aerosol plume extends to approximately 4 m before the emanating pulsed jet becomes neutrally buoyant. A dose–response model, which is based on previous SARS coronavirus (SARS-CoV) data, is exercised on the high-fidelity aerosol transport database to establish relative risk at eighteen virtual receptor probe locations.

59 BASIC BIOLOGICAL SCIENCES↗