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At least 1,261 records · Page 70
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Watson-Crick Base-Pairing Requirements for ssDNA Recognition and Processing in Replication-Initiating HUH Endonucleases

Replication-initiating HUH endonucleases (Reps) are sequence-specific nucleases that cleave and rejoin single-stranded DNA (ssDNA) during rolling-circle replication. These functions are mediated by covalent linkage of the Rep to its substrate post cleavage. Here, we describe the structures of the endonuclease domain from the Muscovy duck circovirus Rep in complex with its cognate ssDNA 10-mer with and without manganese in the active site. Structural and functional analyses demonstrate that divalent cations play both catalytic and structural roles in Reps by polarizing and positioning their substrate. Further structural comparisons highlight the importance of an intramolecular substrate Watson-Crick (WC) base pairing between the -4 and +1 positions. Subsequent kinetic and functional analyses demonstrate a functional dependency on WC base pairing between these positions regardless of the pair’s identity (i.e., A·T, T·A, G·C, or C·G), highlighting a structural specificity for substrate interaction. Finally, considering how well WC swaps were tolerated in vitro, we sought to determine to what extent the canonical -4T·+1A pairing is conserved in circular Rep-encoding single-stranded DNA viruses and found evidence of noncanonical pairings in a minority of these genomes. Altogether, our data suggest that substrate intramolecular WC base pairing is a universal requirement for separation and reunion of ssDNA in Reps.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Structural basis for varying drug resistance of SARS-CoV-2 M pro E166 variants

ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M pro ) has an essential role in the virus lifecycle and, accordingly, it is a target for antiviral drugs. Multiple studies have identified an M pro mutation (E166V) that confers strong resistance to clinically relevant inhibitors, including nirmatrelvir, but the underlying mechanism is not fully understood. Here, we report on crystal structures of SARS-CoV-2 M pro E166V in complex with nirmatrelvir, ensitrelvir, and bofutrelvir. The structures suggest that resistance is caused in part by the loss of a direct hydrogen bond and also, especially for nirmatrelvir, by a steric clash with the substituted valine residue. In comparison, the binding of bofutrelvir shows greater flexibility, which may help alleviate this steric effect and allow bofutrelvir to fit the mutant active site despite the loss of a direct polar contact. Thermal stability analyses also corroborate E166V most severely affecting the binding of nirmatrelvir and, to lesser and different extents, ensitrelvir and bofutrelvir. We further show that E166I causes even more severe nirmatrelvir resistance, whereas E166A and E166L have much milder effects. These studies shed light on the molecular mechanisms of a key M pro drug resistance mutation and may help inform the design of next-generation inhibitors. IMPORTANCE Using a combination of high-resolution X-ray crystallographic and biochemical analyses, we reveal the molecular mechanisms by which a mutation in the severe acute respiratory syndrome coronavirus 2 main protease (M pro ) confers strong resistance against clinically relevant antiviral drugs that inhibit M pro activity. The results presented here may help inform the design of next-generation inhibitors to combat the problem of therapy resistance.

Microbiology↗
DOE OSTI2022

Structure of the Core Postfusion Porcine Endogenous Retrovirus Fusion Protein

Retroviral elements from endogenous retroviruses have functions in mammalian physiology. The best-known examples are the envelope proteins that function in placenta development and immune suppression. Porcine endogenous retroviruses (PERVs) are an understudied class of endogenous retroviruses that infect cultured human cells, raising concern regarding porcine xenografts. The PERV envelope glycoprotein has also been proposed as a possible swine syncytin with a role in placental development. Despite the growing interest in PERVs, their envelope glycoproteins remain poorly characterized. Here, we successfully determined the postfusion crystal structure of the PERV core fusion ectodomain. The PERV fusion protein structure reveals a conserved class I viral fusion protein six-helix bundle. Biophysical experiments demonstrated that the thermodynamic stability of the PERV fusion protein secondary structure was the same at physiological and acidic pHs. A conserved surface analysis highlights the high degree of sequence conservation among retroviral fusogens in the chain reversal region that facilitates the large-scale conformational change required for membrane fusion. Further structural alignment of class I viral fusogens revealed a phylogenetic clustering that shows evolution into various lineages that correlate with virus mechanisms of cell entry. Our work indicates that structural dendrograms can be used to qualitatively infer insights into the fusion mechanisms of newly discovered class I viral fusogen structures.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

SARS-CoV-2 Infection Severity Is Linked to Superior Humoral Immunity against the Spike

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently causing a global pandemic. The antigen specificity of the antibody response mounted against this novel virus is not understood in detail. Here, we report that subjects with a more severe SARS-CoV-2 infection exhibit a larger antibody response against the spike and nucleocapsid protein and epitope spreading to subdominant viral antigens, such as open reading frame 8 and nonstructural proteins. Subjects with a greater antibody response mounted a larger memory B cell response against the spike, but not the nucleocapsid protein. Additionally, we revealed that antibodies against the spike are still capable of binding the D614G spike mutant and cross-react with the SARS-CoV-1 receptor binding domain. Together, this study reveals that subjects with a more severe SARS-CoV-2 infection exhibit a greater overall antibody response to the spike and nucleocapsid protein and a larger memory B cell response against the spike.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Aerosol biome of a cafeteria and medical facility in Los Alamos, New Mexico, USA

Aerosol sampling with next-generation sequencing was used to characterize microbial communities in a cafeteria and medical facility waiting room in Los Alamos, New Mexico, USA. We detected sequences from human, bacteria, archaea, fungi, other eukaryotes, and viruses, providing insights into the diversity of the aerosol microbiome.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2024

Genomic insights into redox-driven microbial processes for carbon decomposition in thawing Arctic soils and permafrost

Climate change is rapidly transforming Arctic landscapes where increasing soil temperatures speed up permafrost thaw. This exposes large carbon stocks to microbial decomposition, possibly worsening climate change by releasing more greenhouse gases. Understanding how microbes break down soil carbon, especially under the anaerobic conditions of thawing permafrost, is important to determine future changes. Here, we studied the microbial community dynamics and soil carbon decomposition potential in permafrost and active layer soils under anaerobic laboratory conditions that simulated an Arctic summer thaw. The microbial and viral compositions in the samples were analyzed based on metagenomes, metagenome-assembled genomes, and metagenomic viral contigs (mVCs). Following the thawing of permafrost, there was a notable shift in microbial community structure, with fermentative Firmicutes and Bacteroidota taking over from Actinobacteria and Proteobacteria over the 60-day incubation period. The increase in iron and sulfate-reducing microbes had a significant role in limiting methane production from thawed permafrost, underscoring the competition within microbial communities. We explored the growth strategies of microbial communities and found that slow growth was the major strategy in both the active layer and permafrost. Our findings challenge the assumption that fast-growing microbes mainly respond to environmental changes like permafrost thaw. Instead, they indicate a common strategy of slow growth among microbial communities, likely due to the thermodynamic constraints of soil substrates and electron acceptors, and the need for microbes to adjust to post-thaw conditions. The mVCs harbored a wide range of auxiliary metabolic genes that may support cell protection from ice formation in virus-infected cells.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2022

Defining the HIV Capsid Binding Site of Nucleoporin 153

The human immunodeficiency virus (HIV) can infect nondividing cells by interacting with the host nuclear pore complex. The host nuclear pore protein NUP153 directly interacts with the HIV capsid to promote viral nuclear entry.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Exploring life’s hidden majority: microbial dark matter symposium highlights

The Microbial Dark Matter Symposium held on August 28–29, 2025, in Laguna Beach, Orange County, CA, convened a multidisciplinary group of scientists to address the vast unknowns in microbial life—from uncultured taxa and uncharacterized proteins to elusive viruses and spacefaring microbes. Set against a scenic coastal backdrop, the symposium highlighted advances in single-cell genomics, proximity ligation sequencing, and artificial intelligence-ready bioinformatics, while also probing the limits of microbial persistence, metabolism, and ecological distribution. Sessions explored microbial dark matter from multiple dimensions: cultivability, where new strategies are enabling recovery of elusive microbes; functional ambiguity, where metagenomic dark zones are illuminated by computational annotation; and genomic representation, where single-cell methods bridge gaps left by shotgun community sequencing. Researchers shared breakthroughs in identifying atmospheric microbiomes, “dark oxygen” production in groundwater ecosystems, and microbial survival on the International Space Station. The symposium emphasized integration of methods, disciplines, and ecosystems, advancing a collective push to illuminate the microbial dark matter on Earth and beyond. By highlighting emerging tools, pressing questions, and cross-domain insights, the symposium underscored the need for collaborative, open, and adaptive approaches to study the microbial unknown. The meeting marks a pivotal moment in microbiology, where cultivating knowledge of the uncultivated promises transformative understanding of life, everywhere.

Podar, Mircea [ORNL] (ORCID:0000000327760205)↗
DOE OSTI2020

Discovering the Molecular Determinants of Phaeobacter inhibens Susceptibility to Phaeobacter Phage MD18

Bacteriophages are useful nonantibiotic therapeutics for bacterial infections as well as threats to industries utilizing bacterial agents. This study identified Phaeobacter virus MD18 , a phage antagonist of Phaeobacter inhibens , a bacterium with promising use as a probiotic for aquatic farming industries. Genomic analysis suggested that Phaeobacter phage MD18 has evolved to enhance its replication in P. inhibens by adopting favorable tRNA genes as well as through genomic sequence adaptation to resemble host codon usage. Lastly, a high-throughput analysis of P. inhibens transposon insertion mutants identified genes that modulate host susceptibility to phage MD18 and implicated the type IV pilus as the likely receptor recognized for adsorption. This study marks the first characterization of the relationship between P. inhibens and an environmentally sampled phage, which informs our understanding of natural threats to the bacterium and may promote the development of novel phage technologies for genetic manipulation of this host.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Ecological Assembly Processes Are Coordinated between Bacterial and Viral Communities in Fractured Shale Ecosystems

The ecological drivers that concurrently act upon both a virus and its host and that drive community assembly are poorly understood despite known interactions between viral populations and their microbial hosts. Hydraulically fractured shale environments provide access to a closed ecosystem in the deep subsurface where constrained microbial and viral community assembly processes can be examined. Here, we used metagenomic analyses of time-resolved-produced fluid samples from two wells in the Appalachian Basin to track viral and host dynamics and to investigate community assembly processes. Hypersaline conditions within these ecosystems should drive microbial community structure to a similar configuration through time in response to common osmotic stress. However, viral predation appears to counterbalance this potentially strong homogeneous selection and pushes the microbial community toward undominated assembly. In comparison, while the viral community was also influenced by substantial undominated processes, it assembled, in part, due to homogeneous selection. When the overall assembly processes acting upon both these communities were directly compared with each other, a significant relationship was revealed, suggesting an association between microbial and viral community development despite differing selective pressures. These results reveal a potentially important balance of ecological dynamics that must be in maintained within this deep subsurface ecosystem in order for the microbial community to persist over extended time periods. More broadly, this relationship begins to provide knowledge underlying metacommunity development across trophic levels.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2020

Coordinating and Assisting Research at the SARS-CoV-2/Microbiome Nexus

Although the COVID-19 pandemic is caused by a single virus, the rest of the human microbiome appears to be involved in the disease and could influence vaccine responses while offering opportunities for microbiome-directed therapeutics. The newly formed Microbiome Centers Consortium (MCC) surveyed its membership and identified four ways to leverage the strengths and experience of microbiome centers in the response to the COVID-19 pandemic. To meet these needs, the MCC will provide a platform to coordinate clinical and environmental research, assist with practical obstacles, and help communicate the connections between the microbiome and COVID-19. We ask that microbiome researchers join us in these efforts to address the ongoing pandemic.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Integration of SARS-CoV-2 testing and genomic sequencing into influenza sentinel surveillance in Uganda, January to December 2022

The Uganda Virus Research Institute, National Influenza Center laboratory integrated SARS-CoV-2 polymerase chain reaction testing and genomic sequencing into the influenza surveillance program that was established in 2007. A total of 7,698 nasopharyngeal/oropharyngeal (NP/OP) swab samples were collected and analyzed from ILI/SARI sentinel sites across the country from January to December 2022. All samples were tested for influenza and SARS-CoV-2. Of these, 252 (3.3%), 162 (2.1%), and 589 (7.7%) were positive for influenza A, influenza B, and SARS-CoV-2, respectively. Out of 414 influenza-positive samples, 122 (29.5%) were AH1pdm09, 130 (31.4%) were AH3, and 162 (39.1%) were B-Victoria. All SARS-CoV-2 sequenced samples were of the Omicron variant, with subvariants of concern known to evade the immune system being detected, such as BQ.1 and XBB.2. Other SARS-CoV-2 positive samples collected from other health centers in the community outside the surveillance sites were included into SARS-CoV-2 genomic sequencing with similar patterns with respect to variants. In all, the ILI/SARI surveillance system has shown to be an efficient, cost-effective, and sustainable program, providing a ready platform to monitor the circulation of SARS-CoV-2 in communities at the national level while remaining vigilant for the persistent threat of influenza. The integration of SARS-CoV-2 detection and genomic surveillance into the influenza surveillance program will strengthen the laboratory response capacity, as well as facilitate the timely release of SARS-CoV-2 genomic information to be used to complement the multiple response strategies for COVID-19 pandemic mitigation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Structural and functional analyses of SARS-CoV-2 Nsp3 and its specific interactions with the 5’ UTR of the viral genome

ABSTRACT Non-structural protein 3 (Nsp3) is the largest open reading frame encoded in the SARS-CoV-2 genome, essential for the formation of double-membrane vesicles (DMV) wherein viral RNA replication occurs. We conducted an extensive structure-function analysis of Nsp3 and determined the crystal structures of the ubiquitin-like 1 (Ubl1), nucleic acid binding (NAB), β-coronavirus-specific marker (βSM) domains, and a sub-region of the Y domain of this protein. We show that the Ubl1, ADP-ribose phosphatase (ADRP), human SARS Unique (HSUD), NAB, and Y domains of Nsp3 bind the 5’ UTR of the viral genome and that the Ubl1 and Y domains possess affinity for recognition of this region, suggesting high specificity. The Ubl1-Nucleocapsid (N) protein complex binds the 5’ UTR with greater affinity than the individual proteins alone. Our results suggest that multiple domains of Nsp3, particularly Ubl1 and Y, shepherd the 5’ UTR of the viral genome during translocation through the DMV membrane, priming the Ubl1 domain to load the genome onto N protein. IMPORTANCE The largest protein encoded by the SARS-CoV-2 genome is Nsp3. In infected cells, this multi-domain protein forms a pore structure in the virus-induced double-membrane vesicles (DMV). We have incomplete data on Nsp3 molecular structure, and here, we describe crystal structures for multiple domains of Nsp3. It is thought that newly replicated viral RNA transits through the DMV pore; however, we possess incomplete data on which regions of Nsp3 actually interact with RNA. Here, we present data showing that five domains of Nsp3 interact with the 5’ UTR of the SARS-CoV-2 RNA, including the Y domain for which no function has ever been discovered. These data suggest that the pore structure plays an active role in recognizing the terminal end of the genome, transiting and loading the viral RNA onto the cytoplasmic nucleocapsid protein. These data help expand our knowledge of Nsp3 structure and function and the SARS-CoV-2 replication cycle.

Microbiology↗
DOE OSTI2021

Evaluation of a laboratory-developed multiplex real-time PCR assay for diagnosis of syphilis, herpes and chancroid genital ulcers in four public health laboratories in the USA

Objective To evaluate the field performance of a multiplex PCR (M-PCR) assay for detection of herpes simplex virus (HSV)-1 and HSV-2, Treponema pallidum ( T. pallidum ) and Haemophilus ducreyi ( H. ducreyi ) in genital ulcer disease (GUD) specimens. Methods GUD M-PCR was performed on 186 remnant specimens, previously collected for HSV testing, by four public health laboratories (PHLs) and the Laboratory Reference and Research Branch (LRRB) at the Centers for Disease Control and Prevention. The results from the PHLs were compared with those of LRRB, which served as the reference testing method, and percentage agreement was calculated. Results HSV was detected in 31 of 52 (59.6%), 20 of 40 (50%), 43 of 44 (97.7%) and 19 of 50 (38.0%) specimens from PHL1, PHL2, PHL3 and PHL4, respectively. There were seven discrepant results for HSV, and the overall percent agreement between the PHLs and the LRRB was 94%–100%, with a kappa value of 0.922, which demonstrates high agreement. T. pallidum was identified in 7 of 51 (13.7%) specimens from PHL1 with 94.1% agreement and in 2 of 40 (5.0%) specimens from PHL2 with 100% agreement. The LRRB identified three additional T. pallidum -positive specimens from PHL1. The kappa value (0.849) for T. pallidum testing suggests good agreement. Consistent with the LRRB results, no T. pallidum was detected in specimens from PHL3 and PHL4, and H. ducreyi was not detected at any of the study sites. Conclusions The GUD M-PCR assay performed well in four independent PHLs and 12 suspected syphilis cases were identified in this study. The M-PCR assay could provide improved diagnostic options for GUD infections in state and local PHLs.

Infectious Diseases↗
DOE OSTI2023

Nonparametric Inference for the Reproductive Rate in Generalized Compartmental Models

We develop a tractable nonparametric model for the time-varying reproductive rate of infectious diseases that combines the structure of a deterministic compartmental model and a stochastic model for incidence data. We use Bayesian inference to estimate, with uncertainty, the reproductive rate of the Coronavirus 2019 outbreak in the U.S. states of California, Florida, Michigan, New Mexico, New York, and Texas from January 2020 to March 2022. Employing the inferred reproductive rates, we estimate the posterior distribution of the time-varying reproduction numbers for each state. Compering the time-varying reproduction numbers across the states, we identify some epidemic waves, potentially driven from changes in human behavior and virus mutations.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2020

The coronavirus spread: the Italian case

A model based on population growth, chaotic maps and turbulent flows is applied to the spread of Coronavirus for each Italian region in order to obtain useful information and help to contrast it. We divide the regions into different risk categories and discuss anomalies. The worst cases are confined between the Appenine and the Alps mountain ranges but the situation seem to improve closer to the sea. The Veneto region gave the most efficient response so far and some of their resources could be diverted to other regions, in particular more tests to the Lombardia, Liguria, Piemonte, Marche and V. Aosta regions, which seem to be worst affected. We noticed worrying anomalies in the Lazio, Campania and Sicilia regions to be monitored. We stress that the number of fatalities we predicted on March 12 has been confirmed daily by the bulletins. This suggests a change of strategy in order to reduce such number maybe moving the weaker population (and negative to the virus test) to beach resorts, which should be empty presently. The ratio deceased/positives on April 4, 2020 is 5.4% worldwide, 12.3% in Italy, 1.4% in Germany, 2.7% in the USA, 10.3% in the UK and 4.1% in China. Furthermore, these large fluctuations should be investigated starting from the Italian regions, which show similar large fluctuations.

73 NUCLEAR PHYSICS AND RADIATION PHYSICS↗
DOE OSTI2020

Chaos, percolation and the coronavirus spread: a two-step model

We discuss a two-step model for the rise and decay of a new coronavirus (Severe Acute Respiratory Syndrome-CoV-2) first reported in December 2019, COVID-19. The first stage is well described by the same equation for turbulent flows, population growth and chaotic maps: a small number of infected, d 0 , grows exponentially to a saturation value, d ∞ . The typical growth time (aggressive spreading of the virus) is given by τ = 1/λ where λ is the Lyapunov exponent. After a time t crit determined by social distancing and/or other measures, the spread decreases exponentially analogous to nuclear decays and non-chaotic maps. Some countries, like China, S. Korea and Italy, are in this second stage while others including the USA are near the end of the growth stage. The model predicted 15,000 (±2250) casualties for the Lombardy region (Italy) at the end of the spreading around May 10, 2020. Without the quarantine, the casualties would have been more than 50,000, one hundred days after the start of the pandemic. Here, the data from the 50 US states are of very poor quality because of an extremely late and confused response to the pandemic, resulting unfortunately in a large number of casualties, more than 70,000 on May 6, 2020, and more than 170,000 on August 21, 2020. S. Korea, notwithstanding the high population density (511/km 2 ) and the closeness to China, responded best to the pandemic with 255 deceased as of May 6, 2020, and 301 on August 21, 2020.

73 NUCLEAR PHYSICS AND RADIATION PHYSICS↗