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At least 595 records · Page 33
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Novel sterol binding domains in bacteria

Sterol lipids are widely present in eukaryotes and play essential roles in signaling and modulating membrane fluidity. Although rare, some bacteria also produce sterols, but their function in bacteria is not known. Moreover, many more species, including pathogens and commensal microbes, acquire or modify sterols from eukaryotic hosts through poorly understood molecular mechanisms. The aerobic methanotroph Methylococcus capsulatus was the first bacterium shown to synthesize sterols, producing a mixture of C-4 methylated sterols that are distinct from those observed in eukaryotes. C-4 methylated sterols are synthesized in the cytosol and localized to the outer membrane, suggesting that a bacterial sterol transport machinery exists. Until now, the identity of such machinery remained a mystery. In this study, we identified three novel proteins that may be the first examples of transporters for bacterial sterol lipids. The proteins, which all belong to well-studied families of bacterial metabolite transporters, are predicted to reside in the inner membrane, periplasm, and outer membrane of M. capsulatus, and may work as a conduit to move modified sterols to the outer membrane. Quantitative analysis of ligand binding revealed their remarkable specificity for 4-methylsterols, and crystallographic structures coupled with docking and molecular dynamics simulations revealed the structural bases for substrate binding by two of the putative transporters. Their striking structural divergence from eukaryotic sterol transporters signals that they form a distinct sterol transport system within the bacterial domain. Finally, bioinformatics revealed the widespread presence of similar transporters in bacterial genomes, including in some pathogens that use host sterol lipids to construct their cell envelopes. The unique folds of these bacterial sterol binding proteins should now guide the discovery of other proteins that handle this essential metabolite.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Air Return Strategies and Airborne SARS-CoV-2

Dedicated ducted air return per zone for heating, ventilating, and air-conditioning (HVAC) systems is sometimes claimed to be a superior technique over plenum return strategy from the viewpoint of exposure reduction to airborne pathogens. While both the return strategies have advantages, there is limited evidence in the literature as to which strategy is superior merely from a standpoint of building vulnerability to airborne contaminants. We performed multizonal airborne contaminant dispersion modelling using CONTAM to simulate the overall building vulnerability to airborne SARS-CoV-2 aerosols when released in an office building and evaluated the two air return strategies. Results showed that for ducted returns, maintaining negative pressure in the release zone coupled with 100% outdoor air supply can greatly reduce overall building vulnerability. However, for a building maintained under a slight positive pressure and a recirculated air percentage as low as 31%, ducted returns do not necessarily outperform plenum returns in terms of overall building vulnerability to airborne pathogens. Building-specific details and factors that are not easily represented with multizone modelling are important, making general preferential statements for either strategy difficult to make. Insights from this study can guide new construction and retrofits of buildings both during and after the COVID-19 pandemic with the aim of safe re-occupancy of buildings while keeping the buildings resilient against potential future epidemics spread by airborne agents.

Shrestha, Prateek↗
DOE OSTI2022

Chapter 8: Agricultural Use

Biochar has potential to reduce the environmental footprint in nearly every aspect of agricultural production. The use of biochar has been proposed to manage agricultural biomass (reference), to process animal manure and poultry litter (reference), to improve the nutritive value of feed (reference), and to mitigate the offsite movement of pesticides (reference) and soil nutrients (reference). The coproducts of biochar production hold similar potential. For example, on farm production of biochar can provide bioenergy to heat greenhouses and barns and to power farm equipment (reference). Pyroligneous acid, a coproduct of pyrolysis, has the ability to control fungal pathogens and deter pathogenic insects (reference). Although these environmental benefits are potentially substantial, their on-farm use has not been widely studied. Furthermore, the on-farm installation of biochar production facilities presents challenges that reduce the feasibility of co-production scenarios (Phillips 2018). As such, this section primarily addresses the application of biochar to agricultural soils.

agriculture↗
DOE OSTI2022

Lake Arrowhead Microbial Genomics Conference

The Lake Arrowhead Microbial Genomics Conference (formerly the E. coli and Small Genomes Conference, and the Microbial Genomes Conference) was held September 11-15, 2022, at the UCLA Conference Center at Lake Arrowhead, California. This conference is part of a yearly meeting initiated in 1991 to bring together genome sequencers, bioinformatics specialists, biologists, and geneticists, to forge interactions that would result in meaningful functional genomics. The goal of the meeting was to translate the influx of new genome sequencing information into useful biological studies. The Lake Arrowhead 2022 meeting had a major focus on microbial communities, the human microbiome, pathogens, phage therapy, bioinformatic methods of analysis, bioenergenics, and environmental microbiology. The field of genomics has reached the point where deriving the sequence of an organism’s entire genome is now seen as a beginning rather than an endpoint. Moreover, understanding the sequences of whole communities, and particularly those that make up different microbiomes, is now a central point of the field. The 2022 meeting covered microorganisms for which extensive analyses exist, and those for which new biological and technical strategies are being developed. The focus on biodiversity, the human microbiome, pathogenic organisms and methods of countering them, and bioenergetics added special significance to this meeting. This meeting was designed to have a mix of 36 invited presentations and poster sessions with more than 80 posters, and had 147 participants. This meeting has become established as a major annual microbial genomics conference during the last 29 years and has assured status and quality. It offers a major opportunity for young investigators and students to attend, present posters, and give talks. In fact, 50% of the invited speakers were early career stage scientists. An important impact of the conference was the forging of new collaborations between scientists and particularly young scientists with the array of multidisciplinary researchers at the meeting.

Miller, Jeffrey H.↗
DOE OSTI2025

Exploring phage–host interactions in Burkholderia cepacia complex bacterium to reveal host factors and phage resistance genes using CRISPRi functional genomics and transcriptomics

Complex interactions of bacteriophages with their bacterial hosts determine phage host range and infectivity. While phage defense systems and host factors have been identified in model bacteria, they remain challenging to predict in non-model bacteria. In this paper, we integrate functional genomics and transcriptomics to investigate phage–host interactions, revealing active phage resistance and host factor genes in Burkholderia cenocepacia K56-2. Burkholderia cepacia complex species are commonly found in soil and are opportunistic pathogens in immunocompromised patients. We studied infection of B. cenocepacia K56-2 with Bcep176, a temperate phage isolated from Burkholderia multivorans. A genome-wide dCas9 knockdown library targeting B. cenocepacia K56-2 was constructed, and a pooled infection experiment identified 63 novel genes or operons coding for candidate host factors or phage resistance genes. The activities of a subset of candidate host factor and resistance genes were validated via single-gene knockdowns. Transcriptomics of B. cenocepacia K56-2 during Bcep176 infection revealed that expression of genes coding for host factor and resistance candidates identified in this screen was significantly altered during infection by 4 h post-infection. Identifying which bacterial genes are involved in phage infection is important to understand the ecological niches of B. cenocepacia and its phages, and for designing phage therapies.

Bacterial Pathogenesis↗
DOE OSTI2026

An improved dataset for predicting mammal infecting viruses from genetic sequence information

There have been several attempts to develop machine learning (ML) models to identify human infecting viruses from their genomic sequences, with varying degrees of success. Direct comparison between models is problematic, because these models are typically trained and evaluated on different datasets with alternative data splitting schemes, features, and model performance metrics. In this paper we present a standardized dataset of mammal infecting and non-infecting viral pathogens, refined from the previous work of Mollentze et al. to include the latest literature evidence, roughly doubling the number of curated host-virus records available to the community, and new host target labels, primate and mammal. The new host labels were included for several reasons, including previous reports that classification performance is better at broader taxonomic ranks and the idea that there may be more data for primate infection that might serve as a suitable proxy for zoonotic potential and avoidance of false positives for human infection due to absence of evidence. On this dataset, we report the performance of eight machine learning models for predicting mammal-infecting viruses from their genomic sequences. We find that randomly assigning cases in our improved dataset to training/testing sets, when compared to the original assignments into training/testing in Mollentze et al., increases the overall average ROC AUC of prediction of human infection from 0.663 ± 0.070 to 0.784 ± 0.013, consistent with the reduction in phylogenetic distance between train and test sets (relative entropy change from 3.00 to 0.08). The broadest host category of mammal infection can be predicted most reliably at 0.850 ± 0.020. We share our improved dataset and code to enable standardized comparisons of machine learning methods to predict human host infections. Overall, we have presented preliminary evidence that classification of virus host infection is more tractable at higher taxonomic ranks, that unsurprisingly reducing the phylogenetic distance between training and test sets can improve predictive performance, that peptide kmer features appear to be harmful to out of sample model performance, and we are left with the question of whether models for virus host prediction can reasonably be expected to perform well in out of sample scenarios given the likelihood that viruses do not share a common ancestor. Consistent with this concern, when the data is resampled such that there is no overlap between viral families in training and test sets (relative entropy > 24), models perform no better than random chance at prediction of human infection regardless of whether kmers are included (ROC AUC 0.50 ± 0.08) or not (ROC AUC 0.50 ± 0.04).

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Visualizing and analyzing 3D biomolecular structures using Mol* at RCSB.org: Influenza A H5N1 virus proteome case study

The easiest and often most useful way to work with experimentally determined or computationally predicted structures of biomolecules is by viewing their three-dimensional (3D) shapes using a molecular visualization tool. Mol* was collaboratively developed by RCSB Protein Data Bank (RCSB PDB, RCSB.org) and Protein Data Bank in Europe (PDBe, PDBe.org) as an open-source, web-based, 3D visualization software suite for examination and analyses of biostructures. It is capable of displaying atomic coordinates and related experimental data of biomolecular structures together with a variety of annotations, facilitating basic and applied research, training, education, and information dissemination. Across RCSB.org, the RCSB PDB research-focused web portal, Mol* has been implemented to support single-mouse-click atomic-level visualization of biomolecules (e.g., proteins, nucleic acids, carbohydrates) with bound cofactors, small-molecule ligands, ions, water molecules, or other macromolecules. RCSB.org Mol* can seamlessly display 3D structures from various sources, allowing structure interrogation, superimposition, and comparison. Using influenza A H5N1 virus as a topical case study of an important pathogen, we exemplify how Mol* has been embedded within various RCSB.org tools—allowing users to view polymer sequence and structure-based annotations integrated from trusted bioinformatics data resources, assess patterns and trends in groups of structures, and view structures of any size and compositional complexity. In addition to being linked to every experimentally determined biostructure and Computed Structure Model made available at RCSB.org, Standalone Mol* is freely available for visualizing any atomic-level or multi-scale biostructure at rcsb.org/3d-view.

3D biostructure↗
DOE OSTI2022

Bayesian time-varying occupancy model for West Nile virus in Ontario, Canada

Occupancy models determine the true presence or absence of a species by adjusting for imperfect detection in surveys. They often assume that species presences can be detected only if sites are occupied during a sampling season. We extended these models to estimate occupancy rates that vary throughout a sampling season as well as account for spatial dependence among sites. For these methods, we constructed a fast Gibbs sampler with the Pólya-Gamma augmentation strategy to conduct inference on covariate effects. We applied these methods to evaluate how environmental conditions and surveillance practices are associated with the presence of West Nile virus in mosquito traps across Ontario, Canada from 2002 to 2017. We found that urban land cover and warm temperatures drove viral occupancy, whereas viral testing on pools with higher proportions of Culex mosquitoes was more likely to result in a positive test for West Nile virus. Models with time-varying occupancy effects achieved much lower Watanabe-Akaike information criteria than models without such effects. Our final model had strong predictive performance on test data that included some of the most extreme seasons, demonstrating the promise of these methods in the study of pathogens spread by mosquito vectors.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Phyllosticta paracitricarpa is synonymous with the EU quarantine fungus P. citricarpa based on phylogenomic analyses

Phyllosticta citricarpa is an important citrus-pathogen and a quarantine organism in the European Union. Its recently described relative, P. paracitricarpa, is very closely related and not listed as a quarantine organism. P. paracitricarpa is very difficult to distinguish from P. citricarpa, since its morphological features overlap and the barcoding gene sequences that were originally used to delimit them as distinct species have a low number of species-specific polymorphisms that have subsequently been shown to overlap between the two clades. Therefore, we performed extensive genomic analyses to determine whether the genetic variation between P. citricarpa and P. paracitricarpa strains should be considered to represent infraspecific variation within P. citricarpa, or whether it is indicative of distinct species. Using a phylogenomic analysis with 3,000 single copy ortholog genes and whole-genome comparisons, we determined that the variation between P. citricarpa and P. paracitricarpa can be considered as infraspecies variation within P. citricarpa. We also determined the level of variation in mitochondrial assemblies of several Phyllosticta species and concluded there are only minimal differences between the assemblies of P. citricarpa and P. paracitricarpa. Thus, using several orthogonal approaches, we here demonstrate that variation within the nuclear and mitochondrial genomes of other Phyllosticta species is larger than variation between genomes obtained from P. citricarpa and P. paracitricarpa strains. Thus, P. citricarpa and P. paracitricarpa should be considered as conspecific.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

A human cell type similar to murine central nervous system perivascular fibroblasts

Highlights: • Human diploid cell lines were established from tumor and non-tumor brain tissue. • Human cells share a common transcriptomic profile with murine perivascular fibroblasts. • Human cells resemble commercially available cell of presumed pericyte origin. The brain vasculature has several specific features, one of them being the blood-brain barrier (BBB), which supports and protects the brain by allowing for the passage of oxygen and nutrients, while at the same time preventing passage of pathogens and toxins. The BBB also prevents efficient delivery of drugs to the brain, e.g. for treatment of brain tumors. In the murine brain, perivascular fibroblasts were recently identified as a novel potential constituent of the BBB. Here we present the existence of human cells that could be the equivalent to the murine brain perivascular fibroblasts. Using RNA sequencing, we show a similar transcriptomic profile of cultured human brain cells and murine perivascular fibroblasts. These data open up a window for new hypotheses on cell types involved in human CNS diseases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

CHI3L1 promotes Staphylococcus aureus-induced osteomyelitis by activating p38/MAPK and Smad signaling pathways

Staphylococcus aureus (S. aureus) is the most common causative bacterial pathogen involved in promoting infection-induced osteomyelitis, a disease resulting in severe bone degradation. In this study, we aimed to identify the mechanism behind inhibition of osteoclast survival and differentiation by CHI3L1, a lectin previously reported to regulate S. aureus-induced osteomyelitis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Scavenger receptor MARCO contributes to macrophage phagocytosis and clearance of tumor cells

Highlights: • The MARCO receptor on macrophages was positively correlated with the ability to phagocyte tumor cells. • Macrophage MARCO affects cytoskeleton rearrangement and pseudopodia formation through the SYK-PI3K-Rac1 pathway. • Integrin is the ligand of MARCO on the tumor cells. Macrophage receptor with collagenous structure (MARCO) is a member of the class A scavenger receptor family which is expressed on the cell surface of macrophages. It is well known that MARCO avidly binds to unopsonized pathogens, leading to its ingestion by macrophages. However, the role of MARCO in the recognition and phagocytosis of tumor cells by macrophages remains poorly understood. In this study, we used lentiviral technology to knockdown and overexpress MARCO and investigated the ability of macrophages to phagocytose tumor cells. Our results showed that MARCO expression was correlated with the ability of macrophages to carry on phagocytosis. MARCO knockdown led to significant decreases in the number of engulfment pseudopodia of macrophages and inhibition of the phagocytosis of tumor cells. On the other hand, MARCO overexpression elevated activity of SYK, PI3K and Rac1 in macrophages, which led to changes in macrophage morphology and enhanced phagocytosis by promoting formation of stress fibers and pseudopodia. By Co-IP analysis we showed that MARCO directly binds to the β5 integrin of SL4 tumor cells. In summary, these results demonstrated the important role for MARCO in demonstrated tumor cells uptake and clearance by macrophages.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Antimicrobial Peptides Can Facilitate Whole Blood Safety from Bacteria: A Proof of Concept

With continuous improvements to blood donor deferrals and the availability of sensitive tests for donation screening for infectious agents, bacterial contamination of whole blood (WB) and blood components stored for transfusion is a rare event. Nonetheless, it still occurs and remains a transfusion-associated risk in terms of septic transfusion reactions (STRs) and transfusion-transmitted bacterial infections with morbidity and mortality outcomes. One of the risk mitigation strategies for bacterial contamination is to implement treatment with currently available proactive pathogen reduction technologies (PRTs) for these transfusion products. Here, as a proof of concept, we tested two recently developed unique cationic antimicrobial peptides (AMPs; D-CONGA and D-CONGA-Q7) for WB safety from bacterial contamination. In this study, WB was inoculated with Escherichia coli and Staphylococcus epidermidis and treated with the two peptides to evaluate their bactericidal efficacy. The results demonstrated that D-CONGA and D-CONGA-Q7 exhibit potent inhibitory activity against the bacteria with a minimal inhibitory concentration (MIC) range of 4–8 and 1–8 μM, respectively, depending on the bacterial species tested. Time-kill kinetics further confirmed that the peptides exhibit bactericidal efficacy at 8 μM by achieving a 5-log 10 reduction (99.999%) of the bacterial load in WB with a time-dependent killing profile. Furthermore, even at 20 μM, the AMPs did not negatively impact hemolysis or hemostatic properties. We have further demonstrated using a cationic exchange resin that the cationic AMPs can be separated and removed from WB after the peptide treatments. During 35-day WB storage at 2–8 °C, 4 μM D-CONGA-Q7 one-time treatment prevented S. epidermidis growth and preserved WB quality and integrity. Overall, the results described here provide the first proof of concept that certain AMPs, such as D-CONGA and D-CONGA-Q7, can facilitate WB safety from bacteria during storage.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Origins of glycan selectivity in streptococcal Siglec-like adhesins suggest mechanisms of receptor adaptation

Bacterial binding to host receptors underlies both commensalism and pathogenesis. Many streptococci adhere to protein-attached carbohydrates expressed on cell surfaces using Siglec-like binding regions (SLBRs). The precise glycan repertoire recognized may dictate whether the organism is a strict commensal versus a pathogen. However, it is currently not clear what drives receptor selectivity. Here, we use five representative SLBRs and identify regions of the receptor binding site that are hypervariable in sequence and structure. We show that these regions control the identity of the preferred carbohydrate ligand using chimeragenesis and single amino acid substitutions. We further evaluate how the identity of the preferred ligand affects the interaction with glycoprotein receptors in human saliva and plasma samples. As point mutations can change the preferred human receptor, these studies suggest how streptococci may adapt to changes in the environmental glycan repertoire.

59 BASIC BIOLOGICAL SCIENCES↗
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 OSTI2024

Hormonal steroids induce multidrug resistance and stress response genes in Neisseria gonorrhoeae by binding to MtrR

Abstract Transcriptional regulator MtrR inhibits the expression of the multidrug efflux pump operon mtrCDE in the pathogenic bacterium Neisseria gonorrhoeae . Here, we show that MtrR binds the hormonal steroids progesterone, β-estradiol, and testosterone, which are present at urogenital infection sites, as well as ethinyl estrogen, a component of some hormonal contraceptives. Steroid binding leads to the decreased affinity of MtrR for cognate DNA, increased mtrCDE expression, and enhanced antimicrobial resistance. Furthermore, we solve crystal structures of MtrR bound to each steroid, thus revealing their binding mechanisms and the conformational changes that induce MtrR.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Armillaria root rot fungi host single-stranded RNA viruses

Species of Armillaria are distributed globally and include some of the most important pathogens of forest and ornamental trees. Some of them form large long-living clones that are considered as one of the largest organisms on earth and are capable of long-range spore-mediated transfer as well as vegetative spread by drought-resistant hyphal cords called rhizomorphs. However, the virus community infecting these species has remained unknown. In this study we used dsRNA screening and high-throughput sequencing to search for possible virus infections in a collection of Armillaria isolates representing three different species: Armillaria mellea from South Africa, A. borealis from Finland and Russia (Siberia) and A. cepistipes from Finland. Our analysis revealed the presence of both negative-sense RNA viruses and positive-sense RNA viruses, while no dsRNA viruses were detected. The viruses included putative new members of virus families Mymonaviridae, Botourmiaviridae and Virgaviridae and members of a recently discovered virus group tentatively named “ambiviruses” with ambisense bicistronic genomic organization. We demonstrated that Armillaria isolates can be cured of viruses by thermal treatment, which enables the examination of virus effects on host growth and phenotype using isogenic virus-infected and virus-free strains.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Sneezing and asymptomatic virus transmission

The novel coronavirus disease (COVID-19) spread pattern continues to show that geographical barriers alone cannot contain a virus. Asymptomatic carriers play a critical role in the nature of this virus quickly escalating into a global pandemic. Asymptomatic carriers may transmit the virus unintentionally through sporadic sneezing. A novel Computational Fluid Dynamics (CFD) approach has been proposed with a realistic modeling of a human sneeze achieved by the combination of state-of-the-art experimental and numerical methods. This modeling approach may be suitable for future engineering analyses aimed at reshaping public spaces and common areas, with the main objective to accurately predict the spread of aerosol and droplets that may contain pathogens. This study shows that the biomechanics of a human sneeze, including complex muscle contractions and relaxations, can be accurately modeled by the angular head motion and the dynamic pressure response during sneezing. These have been considered as the human factors and were implemented in the CFD simulation by imposing a momentum source term to the coupled Eulerian–Lagrangian momentum equations. The momentum source was modeled by the measured dynamic pressure response in conjunction with the angular head motion. This approach eliminated the need to create an ad hoc set of inlet boundary conditions. With this proposed technique, it is easier to add multiple fixed and/or moving sources of sneezes in complex computational domains. Additionally, extensive sensitivity analyses based on different environmental conditions were performed, and their impact was described in terms of potential virus spread.

42 ENGINEERING↗