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At least 1,495 records · Page 83
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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 OSTI2014

Coupling Genetic and Chemical Microbiome Profiling Reveals Heterogeneity of Archaeome and Bacteriome in Subsurface Biofilms That Are Dominated by the Same Archaeal Species

Earth harbors an enormous portion of subsurface microbial life, whose microbiome flux across geographical locations remains mainly unexplored due to difficult access to samples. Here, we investigated the microbiome relatedness of subsurface biofilms of two sulfidic springs in southeast Germany that have similar physical and chemical parameters and are fed by one deep groundwater current. Due to their unique hydrogeological setting these springs provide accessible windows to subsurface biofilms dominated by the same uncultivated archaeal species, called SM1 Euryarchaeon. Comparative analysis of infrared imaging spectra demonstrated great variations in archaeal membrane composition between biofilms of the two springs, suggesting different SM1 euryarchaeal strains of the same species at both aquifer outlets. This strain variation was supported by ultrastructural and metagenomic analyses of the archaeal biofilms, which included intergenic spacer region sequencing of the rRNA gene operon. At 16S rRNA gene level, PhyloChip G3 DNA microarray detected similar biofilm communities for archaea, but site-specific communities for bacteria. Both biofilms showed an enrichment of different deltaproteobacterial operational taxonomic units, whose families were, however, congruent as were their lipid spectra. Consequently, the function of the major proportion of the bacteriome appeared to be conserved across the geographic locations studied, which was confirmed by dsrB-directed quantitative PCR. Consequently, microbiome differences of these subsurface biofilms exist at subtle nuances for archaea (strain level variation) and at higher taxonomic levels for predominant bacteria without a substantial perturbation in bacteriome function. The results of this communication provide deep insight into the dynamics of subsurface microbial life and warrant its future investigation with regard to metabolic and genomic analyses.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2015

Genetic Interaction of Aspergillus nidulans galR, xlnR and araR in Regulating D-Galactose and L-Arabinose Release and Catabolism Gene Expression

In Aspergillus nidulans, the xylanolytic regulator XlnR and the arabinanolytic regulator AraR co-regulate pentose catabolism. In nature, the pentose sugars D-xylose and L-arabinose are both main building blocks of the polysaccharide arabinoxylan. In pectin and arabinogalactan, these two monosaccharides are found in combination with D-galactose. GalR, the regulator that responds to the presence of D-galactose, regulates the D-galactose catabolic pathway. In this study we investigated the possible interaction between XlnR, AraR and GalR in pentose and/or D-galactose catabolism in A. nidulans. Growth phenotypes and metabolic gene expression profiles were studied in single, double and triple disruptant A. nidulans strains of the genes encoding these paralogous transcription factors. Our results demonstrate that AraR and XlnR not only control pentose catabolic pathway genes, but also genes of the oxido-reductive D-galactose catabolic pathway. This suggests an interaction between three transcriptional regulators in D-galactose catabolism. Conversely, GalR is not involved in regulation of pentose catabolism, but controls only genes of the oxidoreductive D-galactose catabolic pathway.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

A Genetic Screen for Mutations Affecting Cell Division in the Arabidopsis thaliana Embryo Identifies Seven Loci Required for Cytokinesis

Cytokinesis in plants involves the formation of unique cellular structures such as the phragmoplast and the cell plate, both of which are required to divide the cell after nuclear division. In order to isolate genes that are involved in de novo cell wall formation, we performed a large-scale, microscope-based screen for Arabidopsis mutants that severely impair cytokinesis in the embryo. We recovered 35 mutations that form abnormally enlarged cells with multiple, often polyploid nuclei and incomplete cell walls. These mutants represent seven genes, four of which have previously been implicated in phragmoplast or cell plate function. Mutations in two loci show strongly reduced transmission through the haploid gametophytic generation. Molecular cloning of both corresponding genes reveals that one is represented by hypomorphic alleles of the kinesin-5 gene RADIALLY SWOLLEN 7 (homologous to tobacco kinesin-related protein TKRP125), and that the other gene corresponds to the Arabidopsis FUSED ortholog TWO-IN-ONE (originally identified based on its function in pollen development). No mutations that completely abolish the formation of cross walls in diploid cells were found. Lastly, our results support the idea that cytokinesis in the diploid and haploid generations involve similar mechanisms.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Characterization of genetic variability of Venezuelan equine encephalitis viruses

Venezuelan equine encephalitis virus (VEEV) is a mosquito-borne alphavirus that has caused large outbreaks of severe illness in both horses and humans. New approaches are needed to rapidly infer the origin of a newly discovered VEEV strain, estimate its equine amplification and resultant epidemic potential, and predict human virulence phenotype. We performed whole genome single nucleotide polymorphism (SNP) analysis of all available VEE antigenic complex genomes, verified that a SNP-based phylogeny accurately captured the features of a phylogenetic tree based on multiple sequence alignment, and developed a high resolution genome-wide SNP microarray. We used the microarray to analyze a broad panel of VEEV isolates, found excellent concordance between array- and sequence-based SNP calls, genotyped unsequenced isolates, and placed them on a phylogeny with sequenced genomes. The microarray successfully genotyped VEEV directly from tissue samples of an infected mouse, bypassing the need for viral isolation, culture and genomic sequencing. Lastly, we identified genomic variants associated with serotypes and host species, revealing a complex relationship between genotype and phenotype.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2017

Draft genome sequence of Actinotignum schaalii DSM 15541 T : Genetic insights into the lifestyle, cell fitness and virulence

The permanent draft genome sequence of Actinotignum schaalii DSM 15541 T is presented. The annotated genome includes 2,130,987 bp, with 1777 protein-coding and 58 rRNA-coding genes. Genome sequence analysis revealed absence of genes encoding for: components of the PTS systems, enzymes of the TCA cycle, glyoxylate shunt and gluconeogensis. Genomic data revealed that A. schaalii is able to oxidize carbohydrates via glycolysis, the nonoxidative pentose phosphate and the Entner-Doudoroff pathways. Besides, the genome harbors genes encoding for enzymes involved in the conversion of pyruvate to lactate, acetate and ethanol, which are found to be the end products of carbohydrate fermentation. The genome contained the gene encoding Type I fatty acid synthase required for de novo FAS biosynthesis. The plsY and plsX genes encoding the acyltransferases necessary for phosphatidic acid biosynthesis were absent from the genome. The genome harbors genes encoding enzymes responsible for isoprene biosynthesis via the mevalonate (MVA) pathway. Genes encoding enzymes that confer resistance to reactive oxygen species (ROS) were identified. In addition, A. schaalii harbors genes that protect the genome against viral infections. These include restriction-modification (RM) systems, type II toxin-antitoxin (TA), CRISPR-Cas and abortive infection system. A. schaalii genome also encodes several virulence factors that contribute to adhesion and internalization of this pathogen such as the tad genes encoding proteins required for pili assembly, the nanI gene encoding exo-alpha-sialidase, genes encoding heat shock proteins and genes encoding type VII secretion system. These features are consistent with anaerobic and pathogenic lifestyles. Finally, resistance to ciprofloxacin occurs by mutation in chromosomal genes that encode the subunits of DNA-gyrase (GyrA) and topisomerase IV (ParC) enzymes, while resistant to metronidazole was due to the frxA gene, which encodes NADPH-flavin oxidoreductase.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Laboratory strains of Bacillus anthracis exhibit pervasive alteration in expression of proteins related to sporulation under laboratory conditions relative to genetically related wild strains

The spore forming pathogen Bacillus anthracis is the etiologic agent of anthrax in humans and animals. It cycles through infected hosts as vegetative cells and is eventually introduced into the environment where it generates an endospore resistant to many harsh conditions. The endospores are subsequently taken up by another host to begin the next cycle. Outbreaks of anthrax occur regularly worldwide in wildlife and livestock, and the potential for human infection exists whenever humans encounter infected animals. It is also possible to encounter intentional releases of anthrax spores, as was the case in October 2001. Consequently, it is important to be able to rapidly establish the provenance of infectious strains of B. anthracis . Here, we compare protein expression in seven low-passage wild isolates and four laboratory strains of B. anthracis grown under identical conditions using LC-MS/MS proteomic analysis. Of the 1,023 total identified proteins, 96 had significant abundance differences between wild and laboratory strains. Of those, 28 proteins directly related to sporulation were upregulated in wild isolates, with expression driven by Spo0A, CodY, and AbrB/ScoC. In addition, we observed evidence of changes in cell division and fatty acid biosynthesis between the two classes of strains, despite being grown under identical experimental conditions. These results suggest wild B. anthracis cells are more highly tuned to sporulate than their laboratory cousins, and this difference should be exploited as a method to differentiate between laboratory and low passage wild strains isolated during an anthrax outbreak. This knowledge should distinguish between intentional releases and exposure to strains in nature, providing a basis for the type of response by public health officials and investigators.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2012

Molecular Basis for Genetic Resistance of Anopheles gambiae to Plasmodium : Structural Analysis of TEP1 Susceptible and Resistant Alleles

Thioester-containing protein 1 (TEP1) is a central component in the innate immune response of Anopheles gambiae to Plasmodium infection. Two classes of TEP1 alleles, TEP1*S and TEP1*R, are found in both laboratory strains and wild isolates, related by a greater or lesser susceptibility, respectively to both P. berghei and P. falciparum infection. We report the crystal structure of the full-length TEP1*S1 allele which, while similar to the previously determined structure of full-length TEP1*R1, displays flexibility in the N-terminal fragment comprising domains MG1-MG6. Amino acid differences between TEP1*R1 and TEP1*S1 are localized to the TED-MG8 domain interface that protects the thioester bond from hydrolysis and structural changes are apparent at this interface. As a consequence cleaved TEP1*S1 (TEP1*S1 cut ) is significantly more susceptible to hydrolysis of its intramolecular thioester bond than TEP1*R1 cut . TEP1*S1 cut is stabilized in solution by the heterodimeric LRIM1/APL1C complex, which preserves the thioester bond within TEP1*S1 cut . These results suggest a mechanism by which selective pressure on the TEP1 gene results in functional variation that may influence the vector competence of A. gambiae towards Plasmodium infection.

59 BASIC BIOLOGICAL SCIENCES↗