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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Tapping the treasure trove of atypical phages

With advancements in genomics technologies, a vast diversity of ‘atypical’ phages, that is, with single-stranded DNA or RNA genomes, are being uncovered from different ecosystems. Though these efforts have revealed the existence and prevalence of these nonmodel phages, computational approaches often fail to associate these phages with their specific bacterial host(s), while the lack of methods to isolate these phages has limited our ability to characterize infectivity pathways and new gene function. In this review, we call for the development of generalizable experimental methods to better capture this understudied viral diversity via isolation and study them through gene-level characterization and engineering. Establishing a diverse set of new ‘atypical’ phage model systems has the potential to provide many new biotechnologies, including potential uses of these atypical phages in halting the spread of antibiotic resistance and engineering of microbial communities for beneficial outcomes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Mechanistic basis of atypical TERT promoter mutations

Non-coding mutations in the TERT promoter (TERTp), typically at one of two bases -124 and -146 bp upstream of the start codon, are among the most prevalent driver mutations in human cancer. Several additional recurrent TERTp mutations have been reported but their functions and origins remain largely unexplained. Here, we show that atypical TERTp mutations arise secondary to canonical TERTp mutations in a two-step process. Canonical TERTp mutations create de novo binding sites for ETS family transcription factors that induce favourable conditions for DNA damage formation by UV light, thus creating a hotspot effect but only after a first mutational hit. In agreement, atypical TERTp mutations co-occur with canonical driver mutations in large cancer cohorts and arise subclonally specifically on the TERTp driver mutant chromosome homolog of melanoma cells treated with UV light in vitro. Our study gives an in-depth view of TERTp mutations in cancer and provides a mechanistic explanation for atypical TERTp mutations.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2007

Information Display System for Atypical Flight Phase

Method and system for displaying information on one or more aircraft flights, where at least one flight is determined to have at least one atypical flight phase according to specified criteria. A flight parameter trace for an atypical phase is displayed and compared graphically with a group of traces, for the corresponding flight phase and corresponding flight parameter, for flights that do not manifest atypicality in that phase.

Statler, Irving C.↗
NASA NTRS2005

Identification of atypical flight patterns

Method and system for analyzing aircraft data, including multiple selected flight parameters for a selected phase of a selected flight, and for determining when the selected phase of the selected flight is atypical, when compared with corresponding data for the same phase for other similar flights. A flight signature is computed using continuous-valued and discrete-valued flight parameters for the selected flight parameters and is optionally compared with a statistical distribution of other observed flight signatures, yielding atypicality scores for the same phase for other similar flights. A cluster analysis is optionally applied to the flight signatures to define an optimal collection of clusters. A level of atypicality for a selected flight is estimated, based upon an index associated with the cluster analysis.

Statler, Irving C.↗
DOE OSTI2022

Interwoven atypical quantum states in CeLiBi 2

Here we report the discovery of CeLiBi 2 , the first example of a material in the tetragonal CeTX 2 ( T = transition metal; X = pnictogen) family wherein an alkali cation replaces the typical transition metal. Magnetic susceptibility and neutron powder diffraction measurements are consistent with a crystal-field Γ 6 ground-state Kramers doublet that orders antiferromagnetically below T N = 3.4 K with an incommensurate propagation wave vector k = ( 0, 0.0724(4), 0.5) that generates a nanometric modulation of the magnetic structure. The best model of the ordered state is an elliptical cycloid with Ce moments primarily residing in the ab plane. This is highly unusual, as all other Γ 6 CeTX 2 members order ferromagnetically. Further, we observe an atypical hard-axis metamagnetic transition at 2 T in magnetostriction, magnetization, and resistivity measurements. CeLiBi 2 is a rare example of a highly conductive material with dominant skew scattering leading to a large anomalous Hall effect. Quantum oscillations with five frequencies arise in magnetostriction and magnetic susceptibility data to T = 30 K and μ 0 H = 55 T, which indicate small Fermi pockets of light carriers with effective masses as low as 0.07 m e . Density functional theory calculations indicate that square-net Dirac-like Bi-p bands are responsible for these ultralight carriers. Together, our results show that CeLiBi 2 enables multiple atypical magnetic and electronic properties in a single clean material.

36 MATERIALS SCIENCE↗
DOE OSTI2022

Atypical Carboxysome Loci: JEEPs or Junk?

Carboxysomes, responsible for a substantial fraction of CO 2 fixation on Earth, are proteinaceous microcompartments found in many autotrophic members of domain Bacteria, primarily from the phyla Proteobacteria and Cyanobacteria. Carboxysomes facilitate CO 2 fixation by the Calvin-Benson-Bassham (CBB) cycle, particularly under conditions where the CO 2 concentration is variable or low, or O 2 is abundant. These microcompartments are composed of an icosahedral shell containing the enzymes ribulose 1,5-carboxylase/oxygenase (RubisCO) and carbonic anhydrase. They function as part of a CO 2 concentrating mechanism, in which cells accumulate HCO 3 - in the cytoplasm via active transport, HCO 3 - enters the carboxysomes through pores in the carboxysomal shell proteins, and carboxysomal carbonic anhydrase facilitates the conversion of HCO 3 - to CO 2 , which RubisCO fixes. Two forms of carboxysomes have been described: α-carboxysomes and β-carboxysomes, which arose independently from ancestral microcompartments. The α-carboxysomes present in Proteobacteria and some Cyanobacteria have shells comprised of four types of proteins [CsoS1 hexamers, CsoS4 pentamers, CsoS2 assembly proteins, and α-carboxysomal carbonic anhydrase (CsoSCA)], and contain form IA RubisCO (CbbL and CbbS). In the majority of cases, these components are encoded in the genome near each other in a gene locus, and transcribed together as an operon. Interestingly, genome sequencing has revealed some α-carboxysome loci that are missing genes encoding one or more of these components. Some loci lack the genes encoding RubisCO, others lack a gene encoding carbonic anhydrase, some loci are missing shell protein genes, and in some organisms, genes homologous to those encoding the carboxysome-associated carbonic anhydrase are the only carboxysome-related genes present in the genome. Given that RubisCO, assembly factors, carbonic anhydrase, and shell proteins are all essential for carboxysome function, these absences are quite intriguing. In this review, we provide an overview of the most recent studies of the structural components of carboxysomes, describe the genomic context and taxonomic distribution of atypical carboxysome loci, and propose functions for these variants. We suggest that these atypical loci are JEEPs, which have modified functions based on the presence of Just Enough Essential Parts.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Short incubation periods of atypical H-type BSE in cattle with EK211 and KK211 prion protein genotypes after intracranial inoculation

In 2006, a case of atypical H-type BSE (H-BSE) was found to be associated with a germline mutation in the PRNP gene that resulted in a lysine substitution for glutamic acid at codon 211 (E211K). The E211K amino acid substitution in cattle is analogous to E200K in humans, which is associated with the development of genetic Creutzfeldt-Jakob disease (CJD). In the present study, we aimed to determine the effect of the EK211 prion protein genotype on incubation time in cattle inoculated with the agent of H-BSE; to characterize the molecular profile of H-BSE in KK211 and EK211 genotype cattle; and to assess the influence of serial passage on BSE strain. Eight cattle, representing three PRNP genotype groups (EE211, EK211, and KK211), were intracranially inoculated with the agent of H-BSE originating from either a case in a cow with the EE211 prion protein genotype or a case in a cow with E211K amino acid substitution. All inoculated animals developed clinical disease; post-mortem samples were collected, and prion disease was confirmed through enzyme immunoassay, anti-PrP Sc immunohistochemistry, and western blot. Western blot molecular analysis revealed distinct patterns in a steer with KK211 H-BSE compared to EK211 and EE211 cattle. Incubation periods were significantly shorter in cattle with the EK211 and KK211 genotypes compared to the EE211 genotype. Inoculum type did not significantly influence the incubation period. This study demonstrates a shorter incubation period for H-BSE in cattle with the K211 genotype in both the homozygous and heterozygous forms.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Carbohydrate Deacetylase Unique to Gut Microbe Bacteroides Reveals Atypical Structure

Bacteroides are often the most abundant, commensal species in the gut microbiome of industrialized human populations. One of the most commonly detected species is Bacteroides ovatus. It has been linked to benefits like the suppression of intestinal inflammation but is also correlated with some autoimmune disorders, for example irritable bowel disorder (IBD). Bacterial cell surface carbohydrates, like capsular polysaccharides (CPS), may play a role in modulating these varied host interactions. Recent studies have begun to explore the diversity of CPS loci in Bacteroides; however, there is still much unknown. Here, we present structural and functional characterization of a putative polysaccharide deacetylase from Bacteroides ovatus (BoPDA) encoded in a CPS biosynthetic locus. We solved four high resolution crystal structures (1.36-1.56 Å) of the enzyme bound to divalent cations Co 2+ , Ni 2+ , Cu 2+ , or Zn 2+ and performed carbohydrate binding and deacetylase activity assays. Structural analysis of BoPDA revealed an atypical domain architecture that is unique to this enzyme, with a carbohydrate esterase 4 (CE4) superfamily catalytic domain inserted into a carbohydrate binding module (CBM). Additionally, BoPDA lacks the canonical CE4 His-His-Asp metal binding motif and our structures show it utilizes a noncanonical His-Asp dyad to bind metal ions. BoPDA is the first protein involved in CPS biosynthesis from B. ovatus to be characterized, furthering our understanding of significant biosynthetic processes in this medically relevant gut microbe.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Evidence of Atypical Structural Flexibility of the Active Site Surrounding of an [FeFe] Hydrogenase from Clostridium beijerinkii

[FeFe] hydrogenase from Clostridium beijerinkii (CbHydA1) is an unusual hydrogenase in that it can withstand prolonged exposure to O 2 by reversibly converting into an O 2 -protected, inactive state (Hinact). It has been indicated in the past that an atypical conformation of the “SC 367 CP” loop near the [2Fe] H portion of the six-iron active site (H-cluster) allows the Cys367 residue to adopt an “off-H + -pathway” orientation, promoting a facile transition of the cofactor to Hinact. Here, we investigated the electronic structure of the H-cluster in the oxidized state (H ox ) that directly converts to Hinact under oxidizing conditions and the related CO-inhibited state (H ox -CO). We demonstrate that both states exhibit two distinct forms in electron paramagnetic resonance (EPR) spectroscopy. The ratio between the two forms is pH-dependent but also sensitive to the buffer choice. Our IR and EPR analyses illustrate that the spectral heterogeneity is due to a perturbation of the coordination environment of the H-cluster’s [4Fe4S] H subcluster without affecting the [2Fe] H subcluster. Overall, we conclude that the observation of two spectral components per state is evidence of heterogeneity of the environment of the H-cluster likely associated with conformational mobility of the SCCP loop. Such flexibility may allow Cys367 to switch rapidly between off- and on-H + -pathway rotamers. Consequently, we believe such structural mobility may be the key to maintaining high enzymatic activity while allowing a facile transition to the O 2 -protected state.

08 HYDROGEN↗
DOE OSTI2025

Low Mutation Rate and Atypical Mutation Spectrum in Prasinoderma coloniale : Insights From an Early Diverging Green Lineage

Mutations are the ultimate source of genetic diversity on which natural selection and genetic drift act, playing a crucial role in evolution and long-term adaptation. At the molecular level, the spontaneous mutation rate (µ), defined as the number of mutations per base per generation, thus determines the adaptive potential of a species. Through a mutation accumulation experiment, we estimate the mutation rate and spectrum in Prasinoderma coloniale, a phytoplankton species from an early-branching lineage within the Archaeplastida, characterized by an unusually high genomic guanine-cytosine (GC) content (69.8%). We find that P. coloniale has a very low total mutation rate of µ = 2.00 × 10 -10 . The insertion–deletion mutation rate is almost 5 times lesser than the single nucleotide mutation rate with µ ID = 3.40 × 10 -11 and µ SNM = 1.62 × 10 -10 . Prasinoderma coloniale also exhibits an atypical mutational spectrum: While essentially all other eukaryotes show a bias toward GC to AT mutations, no evidence of this AT-bias is observed in P. coloniale. Since cytosine methylation is known to be mutagenic, we hypothesized that this may result from an absence of C-methylation. Surprisingly, we found high levels of C-methylation (14% in 5mC, 25% in 5mCG contexts). Methylated cytosines did not show increased mutation rates compared with unmethylated ones, not supporting the prevailing notion that C-methylation universally leads to higher mutation rates. Overall, P. coloniale combines a GC-rich genome with a low mutation rate and original mutation spectrum, suggesting the almost universal AT-bias may not have been present in the ancestor of the green lineage.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Diversifying Isoprenoid Platforms via Atypical Carbon Substrates and Non-model Microorganisms

Isoprenoid compounds are biologically ubiquitous, and their characteristic modularity has afforded products ranging from pharmaceuticals to biofuels. Isoprenoid production has been largely successful in Escherichia coli and Saccharomyces cerevisiae with metabolic engineering of the mevalonate (MVA) and methylerythritol phosphate (MEP) pathways coupled with the expression of heterologous terpene synthases. Yet conventional microbial chassis pose several major obstacles to successful commercialization including the affordability of sugar substrates at scale, precursor flux limitations, and intermediate feedback-inhibition. Now, recent studies have challenged typical isoprenoid paradigms by expanding the boundaries of terpene biosynthesis and using non-model organisms including those capable of metabolizing atypical C1 substrates. Conversely, investigations of non-model organisms have historically informed optimization in conventional microbes by tuning heterologous gene expression. Here, we review advances in isoprenoid biosynthesis with specific focus on the synergy between model and non-model organisms that may elevate the commercial viability of isoprenoid platforms by addressing the dichotomy between high titer production and inexpensive substrates.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1997

Atypical form of Alzheimer's disease with prominent posterior cortical atrophy: a review of lesion distribution and circuit disconnection in cortical visual pathways

In recent years, the existence of visual variants of Alzheimer's disease characterized by atypical clinical presentation at onset has been increasingly recognized. In many of these cases post-mortem neuropathological assessment revealed that correlations could be established between clinical symptoms and the distribution of neurodegenerative lesions. We have analyzed a series of Alzheimer's disease patients presenting with prominent visual symptomatology as a cardinal sign of the disease. In these cases, a shift in the distribution of pathological lesions was observed such that the primary visual areas and certain visual association areas within the occipito-parieto-temporal junction and posterior cingulate cortex had very high densities of lesions, whereas the prefrontal cortex had fewer lesions than usually observed in Alzheimer's disease. Previous quantitative analyses have demonstrated that in Alzheimer's disease, primary sensory and motor cortical areas are less damaged than the multimodal association areas of the frontal and temporal lobes, as indicated by the laminar and regional distribution patterns of neurofibrillary tangles and senile plaques. The distribution of pathological lesions in the cerebral cortex of Alzheimer's disease cases with visual symptomatology revealed that specific visual association pathways were disrupted, whereas these particular connections are likely to be affected to a less severe degree in the more common form of Alzheimer's disease. These data suggest that in some cases with visual variants of Alzheimer's disease, the neurological symptomatology may be related to the loss of certain components of the cortical visual pathways, as reflected by the particular distribution of the neuropathological markers of the disease.

Review↗
NASA NTRS2006

Discovering Atypical Flights in Sequences of Discrete Flight Parameters

This paper describes the results of a novel research and development effort conducted at the NASA Ames Research Center for discovering anomalies in discrete parameter sequences recorded from flight data. Many of the discrete parameters that are recorded during the flight of a commercial airliner correspond to binary switches inside the cockpit. The inputs to our system are records from thousands of flights for a given class of aircraft and destination. The system delivers a list of potentially anomalous flights as well as reasons why the flight was tagged as anomalous. This output can be analyzed by safety experts to determine whether or not the anomalies are indicative of a problem that could be addressed with a human factors intervention. The final goal of the system is to help safety experts discover significant human factors issues such as pilot mode confusion, i.e., a flight in which a pilot has lost situational awareness as reflected in atypicality of the sequence of switches that he or she throws during descent compared to a population of similar flights. We view this work as an extension of Integrated System Health Management (ISHM) where the goal is to understand and evaluate the combined health of a class of aircraft ar a given destination.

Budalakoti, Suratna↗
NASA NTRS2006

Statistical Detection of Atypical Aircraft Flights

A computational method and software to implement the method have been developed to sift through vast quantities of digital flight data to alert human analysts to aircraft flights that are statistically atypical in ways that signify that safety may be adversely affected. On a typical day, there are tens of thousands of flights in the United States and several times that number throughout the world. Depending on the specific aircraft design, the volume of data collected by sensors and flight recorders can range from a few dozen to several thousand parameters per second during a flight. Whereas these data have long been utilized in investigating crashes, the present method is oriented toward helping to prevent crashes by enabling routine monitoring of flight operations to identify portions of flights that may be of interest with respect to safety issues.

Statler, Irving↗
DOE OSTI2021

Atypical phase-change alloy Ga 2 Te 3 : atomic structure, incipient nanotectonic nuclei, and multilevel writing

Emerging brain-inspired computing, including artificial optical synapses, photonic tensor cores, neuromorphic networks, etc., needs phase-change materials (PCMs) of the next generation with lower energy consumption and a wider temperature range for reliable long-term operation. Gallium tellurides with higher melting and crystallization temperatures appear to be promising candidates and enable achieving the necessary requirements. Here, using high energy X-ray diffraction and Raman spectroscopy supported by first-principles simulations, we show that vitreous g-Ga 2 Te 3 films essentially have a tetrahedral local structure and sp 3 hybridization, similar to those in the stable fcc Ga 2 Te 3 polymorph and in contrast to a vast majority of typical PCMs. Nevertheless, optical pump–probe laser experiments revealed high-contrast, fast and reversible multilevel SET-RESET transitions raising a question related to the phase change mechanism. A recently observed nanotectonic compression in bulk glassy Ga–Te alloys seems to be responsible for the PCM performance. Incipient nanotectonic nuclei, reminiscent of monoclinic high-pressure HP-Te II and rhombohedral HP-Ga 2 Te 3 , are present as minorities (2–4%) in g-Ga 2 Te 3 but are suggested to grow dramatically with increasing temperature while interacting with appropriate laser pulses. This leads to co-crystallization of HP-polymorphs amplified by a high internal local pressure reaching 4–8 GPa. The metallic HP-forms provide an increasing optical and electrical contrast, favorable for reliable PCM operations, and higher energy efficiency.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗