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At least 415 records · Page 23
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Structure of 3'-PO 4 /5'-OH RNA ligase RtcB in complex with a 5'-OH oligonucleotide

RtcB enzymes comprise a widely distributed family of manganese- and GTP-dependent RNA repair enzymes that join 2',3'-cyclic phosphate ends to 5'-OH ends via RtcB-(histidinyl-N)–GMP, RNA 3'-phosphate, and RNA 3 'pp 5 'G intermediates. RtcB can ligate either 5'-OH RNA or 5'-OH DNA strands in vitro. The nucleic acid contacts of RtcB are uncharted. In this work, we report a 2.7 Å crystal structure of Pyrococcus horikoshii RtcB in complex with a 6-mer 5'-OH DNA oligonucleotide HO A 1 pT 2 pG 3 pT 4 pC 5 pC 6 , which reveals enzymic contacts of Asn202 to the terminal 5'-OH nucleophile; Arg238 to the A1pT2 and T2pG3 phosphates; Arg190 and Gln194 to the T 2 pG 3 phosphate; and an Arg190 π-cation interaction with the G 3 nucleobase. The structural insights affirm functional studies of E. coli RtcB that implicated the conserved counterpart of Arg238 in engagement of the 5'-OH strand for ligation. The essential active site Cys98 that coordinates two manganese ions is oxidized to cysteine sulfonic acid in our structure, raising the prospect that RtcB activity might be sensitive to modulation during oxidative stress.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

A method for achieving complete microbial genomes and improving bins from metagenomics data

Metagenomics facilitates the study of the genetic information from uncultured microbes and complex microbial communities. Assembling complete genomes from metagenomics data is difficult because most samples have high organismal complexity and strain diversity. Some studies have attempted to extract complete bacterial, archaeal, and viral genomes and often focus on species with circular genomes so they can help confirm completeness with circularity. However, less than 100 circularized bacterial and archaeal genomes have been assembled and published from metagenomics data despite the thousands of datasets that are available. Circularized genomes are important for (1) building a reference collection as scaffolds for future assemblies, (2) providing complete gene content of a genome, (3) confirming little or no contamination of a genome, (4) studying the genomic context and synteny of genes, and (5) linking protein coding genes to ribosomal RNA genes to aid metabolic inference in 16S rRNA gene sequencing studies. We developed a semi-automated method called Jorg to help circularize small bacterial, archaeal, and viral genomes using iterative assembly, binning, and read mapping. In addition, this method exposes potential misassemblies from k-mer based assemblies. We chose species of the Candidate Phyla Radiation (CPR) to focus our initial efforts because they have small genomes and are only known to have one ribosomal RNA operon. In addition to 34 circular CPR genomes, we present one circular Margulisbacteria genome, one circular Chloroflexi genome, and two circular megaphage genomes from 19 public and published datasets. We demonstrate findings that would likely be difficult without circularizing genomes, including that ribosomal genes are likely not operonic in the majority of CPR, and that some CPR harbor diverged forms of RNase P RNA. Code and a tutorial for this method is available at https://github.com/lmlui/Jorg and is available on the DOE Systems Biology KnowledgeBase as a beta app.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Demonstrating the importance of porcine reproductive and respiratory syndrome virus papain-like protease 2 deubiquitinating activity in viral replication by structure-guided mutagenesis

Deubiquitination of cellular substrates by viral proteases is a mechanism used to interfere with host cellular signaling processes, shared between members of the coronavirus- and arterivirus families. In the case of Arteriviruses, deubiquitinating and polyprotein processing activities are accomplished by the virus-encoded papain-like protease 2 (PLP2). Several studies have implicated the deubiquitinating activity of the porcine reproductive and respiratory syndrome virus (PRRSV) PLP2 in the downregulation of cellular interferon production, however to date, the only arterivirus PLP2 structure described is that of equine arteritis virus (EAV), a distantly related virus. Here we describe the first crystal structure of the PRRSV PLP2 domain both in the presence and absence of its ubiquitin substrate, which reveals unique structural differences in this viral domain compared to PLP2 from EAV. To probe the role of PRRSV PLP2 deubiquitinating activity in host immune evasion, we selectively removed this activity from the domain by mutagenesis and found that the viral domain could no longer downregulate cellular interferon production. Interestingly, unlike EAV, and also unlike the situation for MERS-CoV, we found that recombinant PRRSV carrying PLP2 DUB-specific mutations faces significant selective pressure to revert to wild-type virus in MARC-145 cells, suggesting that the PLP2 DUB activity, which in PRRSV is present as three different versions of viral protein nsp2 expressed during infection, is critically important for PRRSV replication.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

2019 Novel Coronavirus (COVID-19)

Coronavirus is a family of common viruses, some causing illness in people and others that circulate among animals, including camels, cats and bats. Analysis of the genetic tree of this virus is ongoing to know the specific source of the virus. SARS, another coronavirus that emerged to infect people, came from civet cats, while MERS, another coronavirus that emerged to infect people, came from camels. A novel coronavirus is a virus that has not previously been identified. The first infection was reported in Wuhan, China in Dec. 2019, with a source probably originating from a livestock market, and a suspected origination from bats.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Using Deep Mutational Data and Machine Learning to Guide Outbreak and Pandemic Response

A significant fraction of pathogens known to infect humans originate in non-human (zoonotic) hosts (Taylor, Latham, and Woolhouse 2001), and new and emerging pathogens continue to spill over into the human population more frequently at an alarming rate (e.g., SARS, MERS, Cholera, etc.). The recent outbreaks of Ebola virus in West Africa and the ongoing SARS-CoV-2 pandemic demonstrate the need for rapid and reliable assessments of viral phenotype information to help inform scientists and policy makers how best to control the spread of disease. Further understanding of the virus pathogenic evolutionary space and potential trajectory could guide appropriate control measures to limit the spread of a new virus throughout the local and global human population.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Omics-Lethal Human Viruses, Influenza A Experiment ICL106

The purpose of this experiment was to evaluate the human host epigenetic response to Influenza A H5N1 virus and MERS-CoV viral infection from human lung adenocarcinoma cell (Calu-3) high throughput sequencing (MeDIP-Seq) sample data. Host-associated viral downloads contain one or more primary host-pathogen experimental study metadata design workbooks (supporting metadata only).

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Effects of HLA single chain trimer design on peptide presentation and stability

MHC class I “single-chain trimer” molecules, coupling MHC heavy chain, β 2 -microglobulin, and a specific peptide into a single polypeptide chain, are widely used in research. To more fully understand caveats associated with this design that may affect its use for basic and translational studies, we evaluated a set of engineered single-chain trimers with combinations of stabilizing mutations across eight different classical and non-classical human class I alleles with 44 different peptides, including a novel human/murine chimeric design. While, overall, single-chain trimers accurately recapitulate native molecules, care was needed in selecting designs for studying peptides longer or shorter than 9-mers, as single-chain trimer design could affect peptide conformation. In the process, we observed that predictions of peptide binding were often discordant with experiment and that yields and stabilities varied widely with construct design. We also developed novel reagents to improve the crystallizability of these proteins and confirmed novel modes of peptide presentation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Discovery of Small-Molecule Inhibitors of SARS-CoV-2 Proteins Using a Computational and Experimental Pipeline

A rapid response is necessary to contain emergent biological outbreaks before they can become pandemics. The novel coronavirus (SARS-CoV-2) that causes COVID-19 was first reported in December of 2019 in Wuhan, China and reached most corners of the globe in less than two months. In just over a year since the initial infections, COVID-19 infected almost 100 million people worldwide. Although similar to SARS-CoV and MERS-CoV, SARS-CoV-2 has resisted treatments that are effective against other coronaviruses. Crystal structures of two SARS-CoV-2 proteins, spike protein and main protease, have been reported and can serve as targets for studies in neutralizing this threat. We have employed molecular docking, molecular dynamics simulations, and machine learning to identify from a library of 26 million molecules possible candidate compounds that may attenuate or neutralize the effects of this virus. The viability of selected candidate compounds against SARS-CoV-2 was determined experimentally by biolayer interferometry and FRET-based activity protein assays along with virus-based assays. In the pseudovirus assay, imatinib and lapatinib had IC 50 values below 10 μM, while candesartan cilexetil had an IC 50 value of approximately 67 µM against M pro in a FRET-based activity assay. Comparatively, candesartan cilexetil had the highest selectivity index of all compounds tested as its half-maximal cytotoxicity concentration 50 (CC 50 ) value was the only one greater than the limit of the assay (>100 μM).

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Pseudomonas aeruginosa gene PA4880 encodes a Dps-like protein with a Dps fold, bacterioferritin-type ferroxidase centers, and endonuclease activity

We report the biochemical, structural, and functional characterization of the protein coded by gene PA4880 in the P. aeruginosa PAO1 genome. The PA4880 gene had been annotated as coding a probable bacterioferritin. Our structural work shows that the product of gene PA4880 is a protein that adopts the Dps subunit fold, which oligomerizes into a 12-mer quaternary structure. Unlike Dps, however, the ferroxidase di-iron centers and iron coordinating ligands are buried within each subunit, in a manner identical to that observed in the ferroxidase center of P. aeruginosa bacterioferritin. Since these structural characteristics correspond to Dps-like proteins, we term the protein as P. aeruginosa Dps-like, or Pa DpsL. The ferroxidase centers in Pa DpsL catalyze the oxidation of Fe 2+ utilizing O 2 or H 2 O 2 as oxidant, and the resultant Fe 3+ is compartmentalized in the interior cavity. Interestingly, incubating Pa DpsL with plasmid DNA results in efficient nicking of the DNA and at higher concentrations of Pa DpsL the DNA is linearized and eventually degraded. The nickase and endonuclease activities suggest that Pa DpsL, in addition to participating in the defense of P. aeruginosa cells against iron-induced toxicity, may also participate in the innate immune mechanisms consisting of restriction endonucleases and cognate methyl transferases.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1979

Low-cost directionally-solidified turbine blades, volume 2

An endothermically heated technology was used to manufacture low cost, directionally solidified, uncooled nickel-alloy blades for the TFE731-3 turbofan engine. The MAR-M 247 and MER-M 100+Hf blades were finish processed through heat treatment, machining, and coating operations prior to 150 hour engine tests consisting of the following sequences: (1) 50 hours of simulated cruise cycling (high fatigue evaluation); (2) 50 hours at the maximum continuous power rating (stress rupture endurance (low cycle fatigue). None of the blades visually showed any detrimental effects from the test. This was verified by post test metallurgical evaluation. The specific fuel consumption was reduced by 2.4% with the uncooled blades.

Dennis, R. E.↗
NASA NTRS1988

Moorable spectroradiometers in the BIOWATT experiment

A new oceanographic instrument, the MER-2020, has been developed for the long term measurement of bio-optical properties. This instrument is a self-contained reflectance spectroradiometer with 40 megabytes of internal data storage and battery power permitting deployments for as long as 6 months. It can serve as the control and recording center for a variety of other sensors including fluorometers, transmissometers, temperature and conductivity probes. Instruments of this type were deployed at depths to 70 meters on a 5000 meter mooring during the BIOWATT experiment between February and November 1987. Measurements of the spectral diffuse attenuation coefficient and of the remote sensed reflectance from the ten month period in 1987 in the Northern Sargasso Sea are presented. In addition, the temperature, pressure, package orientation and sunlight stimulated natural fluorescence of phytoplankton are discussed. This instrument will be a key part of in situ optical calibration for future remote color sensors, and presently permits direct measurement of long term optical variability, important in visibility and communication problems.

Booth, C. R.↗
NASA NTRS1992

Oligomeric baroeffect and gas aggregation states

The baroeffect is analyzed to include a gas that aggregates into higher-order polymers or oligomers. The resulting pressure change is found to vary independently of the molecular weight of the gas components and to depend only on the aggregation or oligomeric order of the gas. With increasing aggregation, diffusive slip velocities are found to increase. The calculations are extended to include general counterdiffusion of two distinct aggregation states (k-, j-mer) for the gas, and the pressure change is derived as a function that is independent of both molecular weight and the absolute aggregation. The only parameter that determines the baroeffect is the ratio of aggregated states, beta = k/j. For gases that reversibly aggregate, possible oscillatory behavior and complex dynamics for pressure are discussed. Gas aggregation may play a role for low-temperature crystal-growth conditions in which vapor concentrations of one (or more) species are high.

Noever, David A.↗
NASA NTRS1995

SeaWiFS technical report series. Volume 27: Case studies for SeaWiFS calibration and validation, part 3

This document provides brief reports, or case studies, on a number of investigations sponsored by the Calibration and Validation Team (CVT) within the Sea-viewing Wide Field-of-view Sensor (SeaWiFS) Project. Chapter I describes a comparison of the irradiance immersion coefficients determined for several different marine environmental radiometers (MERs). Chapter 2 presents an analysis of how light absorption by atmospheric oxygen will influence the radiance measurements in band 7 of the SeaWiFS instrument. Chapter 3 gives the results of the second ground-based solar calibration of the instrument, which was undertaken after the sensor was modified to reduce the effects of internal stray light. (The first ground-based solar calibration of SeaWiFS is described in Volume 19 in the SeaWiFS Technical Report Series.) Chapter 4 evaluates the effects of ship shadow on subsurface irradiance and radiance measurements deployed from the deck of the R/V Weatherbird 11 in the Atlantic Ocean near Bermuda. Chapter 5 illustrates the various ways in which a single data day of SeaWiFS observations can be defined, and why the spatial definition is superior to the temporal definition for operational usage.

Hooker, Stanford B.↗
NASA NTRS1994

A redox beginning: Which came first phosphoryl, acyl, or electron transfer ?

Thermodynamic and kinetic information available on the synthesis of prebiotic monomers and polymers will be examined in order to illuminate the prebiotic plausibility of polymer syntheses based on (a) phosphoryl transfer that yields phosphodiester polymers, (b) acyl transfer that gives polyamides, and (c) electron transfer that produces polydisulfide or poly(thio)ester polymers. New experimental results on the oxidative polymerization of 2,3-dimercaptopropanol by ferric ions on the surface of ferric hydroxide oxide will be discussed as a chemical model of polymerization by electron transfer. This redox polymerization that yields polymers with a polydisulfide backbone was found to give oligomers up to the 15-mer from 1 mM of 2,3-dimercaptopropanol after one day at 25 C. High pressure liquid chromatography (HPLC) analysis of the oligomers was carried out on an Alltech OH-100 column eluted with acetonitrile-water.

Weber, Arthur L.↗
NASA NTRS1995

Prebiotic polymerization: Oxidative polymerization of 2, 3-dimercapto-1-propanol on the surface of iron(III) hydroxide oxide

The oxidation of 2, 3-dimercapto-1-propanol by ferric ions on the surface of iron(III) hydroxide oxide (Fe(OH)O) yielded polydisulfide oligomers. This polymerization occurred readily at low dithiol concentration under mild aqueous conditions. Polydisulfide polymers up to the 15-mer were synthesized from 1 mM dithiol in 5 ml water reacted with iron(III) hydroxide oxide (20 mg, 160 micromole Fe) for 3 days under anaerobic conditions at 40 C and pH 4. About 91% of the dithiol was converted to short soluble oligomers and 9% to insoluble larger oligomers that were isolated with the Fe(OH)O phase. Reactions carried out at the same ratio of dithiol to Fe(OH)O but at higher dithiol concentrations gave higher yields of the larger insoluble oligomers. The relationship of these results to prebiotic polymer synthesis is discussed.

Weber, Arthur L.↗
NASA NTRS1996

Synthesis of long Prebiotic Oligomers on Mineral Surfaces

Most theories of the origin of biological organization assume that polymers with lengths in the range of 30-60 monomers are needed to make a genetic system viable. But it has not proved possible to synthesize plausibly prebiotic polymers this long by condensation in aqueous solution, because hydrolysis competes with polymerization. The potential of mineral surfaces to facilitate prebiotic polymerization was pointed out long ago. Here we describe a system that models prebiotic polymerization by the oligomerization of activated monomers -both nucleotides and amino acids. We find that whereas the reactions in solution produce only short oligomers (the longest typically being a 10-mer), the presence of mineral surfaces (montmorillonite for nucleotides, illite and hydroxylapatite for amino adds) induces the formation of oligomers up to 55 monomers long. These are formed by successive "feedings" with the monomers; polymerization takes place on the mineral surfaces in a manner akin to solid-phase synthesis of biopolymers.

Ferris, James P.↗
NASA NTRS1997

Participation in the 1996 Arlindo Cruise to the Indonesian Seas

The objective of Arlindo-Productivity is to understand the factors responsible for regional differences in the response of phytoplankton and zooplankton to the SE and NW Monsoons in Indonesia. The hypothesis is that an interplay between circulation and shoaling of the nutricline, as a response to the monsoons, regulates productivity in the Indonesian Seas. My o@jective for the cruise in 1996 was to continue our collaboration with Indonesian scientists by conducting a set of hydrographic, primary production and spectral irradiance observations in the Indonesian Seas. This grant paid for shipping, travel and incidental costs associated with participation in the cruise in December, 1996. Ship costs were borne by the Indonesian Institute of Sciences as part of the collaborative effort. A plan for Arlindo in 1996 was agreed upon in March, 1996, by Indonesian scientists together with Arnold Gordon. The plan called for a 20-day physical oceanography and mooring cruise in November, 1996, followed by a 5-day bio-optical cruise. The bio-optical cruise departed from, and returned to, Ambon, and sampled in the Banda Sea. We completed a series of chlorophyll analyses, both a sampling of surface variability and depth profiles in the Banda Sea. We also completed three MER profiles for depth profiles of spectral irradiance. These data have a useful by-product in that they can be used for vicarious calibration of the OCTS sensor aboard the ADEOS satellite. As such, the data has been transmitted to NASDA in Japan for their use.

Marra, John↗
NASA NTRS1994

Prebiotic Oxidative Polymerization of 2,3 Dimercaptopropanol on the Surface of Iron(III) Hydroxide Oxide

The oxidation of 2,3-Dimercapto-1-propanol by ferric ions on the surface of iron (III) hydroxide oxide yielded polydisulfide polymers. This polymerization occured readily at low dithiol concentration under mild aqueous conditions. Polydisulfide polymers up to the 15-mer were synthesized from 1 mM dithiol in 5 ml water reacted with iron (III) hydroxide oxide (20 mg, 160 micro mole Fe) for 3 days under anaerobic conditions at 40 C and pH 4. About 91% of the dithiol was converted to short soluble oligomers and 9% to insoluble larger oligomers that were isolated with the mineral phase. Reactions at higher dithiol concentrations with the same ratio of dithiol to mineral gave a higher yield of the larger insoluble oligomers. The relationship of these results to prebiotic polymer synthesis will be discussed.

Weber, Arthur L.↗