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At least 397 records · Page 22
All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

Crystal Structure of Borrelia turicatae protein, BTA121, a differentially regulated gene in the tick-mammalian transmission cycle of relapsing fever spirochetes

Tick-borne relapsing fever (RF) borreliosis is a neglected disease that is often misdiagnosed. RF species circulating in the United States include Borrelia turicatae, which is transmitted by argasid ticks. Environmental adaptation by RF Borrelia is poorly understood, however our previous studies indicated differential regulation of B. turicatae genes localized on the 150 kb linear megaplasmid during the tick-mammalian transmission cycle, including bta121. This gene is up-regulated by B. turicatae in the tick versus the mammal, and the encoded protein (BTA121) is predicted to be surface localized. The structure of BTA121 was solved by single-wavelength anomalous dispersion (SAD) using selenomethionine-derivative protein. The topology of BTA121 is unique with four helical domains organized into two helical bundles. Due to the sequence similarity of several genes on the megaplasmid, BTA121 can serve as a model for their tertiary structures. BTA121 has large interconnected tunnels and cavities that can accommodate ligands, notably long parallel helices, which have a large hydrophobic central pocket. Preliminary in-vitro studies suggest that BTA121 binds lipids, notably palmitate with a similar order of binding affinity as tablysin-15, a known palmitate-binding protein. The reported data will guide mechanistic studies to determine the role of BTA121 in the tick-mammalian transmission cycle of B. turicatae.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Long-term bat abundance in sagebrush steppe

Bats of western North America face many threats, but little is known about current population changes in these mammals. We compiled 283 surveys from 49 hibernacula over 32 years to investigate population changes of Townsend’s big-eared bats (Corynorhinus townsendii townsendii) and western small-footed myotis (Myotis ciliolabrum) in Idaho, USA. This area comprises some of the best bat habitat in the western USA, but is threatened by land-use change. Bats in this area also face invasion by the pathogen causing white-nose syndrome. Little is known about long-term trends of abundance of these two species. In our study, estimated population changes for Townsend’s big-eared bats varied by management area, with relative abundance increasing by 186% and 326% in two management areas, but decreasing 55% in another. For western small-footed myotis, analysis of estimated population trend was complicated by an increase in detection of 141% over winter. After accounting for differences in detection, this species declined region-wide by 63% to winter of 1998–1999. The population fully recovered by 2013–2014, likely because 12 of 23 of its hibernacula were closed to public access from 1994 to 1998. Our data clarify long-term population patterns of two bat species of conservation concern, and provide important baseline understanding of western small-footed myotis prior to the arrival of white-nose syndrome in this area.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2021

Seasonal calibration of the end-cretaceous Chicxulub impact event

The end-Cretaceous Chicxulub impact triggered Earth’s last mass-extinction, extinguishing ~ 75% of species diversity and facilitating a global ecological shift to mammal-dominated biomes. Temporal details of the impact event on a fine scale (hour-to-day), important to understanding the early trajectory of mass-extinction, have largely eluded previous studies. This study employs histological and histo-isotopic analyses of fossil fish that were coeval with a unique impact-triggered mass-death assemblage from the Cretaceous-Paleogene (KPg) boundary in North Dakota (USA). Patterns of growth history, including periodicity of δ 18 O and δ 13 C and growth band morphology, plus corroborating data from fish ontogeny and seasonal insect behavior, reveal that the impact occurred during boreal Spring/Summer, shortly after the spawning season for fish and most continental taxa. The severity and taxonomic symmetry of response to global natural hazards are influenced by the season during which they occur, suggesting that post-impact perturbations could have exerted a selective force that was exacerbated by seasonal timing. Data from this study can also provide vital hindsight into patterns of extant biotic response to global-scale hazards that are relevant to both current and future biomes.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2021

In-depth quantitative proteomic characterization of organotypic hippocampal slice culture reveals sex-specific differences in biochemical pathways

Sex differences in the brain of mammals range from neuroarchitecture through cognition to cellular metabolism. The hippocampus, a structure mostly associated with learning and memory, presents high vulnerability to neurodegeneration and aging. Therefore, we explored basal sex-related differences in the proteome of organotypic hippocampal slice culture, a major in vitro model for studying the cellular and molecular mechanisms related to neurodegenerative disorders. Results suggest a greater prevalence of astrocytic metabolism in females and significant neuronal metabolism in males. The preference for glucose use in glycolysis, pentose phosphate pathway and glycogen metabolism in females and high abundance of mitochondrial respiration subunits in males support this idea. An overall upregulation of lipid metabolism was observed in females. Upregulation of proteins responsible for neuronal glutamate and GABA synthesis, along with synaptic associated proteins, were observed in males. In general, the significant spectrum of pathways known to predominate in neurons or astrocytes, together with the well-known neuronal and glial markers observed, revealed sex-specific metabolic differences in the hippocampus. TEM qualitative analysis might indicate a greater presence of mitochondria at CA1 synapses in females. These findings are crucial to a better understanding of how sex chromosomes can influence the physiology of cultured hippocampal slices and allow us to gain insights into distinct responses of males and females on neurological diseases that present a sex-biased incidence.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2023

Habitat quality influences trade-offs in animal movement along the exploration–exploitation continuum

Abstract To successfully establish itself in a novel environment, an animal must make an inherent trade-off between knowledge accumulation and exploitation of knowledge gained (i.e., the exploration–exploitation dilemma). To evaluate how habitat quality affects the spatio-temporal scale of switching between exploration and exploitation during home range establishment, we conducted experimental trials comparing resource selection and space-use of translocated animals to those of reference individuals using reciprocal translocations between habitat types of differing quality. We selected wild pigs ( Sus scrofa ) as a model species to investigate hypotheses related to the movement behavior of translocated individuals because they are globally distributed large mammals that are often translocated within their introduced range to facilitate recreational hunting. Individuals translocated to higher quality habitat (i.e. higher proportions of bottomland hardwood habitats) exhibited smaller exploratory movements and began exploiting resources more quickly than those introduced to lower quality areas, although those in lower-quality areas demonstrated an increased rate of selection for preferred habitat as they gained knowledge of the landscape. Our data demonstrate that habitat quality mediates the spatial and temporal scale at which animals respond behaviorally to novel environments, and how these processes may determine the success of population establishment.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

DNA metabarcoding reveals consumption of diverse community of amphibians by invasive wild pigs (Sus scrofa) in the southeastern United States

Abstract Invasive wild pigs ( Sus scrofa ) are one of the most widespread, destructive vertebrate species globally. Their success can largely be attributed to their generalist diets, which are dominated by plant material but also include diverse animal taxa. Wild pigs are demonstrated nest predators of ground-nesting birds and reptiles, and likely pose a threat to amphibians given their extensive overlap in wetland use. DNA metabarcoding of fecal samples from 222 adult wild pigs culled monthly from 2017 to 2018 revealed a diverse diet dominated by plant material, with 166 plant genera from 56 families and 18 vertebrate species identified. Diet composition varied seasonally with availability for plants and was consistent between sexes. Amphibians were the most frequent vertebrate group consumed and represented the majority of vertebrate species detected, suggesting amphibians are potentially vulnerable to predation by wild pigs in our study region. Mammal, reptile, and bird species were also detected in pig diets, but infrequently. Our results highlight the need for research on the impacts of wild pigs on amphibians to better inform management and conservation of imperiled species.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2015

Structure, Function and Inhibition of the Phosphoethanolamine Methyltransferases of the Human Malaria Parasites Plasmodium vivax and Plasmodium knowlesi

Phosphoethanolamine methyltransferases (PMTs) catalyze the three-step methylation of phosphoethanolamine to form phosphocholine, a critical step in the synthesis of phosphatidylcholine in a select number of eukaryotes including human malaria parasites, nematodes and plants. Genetic studies in the malaria parasite Plasmodium falciparum have shown that the methyltransferase PfPMT plays a critical function in parasite development and differentiation. The presence of PMT orthologs in other malaria parasites that infect humans and their absence in mammals make them ideal targets for the development of selective antimalarials with broad specificity against different Plasmodium species. Here we describe the X-ray structures and biochemical properties of PMT orthologs from Plasmodium vivax and Plasmodium knowlesi and show that both enzymes are inhibited by amodiaquine and NSC158011, two drugs with potent antimalarial activity. Metabolic studies in a yeast mutant that relies on PkPMT or PvPMT for survival demonstrated that these compounds inhibit phosphatidylcholine biosynthesis from ethanolamine. Our structural and functional data provide insights into the mechanism of catalysis and inhibition of PMT enzymes and set the stage for a better design of more specific and selective antimalarial drugs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

Mechanistic insights into the recognition of 5-methylcytosine oxidation derivatives by the SUVH5 SRA domain

5-Methylcytosine (5 mC) is associated with epigenetic gene silencing in mammals and plants. 5 mC is consecutively oxidized to 5-hydroxymethylcytosine (5 hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) by ten-eleven translocation enzymes. We performed binding and structural studies to investigate the molecular basis of the recognition of the 5 mC oxidation derivatives in the context of a CG sequence by the SET- and RING-associated domain (SRA) of the SUVH5 protein (SUVH5 SRA). Using calorimetric measurements, we demonstrate that the SRA domain binds to the hydroxymethylated CG (5hmCG) DNA duplex in a similar manner to methylated CG (5mCG). Interestingly, the SUVH5 SRA domain exhibits weaker affinity towards carboxylated CG (5caCG) and formylated CG (5fCG). We report the 2.6 Å resolution crystal structure of the SUVH5 SRA domain in a complex with fully hydroxymethyl-CG and demonstrate a dual flip-out mechanism, whereby the symmetrical 5hmCs are simultaneously extruded from the partner strands of the DNA duplex and are positioned within the binding pockets of individual SRA domains. The hydroxyl group of 5hmC establishes both intra- and intermolecular interactions in the binding pocket. Collectively, we show that SUVH5 SRA recognizes 5hmC in a similar manner to 5 mC, but exhibits weaker affinity towards 5 hmC oxidation derivatives.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

Structure of the Dictyostelium Myosin-II Heavy Chain Kinase A (MHCK-A) α-kinase domain apoenzyme reveals a novel autoinhibited conformation

The α-kinases are a family of a typical protein kinases present in organisms ranging from protozoa to mammals. Here we report an autoinhibited conformation for the α-kinase domain of Dictyostelium myosin-II heavy chain kinase A (MHCK-A) in which nucleotide binding to the catalytic cleft, located at the interface between an N-terminal and C-terminal lobe, is sterically blocked by the side chain of a conserved arginine residue (Arg592). Previous α-kinase structures have shown that an invariant catalytic aspartic acid residue (Asp766) is phosphorylated. Unexpectedly, in the autoinhibited conformation the phosphoryl group is transferred to the adjacent Asp663, creating an interaction network that stabilizes the autoinhibited state. The results suggest that Asp766 phosphorylation may play both catalytic and regulatory roles. The autoinhibited structure also provides the first view of a phosphothreonine residue docked into the phospho-specific allosteric binding site (Pi-pocket) in the C-lobe of the α-kinase domain.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2026

Diacylglycerol enantiomer selectivity of diacylglycerol acyltransferases highlights metabolic specialization in triacylglycerol synthesis across the tree of life

Triacylglycerols are the major energy storage lipids in plants, animals, and microorganisms, and are predominantly produced by acyl-CoA:diacylglycerol (DAG) acyltransferases (DGATs). Two enantiomers of the DAG substrate, sn -1,2 and sn -2,3, can be produced by different biological mechanisms; however, little is known about which species produce each enantiomer, the selectivity of DGAT isoforms for either enantiomer, or whether DGAT enantiomer selectivity varies across organisms. Here, DAG enantiomer selectivity of DGAT1 and DGAT2 was measured from eight seed plants, two mammals, one oleaginous yeast, and one photosynthetic microalga using enantiomer-specific in vitro DGAT assays. Across most plants, DGAT1 favored sn -1,2-DAG, whereas DGAT2 preferentially utilized sn -2,3-DAG. However, there were several exceptions. Mammalian DGAT1, DGAT2, and microbial DGAT1s efficiently used both DAG enantiomers, while microbial DGAT2s had unique selectivity. The selectivity of several DGATs for combined acyl-CoA and DAG enantiomer molecular species were also evaluated for biotechnical applications. Therefore, DGAT DAG enantiomer selectivity is common yet strongly dependent on lineage and isoform and likely shaped in part by species-specific metabolic context of triacylglycerol synthesis, turnover, and remodeling. This work expands our understanding of DGAT function and establishes a foundation for leveraging enantiomer-selective acyltransferases in metabolic engineering of tailored lipid products.

Arabidopsis thaliana↗
DOE OSTI2020

Phosphatidic acid: an emerging versatile class of cellular mediators

Abstract Lipids function not only as the major structural components of cell membranes, but also as molecular messengers that transduce signals to trigger downstream signaling events in the cell. Phosphatidic acid (PA), the simplest and a minor class of glycerophospholipids, is a key intermediate for the synthesis of membrane and storage lipids, and also plays important roles in mediating diverse cellular and physiological processes in eukaryotes ranging from microbes to mammals and higher plants. PA comprises different molecular species that can act differently, and is found in virtually all organisms, tissues, and organellar membranes, with variations in total content and molecular species composition. The cellular levels of PA are highly dynamic in response to stimuli and multiple enzymatic reactions can mediate its production and degradation. Moreover, its unique physicochemical properties compared with other glycerophospholipids allow PA to influence membrane structure and dynamics, and interact with various proteins. PA has emerged as a class of new lipid mediators modulating various signaling and cellular processes via its versatile effects, such as membrane tethering, conformational changes, and enzymatic activities of target proteins, and vesicular trafficking.

Biochemistry & Molecular Biology↗
DOE OSTI2023

Glycosyltransferase family 47 (GT47) proteins in plants and animals

Glycosyltransferases (GTs) are carbohydrate-active enzymes that are encoded by the genomes of organisms spanning all domains of life. GTs catalyze glycosidic bond formation, transferring a sugar monomer from an activated donor to an acceptor substrate, often another saccharide. GTs from family 47 (GT47, PF03016) are involved in the synthesis of complex glycoproteins in mammals and insects and play a major role in the synthesis of almost every class of polysaccharide in plants, with the exception of cellulose, callose, and mixed linkage β-1,3/1,4-glucan. GT47 enzymes adopt a GT-B fold and catalyze the formation of glycosidic bonds through an inverting mechanism. Unlike animal genomes, which encode few GT47 enzymes, plant genomes contain 30 or more diverse GT47 coding sequences. With our current knowledge of the GT47 family across plant species brings us an interesting view, showcasing how members exhibit a great diversity in both donor and acceptor substrate specificity, even for members that are classified in the same phylogenetic clade. Thus, we discuss how plant GT47 family members represent a great case to study the relationship between substrate specificity, protein structure, and protein evolution. Most of the plant GT47 enzymes that are identified to date are involved in biosynthesis of plant cell wall polysaccharides, including xyloglucan, xylan, mannan, and pectins. This indicates unique and crucial roles of plant GT47 enzymes in cell wall formation. The aim of this review is to summarize findings about GT47 enzymes and highlight new challenges and approaches on the horizon to study this family.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2016

First Results of an “Artificial Retina” Processor Prototype

We report on the performance of a specialized processor capable of reconstructing charged particle tracks in a realistic LHC silicon tracker detector, at the same speed of the readout and with sub-microsecond latency. The processor is based on an innovative pattern-recognition algorithm, called “artificial retina algorithm”, inspired from the vision system of mammals. A prototype of the processor has been designed, simulated, and implemented on Tel62 boards equipped with high-bandwidth Altera Stratix III FPGA devices. The prototype is the first step towards a real-time track reconstruction device aimed at processing complex events of high-luminosity LHC experiments at 40 MHz crossing rate.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗
DOE OSTI2016

Graphene oxide and adsorption of chloroform: A density functional study

Chlorinated hydrocarbon compounds are of environmental concerns, since they are toxic to humans and other mammals, and are widespread, and exposure is hard to avoid. Understanding and improving methods to reduce the amount of the substances are important. We present an atomic-scale calculational study of the adsorption of chlorine-based substance chloroform (CHCl{sub 3}) on graphene oxide, as a step in estimating the capacity of graphene oxide for filtering out such substances, e.g., from drinking water. The calculations are based on density functional theory, and the recently developed consistent-exchange functional for the van der Waals density-functional method is employed. We obtain values of the chloroform adsorption energy varying from roughly 0.2 to 0.4 eV per molecule. This is comparable to previously found results for chloroform adsorbed directly on clean graphene, using similar calculations. In a wet environment, like filters for drinking water, the graphene will not stay clean and will likely oxidize, and thus adsorption onto graphene oxide, rather than clean graphene, is a more relevant process to study.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2016

Structure and function of the yeast listerin (Ltn1) conserved N-terminal domain in binding to stalled 60S ribosomal subunits

The Ltn1 E3 ligase (listerin in mammals) has emerged as a paradigm for understanding ribosome-associated ubiquitylation. Ltn1 binds to 60S ribosomal subunits to ubiquitylate nascent polypeptides that become stalled during synthesis; among Ltn1’s substrates are aberrant products of mRNA lacking stop codons [nonstop translation products (NSPs)]. Here, we report the reconstitution of NSP ubiquitylation in Neurospora crassa cell extracts. Upon translation in vitro, ribosome-stalled NSPs were ubiquitylated in an Ltn1-dependent manner, while still ribosome-associated. Furthermore, we provide biochemical evidence that the conserved N-terminal domain (NTD) plays a significant role in the binding of Ltn1 to 60S ribosomal subunits and that NTD mutations causing defective 60S binding also lead to defective NSP ubiquitylation, without affecting Ltn1’s intrinsic E3 ligase activity. Finally, we report the crystal structure of the Ltn1 NTD at 2.4-Å resolution. The structure, combined with additional mutational studies, provides insight to NTD’s role in binding stalled 60S subunits. Furthermore, our findings show that Neurospora extracts can be used as a tool to dissect mechanisms underlying ribosome-associated protein quality control and are consistent with a model in which Ltn1 uses 60S subunits as adapters, at least in part via its NTD, to target stalled NSPs for ubiquitylation.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2017

Improved regulatory element prediction based on tissue-specific local epigenomic signatures

Significance In mammals, when and where a gene is transcribed are primarily regulated by the activity of regulatory DNA elements, or enhancers. Genetic mutation disrupting enhancer function is emerging as one of the major causes of human diseases. However, our knowledge remains limited about the location and activity of enhancers in the numerous and distinct cell types and tissues. Here, we develop a computational approach, regulatory element prediction based on tissue-specific local epigenetic marks (REPTILE), to precisely locate enhancers based on genome-wide DNA methylation and histone modification profiling. We systematically tested REPTILE on a variety of human and mouse cell types and tissues. Compared with existing methods, we found that enhancer predictions from REPTILE are more likely to be active in vivo and the predicted locations are more accurate.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2017

Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma

The enzyme serine hydroxymethyltransferse (SHMT) converts serine into glycine and a tetrahydrofolate-bound one-carbon unit. Folate one-carbon units support purine and thymidine synthesis, and thus cell growth. Mammals have both cytosolic SHMT1 and mitochondrial SHMT2, with the mitochondrial isozyme strongly up-regulated in cancer. Here we show genetically that dual SHMT1/2 knockout blocks HCT-116 colon cancer tumor xenograft formation. Building from a pyrazolopyran scaffold that inhibits plant SHMT, we identify small-molecule dual inhibitors of human SHMT1/2 (biochemical IC 50 ~ 10 nM). Metabolomics and isotope tracer studies demonstrate effective cellular target engagement. A cancer cell-line screen revealed that B-cell lines are particularly sensitive to SHMT inhibition. The one-carbon donor formate generally rescues cells from SHMT inhibition, but paradoxically increases the inhibitor’s cytotoxicity in diffuse large B-cell lymphoma (DLBCL). Here, we show that this effect is rooted in defective glycine uptake in DLBCL cell lines, rendering them uniquely dependent upon SHMT enzymatic activity to meet glycine demand. Thus, defective glycine import is a targetable metabolic deficiency of DLBCL.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

TIMELESS mutation alters phase responsiveness and causes advanced sleep phase

Many components of the circadian molecular clock are conserved from flies to mammals; however, the role of mammalian Timeless remains ambiguous. Here, we report a mutation in the human TIMELESS (h TIM ) gene that causes familial advanced sleep phase (FASP). Tim CRISPR mutant mice exhibit FASP with altered photic entrainment but normal circadian period. We demonstrate that the mutation prevents TIM accumulation in the nucleus and has altered affinity for CRY2, leading to destabilization of PER/CRY complex and a shortened period in nonmature mouse embryonic fibroblasts (MEFs). Here, we conclude that TIM, when excluded from the nucleus, can destabilize the negative regulators of the circadian clock, alter light entrainment, and cause FASP.

59 BASIC BIOLOGICAL SCIENCES↗