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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 1,027 records · Page 57
All sourcesNASA NTRSDOE OSTI
DOE OSTI2019

Genetic risk for Alzheimer’s dementia predicts motor deficits through multi-omic systems in older adults

Alzheimer’s disease manifests with both cognitive and motor deficits. However, the degree to which genetic risk of Alzheimer’s dementia contributes to late-life motor impairment, and the specific molecular systems underlying these associations, are uncertain. Here, we adopted an integrative multi-omic approach to assess genetic influence on motor impairment in older adults and identified key molecular pathways that may mediate this risk. We built a polygenic risk score for clinical diagnosis of Alzheimer’s dementia (AD-PRS) and examined its relationship to several motor phenotypes in 1885 older individuals from two longitudinal aging cohorts. We found that AD-PRS was associated with a previously validated composite motor scores and their components. The major genetic risk factor for sporadic Alzheimer’s dementia, the APOE/TOMM40 locus, was not a major driver of these associations. To identify specific molecular features that potentially medicate the genetic risk into motor dysfunction, we examined brain multi-omics, including transcriptome, DNA methylation, histone acetylation (H3K9AC), and targeted proteomics, as well as diverse neuropathologies. We found that a small number of factors account for the majority of the influence of AD-PRS on motor function, which comprises paired helical filament tau-tangle density, H3K9AC in specific chromosomal regions encoding genes involved in neuromuscular process. These multi-omic factors have the potential to elucidate key molecular mechanisms developing motor impairment in the context of Alzheimer’s dementia.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Advances and perspectives in discovery and functional analysis of small secreted proteins in plants

Small secreted proteins (SSPs) are less than 250 amino acids in length and are actively transported out of cells through conventional protein secretion pathways or unconventional protein secretion pathways. In plants, SSPs have been found to play important roles in various processes, including plant growth and development, plant response to abiotic and biotic stresses, and beneficial plant–microbe interactions. Over the past 10 years, substantial progress has been made in the identification and functional characterization of SSPs in several plant species relevant to agriculture, bioenergy, and horticulture. Yet, there are potentially a lot of SSPs that have not been discovered in plant genomes, which is largely due to limitations of existing computational algorithms. Recent advances in genomics, transcriptomics, and proteomics research, as well as the development of new computational algorithms based on machine learning, provide unprecedented capabilities for genome-wide discovery of novel SSPs in plants. In this review, we summarize known SSPs and their functions in various plant species. Then we provide an update on the computational and experimental approaches that can be used to discover new SSPs. Finally, we discuss strategies for elucidating the biological functions of SSPs in plants.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2017

Dual impact of elevated temperature on plant defence and bacterial virulence in Arabidopsis

Environmental conditions profoundly affect plant disease development; however, the underlying molecular bases are not well understood. Here we show that elevated temperature significantly increases the susceptibility of Arabidopsis to Pseudomonas syringae pv. tomato (Pst) DC3000 independently of the phyB/PIF thermosensing pathway. Instead, elevated temperature promotes translocation of bacterial effector proteins into plant cells and causes a loss of ICS1-mediated salicylic acid (SA) biosynthesis. Global transcriptome analysis reveals a major temperature-sensitive node of SA signalling, impacting ~60% of benzothiadiazole (BTH)-regulated genes, including ICS1 and the canonical SA marker gene, PR1. Remarkably, BTH can effectively protect Arabidopsis against Pst DC3000 infection at elevated temperature despite the lack of ICS1 and PR1 expression. Our results highlight the broad impact of a major climate condition on the enigmatic molecular interplay between temperature, SA defence and function of a central bacterial virulence system in the context of a widely studied susceptible plant–pathogen interaction.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors

Pulmonary large-cell neuroendocrine carcinomas (LCNECs) have similarities with other lung cancers, but their precise relationship has remained unclear. Here in this paper we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: “type I LCNECs” with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and “type II LCNECs” enriched for bi-allelic inactivation of TP53 and RB1 (42%). Despite sharing genomic alterations with adenocarcinomas and squamous cell carcinomas, no transcriptional relationship was found; instead LCNECs form distinct transcriptional subgroups with closest similarity to SCLC. While type I LCNECs and SCLCs exhibit a neuroendocrine profile with ASCL1 high /DLL3 high /NOTCH low , type II LCNECs bear TP53 and RB1 alterations and differ from most SCLC tumors with reduced neuroendocrine markers, a pattern of ASCL1 low /DLL3 low /NOTCH high , and an upregulation of immune-related pathways. In conclusion, LCNECs comprise two molecularly defined subgroups, and distinguishing them from SCLC may allow stratified targeted treatment of high-grade neuroendocrine lung tumors.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Improving wood properties for wood utilization through multi-omics integration in lignin biosynthesis

A multi-omics quantitative integrative analysis of lignin biosynthesis can advance the strategic engineering of wood for timber, pulp, and biofuels. Lignin is polymerized from three monomers (monolignols) produced by a grid-like pathway. The pathway in wood formation of Populus trichocarpa has at least 21 genes, encoding enzymes that mediate 37 reactions on 24 metabolites, leading to lignin and affecting wood properties. We perturb these 21 pathway genes and integrate transcriptomic, proteomic, fluxomic and phenomic data from 221 lines selected from ~2000 transgenics (6-month-old). The integrative analysis estimates how changing expression of pathway gene or gene combination affects protein abundance, metabolic-flux, metabolite concentrations, and 25 wood traits, including lignin, tree-growth, density, strength, and saccharification. The analysis then predicts improvements in any of these 25 traits individually or in combinations, through engineering expression of specific monolignol genes. The analysis may lead to greater understanding of other pathways for improved growth and adaptation.

09 BIOMASS FUELS↗
DOE OSTI2019

Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation

Global loss of DNA methylation and CpG island (CGI) hypermethylation are key epigenomic aberrations in cancer. Global loss manifests itself in partially methylated domains (PMDs) which extend up to megabases. However, the distribution of PMDs within and between tumor types, and their effects on key functional genomic elements including CGIs are poorly defined. We comprehensively show that loss of methylation in PMDs occurs in a large fraction of the genome and represents the prime source of DNA methylation variation. PMDs are hypervariable in methylation level, size and distribution, and display elevated mutation rates. They impose intermediate DNA methylation levels incognizant of functional genomic elements including CGIs, underpinning a CGI methylator phenotype (CIMP). Repression effects on tumor suppressor genes are negligible as they are generally excluded from PMDs. The genomic distribution of PMDs reports tissue-of-origin and may represent tissue-specific silent regions which tolerate instability at the epigenetic, transcriptomic and genetic level.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

The structural basis for RNA selectivity by the IMP family of RNA-binding proteins

The IGF2 mRNA-binding proteins (ZBP1/IMP1, IMP2, IMP3) are highly conserved post-transcriptional regulators of RNA stability, localization and translation. They play important roles in cell migration, neural development, metabolism and cancer cell survival. The knockout phenotypes of individual IMP proteins suggest that each family member regulates a unique pool of RNAs, yet evidence and an underlying mechanism for this is lacking. Here, we combine systematic evolution of ligands by exponential enrichment (SELEX) and NMR spectroscopy to demonstrate that the major RNA-binding domains of the two most distantly related IMPs (ZBP1 and IMP2) bind to different consensus sequences and regulate targets consistent with their knockout phenotypes and roles in disease. We find that the targeting specificity of each IMP is determined by few amino acids in their variable loops. As variable loops often differ amongst KH domain paralogs, we hypothesize that this is a general mechanism for evolving specificity and regulation of the transcriptome.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Fecal microbiota transplant rescues mice from human pathogen mediated sepsis by restoring systemic immunity

Death due to sepsis remains a persistent threat to critically ill patients confined to the intensive care unit and is characterized by colonization with multi-drug-resistant healthcare-associated pathogens. Here we report that sepsis in mice caused by a defined four-member pathogen community isolated from a patient with lethal sepsis is associated with the systemic suppression of key elements of the host transcriptome required for pathogen clearance and decreased butyrate expression. More specifically, these pathogens directly suppress interferon regulatory factor 3. Fecal microbiota transplant (FMT) reverses the course of otherwise lethal sepsis by enhancing pathogen clearance via the restoration of host immunity in an interferon regulatory factor 3-dependent manner. This protective effect is linked to the expansion of butyrate-producing Bacteroidetes. Taken together these results suggest that fecal microbiota transplantation may be a treatment option in sepsis associated with immunosuppression.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

High-throughput and high-efficiency sample preparation for single-cell proteomics using a nested nanowell chip

Abstract Global quantification of protein abundances in single cells could provide direct information on cellular phenotypes and complement transcriptomics measurements. However, single-cell proteomics is still immature and confronts many technical challenges. Herein we describe a nested nanoPOTS (N2) chip to improve protein recovery, operation robustness, and processing throughput for isobaric-labeling-based scProteomics workflow. The N2 chip reduces reaction volume to <30 nL and increases capacity to >240 single cells on a single microchip. The tandem mass tag (TMT) pooling step is simplified by adding a microliter droplet on the nested nanowells to combine labeled single-cell samples. In the analysis of ~100 individual cells from three different cell lines, we demonstrate that the N2 chip-based scProteomics platform can robustly quantify ~1500 proteins and reveal membrane protein markers. Our analyses also reveal low protein abundance variations, suggesting the single-cell proteome profiles are highly stable for the cells cultured under identical conditions.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Interdependent iron and phosphorus availability controls photosynthesis through retrograde signaling

Abstract Iron deficiency hampers photosynthesis and is associated with chlorosis. We recently showed that iron deficiency-induced chlorosis depends on phosphorus availability. How plants integrate these cues to control chlorophyll accumulation is unknown. Here, we show that iron limitation downregulates photosynthesis genes in a phosphorus-dependent manner. Using transcriptomics and genome-wide association analysis, we identify two genes, PHT4;4 encoding a chloroplastic ascorbate transporter and bZIP58 , encoding a nuclear transcription factor, which prevent the downregulation of photosynthesis genes leading to the stay-green phenotype under iron-phosphorus deficiency. Joint limitation of these nutrients induces ascorbate accumulation by activating expression of an ascorbate biosynthesis gene, VTC4 , which requires bZIP58. Furthermore, we demonstrate that chloroplastic ascorbate transport prevents the downregulation of photosynthesis genes under iron-phosphorus combined deficiency through modulation of ROS homeostasis. Our study uncovers a ROS-mediated chloroplastic retrograde signaling pathway to adapt photosynthesis to nutrient availability.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Insights into pulmonary phosphate homeostasis and osteoclastogenesis emerge from the study of pulmonary alveolar microlithiasis

Pulmonary alveolar microlithiasis is an autosomal recessive lung disease caused by a deficiency in the pulmonary epithelial Npt2b sodium-phosphate co-transporter that results in accumulation of phosphate and formation of hydroxyapatite microliths in the alveolar space. The single cell transcriptomic analysis of a pulmonary alveolar microlithiasis lung explant showing a robust osteoclast gene signature in alveolar monocytes and the finding that calcium phosphate microliths contain a rich protein and lipid matrix that includes bone resorbing osteoclast enzymes and other proteins suggested a role for osteoclast-like cells in the host response to microliths. While investigating the mechanisms of microlith clearance, we found that Npt2b modulates pulmonary phosphate homeostasis through effects on alternative phosphate transporter activity and alveolar osteoprotegerin, and that microliths induce osteoclast formation and activation in a receptor activator of nuclear factor-κB ligand and dietary phosphate dependent manner. This work reveals that Npt2b and pulmonary osteoclast-like cells play key roles in pulmonary homeostasis and suggest potential new therapeutic targets for the treatment of lung disease.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Guided construction of single cell reference for human and mouse lung

Accurate cell type identification is a key and rate-limiting step in single-cell data analysis. Single-cell references with comprehensive cell types, reproducible and functionally validated cell identities, and common nomenclatures are much needed by the research community for automated cell type annotation, data integration, and data sharing. Here, we develop a computational pipeline utilizing the LungMAP CellCards as a dictionary to consolidate single-cell transcriptomic datasets of 104 human lungs and 17 mouse lung samples to construct LungMAP single-cell reference (CellRef) for both normal human and mouse lungs. CellRefs define 48 human and 40 mouse lung cell types catalogued from diverse anatomic locations and developmental time points. We demonstrate the accuracy and stability of LungMAP CellRefs and their utility for automated cell type annotation of both normal and diseased lungs using multiple independent methods and testing data. We develop user-friendly web interfaces for easy access and maximal utilization of the LungMAP CellRefs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations

DNA methyltransferases DNMT3A- and DNMT3B-mediated DNA methylation critically regulate epigenomic and transcriptomic patterning during development. The hotspot DNMT3A mutations at the site of Arg822 (R882) promote polymerization, leading to aberrant DNA methylation that may contribute to the pathogenesis of acute myeloid leukemia (AML). However, the molecular basis underlying the mutation-induced functional misregulation of DNMT3A remains unclear. Here, we report the crystal structures of the DNMT3A methyltransferase domain, revealing a molecular basis for its oligomerization behavior distinct to DNMT3B, and the enhanced intermolecular contacts caused by the R882H or R882C mutation. Our biochemical, cellular, and genomic DNA methylation analyses demonstrate that introducing the DNMT3B-converting mutations inhibits the R882H-/R882C-triggered DNMT3A polymerization and enhances substrate access, thereby eliminating the dominant-negative effect of the DNMT3A R882 mutations in cells. Together, this study provides mechanistic insights into DNMT3A R882 mutations-triggered aberrant oligomerization and DNA hypomethylation in AML, with important implications in cancer therapy.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Single-cell RNA sequencing reveals plasmid constrains bacterial population heterogeneity and identifies a non-conjugating subpopulation

Transcriptional heterogeneity in isogenic bacterial populations can play various roles in bacterial evolution, but its detection remains technically challenging. Here, we use microbial split-pool ligation transcriptomics to study the relationship between bacterial subpopulation formation and plasmid-host interactions at the single-cell level. We find that single-cell transcript abundances are influenced by bacterial growth state and plasmid carriage. Moreover, plasmid carriage constrains the formation of bacterial subpopulations. Plasmid genes, including those with core functions such as replication and maintenance, exhibit transcriptional heterogeneity associated with cell activity. Notably, we identify a cell subpopulation that does not transcribe conjugal plasmid transfer genes, which may help reduce plasmid burden on a subset of cells. Our study advances the understanding of plasmid-mediated subpopulation dynamics and provides insights into the plasmid-bacteria interplay.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Symmetric and asymmetric DNA N6-adenine methylation regulates different biological responses in Mucorales

DNA N6-adenine methylation (6mA) has recently gained importance as an epigenetic modification in eukaryotes. Its function in lineages with high levels, such as early-diverging fungi (EDF), is of particular interest. Here, we investigated the biological significance and evolutionary implications of 6mA in EDF, which exhibit divergent evolutionary patterns in 6mA usage. The analysis of two Mucorales species displaying extreme 6mA usage reveals that species with high 6mA levels show symmetric methylation enriched in highly expressed genes. In contrast, species with low 6mA levels show mostly asymmetric 6mA. Interestingly, transcriptomic regulation throughout development and in response to environmental cues is associated with changes in the 6mA landscape. Furthermore, we identify an EDF-specific methyltransferase, likely originated from endosymbiotic bacteria, as responsible for asymmetric methylation, while an MTA-70 methylation complex performs symmetric methylation. The distinct phenotypes observed in the corresponding mutants reinforced the critical role of both types of 6mA in EDF.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Complex transcriptional regulations of a hyperparasitic quadripartite system in giant viruses infecting protists

Abstract Hyperparasitism is a common pattern in nature that is not limited to cellular organisms. Giant viruses infecting protists can be hyperparasitized by smaller ones named virophages. In addition, both may carry episomal DNA molecules known as transpovirons in their particles. They all share transcriptional regulatory elements that dictate the expression of their genes within viral factories built by giant viruses in the host cytoplasm. This suggests the existence of interactions between their respective transcriptional networks. Here we investigatedAcanthamoeba castellaniicells infected by a giant virus (megavirus chilensis), and coinfected with a virophage (zamilon vitis) and/or a transpoviron (megavirus vitis transpoviron). Infectious cycles were monitored through time-course RNA sequencing to decipher the transcriptional program of each partner and its impact on the gene expression of the others. We found highly diverse transcriptional responses. While the giant virus drastically reshaped the host cell transcriptome, the transpoviron had no effect on the gene expression of any of the players. In contrast, the virophage strongly modified the giant virus gene expression, albeit transiently, without altering the protein composition of mature viral particles. The virophage also induced the overexpression of transpoviron genes, likely through the indirect upregulation of giant virus-encoded transcription factors. Together, these analyses document the intricated transcriptionally regulated networks taking place in the infected cell.

Science & Technology - Other Topics↗
DOE OSTI2025

A cytosolic glyoxylate shunt complements the canonical photorespiratory pathway in Arabidopsis

Photorespiration functions in part to support photosynthetic performance, especially under stress such as high light, yet the underlying mechanisms are poorly understood. To identify modulators of photorespiration under high light, we have isolated genetic suppressors of the photorespiratory mutant hpr1 (hydroxypyruvate reductase 1) from Arabidopsis. A suppressor that partially rescues hpr1 is mapped to GLYR1, which encodes the cytosolic glyoxylate reductase 1 that converts glyoxylate to glycolate. Independent glyr1 mutants also partially rescue hpr1 and another photorespiratory mutant, catalase 2. Our genetic, transcriptomic and metabolic profiling analyses together reveal a connection between cytosolic glyoxylate and a non-canonical photorespiratory route mediated by HPR2, which we name the photorespiratory glyoxylate shunt. This shunt complements the canonical photorespiratory pathway and is especially critical when high photorespiratory fluxes are required and when the major photorespiratory pathway is deficient. Our findings support the metabolic flexibility of photorespiration and may help to improve crop performance under stress.

Light stress↗
DOE OSTI2025

Genome-resolved biogeography of Phaeocystales, cosmopolitan bloom-forming algae

Phaeocystales, comprising the genus Phaeocystis and an uncharacterized sister lineage, are nanoplanktonic haptophytes widespread in the global ocean. Several species form mucilaginous colonies and influence key biogeochemical cycles, yet their underlying diversity and ecological strategies remain underexplored. Here, we present new genomic data from 13 strains, including three high-quality reference genomes (N50 > 30 kbp), and integrate previous metagenome-assembled genomes to resolve a robust phylogeny. Divergence timing of P. antarctica aligns with Miocene cooling and Southern Ocean isolation. Genomic traits reveal metabolic flexibility, including mixotrophic nitrogen acquisition in temperate waters and gene expansions linked to polar nutrient adaptation. Concordantly, transcriptomic comparisons between temperate and polar Phaeocystis suggest Southern Ocean populations experience iron and B12 limitation. We also identify signatures of horizontal gene transfer and endogenous giant virus/virophage insertions. Together, these findings highlight Phaeocystales as an ecologically versatile and geographically widespread lineage shaped by evolutionary innovation and adaptation to contrasting environmental stressors.

Füssy, Zoltán↗