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At least 1,009 records · Page 56
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Metabolic Engineering of the Oleaginous Yeast Yarrowia lipolytica PO1f for Production of Erythritol from Glycerol

Yarrowia lipolytica was found natively to produce erythritol, mannitol, and arabitol during growth on glucose, fructose, mannose, and glycerol. Osmotic stress is known to increase sugar alcohol production, and was found to significantly increase erythritol production during growth on glycerol. To better understand erythritol production from glycerol, since it was the most promising sugar alcohol, we measured the expression of key genes and intracellular metabolites. Osmotic stress increased the expression of several key genes in the glycerol catabolic pathway and the pentose phosphate pathway. Analysis of intracellular metabolites revealed that amino acids, sugar alcohols, and polyamines are produced at higher levels in response to osmotic stress. Heterologous overexpression of the sugar alcohol phosphatase increased erythritol production and glycerol utilization in Y. lipolytica . We further increased erythritol production by increasing the expression of native glycerol kinase (GK), and transketolase (TKL). These data show the growth and titers produced.

Conversion↗
DOE OSTI2021

Competitive binding of STATs to receptor phospho-Tyr motifs accounts for altered cytokine responses

Cytokines elicit pleiotropic and non-redundant activities despite strong overlap in their usage of receptors, JAKs and STATs molecules. We use IL-6 and IL-27 to ask how two cytokines activating the same signaling pathway have different biological roles. We found that IL-27 induces more sustained STAT1 phosphorylation than IL-6, with the two cytokines inducing comparable levels of STAT3 phosphorylation. Mathematical and statistical modeling of IL-6 and IL-27 signaling identified STAT3 binding to GP130, and STAT1 binding to IL-27Rα, as the main dynamical processes contributing to sustained pSTAT1 levels by IL-27. Mutation of Tyr613 on IL-27Rα decreased IL-27-induced STAT1 phosphorylation by 80% but had limited effect on STAT3 phosphorgylation. Strong receptor/STAT coupling by IL-27 initiated a unique gene expression program, which required sustained STAT1 phosphorylation and IRF1 expression and was enriched in classical Interferon Stimulated Genes. Interestingly, the STAT/receptor coupling exhibited by IL-6/IL-27 was altered in patients with systemic lupus erythematosus (SLE). IL-6/IL-27 induced a more potent STAT1 activation in SLE patients than in healthy controls, which correlated with higher STAT1 expression in these patients. Partial inhibition of JAK activation by sub-saturating doses of Tofacitinib specifically lowered the levels of STAT1 activation by IL-6. Our data show that receptor and STATs concentrations critically contribute to shape cytokine responses and generate functional pleiotropy in health and disease.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2002

Expression of the high capacity calcium-binding domain of calreticulin increases bioavailable calcium stores in plants

Modulation of cytosolic calcium levels in both plants and animals is achieved by a system of Ca2+-transport and storage pathways that include Ca2+ buffering proteins in the lumen of intracellular compartments. To date, most research has focused on the role of transporters in regulating cytosolic calcium. We used a reverse genetics approach to modulate calcium stores in the lumen of the endoplasmic reticulum. Our goals were two-fold: to use the low affinity, high capacity Ca2+ binding characteristics of the C-domain of calreticulin to selectively increase Ca2+ storage in the endoplasmic reticulum, and to determine if those alterations affected plant physiological responses to stress. The C-domain of calreticulin is a highly acidic region that binds 20-50 moles of Ca2+ per mole of protein and has been shown to be the major site of Ca2+ storage within the endoplasmic reticulum of plant cells. A 377-bp fragment encoding the C-domain and ER retention signal from the maize calreticulin gene was fused to a gene for the green fluorescent protein and expressed in Arabidopsis under the control of a heat shock promoter. Following induction on normal medium, the C-domain transformants showed delayed loss of chlorophyll after transfer to calcium depleted medium when compared to seedlings transformed with green fluorescent protein alone. Total calcium measurements showed a 9-35% increase for induced C-domain transformants compared to controls. The data suggest that ectopic expression of the calreticulin C-domain increases Ca2+ stores, and that this Ca2+ reserve can be used by the plant in times of stress.

NASA Discipline Plant Biology↗
DOE OSTI2015

Irradiated fibroblasts promote epithelial–mesenchymal transition and HDGF expression of esophageal squamous cell carcinoma

Recent evidence suggested that nonirradiated cancer-associated fibroblasts (CAFs) promoted aggressive phenotypes of cancer cells through epithelial–mesenchymal transition (EMT). Hepatoma-derived growth factor (HDGF) is a radiosensitive gene of esophageal squamous cell carcinoma (ESCC). This study aimed to investigate the effect of irradiated fibroblasts on EMT and HDGF expression of ESCC. Our study demonstrated that coculture with nonirradiated fibroblasts significantly increased the invasive ability of ESCC cells and the increased invasiveness was further accelerated when they were cocultured with irradiated fibroblasts. Scattering of ESCC cells was also accelerated by the supernatant from irradiated fibroblasts. Exposure of ESCC cells to supernatant from irradiated fibroblasts resulted in decreased E-cadherin, increased vimentin in vitro and β-catenin was demonstrated to localize to the nucleus in tumor cells with irradiated fibroblasts in vivo models. The expression of HDGF and β-catenin were increased in both fibroblasts and ESCC cells of irradiated group in vitro and in vivo models. Interestingly, the tumor cells adjoining the stromal fibroblasts displayed strong nuclear HDGF immunoreactivity, which suggested the occurrence of a paracrine effect of fibroblasts on HDGF expression. These data suggested that irradiated fibroblasts promoted invasion, growth, EMT and HDGF expression of ESCC. - Highlights: • Irradiated CAFs accelerated invasiveness and scattering of ESCC cell lines. • Irradiated CAFs promoted EMT of ESCC cells. • Irradiated fibroblasts induced nuclear β-catenin relocalization in ESCC cells. • Irradiated fibroblasts increased HDGF expression in vitro and in vivo.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Data for Rapid and Efficient in planta Genome Editing in Sorghum Using Foxtail Mosaic Virus-mediated sgRNA Delivery

The requirement of in vitro tissue culture for the delivery of gene editing reagents limits the application of gene editing to commercially relevant varieties of many crop species. To overcome this bottleneck, plant RNA viruses have been deployed as versatile tools for in planta delivery of recombinant RNA. Viral delivery of single-guide RNAs (sgRNAs) to transgenic plants that stably express CRISPR-associated (Cas) endonuclease has been successfully used for targeted mutagenesis in several dicotyledonous and few monocotyledonous plants. Progress with this approach in monocotyledonous plants is limited so far by the availability of effective viral vectors. We engineered a set of foxtail mosaic virus (FoMV) and barley stripe mosaic virus (BSMV) vectors to deliver the fluorescent protein AmCyan to track viral infection and movement in Sorghum bicolor . We further used these viruses to deliver and express sgRNAs to Cas9 and Green Fluorescent Protein (GFP) expressing transgenic sorghum lines, targeting Phytoene desaturase (PDS), Magnesium-chelatase subunit I (MgCh), 4-hydroxy-3-methylbut-2-enyl diphosphate reductase, orthologs of maize Lemon white1 (Lw1) or GFP. The recombinant BSMV did neither infect sorghum nor deliver or express AmCyan and sgRNAs. In contrast, the recombinant FoMV systemically spread throughout sorghum plants and induced somatic mutations with frequencies reaching up to 60%. This mutagenesis led to visible phenotypic changes, demonstrating the potential of FoMV for in planta gene editing and functional genomics studies in sorghum.

Feedstock Production↗
DOE OSTI2017

Regulator of G protein signaling 4 is a novel target of GATA-6 transcription factor

GATA transcription factors regulate an array of genes important in cell proliferation and differentiation. Here we report the identification of regulator of G protein signaling 4 (RGS4) as a novel target for GATA-6 transcription factor. Although three sites (a, b, c) within the proximal region of rabbit RGS4 promoter for GATA transcription factors were predicted by bioinformatics analysis, only GATA-a site (16 bp from the core TATA box) is essential for RGS4 transcriptional regulation. RT-PCR analysis demonstrated that only GATA-6 was highly expressed in rabbit colonic smooth muscle cells but GATA-4/6 were expressed in cardiac myocytes and GATA-1/2/3 expressed in blood cells. Adenovirus-mediated expression of GATA-6 but not GATA-1 significantly increased the constitutive and IL-1β-induced mRNA expression of the endogenous RGS4 in colonic smooth muscle cells. IL-1β stimulation induced GATA-6 nuclear translocation and increased GATA-6 binding to RGS4 promoter. These data suggest that GATA factor could affect G protein signaling through regulating RGS4 expression, and GATA signaling may develop as a future therapeutic target for RGS4-related diseases. - Highlights: • GATA-6 is highly expressed in colonic smooth muscle cells. • RGS4 is a novel target for GATA-6 transcription factor. • GATA-a response element is essential to regulate the core promoter of RGS4. • GATA-6 regulates IL-1β-induced RGS4 upregulation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Transcriptional bursting explains the noise–versus–mean relationship in mRNA and protein levels

Recent analysis demonstrates that the HIV-1 Long Terminal Repeat (HIV LTR) promoter exhibits a range of possible transcriptional burst sizes and frequencies for any mean-expression level. However, these results have also been interpreted as demonstrating that cell-tocell expression variability (noise) and mean are uncorrelated, a significant deviation from previous results. Here, we re-examine the available mRNA and protein abundance data for the HIV LTR and find that noise in mRNA and protein expression scales inversely with the mean along analytically predicted transcriptional burst-size manifolds. We then experimentally perturb transcriptional activity to test a prediction of the multiple burst-size model: that increasing burst frequency will cause mRNA noise to decrease along given burst-size lines as mRNA levels increase. In conclusion, the data show that mRNA and protein noise decrease as mean expression increases, supporting the canonical inverse correlation between noise and mean.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Down-regulation of arginine decarboxylase gene-expression results in reactive oxygen species accumulation in Arabidopsis

Highlights: • ROS content and CAT activity is deregulated in a non-lethal line (amiR:ADC-L2) with low polyamine levels. • Catalase exogenous treatment induces a promoting growth in A. thaliana. • Accumulation of ROS in amiR:ADC-L2 line is independent of PA catabolism. Arabidopsis amiR:ADC-L2 is a non-lethal line with several developmental defects, it is characterized by a drastic reduction in free polyamine content. Herein, we found that catalase application had growth-promoting effects in amiR:ADC-L2 and parental Ws seedlings. Differences in ROS content between amiR:ADC-L2 and Ws seedlings were detected. Increased H{sub 2}O{sub 2} levels were found in the amiR:ADC-L2, as well as low AtCAT2 gene expression and reduced catalase activity. Estimation of polyamine oxidase activity in amiR:ADC-L2 line indicated that the over-accumulation of H{sub 2}O{sub 2} is independent of polyamine catabolism. However, increments in NADPH oxidase activity and O{sub 2}{sup • −} content could be associated to the higher H{sub 2}O{sub 2} levels in the amiR:ADC-L2 line. Our data suggest that low polyamine levels in Arabidopsis seedlings are responsible for the accumulation of ROS, by altering the activities of enzymes involved in ROS production and detoxification.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Below-Background Ionizing Radiation as an Environmental Cue for Bacteria

All organisms on earth grow under the influence of a natural and relatively constant dose of ionizing radiation referred to as background radiation, and so cells have different mechanisms to prevent the accumulation of damage caused by its different components. However, current knowledge of the deleterious effects of radiation on cells is based on the exposure to acute and high or to chronic, above background doses of radiation and therefore is not appropriate to explain the cellular and biochemical mechanisms that cells employ to sense and respond to chronic below-background levels. Studies at below-background radiation doses can provide insight into the biological role of radiation, as suggested by several examples of what appears to be a stress response in cells grown at doses that range from 10 to 79 times lower than background. Here, we discuss some of the technical constraints to shield cells from radiation to below-background levels, as well as different approaches used to detect and measure responses to such unusual environmental conditions. Then, we present data from Shewanella oneidensis and Deinococcus radiodurans experiments that show how two taxonomically distant bacterial species sense and respond to unnaturally low levels of radiation. Finally, in brief, we grew S. oneidensis and D. radiodurans in liquid culture at dose rates of 72.05 (control) and 0.91 (treatment) nGy hr -1 (including radon) for up to 72 h and measured cell density and the expression of stress-related genes. Our results suggest that a stress response is triggered in the absence of normal levels of radiation.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗
DOE OSTI2015

Gateways to the FANTOM5 promoter level mammalian expression atlas

The FANTOM5 project investigates transcription initiation activities in more than 1,000 human and mouse primary cells, cell lines and tissues using CAGE. Based on manual curation of sample information and development of an ontology for sample classification, we assemble the resulting data into a centralized data resource (http://fantom.gsc.riken.jp/5/). In conclusion, this resource contains web-based tools and data-access points for the research community to search and extract data related to samples, genes, promoter activities, transcription factors and enhancers across the FANTOM5 atlas.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2015

Rosiglitazone activation of PPARγ-dependent signaling is neuroprotective in mutant huntingtin expressing cells

Peroxisome proliferator-activated receptor gamma (PPARγ) is a crucial transcription factor for neuroprotection in several brain diseases. Using a mouse model of Huntington's Disease (HD), we recently showed that PPARγ not only played a major function in preventing HD, but also oral intake of a PPARγ agonist (thiazolidinedione, TZD) significantly reduced the formation of mutant Huntingtin (mHtt) aggregates in the brain (e.g., cortex and striatum). The molecular mechanisms by which PPARγ exerts its HD neuroprotective effects remain unresolved. We investigated whether the PPARγ agonist (rosiglitazone) mediates neuroprotection in the mHtt expressing neuroblastoma cell line (N2A). Here we show that rosiglitazone upregulated the endogenous expression of PPARγ, its downstream target genes (including PGC1α, NRF-1 and Tfam) and mitochondrial function in mHtt expressing N2A cells. Rosiglitazone treatment also significantly reduced mHtt aggregates that included ubiquitin (Ub) and heat shock factor 1 (HSF1), as assessed by a filter-retardation assay, and increased the levels of the functional ubiquitin–proteasome system (UPS), HSF1 and heat shock protein 27/70 (HSP27/70) in N2A cells. Moreover, rosiglitazone treatment normalized endoplasmic reticulum (ER) stress sensors Bip, CHOP and ASK1, and significantly increased N2A cell survival. Taken together, these findings unveil new insights into the mechanisms by which activation of PPARγ signaling protects against the HD-mediated neuronal impairment. Further, our data also support the concept that PPARγ may be a novel therapeutic target for treating HD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Convergence of hepcidin deficiency, systemic iron overloading, heme accumulation, and REV-ERBα/β activation in aryl hydrocarbon receptor-elicited hepatotoxicity

Persistent aryl hydrocarbon receptor (AhR) agonists elicit dose-dependent hepatic lipid accumulation, oxidative stress, inflammation, and fibrosis in mice. Iron (Fe) promotes AhR-mediated oxidative stress by catalyzing reactive oxygen species (ROS) production. To further characterize the role of Fe in AhR-mediated hepatotoxicity, male C57BL/6 mice were orally gavaged with sesame oil vehicle or 0.01–30 μg/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) every 4 days for 28 days. Duodenal epithelial and hepatic RNA-Seq data were integrated with hepatic AhR ChIP-Seq, capillary electrophoresis protein measurements, and clinical chemistry analyses. TCDD dose-dependently repressed hepatic expression of hepcidin (Hamp and Hamp2), the master regulator of systemic Fe homeostasis, resulting in a 2.6-fold increase in serum Fe with accumulating Fe spilling into urine. Total hepatic Fe levels were negligibly increased while transferrin saturation remained unchanged. Furthermore, TCDD elicited dose-dependent gene expression changes in heme biosynthesis including the induction of aminolevulinic acid synthase 1 (Alas1) and repression of uroporphyrinogen decarboxylase (Urod), leading to a 50% increase in hepatic hemin and a 13.2-fold increase in total urinary porphyrins. Consistent with this heme accumulation, differential gene expression suggests that heme activated BACH1 and REV-ERBα/β, causing induction of heme oxygenase 1 (Hmox1) and repression of fatty acid biosynthesis, respectively. Collectively, these results suggest that Hamp repression, Fe accumulation, and increased heme levels converge to promote oxidative stress and the progression of TCDD-elicited hepatotoxicity. - Highlights: • TCDD represses hepatic hepcidin expression, leading to systemic iron overloading. • Dysregulation of heme biosynthesis is consistent with heme and porphyrin accumulation. • Heme-activated REV-ERBα/β repress circadian-regulated hepatic lipid metabolism. • Disruption of iron homeostasis promotes TCDD-elicited steatohepatitis with fibrosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Orthologs of human circulating miRNAs associated with hepatocellular carcinoma are elevated in mouse plasma months before tumour detection

Research examining the potential for circulating miRNA to serve as markers for preneoplastic lesions or early-stage hepatocellular carcinoma (HCC) is hindered by the difficulties of obtaining samples from asymptomatic individuals. As a surrogate for human samples, we identified hub miRNAs in gene co-expression networks using HCC-bearing C3H mice. We confirmed 38 hub miRNAs as associated with HCC in F2 hybrid mice derived from radiogenic HCC susceptible and resistant founders. When compared to a panel of 12 circulating miRNAs associated with human HCC, two had no mouse ortholog and 7 of the remaining 10 miRNAs overlapped with the 38 mouse HCC hub miRNAs. Using small RNA sequencing data generated from serially collected plasma samples in F2 mice, we examined the temporal levels of these 7 circulating miRNAs and found that the levels of 4 human circulating markers, miR-122-5p, miR-100-5p, miR-34a-5p and miR-365-3p increased linearly as the time approaching HCC detection neared, suggesting a correlation of miRNA levels with oncogenic progression. Estimation of change points in the kinetics of the 4 circulating miRNAs suggested the changes started 17.5 to 6.8 months prior to HCC detection. These data establish these 4 circulating miRNAs as potential sentinels for preneoplastic lesions or early-stage HCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Multi‐omics of the Soil Microbiome

TheArctic is characterized by vast amounts of carbon stored in permafrost and isan important focal point for the study of climate change as increasing temperature may accelerate microbially‐mediated release of carbon stored inpermafrost into the atmosphere as CO 2 and CH 4 . Yet surprisingly, very little is known about the vulnerability of permafrost andresponse of microorganisms in the permafrost to their changing environment. To address these knowledge gaps we used omics technologiesto explore permafrost microbial communities, to reveal hitherto unknown soilmicrobial populations and to link them to specific soil biogeochemical processes. For these projects we employed an omics pipeline that includes metagenomics, metatranscriptomics and metaproteomics to determine the phylogenetic and functional gene compositions and their expression in complex, non‐sterile soil samples collected from the field at several locations in Alaska. These studies have presented several challenges due to the unprecedented large size of the datasets and the insufficiency of available bioinformatic tools & databases to analyze, correlate and integrate thedata. To address these challenges we developed a novel functional gene databaseand used different assembly and analysis algorithms to determine key featuresin the datasets. The data reveal the microbial diversity, composition andfunctional potential in permafrost and how the microbial communities respond toclimate change impacts. Support or Funding Information Microbiomes in Transition, LDRD, Pacific Northwest National Laboratories, Richland, Washington

Jansson, Janet K.↗
DOE OSTI2017

Analysis of individual cells identifies cell-to-cell variability following induction of cellular senescence

Senescent cells play important roles in both physiological and pathological processes, including cancer and aging. In all cases, however, senescent cells comprise only a small fraction of tissues. Senescent phenotypes have been studied largely in relatively homogeneous populations of cultured cells. In vivo, senescent cells are generally identified by a small number of markers, but whether and how these markers vary among individual cells is unknown. We therefore utilized a combination of single-cell isolation and a nanofluidic PCR platform to determine the contributions of individual cells to the overall gene expression profile of senescent human fibroblast populations. Individual senescent cells were surprisingly heterogeneous in their gene expression signatures. This cell-to-cell variability resulted in a loss of correlation among the expression of several senescence associated genes. Many genes encoding senescence-associated secretory phenotype (SASP) factors, a major contributor to the effects of senescent cells in vivo, showed marked variability with a subset of highly induced genes accounting for the increases observed at the population level. Inflammatory genes in clustered genomic loci showed a greater correlation with senescence compared to nonclustered loci, suggesting that these genes are coregulated by genomic location. Together, these data offer new insights into how genes are regulated in senescent cells and suggest that single markers are inadequate to identify senescent cells in vivo.

transcriptomics↗
DOE OSTI2024

The RNA-binding protein Modulo promotes neural stem cell maintenance in Drosophila

A small population of stem cells in the developing Drosophila central nervous system generates the large number of different cell types that make up the adult brain. To achieve this, these neural stem cells (neuroblasts, NBs) divide asymmetrically to produce non-identical daughter cells. The balance between stem cell self-renewal and neural differentiation is regulated by various cellular machinery, including transcription factors, chromatin remodelers, and RNA-binding proteins. The list of these components remains incomplete, and the mechanisms regulating their function are not fully understood, however. Here, we identify a role for the RNA-binding protein Modulo (Mod; nucleolin in humans) in NB maintenance. We employ transcriptomic analyses to identify RNA targets of Mod and assess changes in global gene expression following its knockdown, results of which suggest a link with notable proneural genes and those essential for neurogenesis. Mod is expressed in larval brains and its loss leads to a significant decrease in the number of central brain NBs. Stem cells that remain lack expression of key NB identity factors and exhibit cell proliferation defects. Mechanistically, our analysis suggests these deficiencies arise at least in part from altered cell cycle progression, with a proportion of NBs arresting prior to mitosis. Overall, our data show that Mod function is essential for neural stem cell maintenance during neurogenesis.

Parra, Amalia S.↗
NASA NTRS2004

cWINNOWER algorithm for finding fuzzy dna motifs

The cWINNOWER algorithm detects fuzzy motifs in DNA sequences rich in protein-binding signals. A signal is defined as any short nucleotide pattern having up to d mutations differing from a motif of length l. The algorithm finds such motifs if a clique consisting of a sufficiently large number of mutated copies of the motif (i.e., the signals) is present in the DNA sequence. The cWINNOWER algorithm substantially improves the sensitivity of the winnower method of Pevzner and Sze by imposing a consensus constraint, enabling it to detect much weaker signals. We studied the minimum detectable clique size qc as a function of sequence length N for random sequences. We found that qc increases linearly with N for a fast version of the algorithm based on counting three-member sub-cliques. Imposing consensus constraints reduces qc by a factor of three in this case, which makes the algorithm dramatically more sensitive. Our most sensitive algorithm, which counts four-member sub-cliques, needs a minimum of only 13 signals to detect motifs in a sequence of length N = 12,000 for (l, d) = (15, 4). Copyright Imperial College Press.

Evaluation Studies↗