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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 811 records · Page 45
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Ultraconserved enhancer function does not require perfect sequence conservation

Ultraconserved enhancer sequences show perfect conservation between human and rodent genomes, suggesting that their functions are highly sensitive to mutation. However, current models of enhancer function do not sufficiently explain this extreme evolutionary constraint. We subjected 23 ultraconserved enhancers to different levels of mutagenesis, collectively introducing 1,547 mutations, and examined their activities in transgenic mouse reporter assays. Overall, we find that the regulatory properties of ultraconserved enhancers are robust to mutation. Upon mutagenesis, nearly all (19/23, 83%) still functioned as enhancers at one developmental stage, as did most of those tested again later in development (5/9, 56%). Replacement of endogenous enhancers with mutated alleles in mice corroborated results of transgenic assays, including the functional resilience of ultraconserved enhancers to mutation. Furthermore, our findings show that the currently known activities of ultraconserved enhancers do not necessarily require the perfect conservation observed in evolution and suggest that additional regulatory or other functions contribute to their sequence constraint.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis

Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs. Gata2 and its effector Gata3 are essential for inner-ear efferent neuron (IEE) but not FBMN development. A humanized HCFP1 mouse model extends Gata2 expression, favors the formation of IEEs over FBMNs and is rescued by conditional loss of Gata3. These findings highlight the importance of temporal gene regulation in development and of noncoding variation in rare mendelian disease.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Increased enhancer–promoter interactions during developmental enhancer activation in mammals

Remote enhancers are thought to interact with their target promoters via physical proximity, yet the importance of this proximity for enhancer function remains unclear. Here, in this study, we investigate the three-dimensional (3D) conformation of enhancers during mammalian development by generating high-resolution tissue-resolved contact maps for nearly a thousand enhancers with characterized in vivo activities in ten murine embryonic tissues. Sixty-one percent of developmental enhancers bypass their neighboring genes, which are often marked by promoter CpG methylation. The majority of enhancers display tissue-specific 3D conformations, and both enhancer-promoter and enhancer-enhancer interactions are moderately but consistently increased upon enhancer activation in vivo. Less than 14% of enhancer-promoter interactions form stably across tissues; however, these invariant interactions form in the absence of the enhancer and are likely mediated by adjacent CTCF binding. Our results highlight the general importance of enhancer-promoter physical proximity for developmental gene activation in mammals.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Supervised enhancer prediction with epigenetic pattern recognition and targeted validation

Enhancers are important non-coding elements, but they have traditionally been hard to characterize experimentally. The development of massively parallel assays allows the characterization of large numbers of enhancers for the first time. Here, we developed a framework using Drosophila STARR-seq to create shape-matching filters based on meta-profiles of epigenetic features. We integrated these features with supervised machine-learning algorithms to predict enhancers. We further demonstrated that our model could be transferred to predict enhancers in mammals. We comprehensively validated the predictions using a combination of in vivo and in vitro approaches, involving transgenic assays in mice and transduction-based reporter assays in human cell lines (153 enhancers in total). The results confirmed that our model can accurately predict enhancers in different species without re-parameterization. Finally, we examined the transcription factor binding patterns at predicted enhancers versus promoters. Here, we demonstrated that these patterns enable the construction of a secondary model that effectively distinguishes enhancers and promoters.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Integrative analysis of the 3D genome and epigenome in mouse embryonic tissues

While a rich set of putative cis-regulatory sequences involved in mouse fetal development have been annotated recently on the basis of chromatin accessibility and histone modification patterns, delineating their role in developmentally regulated gene expression continues to be challenging. To fill this gap, here we mapped chromatin contacts between gene promoters and distal sequences across the genome in seven mouse fetal tissues and across six developmental stages of the forebrain. We identified 248,620 long-range chromatin interactions centered at 14,138 protein-coding genes and characterized their tissue-to-tissue variations and developmental dynamics. Integrative analysis of the interactome with previous epigenome and transcriptome datasets from the same tissues revealed a strong correlation between the chromatin contacts and chromatin state at distal enhancers, as well as gene expression patterns at predicted target genes. We predicted target genes of 15,098 candidate enhancers and used them to annotate target genes of homologous candidate enhancers in the human genome that harbor risk variants of human diseases. We present evidence that schizophrenia and other adult disease risk variants are frequently found in fetal enhancers, providing support for the hypothesis of fetal origins of adult diseases.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

First on-line detection of radioactive fission isotopes produced by laser-accelerated protons

Abstract The on-going developments in laser acceleration of protons and light ions, as well as the production of strong bursts of neutrons and multi- $$\hbox {MeV}$$ MeV photons by secondary processes now provide a basis for novel high-flux nuclear physics experiments. While the maximum energy of protons resulting from Target Normal Sheath Acceleration is presently still limited to around $$100 \, \hbox {MeV}$$ 100 MeV , the generated proton peak flux within the short laser-accelerated bunches can already today exceed the values achievable at the most advanced conventional accelerators by orders of magnitude. This paper consists of two parts covering the scientific motivation and relevance of such experiments and a first proof-of-principle demonstration. In the presented experiment pulses of $$200 \, \hbox {J}$$ 200 J at $$\approx \, 500 \, \hbox {fs}$$ ≈ 500 fs duration from the PHELIX laser produced more than $$10^{12}$$ 10 12 protons with energies above $$15 \, \hbox {MeV}$$ 15 MeV in a bunch of sub-nanosecond duration. They were used to induce fission in foil targets made of natural uranium. To make use of the nonpareil flux, these targets have to be very close to the laser acceleration source, since the particle density within the bunch is strongly affected by Coulomb explosion and the velocity differences between ions of different energy. The main challenge for nuclear detection with high-purity germanium detectors is given by the strong electromagnetic pulse caused by the laser-matter interaction close to the laser acceleration source. This was mitigated by utilizing fast transport of the fission products by a gas flow to a carbon filter, where the $$\upgamma$$ γ -rays were registered. The identified nuclides include those that have half-lives down to $$39 \, \hbox {s}$$ 39 s . These results demonstrate the capability to produce, extract, and detect short-lived reaction products under the demanding experimental condition imposed by the high-power laser interaction. The approach promotes research towards relevant nuclear astrophysical studies at conditions currently only accessible at nuclear high energy density laser facilities.

07 ISOTOPE AND RADIATION SOURCES↗
DOE OSTI2022

Transgenic manipulation of triacylglycerol biosynthetic enzymes in B. napus alters lipid-associated gene expression and lipid metabolism

Abstract Oilseed rape ( Brassica napus ) is an important crop that is cultivated for the oil (mainly triacylglycerol; TAG) it produces in its seeds. TAG synthesis is controlled mainly by key enzymes in the Kennedy pathway, such as glycerol 3-phosphate acyltransferase (GPAT), lysophosphatidate acyltransferase (LPAT) and diacylglycerol acyltransferase (DGAT) but can also be produced from phosphoglycerides such as phosphatidylcholine (PC) by the activity of the enzyme phospholipid: diacylglycerol acyltransferase (PDAT). To evaluate the potential for these enzymes to alter oil yields or composition, we analysed transgenic B. napus lines which overexpressed GPAT, LPAT or PDAT using heterologous transgenes from Arabidopsis and Nasturtium and examined lipid profiles and changes in gene expression in these lines compared to WT. Distinct changes in PC and TAG abundance and spatial distribution in embryonic tissues were observed in some of the transgenic lines, together with altered expression of genes involved generally in acyl-lipid metabolism. Overall our results show that up-regulation of these key enzymes differentially affects lipid composition and distribution as well as lipid-associated gene expression, providing important information which could be used to improve crop properties by metabolic engineering.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Long-read metagenomics of soil communities reveals phylum-specific secondary metabolite dynamics

Abstract Microbial biosynthetic gene clusters (BGCs) encoding secondary metabolites are thought to impact a plethora of biologically mediated environmental processes, yet their discovery and functional characterization in natural microbiomes remains challenging. Here we describe deep long-read sequencing and assembly of metagenomes from biological soil crusts, a group of soil communities that are rich in BGCs. Taking advantage of the unusually long assemblies produced by this approach, we recovered nearly 3,000 BGCs for analysis, including 712 full-length BGCs. Functional exploration through metatranscriptome analysis of a 3-day wetting experiment uncovered phylum-specific BGC expression upon activation from dormancy, elucidating distinct roles and complex phylogenetic and temporal dynamics in wetting processes. For example, a pronounced increase in BGC transcription occurs at night primarily in cyanobacteria, implicating BGCs in nutrient scavenging roles and niche competition. Taken together, our results demonstrate that long-read metagenomic sequencing combined with metatranscriptomic analysis provides a direct view into the functional dynamics of BGCs in environmental processes and suggests a central role of secondary metabolites in maintaining phylogenetically conserved niches within biocrusts.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Topologically associating domain boundaries are required for normal genome function

Topologically associating domain (TAD) boundaries partition the genome into distinct regulatory territories. Anecdotal evidence suggests that their disruption may interfere with normal gene expression and cause disease phenotypes1,2,3, but the overall extent to which this occurs remains unknown. Here we demonstrate that targeted deletions of TAD boundaries cause a range of disruptions to normal in vivo genome function and organismal development. We used CRISPR genome editing in mice to individually delete eight TAD boundaries (11–80 kb in size) from the genome. All deletions examined resulted in detectable molecular or organismal phenotypes, which included altered chromatin interactions or gene expression, reduced viability, and anatomical phenotypes. We observed changes in local 3D chromatin architecture in 7 of 8 (88%) cases, including the merging of TADs and altered contact frequencies within TADs adjacent to the deleted boundary. For 5 of 8 (63%) loci examined, boundary deletions were associated with increased embryonic lethality or other developmental phenotypes. For example, a TAD boundary deletion near Smad3/Smad6 caused complete embryonic lethality, while a deletion near Tbx5/Lhx5 resulted in a severe lung malformation. Our findings demonstrate the importance of TAD boundary sequences for in vivo genome function and reinforce the critical need to carefully consider the potential pathogenicity of noncoding deletions affecting TAD boundaries in clinical genetics screening.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Epitaxial Sc x Al 1- x N on GaN exhibits attractive high-K dielectric properties

Epitaxial Sc x Al 1- x N thin films of ~100 nm thickness grown on metal polar GaN substrates are found to exhibit significantly enhanced relative dielectric permittivity (ε r ) values relative to AlN. ε r values of ~17–21 for Sc mole fractions of 17%–25% ( x = 0.17–0.25) measured electrically by capacitance–voltage measurements indicate that Sc x Al 1- x N has the largest relative dielectric permittivity of any existing nitride material. Since epitaxial Sc x Al 1- x N layers deposited on GaN also exhibit large polarization discontinuity, the heterojunction can exploit the in situ high-K dielectric property to extend transistor operation for power electronics and high-speed microwave applications.

36 MATERIALS SCIENCE↗
DOE OSTI2022

Optically pumped deep-UV multimode lasing in AlGaN double heterostructure grown by molecular beam homoepitaxy

Multimode lasing at sub-300 nm wavelengths is demonstrated by optical pumping in AlGaN heterostructures grown on single-crystal AlN substrates by plasma-assisted molecular beam epitaxy. Edge-emitting ridge-based Fabry–Pérot cavities are fabricated with the epitaxial AlN/AlGaN double heterostructure by a combined inductively coupled plasma reactive ion etch and tetramethylammonium hydroxide etch. The emitters exhibit peak gain at 284 nm and modal linewidths on the order of 0.1 nm at room temperature. The applied growth technique and its chemical and heterostructural design characteristics offer certain unique capabilities toward further development of electrically injected AlGaN laser diodes.

36 MATERIALS SCIENCE↗
DOE OSTI2022

Molecular beam homoepitaxy of N-polar AlN on bulk AlN substrates

N-polar AlN epilayers were grown on the N-face of single-crystal bulk AlN substrates by plasma-assisted molecular beam epitaxy. A combination of in situ thermal deoxidation and Al-assisted thermal desorption at high temperature aided in removing native surface oxides and impurities from the N-polar surface of the substrate enabling successful homoepitaxy. Subsequent epitaxial growth of the AlN layer on the in situ cleaned substrates, grown in a sufficiently high Al droplet regime, exhibited smooth surface morphologies with clean and wide atomic steps. KOH etch studies confirmed the N-polarity of the homoepitaxial films. Secondary ion mass spectrometry profiles show Si and H impurity concentrations below the noise levels, whereas O and C impurity concentrations of [Formula: see text] and [Formula: see text] atoms/cm 3 are observed, respectively. Although the structural defect densities are low, they interestingly appear as inversion domains of different dimensionalities.

Singhal, Jashan↗
DOE OSTI2024

Ultrawide bandgap semiconductor heterojunction p–n diodes with distributed polarization-doped p-type AlGaN layers on bulk AlN substrates

Ultrawide bandgap heterojunction p–n diodes with polarization-induced AlGaN p-type layers are demonstrated using plasma-assisted molecular beam epitaxy on bulk AlN substrates. Current–voltage characteristics show a turn-on voltage of Vbi≈5.5 V, a minimum room temperature ideality factor of η≈1.63, and more than 12 orders of current modulation at room temperature. A stable current operation of the ultrawide bandgap semiconductor diode is measured up to a temperature of 300 °C. The one-sided n+–p heterojunction diode design enables a direct measurement of the spatial distribution of polarization-induced mobile hole density in the graded AlGaN layer from the capacitance–voltage profile. The measured average mobile hole density is p∼5.7×1017 cm−3, in close agreement with what is theoretically expected from distributed polarization doping. Light emission peaked at 260 nm (4.78 eV) observed in electroluminescence corresponds to interband radiative recombination in the n+ AlGaN layer. A much weaker deep-level emission band observed at 3.4 eV is attributed to cation-vacancy and silicon complexes in the heavily Si-doped AlGaN layer. These results demonstrate that distributed polarization doping enables ultrawide bandgap semiconductor heterojunction p–n diodes that have wide applications ranging from power electronics to deep-ultraviolet photonics. These devices can operate at high temperatures and in harsh environments.

Physics↗
DOE OSTI2021

Transcriptional network orchestrating regional patterning of cortical progenitors

We uncovered a transcription factor (TF) network that regulates cortical regional patterning in radial glial stem cells. Screening the expression of hundreds of TFs in the developing mouse cortex identified 38 TFs that are expressed in gradients in the ventricular zone (VZ). We tested whether their cortical expression was altered in mutant mice with known patterning defects (Emx2, Nr2f1, and Pax6), which enabled us to define a cortical regionalization TF network (CRTFN). To identify genomic programming underlying this network, we performed TF ChIP-seq and chromatin-looping conformation to identify enhancer–gene interactions. To map enhancers involved in regional patterning of cortical progenitors, we performed assays for epigenomic marks and DNA accessibility in VZ cells purified from wild-type and patterning mutant mice. This integrated approach has identified a CRTFN and VZ enhancers involved in cortical regional patterning in the mouse.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Nr2f1 enhancers have distinct functions in controlling Nr2f1 expression during cortical development

There is evidence that transcription factor (TF) encoding genes, which temporally control development in multiple cell types, can have tens of enhancers that regulate their expression. The NR2F1 TF developmentally promotes caudal and ventral cortical regional fates. Here, we epigenomically compared the activity of Nr2f1’s enhancers during mouse cortical development with their activity in a transgenic assay. We identified at least six that are likely to be important in prenatal cortical development, with three harboring de novo mutants identified in ASD individuals. We chose to study the function of two of the most robust enhancers by deleting them singly or together. We found that they have distinct and overlapping functions in driving Nr2f1’s regional and laminar expression in the developing cortex. Thus, these two enhancers, probably in combination with the others that we defined epigenetically, precisely tune Nr2f1’s regional, cell type, and temporal expression during corticogenesis.

Liu, Zhidong↗
DOE OSTI2025

Creb5 controls its own expression and directly induces the joint interzone regulatory program

Prior studies have indicated that the transcription factor Creb5 is expressed in the joint interzone, which contains the progenitors for all synovial joint tissues in both mouse and human embryos. In the absence of Creb5 function, most synovial joint interzones fail to form and the cartilage templates in the long bones remain fused. This earlier work did not clarify whether Creb5 initiates a cascade of signaling molecules, such as growth and differentiation factor 5 (Gdf5) and Wnt-family members, that in turn induce the formation of the joint interzone, or instead directly activates the expression of joint interzone markers. In the present study, an integrative analysis of the transcriptome, chromatin accessibility, and Creb5-occupancy in joint progenitors revealed that Creb5 directly binds to both its own two promoters and to the regulatory regions of Gdf5 and Sfrp2, each of whose expression in the joint interzone is Creb5-dependent. Functional enhancer analysis indicated that Creb5 binding sites in either the two Creb5 promoters, or in Gdf5 and Sfrp2 regulatory elements are necessary for these sequences to drive transgene expression in the developing synovial joints. While Creb5 directly drives Gdf5 and Sfrp2 expression in the inner joint interzone, Creb5 activates Barx1 expression specifically in the outer joint interzone. Our findings indicate that Creb5 initiates a regulatory network that both promotes the formation of synovial joints, and subsequently activates distinct transcriptional targets in the inner versus the outer regions of the joint interzone, thus regionalizing gene expression in the developing joint.

Zhang, Cheng-Hai↗
DOE OSTI2021

Woolwich, Bruceton, Los Alamos: Munroe Jets and the Trinity Gadget

Prewar work on the hydrodynamics of explosives and U.S./UK scientific cooperation well beyond Los Alamos contributed to the design of the explosive lenses for the Trinity gadget. Researchers were deliberately brought together and encouraged to share ideas by the leaders of the wartime laboratory. James Tuck, one of the British mission scientists, made particularly interesting contributions in this area, but this paper is not a claim of British or any other individual parentage. Rather, it highlights the importance of collaboration at Los Alamos and more widely.

45 MILITARY TECHNOLOGY, WEAPONRY, AND NATIONAL DEF↗
DOE OSTI2024

Neural simulation-based inference of the neutron star equation of state directly from telescope spectra

Neutron stars provide a unique opportunity to study strongly interacting matter under extreme density conditions. The intricacies of matter inside neutron stars and their equation of state are not directly visible, but determine bulk properties, such as mass and radius, which affect the star's thermal X-ray emissions. However, the telescope spectra of these emissions are also affected by the stellar distance, hydrogen column, and effective surface temperature, which are not always well-constrained. Uncertainties on these nuisance parameters must be accounted for when making a robust estimation of the equation of state. In this study, we develop a novel methodology that, for the first time, can infer the full posterior distribution of both the equation of state and nuisance parameters directly from telescope observations. This method relies on the use of neural likelihood estimation, in which normalizing flows use samples of simulated telescope data to learn the likelihood of the neutron star spectra as a function of these parameters, coupled with Hamiltonian Monte Carlo methods to efficiently sample from the corresponding posterior distribution. Our approach surpasses the accuracy of previous methods, improves the interpretability of the results by providing access to the full posterior distribution, and naturally scales to a growing number of neutron star observations expected in the coming years.

79 ASTRONOMY AND ASTROPHYSICS↗