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Results for “Proliferation”

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 523 records · Page 29
All sourcesNASA NTRSDOE OSTI
DOE OSTI2020

RCSB Protein Data Bank tools for 3D structure-guided cancer research: human papillomavirus (HPV) case study

Abstract Atomic-level three-dimensional (3D) structure data for biological macromolecules often prove critical to dissecting and understanding the precise mechanisms of action of cancer-related proteins and their diverse roles in oncogenic transformation, proliferation, and metastasis. They are also used extensively to identify potentially druggable targets and facilitate discovery and development of both small-molecule and biologic drugs that are today benefiting individuals diagnosed with cancer around the world. 3D structures of biomolecules (including proteins, DNA, RNA, and their complexes with one another, drugs, and other small molecules) are freely distributed by the open-access Protein Data Bank (PDB). This global data repository is used by millions of scientists and educators working in the areas of drug discovery, vaccine design, and biomedical and biotechnology research. The US Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB) provides an integrated portal to the PDB archive that streamlines access for millions of worldwide PDB data consumers worldwide. Herein, we review online resources made available free of charge by the RCSB PDB to basic and applied researchers, healthcare providers, educators and their students, patients and their families, and the curious public. We exemplify the value of understanding cancer-related proteins in 3D with a case study focused on human papillomavirus.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

CRL4A DTL degrades DNA-PKcs to modulate NHEJ repair and induce genomic instability and subsequent malignant transformation

Genomic instability induced by DNA damage and improper DNA damage repair is one of the main causes of malignant transformation and tumorigenesis. DNA double strand breaks (DSBs) are the most detrimental form of DNA damage, and nonhomologous end-joining (NHEJ) mechanisms play dominant and priority roles in initiating DSB repair. A well-studied oncogene, the ubiquitin ligase Cullin 4A (CUL4A), is reported to be recruited to DSB sites in genomic DNA, but whether it regulates NHEJ mechanisms of DSB repair is unclear. Here, we discovered that the CUL4A-DTL ligase complex targeted the DNA-PKcs protein in the NHEJ repair pathway for nuclear degradation. Overexpression of either CUL4A or DTL reduced NHEJ repair efficiency and subsequently increased the accumulation of DSBs. Moreover, we demonstrated that overexpression of either CUL4A or DTL in normal cells led to genomic instability and malignant proliferation. Consistent with the in vitro findings, in human precancerous lesions, CUL4A expression gradually increased with increasing malignant tendency and was negatively correlated with DNA-PKcs and positively correlated with γ-H2AX expression. Collectively, this study provided strong evidence that the CUL4A-DTL axis increases genomic instability and enhances the subsequent malignant transformation of normal cells by inhibiting NHEJ repair. These results also suggested that CUL4A may be a prognostic marker of precancerous lesions and a potential therapeutic target in cancer.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

A bioinspired and chemically defined alternative to dimethyl sulfoxide for the cryopreservation of human hematopoietic stem cells

Abstract The cryopreservation of hematopoietic cells using dimethyl sulfoxide (DMSO) and serum is a common procedure used in transplantation. However, DMSO has clinical and biological side effects due to its toxicity, and serum introduces variation and safety risks. Inspired by natural antifreeze proteins, a novel class of ice-interactive cryoprotectants was developed. The corresponding DMSO-, protein-, and serum-free cryopreservation media candidates were screened through a series of biological assays using human cell lines, peripheral blood cells, and bone marrow cells. XT-Thrive-A and XT-Thrive-B were identified as lead candidates to rival cryopreservation with 10% DMSO in serum based on post-thaw cell survival and short-term proliferation assays. The effectiveness of the novel cryopreservation media in freezing hematopoietic stem cells from human whole bone marrow was assessed by extreme limiting dilution analysis in immunodeficient mice. Stem cell frequencies were measured 12 weeks after transplant based on bone marrow engraftment of erythroid, myeloid, B-lymphoid, and CD34 + progenitors measured by flow cytometry. The recovered numbers of cryopreserved stem cells were similar among XT-Thrive A, XT-Thrive B, and DMSO with serum groups. These findings show that cryoprotectants developed through biomimicry of natural antifreeze proteins offers a substitute for DMSO-based media for the cryopreservation of hematopoietic stem cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

A molecular switch regulating transcriptional repression and activation of PPARγ

Nuclear receptor (NR) transcription factors use a conserved activation function-2 (AF-2) helix 12 mechanism for agonist-induced coactivator interaction and NR transcriptional activation. In contrast, ligand-induced corepressor-dependent NR repression appears to occur through structurally diverse mechanisms. We report two crystal structures of peroxisome proliferator-activated receptor gamma (PPARγ) in an inverse agonist/corepressor-bound transcriptionally repressive conformation. Helix 12 is displaced from the solvent-exposed active conformation and occupies the orthosteric ligand-binding pocket enabled by a conformational change that doubles the pocket volume. Paramagnetic relaxation enhancement (PRE) NMR and chemical crosslinking mass spectrometry confirm the repressive helix 12 conformation. PRE NMR also defines the mechanism of action of the corepressor-selective inverse agonist T0070907, and reveals that apo-helix 12 exchanges between transcriptionally active and repressive conformations—supporting a fundamental hypothesis in the NR field that helix 12 exchanges between transcriptionally active and repressive conformations.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Large-scale genome sequencing of mycorrhizal fungi provides insights into the early evolution of symbiotic traits

Mycorrhizal fungi are mutualists that play crucial roles in nutrient acquisition in terrestrial ecosystems. Mycorrhizal symbioses arose repeatedly across multiple lineages of Mucoromycotina, Ascomycota, and Basidiomycota. Considerable variation exists in the capacity of mycorrhizal fungi to acquire carbon from soil organic matter. Here, we present a combined analysis of 135 fungal genomes from 73 saprotrophic, endophytic and pathogenic species, and 62 mycorrhizal species, including 29 new mycorrhizal genomes. This study samples ecologically dominant fungal guilds for which there were previously no symbiotic genomes available, including ectomycorrhizal Russulales, Thelephorales and Cantharellales. Our analyses show that transitions from saprotrophy to symbiosis involve (1) widespread losses of degrading enzymes acting on lignin and cellulose, (2) co-option of genes present in saprotrophic ancestors to fulfill new symbiotic functions, (3) diversification of novel, lineage-specific symbiosis-induced genes, (4) proliferation of transposable elements and (5) divergent genetic innovations underlying the convergent origins of the ectomycorrhizal guild.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Selective and noncovalent targeting of RAS mutants for inhibition and degradation

Activating mutants of RAS are commonly found in human cancers, but to date selective targeting of RAS in the clinic has been limited to KRAS(G12C) through covalent inhibitors. Here, we report a monobody, termed 12VC1, that recognizes the active state of both KRAS(G12V) and KRAS(G12C) up to 400-times more tightly than wild-type KRAS. The crystal structures reveal that 12VC1 recognizes the mutations through a shallow pocket, and 12VC1 competes against RAS-effector interaction. When expressed intracellularly, 12VC1 potently inhibits ERK activation and the proliferation of RAS-driven cancer cell lines in vitro and in mouse xenograft models. 12VC1 fused to VHL selectively degrades the KRAS mutants and provides more extended suppression of mutant RAS activity than inhibition by 12VC1 alone. These results demonstrate the feasibility of selective targeting and degradation of KRAS mutants in the active state with noncovalent reagents and provide a starting point for designing noncovalent therapeutics against oncogenic RAS mutants.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity

ASH1L histone methyltransferase plays a crucial role in the pathogenesis of different diseases, including acute leukemia. While ASH1L represents an attractive drug target, developing ASH1L inhibitors is challenging, as the catalytic SET domain adapts an inactive conformation with autoinhibitory loop blocking the access to the active site. Here, by applying fragment-based screening followed by medicinal chemistry and a structure-based design, we developed first-in-class small molecule inhibitors of the ASH1L SET domain. The crystal structures of ASH1L-inhibitor complexes reveal compound binding to the autoinhibitory loop region in the SET domain. When tested in MLL leukemia models, our lead compound, AS-99, blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo. This work validates the ASH1L SET domain as a druggable target and provides a chemical probe to further study the biological functions of ASH1L as well as to develop therapeutic agents.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

The MuvB complex binds and stabilizes nucleosomes downstream of the transcription start site of cell-cycle dependent genes

The chromatin architecture in promoters is thought to regulate gene expression, but it remains uncertain how most transcription factors (TFs) impact nucleosome position. The MuvB TF complex regulates cell-cycle dependent gene-expression and is critical for differentiation and proliferation during development and cancer. MuvB can both positively and negatively regulate expression, but the structure of MuvB and its biochemical function are poorly understood. Here we determine the overall architecture of MuvB assembly and the crystal structure of a subcomplex critical for MuvB function in gene repression. We find that the MuvB subunits LIN9 and LIN37 function as scaffolding proteins that arrange the other subunits LIN52, LIN54 and RBAP48 for TF, DNA, and histone binding, respectively. Biochemical and structural data demonstrate that MuvB binds nucleosomes through an interface that is distinct from LIN54-DNA consensus site recognition and that MuvB increases nucleosome occupancy in a reconstituted promoter. We find in arrested cells that MuvB primarily associates with a tightly positioned +1 nucleosome near the transcription start site (TSS) of MuvB-regulated genes. These results support a model that MuvB binds and stabilizes nucleosomes just downstream of the TSS on its target promoters to repress gene expression.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin

The calcium-selective oncochannel TRPV6 is an important driver of cell proliferation in human cancers. Despite increasing interest of pharmacological research in developing synthetic inhibitors of TRPV6, natural compounds acting at this channel have been largely neglected. On the other hand, pharmacokinetics of natural small-molecule antagonists optimized by nature throughout evolution endows these compounds with a medicinal potential to serve as potent and safe next-generation anti-cancer drugs. Here we report the structure of human TRPV6 in complex with tetrahydrocannabivarin (THCV), a natural cannabinoid inhibitor extracted from Cannabis sativa . We use cryo-electron microscopy combined with electrophysiology, calcium imaging, mutagenesis, and molecular dynamics simulations to identify THCV binding sites in the portals that connect the membrane environment surrounding the protein to the central cavity of the channel pore and to characterize the allosteric mechanism of TRPV6 inhibition. We also propose the molecular pathway taken by THCV to reach its binding site. Our study provides a foundation for the development of new TRPV6-targeting drugs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

From Stoner to local moment magnetism in atomically thin Cr2Te3

Abstract The field of two-dimensional (2D) ferromagnetism has been proliferating over the past few years, with ongoing interests in basic science and potential applications in spintronic technology. However, a high-resolution spectroscopic study of the 2D ferromagnet is still lacking due to the small size and air sensitivity of the exfoliated nanoflakes. Here, we report a thickness-dependent ferromagnetism in epitaxially grown Cr 2 Te 3 thin films and investigate the evolution of the underlying electronic structure by synergistic angle-resolved photoemission spectroscopy, scanning tunneling microscopy, x-ray absorption spectroscopy, and first-principle calculations. A conspicuous ferromagnetic transition from Stoner to Heisenberg-type is directly observed in the atomically thin limit, indicating that dimensionality is a powerful tuning knob to manipulate the novel properties of 2D magnetism. Monolayer Cr 2 Te 3 retains robust ferromagnetism, but with a suppressed Curie temperature, due to the drastic drop in the density of states near the Fermi level. Our results establish atomically thin Cr 2 Te 3 as an excellent platform to explore the dual nature of localized and itinerant ferromagnetism in 2D magnets.

36 MATERIALS SCIENCE↗
DOE OSTI2023

The complexity of NISQ

Abstract The recent proliferation of NISQ devices has made it imperative to understand their power. In this work, we define and study the complexity class , which encapsulates problems that can be efficiently solved by a classical computer with access to noisy quantum circuits. We establish super-polynomial separations in the complexity among classical computation, , and fault-tolerant quantum computation to solve some problems based on modifications of Simon’s problems. We then consider the power of for three well-studied problems. For unstructured search, we prove that cannot achieve a Grover-like quadratic speedup over classical computers. For the Bernstein-Vazirani problem, we show that only needs a number of queries logarithmic in what is required for classical computers. Finally, for a quantum state learning problem, we prove that is exponentially weaker than classical computers with access to noiseless constant-depth quantum circuits.

42 ENGINEERING↗
DOE OSTI2024

p14 ARF forms meso-scale assemblies upon phase separation with NPM1

NPM1 is an abundant nucleolar chaperone that, in addition to facilitating ribosome biogenesis, contributes to nucleolar stress responses and tumor suppression through its regulation of the p14 Alternative Reading Frame tumor suppressor protein (p14 ARF ). Oncogenic stress induces p14 ARF to inhibit MDM2, stabilize p53 and arrest the cell cycle. Under non-stress conditions, NPM1 stabilizes p14 ARF in nucleoli, preventing its degradation and blocking p53 activation. However, the mechanisms underlying the regulation of p14 ARF by NPM1 are unclear because the structural features of the p14 ARF -NPM1 complex were elusive. Here we show that p14 ARF assembles into a gel-like meso-scale network upon phase separation with NPM1. This assembly is mediated by intermolecular contacts formed by hydrophobic residues in an α-helix and β-strands within a partially folded N-terminal portion of p14 ARF . These hydrophobic interactions promote phase separation with NPM1, enhance p14 ARF nucleolar partitioning, restrict NPM1 diffusion within condensates and nucleoli, and reduce cellular proliferation. Our structural analysis provides insights into the multifaceted chaperone function of NPM1 in nucleoli by mechanistically linking the nucleolar localization of p14 ARF to its partial folding and meso-scale assembly upon phase separation with NPM1.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive states

Abstract Nuclear receptors (NRs) are thought to dynamically alternate between transcriptionally active and repressive conformations, which are stabilized upon ligand binding. Most NR ligand series exhibit limited bias, primarily consisting of transcriptionally active agonists or neutral antagonists, but not repressive inverse agonists—a limitation that restricts understanding of the functional NR conformational ensemble. Here, we report a NR ligand series for peroxisome proliferator-activated receptor gamma (PPARγ) that spans a pharmacological spectrum from repression (inverse agonism) to activation (agonism) where subtle structural modifications switch compound activity. While crystal structures provide snapshots of the fully repressive state, NMR spectroscopy and conformation-activity relationship analysis reveals that compounds within the series shift the PPARγ conformational ensemble between transcriptionally active and repressive conformations that are natively populated in the apo/ligand-free ensemble. Our findings reveal a molecular framework for minimal chemical modifications that enhance PPARγ inverse agonism and elucidate their influence on the dynamic PPARγ conformational ensemble.

Science & Technology - Other Topics↗
DOE OSTI2025

A family of tubular pili from harmful algal bloom forming cyanobacterium Microcystis aeruginosa

Cyanobacteria are vital photosynthetic prokaryotes, but some form harmful algal blooms (cyanoHABs) that disrupt ecosystems and produce toxins. The mechanisms by which these blooms form have yet to be fully understood, particularly the role of extracellular components. Here, we present a 2.4 Å cryo-EM structure of a pilus, termed the cyanobacterial tubular (CT) pilus, found in the cyanoHAB-forming Microcystis aeruginosa. The pilin exhibits a unique protein fold, forming a tubular pilus structure with tight, double-layer anti-parallel β-sheet interactions. We show that CT pili are essential for buoyancy by facilitating the formation of micro-colonies, which increases drag force and prevents sinking. The CT pilus surface is heavily glycosylated with ten monosaccharide modifications per pilin. Furthermore, CT pili can enrich microcystin, potentially enhancing cellular resilience, and co-localize with iron-enriched extracellular matrix components. Thus, we propose that this pilus plays an important role in the proliferation of cyanoHABs. This just discovered pilus family appears to be widely distributed across several cyanobacterial orders. Our structural and functional characterization of CT pili provide insights into cyanobacterial cell morphology, physiology, and toxin interactions, and identify potential targets for disrupting bloom formation.

Cryoelectron microscopy↗
DOE OSTI2023

A Wox3 -patterning module organizes planar growth in grass leaves and ligules

Grass leaves develop from a ring of primordial initial cells within the periphery of the shoot apical meristem, a pool of organogenic stem cells that generates all of the organs of the plant shoot. At maturity, the grass leaf is a flattened, strap-like organ comprising a proximal supportive sheath surrounding the stem and a distal photosynthetic blade. The sheath and blade are partitioned by a hinge-like auricle and the ligule, a fringe of epidermally derived tissue that grows from the adaxial (top) leaf surface. Together, the ligule and auricle comprise morphological novelties that are specific to grass leaves. Understanding how the planar outgrowth of grass leaves and their adjoining ligules is genetically controlled can yield insight into their evolutionary origins. Here we use single-cell RNA-sequencing analyses to identify a ‘rim’ cell type present at the margins of maize leaf primordia. Cells in the leaf rim have a distinctive identity and share transcriptional signatures with proliferating ligule cells, suggesting that a shared developmental genetic programme patterns both leaves and ligules. Moreover, we show that rim function is regulated by genetically redundant Wuschel-like homeobox3 (WOX3) transcription factors. Higher-order mutations in maize Wox3 genes greatly reduce leaf width and disrupt ligule outgrowth and patterning. Together, these findings illustrate the generalizable use of a rim domain during planar growth of maize leaves and ligules, and suggest a parsimonious model for the homology of the grass ligule as a distal extension of the leaf sheath margin.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Point-of-use filtration units as drinking water distribution system sentinels

Abstract Municipal drinking water distribution systems (DWDSs) and associated premise plumbing (PP) systems are vulnerable to proliferation of opportunistic pathogens, even when chemical disinfection residuals are present, thus presenting a public health risk. Monitoring the structure of microbial communities of drinking water is challenging because of limited continuous access to faucets, pipes, and storage tanks. We propose a scalable household sampling method, which uses spent activated carbon and reverse osmosis (RO) membrane point-of-use (POU) filters to evaluate mid- to long-term occurrence of microorganisms in PP systems that are relevant to consumer exposure. As a proof of concept, POU filter microbiomes were collected from four different locations and analyzed with 16S rRNA gene amplicon sequencing. The analyses revealed distinct microbial communities, with occasional detection of potential pathogens. The findings highlight the importance of local, and if possible, continuous monitoring within and across distribution systems. The continuous operation of POU filters offers an advantage in capturing species that may be missed by instantaneous sampling methods. We suggest that water utilities, public institutions, and regulatory agencies take advantage of end-of-life POU filters for microbial monitoring. This approach can be easily implemented to ensure drinking water safety, especially from microbes of emerging concerns; e.g., pathogenic Legionella and Mycobacterium species.

42 ENGINEERING↗
DOE OSTI2020

Open Science principles for accelerating trait-based science across the Tree of Life

Synthesizing trait observations and knowledge across the Tree of Life remains a grand challenge for biodiversity science. Species traits are widely used in ecological and evolutionary science, and new data and methods have proliferated rapidly. Yet accessing and integrating disparate data sources remains a considerable challenge, slowing progress toward a global synthesis to integrate trait data across organisms. Trait science needs a vision for achieving global integration across all organisms. In this perspective, we outline how the adoption of key Open Science principles—open data, open source and open methods—is transforming trait science, increasing transparency, democratizing access and accelerating global synthesis. To enhance widespread adoption of these principles, we introduce the Open Traits Network (OTN), a global, decentralized community welcoming all researchers and institutions pursuing the collaborative goal of standardizing and integrating trait data across organisms. We demonstrate how adherence to Open Science principles is key to the OTN community and outline five activities that can accelerate the synthesis of trait data across the Tree of Life, thereby facilitating rapid advances to address scientific inquiries and environmental issues. Lessons learned along the path to a global synthesis of trait data will provide a framework for addressing similarly complex data science and informatics challenges.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Spectroscopic fingerprint of charge order melting driven by quantum fluctuations in a cuprate

Copper oxide high-T C superconductors possess a number of exotic orders that coexist with or are proximal to superconductivity. Quantum fluctuations associated with these orders may account for the unusual characteristics of the normal state, and possibly affect the superconductivity. Yet, spectroscopic evidence for such quantum fluctuations remains elusive. Here in this paper, we use resonant inelastic X-ray scattering to reveal spectroscopic evidence of fluctuations associated with a charge order in nearly optimally doped Bi 2 Sr 2 CaCu 2 O 8+δ . In the superconducting state, while the quasielastic charge order signal decreases with temperature, the interplay between charge order fluctuations and bond-stretching phonons in the form of a Fano-like interference increases, an observation that is incompatible with expectations for competing orders. Invoking general principles, we argue that this behaviour reflects the properties of a dissipative system near an order–disorder quantum critical point, where the dissipation varies with the opening of the pseudogap and superconducting gap at low temperatures, leading to the proliferation of quantum critical fluctuations, which melt charge order.

36 MATERIALS SCIENCE↗