Search NASA⌕ Search

SEARCH · Search NASA

Results for “Protein aggregation”

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.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 487 records · Page 27
All sourcesNASA NTRSDOE OSTI
DOE OSTI2011

A phosphate-dependent shift in redox state of cerium oxide nanoparticles and its effects on catalytic properties

Cerium oxide nanoparticles (CeNPs) have shown promise as catalytic antioxidants in cell culture and animal models as both superoxide dismutase and catalase mimetics. The reactivity of the cerium (Ce) atoms at the surface of its oxide particle is critical to such therapeutic properties, yet little is known about the potential for a protein or small molecule corona to form on these materials in vivo. Moreover Ce atoms in these active sites have the potential to interact with small molecule anions, peptides, or sugars when administered in culture or animal models. Several nanomaterials have been shown to alter or aggregate under these conditions, rendering them less useful for biomedical applications. In this work we have studied the change in catalytic properties of CeNPs when exposed to various biologically relevant conditions in vitro. We have found that CeNPs are resistant to broad changes in pH and also not altered by incubation in cell culture medium. However to our surprise phosphate anions significantly altered the characteristics of these nanomaterials and shifted the catalytic behavior due to the binding of phosphate anions to cerium. Given the abundance of phosphate in biological systems in an inorganic form, it is likely that the action of CeNPs as a catalyst may be strongly influenced by the local concentration of phosphate in the cells and/or tissues in which it has been introduced.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Trifunctional High-Throughput Screen Identifies Promising Scaffold To Inhibit Grp94 and Treat Myocilin-Associated Glaucoma

Gain-of-function mutations within the olfactomedin (OLF) domain of myocilin result in its toxic intracellular accumulation and hasten the onset of open-angle glaucoma. The absence of myocilin does not cause disease; therefore, strategies aimed at eliminating myocilin could lead to a successful glaucoma treatment. The endoplasmic reticulum Hsp90 paralog Grp94 accelerates OLF aggregation. Knockdown or pharmacological inhibition of Grp94 in cells facilitates clearance of mutant myocilin via a non-proteasomal pathway. In this work, we expanded our support for targeting Grp94 over cytosolic paralogs Hsp90α and Hsp90β. We then developed a high-throughput screening assay to identify new chemical matter capable of disrupting the Grp94/OLF interaction. When applied to a blind, focused library of 17 Hsp90 inhibitors, our miniaturized single-read in vitro thioflavin T -based kinetics aggregation assay exclusively identified compounds that target the chaperone N-terminal nucleotide binding site. In follow up studies, one compound ( 2 ) decreased the extent of co-aggregation of Grp94 with OLF in a dose-dependent manner in vitro , and enabled clearance of the aggregation-prone full-length myocilin variant I477N in cells without inducing the heat shock response or causing cytotoxicity. Comparison of the co-crystal structure of compound 2 and another non-selective hit in complex with the N-terminal domain of Grp94 reveals a docking mode tailored to Grp94 and explains its selectivity. A new lead compound has been identified, supporting a targeted chemical biology assay approach to develop a protein degradation-based therapy for myocilin-associated glaucoma by selectively inhibiting Grp94.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2015

ABT737 enhances cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics

Cholangiocarcinoma responses weakly to cisplatin. Mitochondrial dynamics participate in the response to various stresses, and mainly involve mitophagy and mitochondrial fusion and fission. Bcl-2 family proteins play critical roles in orchestrating mitochondrial dynamics, and are involved in the resistance to cisplatin. Here we reported that ABT737, combined with cisplatin, can promote cholangiocarcinoma cells to undergo apoptosis. We found that the combined treatment decreased the Mcl-1 pro-survival form and increased Bak. Cells undergoing cisplatin treatment showed hyperfused mitochondria, whereas fragmentation was dominant in the mitochondria of cells exposed to the combined treatment, with higher Fis1 levels, decreased Mfn2 and OPA1 levels, increased ratio of Drp1 60 kD to 80 kD form, and more Drp1 located on mitochondria. More p62 aggregates were observed in cells with fragmented mitochondria, and they gradually translocated to mitochondria. Mitophagy was induced by the combined treatment. Knockdown p62 decreased the Drp1 ratio, increased Tom20, and increased cell viability. Our data indicated that mitochondrial dynamics play an important role in the response of cholangiocarcinoma to cisplatin. ABT737 might enhance cholangiocarcinoma sensitivity to cisplatin through regulation of mitochondrial dynamics and the balance within Bcl-2 family proteins. Furthermore, p62 seems to be critical in the regulation of mitochondrial dynamics. - Highlights: • Cholangiocarcinoma may adapt to cisplatin through mitochondrial fusion. • ABT737 sensitizes cholangiocarcinoma to cisplatin by promoting fission and mitophagy. • p62 might participate in the regulation of mitochondrial fission and mitophagy.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1996

Analysis of Monomer Aggregation and Crystal Growth Rates of Lysozyme

This project was originally conceived to analyze the extensive data of tetragonal lysozyme crystal growth rates collected at NASA/MSFC by Dr. Marc L. Pusey's research group. At that time the lack of analysis of the growth rates was hindering progress in understanding the growth mechanism of tetragonal lysozyme and other protein crystals. After the project was initiated our initial analysis revealed unexpected complexities in the growth rate behavior. This resulted in an expansion in the scope of the project to include a comprehensive investigation of the growth mechanisms of tetragonal lysozyme crystals. A discussion of this research is included as well a list of presentations and publications resulting from the research. This project contributed significantly toward the education of several students and fostered extensive collaborations between investigators.

Nadarajah, Arunan↗
DOE OSTI2019

A biradical-tagged phospholipid as a polarizing agent for solid-state MAS Dynamic Nuclear Polarization NMR of membrane proteins

We report a novel Dynamic Nuclear Polarization (DNP) NMR polarizing agent ToSMTSL-PTE representing a phospholipid with a biradical TOTAPOL tethered to the polar head group has been synthesized, characterized, and employed to enhance solid-state Nuclear Magnetic Resonance (SSNMR) signal of a lipid-reconstituted integral membrane protein proteorhodopsin (PR). A matrix-free PR formulation for DNP improved the absolute sensitivity of NMR signal by a factor of ca. 4 compared to a conventional preparation with TOTAPOL dispersed in a glassy glycerol/water matrix. DNP enhancements measured at 400 MHz/263 GHz and 600 MHz/395 GHz showed a strong field dependence but remained moderate at both fields, and comparable to those obtained for PR covalently modified with ToSMTSL. Additional continuous wave (CW) X-band electron paramagnetic resonance (EPR) experiments with ToSMTSL-PTE in solutions and in lipid bilayers revealed that an unfavorable conformational change of the linker connecting mononitroxides could be one of the reasons for moderate DNP enhancements. Further, differential scanning calorimetry (DSC) and CW EPR experiments indicated an inhomogeneous distribution and/or a possibility of a partial aggregation of ToSMTSL-PTE in DMPC:DMPA bilayers when the concentration of the polarizing agent was increased to 20 mol% to maximize the DNP enhancement. Thus, conformational changes and an inhomogeneous distribution of the lipid-based biradicals in lipid bilayers emerged as important factors to consider for further development of this matrix-free approach for DNP of membrane proteins.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2015

Crystal Structures of IAPP Amyloidogenic Segments Reveal a Novel Packing Motif of Out-of-Register Beta Sheets

Structural studies of amyloidogenic segments by X-ray crystallography have revealed a novel packing motif, consisting of out-of-register β sheets, which may constitute one of the toxic species in aggregation related diseases. Here we sought to determine the presence of such a motif in islet amyloid polypeptide (IAPP), whose amyloidogenic properties are associated with type 2 diabetes. We determined four new crystal structures of segments within IAPP, all forming steric zippers. Most interestingly, one of the segments in the fibril core of IAPP forms an out-of-register steric zipper. Analysis of this structure reveals several commonalities with previously solved out-of-register fibrils. Furthermore, our results provide additional evidence of out-of-register β sheets as a common structural motif in amyloid aggregates.

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

Knowledge Graph of RB-Tnseq Data from Fitness Browser (KP-DP1)

Motivation: Predicting microbial gene fitness across environmental conditions remains a central challenge for predictive phenomics and autonomous experimentation. Fitness assays generate large volumes of genotype–phenotype measurements difficult to integrate with experimental metadata and biological function in a form that supports mechanistic reasoning. Knowledge graphs offer a semantic framework for unifying modalities and enabling context-aware inference. Results: We build GIMME (Graph Inference for Microbial Metabolism Exploration), a semantically grounded knowledge graph that unifies gene fitness measurements spanning 10 Pseudomonas species with experimental metadata and biological context. Media are decomposed into chemical components and experiments carry structured links to natural-language descriptions. The resulting graph supports two inference modes: (1) symbolic graph traversal to surface candidate gene–environment and gene–chemical associations, and (2) learned inference using heterogeneous graph neural networks that propagate information across neighborhoods. We formulate link regression over (gene, media, experiment) triplets, combining learned gene embeddings with pretrained LLM sourced text embeddings of node descriptions to predict gene fitness. We then augment a baseline MLP with an auxiliary message-passing encoder (GraphSAGE/GAT) that propagates information over gene–protein–function and media–chemical subgraphs, and fuse the two pathways with a gated residual connection. This approach produces strong agreement with held-out fitness measurements (GraphSAGE Pearson r 0.74) while also highlighting inference challenges in extreme-fitness regimes. We aggregate GAT edge-attention weights by relation type and layer to estimate which biological and environmental relations most influence fitness predictions. Conclusion: This work explores using knowledge graphs as “context graphs” for microbial phenotype prediction. They provide a rich substrate which enables explainable retrieval of supporting evidence, and provides a natural bridge to autonomous workflows that prioritize the next experiment.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

De novo design of small beta barrel proteins

Small beta barrel proteins are attractive targets for computational design because of their considerable functional diversity despite their very small size (<70 amino acids). However, there are considerable challenges to designing such structures, and there has been little success thus far. Because of the small size, the hydrophobic core stabilizing the fold is necessarily very small, and the conformational strain of barrel closure can oppose folding; also intermolecular aggregation through free beta strand edges can compete with proper monomer folding. Here, we explore the de novo design of small beta barrel topologies using both Rosetta energy–based methods and deep learning approaches to design four small beta barrel folds: Src homology 3 (SH3) and oligonucleotide/oligosaccharide-binding (OB) topologies found in nature and five and six up-and-down-stranded barrels rarely if ever seen in nature. Both approaches yielded successful designs with high thermal stability and experimentally determined structures with less than 2.4 Å rmsd from the designed models. Using deep learning for backbone generation and Rosetta for sequence design yielded higher design success rates and increased structural diversity than Rosetta alone. The ability to design a large and structurally diverse set of small beta barrel proteins greatly increases the protein shape space available for designing binders to protein targets of interest.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Conjugation of Amphiphilic Proteins to Hydrophobic Ligands in Organic Solvent

Protein–ligand conjugations are usually carried out in aqueous media in order to mimic the environment within which the conjugates will be used. Here, we focus on the conjugation of amphiphilic variants of elastin-like polypeptide (ELP), short elastin (sEL), to poorly water-soluble compounds like OPPVs (p-phenylenevinylene oligomers), triarylamines, and polypyridine-metal complexes. These conjugations are problematic when carried out in aqueous phase because hydrophobic ligands tend to avoid exposure to water, which in turn causes the ligand to self-aggregate and/or interact noncovalently with hydrophobic regions of the amphiphile. Ultimately, this behavior leads to low conjugation efficiency and contamination with strong noncovalent “conjugates”. After exploring the solubility of sEL in various organic solvents, we have established an efficient conjugation methodology for obtaining covalent conjugates virtually free of contaminating noncovalent complexes. When conjugating carboxylated ligands to the amphiphile amines, we demonstrate that even when only one amine (the N-terminus) is present, its derivatization is 98% efficient. When conjugating amine moieties to the amphiphile carboxyls (a problematic configuration), protein multimerization is avoided, 98–100% of the protein is conjugated, and the unreacted ligand is recovered in pure form. Our syntheses occur in “one pot”, and our purification procedure is a simple workup utilizing a combination of water and organic solvent extractions. This conjugation methodology might provide a solution to problems arising from solubility mismatch of protein and ligand, and it is likely to be widely applied for modification of recombinant amphiphiles used for drug delivery (PEG-antibodies, polymer-enzymes, food proteins), cell adhesion (collagen, hydrophobins), synthesis of nanostructures (peptides), and engineering of biocompatible optoelectronics (biological polymers), to cite a few.

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

Mass spectrometry and spectroscopic characterization of a tetrameric photosystem I supercomplex from Leptolyngbya ohadii , a desiccation-tolerant cyanobacterium

Cyanobacteria inhabiting desert biological soil crusts face the harsh conditions of the desert. They evolved a suite of strategies toward desiccation-hydration cycles mixed with high light irradiations, etc. In this study we purified and characterized the structure and function of Photosystem I (PSI) from Leptolyngbya ohadii, a desiccation-tolerant desert cyanobacterium. We discovered that PSI forms tetrameric (PSI-Tet) aggregate. We investigated it by using sucrose density gradient centrifugation, clear native PAGE, high performance liquid chromatography, mass spectrometry (MS), time-resolved fluorescence (TRF) and time-resolved transient absorption (TA) spectroscopy. MS analysis identified the presence of two PsaB and two PsaL proteins in PSI-Tet and uniquely revealed that PsaLs are N-terminally acetylated in contrast to non-modified PsaL in the trimeric PSI from Synechocystis sp. PCC 6803. Chlorophyll (Chl) a fluorescence decay profiles of the PSI-Tet performed at 77 K revealed two emission bands at ∼690 nm and 725 nm with the former appearing only at early delay time. The main fluorescence emission peak, associated with emission from the low energy Chls a, decays within a few nanoseconds. TA studies demonstrated that the 725 nm emission band is associated with low energy Chls a with absorption band clearly resolved at ∼710 nm at 77 K. As a result, our work suggests that the heterogenous composition of PsaBs and PsaL in PSI-Tet is related with the adaptation mechanisms needed to cope with stressful conditions under which this bacterium naturally grows.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Analysis of a vinculin homolog in a sponge (phylum Porifera) reveals that vertebrate-like cell adhesions emerged early in animal evolution

The evolution of cell-adhesion mechanisms in animals facilitated the assembly of organized multicellular tissues. Studies in traditional animal models have revealed two predominant adhesion structures, the adherens junction (AJ) and focal adhesions (FAs), which are involved in the attachment of neighboring cells to each other and to the secreted extracellular matrix (ECM), respectively. The AJ (containing cadherins and catenins) and FAs (comprising integrins, talin, and paxillin) differ in protein composition, but both junctions contain the actin-binding protein vinculin. The near ubiquity of these structures in animals suggests that AJ and FAs evolved early, possibly coincident with multicellularity. However, a challenge to this perspective is that previous studies of sponges—a divergent animal lineage—indicate that their tissues are organized primarily by an alternative, sponge-specific cell-adhesion mechanism called “aggregation factor.” In this study, we examined the structure, biochemical properties, and tissue localization of a vinculin ortholog in the sponge Oscarella pearsei (Op). Our results indicate that Op vinculin localizes to both cell–cell and cell–ECM contacts and has biochemical and structural properties similar to those of vertebrate vinculin. We propose that Op vinculin played a role in cell adhesion and tissue organization in the last common ancestor of sponges and other animals. Furthermore, these findings provide compelling evidence that sponge tissues are indeed organized like epithelia in other animals and support the notion that AJ- and FA-like structures extend to the earliest periods of animal evolution.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

Enhanced detection of prion infectivity from blood by preanalytical enrichment with peptoid-conjugated beads

Prions cause transmissible infectious diseases in humans and animals and have been found to be transmissible by blood transfusion even in the presymptomatic stage. However, the concentration of prions in body fluids such as blood and urine is extremely low; therefore, direct diagnostic tests on such specimens often yield false-negative results. Quantitative preanalytical prion enrichment may significantly improve the sensitivity of prion assays by concentrating trace amounts of prions from large volumes of body fluids. Here, we show that beads conjugated to positively charged peptoids not only captured PrP aggregates from plasma of prion-infected hamsters, but also adsorbed prion infectivity in both the symptomatic and preclinical stages of the disease. Bead absorbed prion infectivity efficiently transmitted disease to transgenic indicator mice. We found that the readout of the peptoid-based misfolded protein assay (MPA) correlates closely with prion infectivity in vivo, thereby validating the MPA as a simple, quantitative, and sensitive surrogate indicator of the presence of prions. The reliable and sensitive detection of prions in plasma will enable a wide variety of applications in basic prion research and diagnostics.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

A critical review of 25 years of glomalin research: a better mechanical understanding and robust quantification techniques are required

Arbuscular mycorrhizal fungi (AMF) are important contributors to both plant and soil health. Twenty-five years ago, researchers discovered ‘glomalin’, a soil component potentially produced by AMF, which was unconventionally extracted from soil and bound by a monoclonal antibody raised against Rhizophagus irregularis spores. ‘Glomalin’ can resist boiling, strong acids and bases, and protease treatment. Researchers proposed that ‘glomalin’ is a 60 kDa heat shock protein produced by AMF, while others suggested that it is a mixture of soil organic materials that are not unique to AMF. Despite disagreements on the nature of ‘glomalin’, it has been consistently associated with a long list of plant and soil health benefits, including soil aggregation, soil carbon storage and enhancing growth under abiotic stress. The benefits attributed to ‘glomalin’ have caused much excitement in the plant and soil health community; however, the mechanism(s) for these benefits have yet to be established. This review provides insights into the current understanding of the identity of ‘glomalin’, ‘glomalin’ quantification, and the associated benefits of ‘glomalin’. We invite the community to think more critically about how glomalin-associated benefits are generated. We suggest a series of experiments to test hypotheses regarding the nature of ‘glomalin’ and associated health benefits.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

A Simple Technique to Improve Microcrystals Using Gel Exclusion of Nucleation Inducing Elements

A technique is described for generating large well diffracting crystals from conditions that yield microcrystals. Crystallization using this technique is both rapid (crystals appear in <1 h) and robust (48 out of 48 co-crystallized with a fragment library, compared with 26 out of 48 using conventional hanging drop). Agarose gel is used to exclude nucleation inducing elements from the remaining crystallization cocktail. The chemicals in the crystallization cocktail are partitioned into high concentration components (presumed to induce aggregation by reducing water activity) and low concentration nucleation agents (presumed to induce nucleation through direct interaction). The nucleation agents are then combined with 2% agarose gel and deposited on the crystallization shelf of a conventional vapor diffusion plate. The remaining components are mixed with the protein and placed in contact with the agarose drop. This technique yielded well diffracting crystals of lysozyme, cubic insulin, proteinase k, and ferritin (ferritin crystals diffracted to 1.43 Å). The crystals grew rapidly, reaching large size in less than one hour (maximum size was achieved in 1–12 h). This technique is not suitable for poorly expressing proteins because small protein volumes diffuse out of the agarose gel too quickly. Nonetheless, it is a useful technique for situations where crystals must grow rapidly (such as educational applications and preparation of beamline test specimens) and in situations where crystals must grow robustly (such as co-crystallization with a fragment library).

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2009

Toxicity of Lunar Dust in Lungs Assessed by Examining Biomarkers in Exposed Mice

NASA plans to build an outpost on the Moon for prolonged human habitation and research. The lunar surface is covered by a layer of soil, of which the finest portion is highly reactive dust. NASA has invited NIOSH to collaboratively investigate the toxicity of lunar dust. Dust samples of respirable sizes were aerodynamically isolated from two lunar soil samples of different maturities (cosmic exposure ages) collected during the Apollo 16 mission. The lunar dust samples, titanium dioxide, or quartz, suspended in normal saline or in Survanta (a bovine lung surfactant), were given to groups of 5 mice (C-57 male) by intrapharyngeal aspiration at 1, 0.3, or 0.1 mg/mouse. The mice were euthanized 7 or 30 days later, and their lungs were lavaged to assess the toxicity biomarkers in bronchioalveolar lavage fluids. The acellular fractions were assayed for total proteins, lactate dehydrogenase activities, and cytokines; the cellular portions were assessed for total cell counts and cell differentials. Results from the high-dose groups showed that lunar dust, suspended in saline, was more toxic than TiO 2, but less toxic than quartz. Lunar dust particles aggregate and settle out rapidly in water or saline, but not in Survanta. Lunar dust suspended in Survanta manifested greater toxicity than lunar dust in saline. The increase in toxicity presumably was due to that Survanta gave a better particle dispersion in the lungs. The two lunar dust samples showed similar toxicity. The overall results showed that lunar dust is more toxic than TiO 2 but less toxic than quartz.

Lam, C.-W.↗
DOE OSTI2024

Effects of Charge Sequence Pattern and Lysine-to-Arginine Substitution on the Structural Stability of Bioinspired Polyampholytes

A comprehensive study focusing on the combined influence of the charge sequence pattern and the type of positively charged amino acids on the formation of secondary structures in sequence-specific polyampholytes is presented. The sequences of interest consisting exclusively of ionizable amino acids (lysine, K; arginine, R; and glutamic acid, E) are (EKEK) 5 , (EKKE) 5 , (ERER) 5 , (ERRE) 5 , and (EKER) 5 . The stability of the secondary structure was examined at three pH values in the presence of urea and NaCl. The results presented here underscore the combined prominent effects of the charge sequence pattern and the type of positively charged monomers on secondary structure formation. Additionally, (ERRE) 5 readily aggregated across a wide range of pH. In contrast, sequences with the same charge pattern, (EKKE) 5 , as well as the sequences with the equivalent amino acid content, (ERER) 5 , exhibited no aggregate formation under equivalent pH and concentration conditions.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2018

DUSP14 knockout accelerates cardiac ischemia reperfusion (IR) injury through activating NF-κB and MAPKs signaling pathways modulated by ROS generation

Highlights: • DUSP14 expression is decreased in the infarcted area following myocardial I/R. • DUSP14 knockout aggregates cardiac function following myocardial I/R. • DUSP14 ablation intensifies inflammation in murine hearts with IR injury. • DUSP14 deficiency exacerbates MAPKs pathway and oxidative stress in murine hearts. Inflammation and oxidative stress are significantly involved in the progression of a variety of diseases, including myocardial ischemia/reperfusion (IR). In the present study, we hypothesized a protective role of dual-specificity phosphatase 14 (DUSP14) in myocardial IR, as well as the underlying molecular mechanism. The results indicated that DUSP14 was down-regulated following cardiac IR injury. Subsequently, the wild type (WT) and DUSP14-knockout (KO) mice were included to further reveal the potential role of DUSP14 in cardiac IR injury progression. DUSP14-KO mice exhibited increased infarction area and elevated apoptosis, as evidenced by the increased TUNEL-positive cells in ischemia heart following reperfusion compared to WT mice. Further, DUSP14-KO significantly aggregated cardiac dysfunction of mice after IR injury. Cardiac IR injury to DUSP14-KO mice led to markedly increased expression of pro-inflammatory cytokines and activated nuclear factor-κB (NF-κB) pathway in the heart in comparison to WT mice. Meanwhile, mitogen-activated protein kinases (MAPKs), including p38, ERK1/2 and JNK, were significantly activated by DUSO14-KO in mice after IR injury. Compared to WT mice, DUSP14-KO mice showed markedly increased oxidative stress markers in cardiac tissues, including malondialdehyde (MDA), NADPH oxidase-4 (NOX4) and p47, while decreased activities or expressions of anti-oxidants, such as glutathione (GSH), glutathione peroxidase (GPx), glutathion reductases (GR), superoxide dismutase (SOD) and hemeoxygenase-1 (HO-1). DUSP14-knockdown (KD) in primary cardiomyocytes using its specific siRNA sequence elevated hypoxia and reoxygenation (HR)-induced activation of NF-κB and MAPKs signaling pathways, and reactive oxygen species (ROS) generation. Intriguingly, pre-treatment of ROS scavenger, N-acetylcysteine (NAC), markedly abolished DUSP14-KD-augmented NF-κB and MAPKs activation in HR-stimulated primary cardiomyocytes. Together, the results above indicated that DUSP14 might be served as a positive regulator to attenuate cardiac IR injury. Suppressing DUSP14 exacerbated cardiac injury through activating NF-κB and MAPKs signaling pathways regulated by ROS production. Thus, DUSP14 could be a valuable target for developing treatments for myocardial IR injury.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

CoarsenConf: Equivariant Coarsening with Aggregated Attention for Molecular Conformer Generation

Molecular conformer generation (MCG) is an important task in cheminformatics and drug discovery. The ability to efficiently generate low-energy 3D structures can avoid expensive quantum mechanical simulations, leading to accelerated virtual screenings and enhanced structural exploration. Several generative models have been developed for MCG, but many struggle to consistently produce high-quality conformers for meaningful downstream applications. To address these issues, we introduce CoarsenConf, which coarse-grains molecular graphs based on torsional angles and integrates them into an SE(3)-equivariant hierarchical variational autoencoder. Through equivariant coarse-graining, we aggregate the fine-grained atomic coordinates of subgraphs connected via rotatable bonds, creating a variable-length coarse-grained latent representation. Our model uses a novel aggregated attention mechanism to restore fine-grained coordinates from the coarse-grained latent representation, enabling efficient generation of accurate conformers. Furthermore, we evaluate the chemical and biochemical quality of our generated conformers on multiple downstream applications, including property prediction and large-scale oracle-based protein docking. Overall, CoarsenConf generates more accurate conformer ensembles compared to prior generative models.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗