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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 253 records · Page 14
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Influence of chemical strains on the electrocaloric response, polarization morphology, tetragonality, and negative-capacitance effect of ferroelectric core-shell nanorods and nanowires

Using Landau-Ginzburg-Devonshire (LGD) approach, we proposed the analytical description of the influence of chemical strains on spontaneous polarization and the electrocaloric response in ferroelectric core-shell nanorods. We postulate that the nanorod core presents a defect-free single-crystalline ferroelectric material, and elastic defects are accumulated in the ultrathin shell, where they can induce tensile or compressive chemical strains. Finite-element modeling (FEM) based on the LGD approach reveals transitions of domain-structure morphology induced by chemical strains in the Ba Ti O 3 nanorods. Namely, tensile chemical strains induce and support the single-domain state in the central part of the nanorod, while the curled domain structures appear near the unscreened or partially screened ends of the rod. The vortexlike domains propagate toward the central part of the rod and fill it entirely, when the rod is covered by a shell with compressive chemical strains above some critical value. The critical value depends on the nanorod sizes, aspect ratio, and screening conditions at its ends. Both analytical theory and FEM predict that the tensile chemical strains in the shell increase the nanorod polarization, lattice tetragonality, and electrocaloric response well above the values corresponding to the bulk material. The physical reason for the increase is strong electrostriction coupling between the mismatch-type elastic strains induced in the core by chemical strains in the shell. Comparison with earlier XRD data confirmed an increase of the tetragonality ratio in tensile Ba Ti O 3 nanorods compared to the bulk material. Obtained analytical expressions, which are suitable for the description of strain-induced changes in a wide range of multiaxial ferroelectric core-shell nanorods and nanowires, can be useful for strain engineering of advanced ferroelectric nanomaterials for energy storage, harvesting, electrocaloric applications, and negative capacitance elements. Published by the American Physical Society 2024

36 MATERIALS SCIENCE↗
DOE OSTI2021

GRIM-19 inhibits proliferation and induces apoptosis in a p53-dependent manner in colorectal cancer cells through the SIRT7/PCAF/MDM2 axis

Colorectal cancer (CRC) is the leading deadly cancer worldwide. Gene associated with retinoid-IFN-induced mortality-19 (GRIM-19), a novel tumor suppressor, has been reported to be expressed at low levels in human CRC. However, the role of GRIM-19 in CRC progression and the corresponding detailed mechanisms are unclear. The results of this study indicated that GRIM-19 expression is related to CRC progression. Overexpression of GRIM-19 was found to inhibit CRC cell proliferation and induce apoptosis in vitro and in vivo. Our results demonstrated that GRIM-19 suppresses CRC through posttranslational regulation of p53, in which SIRT7 is activated by GRIM-19 and triggers PCAF-mediated MDM2 ubiquitination, eventually stabilizing the p53 protein. We also observed that GRIM-19 enhances the effect of oxaliplatin against CRC. In conclusion, GRIM-19 plays an important role in CRC development and is a potential biomarker and therapeutic target for clinical treatment of CRC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

PPARα agonist exerts protective effects in podocyte injury via inhibition of the ANGPTL3 pathway

Peroxisome proliferator-activated receptor α (PPARα) activation has been reported to exert protective effects on podocytes, whereas angiopoietin-like 3 (ANGPTL3) has been shown to exert significant pathogenic effects on these cells. This study aimed to investigate the link between the protective effects of PPARα activation and the pathogenic effects of ANGPTL3 in podocytes. Both PPARα and ANGPTL3 were expressed in cultured podocytes. PPARα mRNA and protein levels decreased whereas ANGPTL3 mRNA and protein levels increased in a time-dependent manner in podocytes treated with puromycin aminonucleoside (PAN). Gemfibrozil, a pharmacological agonist of PPARα, increased PPARα levels and activity in podocytes. The drug also decreased ANGPTL3 levels by potentially weakening ANGPTL3 promoter activity in both normal and PAN-treated podocytes. Furthermore, gemfibrozil significantly decreased PAN-induced apoptosis and F-actin rearrangement. Primary podocytes from Angptl3-knockout mice were cultured. There was no significant difference between Angptl3{sup −/−} podocytes treated with or without gemfibrozil in the lamellipodia numbers after PAN treatment. The results suggested that the protective effects of gemfibrozil on podocytes were not exerted following knockout of the Angptl3 gene. This study identified a novel mechanism of the PPARα agonist gemfibrozil that exerts its protective effects by inhibiting PAN-induced apoptosis and cytoskeleton rearrangements through inhibition of ANGPTL3 expression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Machine Learning‐Augmented Molecular Dynamics Simulations (MD) Reveal Insights Into the Disconnect Between Affinity and Activation of ZTP Riboswitch Ligands

Abstract The challenge of targeting RNA with small molecules necessitates a better understanding of RNA–ligand interaction mechanisms. However, the dynamic nature of nucleic acids, their ligand‐induced stabilization, and how conformational changes influence gene expression pose significant difficulties for experimental investigation. This work employs a combination of computational and experimental methods to address these challenges. By integrating structure‐informed design, crystallography, and machine learning‐augmented all‐atom molecular dynamics simulations (MD), we synthesized, biophysically and biochemically characterized, and studied the dissociation of a library of small molecule activators of the 5‐aminoimidazole–4–carboxamide ribonucleotide triphosphate (ZTP) riboswitch, a ligand‐binding RNA motif that regulates bacterial gene expression. We uncovered key interaction mechanisms, revealing valuable insights into the role of ligand binding kinetics on riboswitch activation. Further, we established that ligand on‐rates determine activation potency as opposed to binding affinity and elucidated RNA structural differences, which provide mechanistic insights into the interplay of RNA structure on riboswitch activation.

Chemistry↗
DOE OSTI2021

A HIF1A/miR-485–5p/SRPK1 axis modulates the aggressiveness of glioma cells upon hypoxia

The high aggressiveness of gliomas remains a huge challenge to clinical therapies, and the hypoxic microenvironment in the core region is a critical contributor to glioma aggressiveness. In this study, it was found that miR-485–5p was low expressed within glioma tissue samples and cells. GO enrichment annotation indicated that the predicted downstream targets miR-485–5p were enriched in hypoxia response and decreased oxygen level. In glioma cells, miR-485–5p overexpression suppressed cell viability, migratory ability, and invasive ability under both normoxic and hypoxic conditions. Through direct binding, miR-485–5p suppressed SRPK1 expression. Under hypoxia, SRPK1 overexpression enhanced hypoxia-induced glioma cell aggressiveness and significantly reversed the effects of miR-485–5p overexpression. Moreover, HIF1A could target the miR-485–5p promoter region to inhibit the transcription. HIF1A, miR-485–5p, and SRPK1 form a regulatory axis, which modulates glioma cell aggressiveness under hypoxia. In conclusion, we identify a HIF1A/miR-485–5p/SRPK1 axis that modulates the aggressiveness of glioma cells under hypoxia. The axis could potentially provide new research avenues in the treatment of gliomas considering the hypoxic environment in its core.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

HMMR is a downstream target of FOXM1 in enhancing proliferation and partial epithelial-to-mesenchymal transition of bladder cancer cells

Our previous that HMMR upregulation independently predicts poor survival in patients with papillary muscle-invasive bladder cancer (MIBC). In this study, we explored its downstream regulations and the potential transcriptional factors activating its expression. MIBC derived T24 cells, and non-MIBC (NMIBC) derived RT4 cells were used for in vitro and in vivo studies. HMMR expression enhanced cell proliferation, the expression of mesenchymal markers, and cell invasion. It induced the nuclear entry of β-catenin, increased its active form in the nuclear part, and elevated the relative TOP/FOP activity. The promoter region of HMMR has a canonical FKH motif. FOXM1 bound to this site and activated HMMR transcription. HMMR knockdown significantly weakened FOXM1 overexpression induced bladder cancer growth, invasion, partial epithelial-to-mesenchymal transition (pEMT), as well as the activation of the Wnt/β-catenin signaling pathway. In conclusion, the findings in this study expanded our understanding of the mechanisms underlying HMMR dysregulation and the functional role of the FOXM1-HMMR axis in bladder cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Viral afterlife: SARS-CoV-2 as a reservoir of immunomimetic peptides that reassemble into proinflammatory supramolecular complexes

It is unclear how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to the strong but ineffective inflammatory response that characterizes severe Coronavirus disease 2019 (COVID-19), with amplified immune activation in diverse cell types, including cells without angiotensin-converting enzyme 2 receptors necessary for infection. Proteolytic degradation of SARS-CoV-2 virions is a milestone in host viral clearance, but the impact of remnant viral peptide fragments from high viral loads is not known. Here, we examine the inflammatory capacity of fragmented viral components from the perspective of supramolecular self-organization in the infected host environment. Interestingly, a machine learning analysis to SARS-CoV-2 proteome reveals sequence motifs that mimic host antimicrobial peptides (xenoAMPs), especially highly cationic human cathelicidin LL-37 capable of augmenting inflammation. Such xenoAMPs are strongly enriched in SARS-CoV-2 relative to low-pathogenicity coronaviruses. Moreover, xenoAMPs from SARS-CoV-2 but not low-pathogenicity homologs assemble double-stranded RNA (dsRNA) into nanocrystalline complexes with lattice constants commensurate with the steric size of Toll-like receptor (TLR)-3 and therefore capable of multivalent binding. Such complexes amplify cytokine secretion in diverse uninfected cell types in culture (epithelial cells, endothelial cells, keratinocytes, monocytes, and macrophages), similar to cathelicidin’s role in rheumatoid arthritis and lupus. The induced transcriptome matches well with the global gene expression pattern in COVID-19, despite using <0.3% of the viral proteome. Delivery of these complexes to uninfected mice boosts plasma interleukin-6 and CXCL1 levels as observed in COVID-19 patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Unisexual flower initiation in the monoecious Quercus suber L.: a molecular approach

Abstract Several plant species display a temporal separation of the male and female flower organ development to enhance outbreeding; however, little is known regarding the genetic mechanisms controlling this temporal separation. Quercus suber is a monoecious oak tree with accentuated protandry: in late winter, unisexual male flowers emerge adjacent to the swollen buds, whereas unisexual female flowers emerge in the axils of newly formed leaves formed during spring (4–8 weeks after male flowering). Here, a phylogenetic profiling has led to the identification of cork oak homologs of key floral regulatory genes. The role of these cork oak homologs during flower development was identified with functional studies in Arabidopsis thaliana. The expression profile throughout the year of flower regulators (inducers and repressors), in leaves and buds, suggests that the development of male and female flowers may be preceded by separated induction events. Female flowers are most likely induced during the vegetative flush occurring in spring, whereas male flowers may be induced in early summer. Male flowers stay enclosed within the pre-dormant buds, but complete their development before the vegetative flush of the following year, displaying a long period of anthesis that spans the dormant period. Our results portray a genetic mechanism that may explain similar reproductive habits in other monoecious tree species.

Sobral, Rómulo↗
DOE OSTI2024

Regulation of β-cell death by ADP-ribosylhydrolase ARH3 via lipid signaling in insulitis

Lipids are regulators of insulitis and β-cell death in type 1 diabetes development, but the underlying mechanisms are poorly understood. Here, we investigated how the islet lipid composition and downstream signaling regulate β-cell death. We performed lipidomics using three models of insulitis: human islets and EndoC-βH1 β cells treated with the pro-inflammatory cytokines interlukine-1β and interferon-γ, and islets from pre-diabetic non-obese mice. We also performed mass spectrometry and fluorescence imaging to determine the localization of lipids and enzyme in islets. RNAi, apoptotic assay, and qPCR were performed to determine the role of a specific factor in lipid-mediated cytokine signaling. Across all three models, lipidomic analyses showed a consistent increase of lysophosphatidylcholine species and phosphatidylcholines with polyunsaturated fatty acids and a reduction of triacylglycerol species. Imaging assays showed that phosphatidylcholines with polyunsaturated fatty acids and their hydrolyzing enzyme phospholipase PLA2G6 are enriched in islets. In downstream signaling, omega-3 fatty acids reduce cytokine-induced β-cell death by improving the expression of ADP-ribosylhydrolase ARH3. The mechanism involves omega-3 fatty acid-mediated reduction of the histone methylation polycomb complex PRC2 component Suz12, upregulating the expression of Arh3, which in turn decreases cell apoptosis. Our data provide insights into the change of lipidomics landscape in β cells during insulitis and identify a protective mechanism by omega-3 fatty acids.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Construction of chicken infectious anemia virus infectious clone and study on its pathogenicity

Chicken infectious anemia virus (CIAV) can be transmitted through contaminated live poultry vaccine. However, the pathogenicity of contaminated CIAV strains is rarely reported. Previously, the chickens showed the typical symptoms of anemia after using the attenuated live fowl pox virus (FPV) vaccine. Therefore, exogenous CIAV contamination was suspected. We detected anti-CIAV antibodies in SPF chicks vaccinated with the FPV vaccine. CIAV contamination was confirmed in the FPV vaccine, and the CIAV strain was named JS2020-FPV. This study aims to rescue JS2020-FPV by reverse genetic assays and investigate its pathogenicity. Firstly, double-copies infectious clone of JS2020-FPV was constructed. For the pathogenicity study, infectious clone of JS2020-FPV was used to inoculate 1-day-old SPF chicks. The typical symptoms of anemia were observed in the JS2020-PFV group 14 days post inoculation. The hematocrit and body weight of chicks in the JS2020-PFV group were significantly lower than those in the mock group. Notably, the thymus development index and antibody levels of NDV were lower in chicks in the JS2020-PFV group than those in the mock group. Different degrees of apoptosis of MSB1 and DF-1 were observed after inoculated with the JS2020-FPV VP3 recombinant fusion protein expressed by E. coli system, indicating that VP3 induced apoptosis in the transformed cells. Overall, the pathogenicity of the CIAV detected in the contaminated vaccine was confirmed by inoculating SPF chicks with the double-copies infectious DNA clone in this study. Our findings indicate that the dangers of vaccine contamination cannot be ignored.

Wang, Jinjin↗
DOE OSTI2021

AGTR1 blocker attenuates activation of Tenon's capsule fibroblasts after glaucoma filtration surgery via the NF-κB signaling pathway

Activation of Tenon's capsule fibroblasts limits the success rate of glaucoma filtration surgery (GFS), the most efficacious therapy for patients with glaucoma. Angiotensin type 1 receptor (AGTR1) is involved in tissues remodeling and fibrogenesis. However, whether AGTR1 is involved in the progress of fibrogenesis after GFS is not fully elucidated. The aim of this study was to investigate the role of an AGTR1 in scar formation after GFS and the potential anti-fibrosis effect of AGTR1 blocker. AGTR1 expression level was increased in subconjunctival tissues in a rat model of GFS and transforming growth factor-beta 2 (TGF-β2)-induced human Tenon's capsule fibroblasts (HTFs). AGTR1 blocker treatment suppressed TGF-β2-induced HTF migration and α-smooth muscle actin (α-SMA) and fibronectin (FN) expression. AGTR1 blocker treatment also attenuated collagen deposition and α-SMA and FN expression in subconjunctival tissues of the rat model after GFS. Moreover, AGTR1 blocker decreased TGF-β2-induced P65 phosphorylation, P65 nuclear translocation, and nuclear factor kappa B (NF-κB) luciferase activity. Additionally, BAY 11–7082 (an NF-κB inhibitor) significantly suppressed HTF fibrosis. In conclusion, our results indicate that AGTR1 is involved in scar formation after GFS. The AGTR1 blocker attenuates subconjunctival fibrosis after GFS by inhibiting the NF-κB signaling pathway. These findings indicate that targeting AGTR1 is a potential approach to attenuate fibrosis after GFS.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Macrophage-derived MLKL in alcohol-associated liver disease: Regulation of phagocytosis

Mixed lineage kinase domain-like pseudokinase (MLKL), a key terminal effector of necroptosis, also plays a role in intracellular vesicle trafficking that is critical for regulating liver inflammation and injury in alcohol-associated liver disease (ALD). Although receptor interacting protein kinase 3 (Rip3) -/- mice are completely protected from ethanol-induced liver injury, Mlkl -/- mice are only partially protected. Therefore, we hypothesized that cell-specific functions of MLKL may contribute to ethanol-induced injury. Bone marrow transplants between Mlkl -/- mice and littermates were conducted to distinguish the role of myeloid versus nonmyeloid Mlkl in the Gao-binge model of ALD. Ethanol-induced hepatic injury, steatosis, and inflammation were exacerbated in Mlkl -/- →wild-type (WT) mice, whereas Mlkl deficiency in nonmyeloid cells (WT→Mlkl -/- ) had no effect on Gao-binge ethanol-induced injury. Importantly, Mlkl deficiency in myeloid cells exacerbated ethanol-mediated bacterial burden and accumulation of immune cells in livers. Mechanistically, challenging macrophages with lipopolysaccharide (LPS) induced signal transducer and activator of transcription 1–mediated expression and phosphorylation of MLKL, as well as translocation and oligomerization of MLKL to intracellular compartments, including phagosomes and lysosomes but not plasma membrane. Importantly, pharmacological or genetic inhibition of MLKL suppressed the phagocytic capability of primary mouse Kupffer cells (KCs) at baseline and in response to LPS with/without ethanol as well as peripheral monocytes isolated from both healthy controls and patients with alcohol-associated hepatitis. Further, in vivo studies revealed that KCs of Mlkl -/- mice phagocytosed fewer bioparticles than KCs of WT mice. Together, these data indicate that myeloid MLKL restricts ethanol-induced liver inflammation and injury by regulating hepatic immune cell homeostasis and macrophage phagocytosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

A small molecule antagonizes jasmonic acid perception and auxin responses in vascular and nonvascular plants

The phytohormone jasmonoyl-L-isoleucine (JA-Ile) regulates many stress responses and developmental processes in plants. A co-receptor complex formed by the F-box protein Coronatine Insensitive 1 (COI1) and a Jasmonate (JA) ZIM-domain (JAZ) repressor perceives the hormone. JA-Ile antagonists are invaluable tools for exploring the role of JA-Ile in specific tissues and developmental stages, and for identifying regulatory processes of the signaling pathway. Using two complementary chemical screens, we identified three compounds that exhibit a robust inhibitory effect on both the hormone-mediated COI–JAZ interaction and degradation of JAZ1 and JAZ9 in vivo. One molecule, J4, also restrains specific JA-induced physiological responses in different angiosperm plants, including JA-mediated gene expression, growth inhibition, chlorophyll degradation, and anthocyanin accumulation. Interaction experiments with purified proteins indicate that J4 directly interferes with the formation of the Arabidopsis (Arabidopsis thaliana) COI1–JAZ complex otherwise induced by JA. The antagonistic effect of J4 on COI1–JAZ also occurs in the liverwort Marchantia polymorpha, suggesting the mode of action is conserved in land plants. Besides JA signaling, J4 works as an antagonist of the closely related auxin signaling pathway, preventing Transport Inhibitor Response1/Aux–indole-3-acetic acid interaction and auxin responses in planta, including hormone-mediated degradation of an auxin repressor, gene expression, and gravitropic response. However, J4 does not affect other hormonal pathways. Altogether, our results show that this dual antagonist competes with JA-Ile and auxin, preventing the formation of phylogenetically related receptor complexes. J4 may be a useful tool to dissect both the JA-Ile and auxin pathways in particular tissues and developmental stages since it reversibly inhibits these pathways. One-sentence summary: A chemical screen identified a molecule that antagonizes jasmonate perception by directly interfering with receptor complex formation in phylogenetically distant vascular and nonvascular plants.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Cacao pod transcriptome profiling of seven genotypes identifies features associated with post-penetration resistance to Phytophthora palmivora

Abstract The oomycete Phytophthora palmivora infects the fruit of cacao trees ( Theobroma cacao ) causing black pod rot and reducing yields. Cacao genotypes vary in their resistance levels to P. palmivora , yet our understanding of how cacao fruit respond to the pathogen at the molecular level during disease establishment is limited. To address this issue, disease development and RNA-Seq studies were conducted on pods of seven cacao genotypes (ICS1, WFT, Gu133, Spa9, CCN51, Sca6 and Pound7) to better understand their reactions to the post-penetration stage of P. palmivora infection. The pod tissue- P. palmivora pathogen assay resulted in the genotypes being classified as susceptible (ICS1, WFT, Gu133 and Spa9) or resistant (CCN51, Sca6 and Pound7). The number of differentially expressed genes (DEGs) ranged from 1625 to 6957 depending on genotype. A custom gene correlation approach identified 34 correlation groups. De novo motif analysis was conducted on upstream promoter sequences of differentially expressed genes, identifying 76 novel motifs, 31 of which were over-represented in the upstream sequences of correlation groups and associated with gene ontology terms related to oxidative stress response, defense against fungal pathogens, general metabolism and cell function. Genes in one correlation group (Group 6) were strongly induced in all genotypes and enriched in genes annotated with defense-responsive terms. Expression pattern profiling revealed that genes in Group 6 were induced to higher levels in the resistant genotypes. An additional analysis allowed the identification of 17 candidate cis -regulatory modules likely to be involved in cacao defense against P. palmivora . This study is a comprehensive exploration of the cacao pod transcriptional response to P. palmivora spread after infection. We identified cacao genes, promoter motifs, and promoter motif combinations associated with post-penetration resistance to P. palmivora in cacao pods and provide this information as a resource to support future and ongoing efforts to breed P. palmivora -resistant cacao.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

PGC1α regulates mitochondrial oxidative phosphorylation involved in cisplatin resistance in ovarian cancer cells via nucleo-mitochondrial transcriptional feedback

Mitochondria play an important role in effective cell energy production and cell survival under stress conditions, such as treatment with chemotherapeutic drugs. Mitochondrial biogenesis is increased in ovarian cancer tissues, which is accompanied by alteration of mitochondrial energy metabolism, structure, and dynamics. These factors are involved in tumorigenesis and apoptosis resistance, highlighting the role of mitochondria in resisting cisplatin toxicity. Cisplatin-resistant ovarian cancer cells are dependent on mitochondrial OXPHOS for energy supply, and intracellular PGC1α-mediated mitochondrial biogenesis levels are increased in this cell line, indicating the important role of mitochondrial oxidative phosphorylation in cisplatin resistance. As PGC1α is a key molecule for integrating and coordinating nuclear DNA and mitochondrial DNA transcriptional machinery, an investigation into the regulatory mechanism PGC1α in mitochondrial energy metabolism via transcription may provide new clues for solving chemotherapy resistance. In the present study, it was demonstrated that inhibiting the expression of PGC1α decreased nuclear and mitochondrial DNA transcription factor expression, leading to increased lactic acid production and decreased cellular oxygen consumption and mitochondrial oxidative phosphorylation. Furthermore, mitochondrial stress-induced ROS production, as a feedback signal from mitochondria to the cell nucleus, increased PGC1α expression in SKOV3/DDP cells, which was involved in mitochondrial oxidative phosphorylation regulation. Collectively, the present study provides evidence that PGC1α-mediated nuclear and mitochondrial transcription feedback regulates energy metabolism and is involved in ovarian cancer cells escaping apoptosis during cisplatin treatment.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

SAA1 is transcriptionally activated by STAT3 and accelerates renal interstitial fibrosis by inducing endoplasmic reticulum stress

Renal interstitial fibrosis (RIF) is the common irreversible pathway by which chronic kidney disease (CKD) progresses to the end stage. The transforming growth factor-β (TGF-β)/signal transducer and activator of transcription 3 (STAT3) signaling pathway is a common factor leading to inflammation-mediated RIF, but its downstream regulatory mechanism is still unclear. Bioinformatics analysis predicted that serum amyloid A protein 1 (SAA1) was one of the target genes for transcriptional activation of STAT3 signaling. As an acute phase reaction protein, SAA1 plays an important role in many inflammatory reactions, and research has suggested that SAA1 is significantly elevated in the serum of patients with CKD. In this research, multiple experiments were performed to investigate the role of SAA1 in the process of RIF. SAA1 was abnormally highly expressed in kidney tissue from individuals who underwent unilateral ureteral obstruction (UUO) and TGF-β-induced HK2 cells, and the abnormal expression was directly related to the transcriptional activation of STAT3. Additionally, SAA1 can directly target and bind valosin-containing protein (VCP)-interacting membrane selenoprotein (VIMP) to inhibit the function of the Derlin-1/VCP/VIMP complex, preventing the transportation and degradation of the misfolded protein, resulting in endoplasmic reticulum (ER) stress characterized by an increase in glucose-regulated protein 78 (GRP78) levels and ultimately promoting the occurrence and development of RIF.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Time-resolved multi-omics reveals diverse metabolic strategies of Salmonella during diet-induced inflammation

With a rise in antibiotic resistance and chronic infection, the metabolic response of Salmonella enterica serovar Typhimurium to various dietary conditions over time remains an understudied avenue for novel, targeted therapeutics. Elucidating how enteric pathogens respond to dietary variation not only helps us decipher the metabolic strategies leveraged for expansion but also assists in proposing targets for therapeutic interventions. In this study, we use a multi-omics approach to identify the metabolic response of Salmonella enterica serovar Typhimurium in mice on both a fibrous diet and high-fat diet over time. When comparing Salmonella gene expression between diets, we found a preferential use of respiratory electron acceptors consistent with increased inflammation in high-fat diet mice. Looking at the high-fat diet over the course of infection, we noticed heterogeneity in samples based on Salmonella ribosomal activity, which is separated into three infection phases: early, peak, and late. We identified key respiratory, carbon, and pathogenesis gene expressions descriptive of each phase. Surprisingly, we identified genes associated with host cell entry expressed throughout infection, suggesting subpopulations of Salmonella or stress-induced dysregulation. Collectively, these results highlight not only the sensitivity of Salmonella to its environment but also identify phase-specific genes that may be used as therapeutic targets to reduce infection.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

O-GlcNAc transferase regulates collagen deposition and fibrosis resolution in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disease that is characterized by an excessive accumulation of extracellular matrix (ECM) proteins (e.g. collagens) in the parenchyma, which ultimately leads to respiratory failure and death. While current therapies exist to slow the progression, no therapies are available to resolve fibrosis. We characterized the O-linked N-Acetylglucosamine (O-GlcNAc) transferase (OGT)/O-GlcNAc axis in IPF using single-cell RNA-sequencing (scRNA-seq) data and human lung sections and isolated fibroblasts from IPF and non-IPF donors. The underlying mechanism(s) of IPF were further investigated using multiple experimental models to modulate collagen expression and accumulation by genetically and pharmacologically targeting OGT. Furthermore, we hone in on the transforming growth factor-beta (TGF-β) effector molecule, Smad3, by co-expressing it with OGT to determine if it is modified and its subsequent effect on Smad3 activation. We found that OGT and O-GlcNAc levels are upregulated in patients with IPF compared to non-IPF. We report that the OGT regulates collagen deposition and fibrosis resolution, which is an evolutionarily conserved process demonstrated across multiple species. Co-expression of OGT and Smad3 showed that Smad3 is O-GlcNAc modified. Blocking OGT activity resulted in decreased phosphorylation at Ser-423/425 of Smad3 attenuating the effects of TGF-β1 induced collagen expression/deposition. OGT inhibition or knockdown successfully blocked and reversed collagen expression and accumulation, respectively. Smad3 is discovered to be a substrate of OGT and its O-GlcNAc modification(s) directly affects its phosphorylation state. These data identify OGT as a potential target in pulmonary fibrosis resolution, as well as other diseases that might have aberrant ECM/collagen accumulation.

59 BASIC BIOLOGICAL SCIENCES↗