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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 91 records · Page 5
All sourcesNASA NTRSDOE OSTI
DOE OSTI2020

Biology of extracellular vesicles secreted from senescent cells as senescence‐associated secretory phenotype factors

The increase of the morbidity rate in age‐related diseases, such as cancer, Alzheimer’s disease, arteriosclerosis and pulmonary fibrosis, has become a profound social problem. Recent reports have pointed out that senescent cells accumulated in the body with aging might cause these aged‐related pathologies. Cellular senescence is known as an irreversible cell cycle arrest induced by various stresses, and can function as an important tumor suppression mechanism to exclude the premalignant cells. In contrast, senescent cells provoke the phenomenon, termed the senescence‐associated secretory phenotype, which causes the secretion of various inflammatory proteins, and it is at risk of facilitating chronic inflammation and oncogenic transformation to surrounding cells. We have previously reported that senescent cells secrete not only inflammatory proteins, but also extracellular vesicles (EV). EV include various cellular components, such as proteins, lipids and nucleic acids, which are proven to be important factors for cell‐to‐cell communication. Recent evidence suggests that EV secreted from senescent cells might contribute to tumorigenesis and age‐associated pathologies as new senescence‐associated secretory phenotype factors. In addition, we also showed that the EV secretion pathway is one of the essential defense mechanisms to maintain cellular homeostasis by excretion of intercellular toxic substances into extracellular space. Herein, this review shows the biological functions of EV secreted from senescent cells. Geriatr Gerontol Int 2020; ••: ••–•• .

Misawa, Tomoka↗
DOE OSTI2020

Knockout of AKAP150 improves impaired BK channel‐mediated vascular dysfunction through the Akt/GSK3β signalling pathway in diabetes mellitus

Abstract Vascular dysfunction resulting from diabetes is an important factor in arteriosclerosis. Previous studies have shown that during hyperglycaemia and diabetes, AKAP150 promotes vascular tone enhancement by intensifying the remodelling of the BK channel. However, the interaction between AKAP150 and the BK channel remains open to discussion. In this study, we investigated the regulation of impaired BK channel‐mediated vascular dysfunction in diabetes mellitus. Using AKAP150 null mice (AKAP150 −/− ) and wild‐type (WT) control mice (C57BL/6J), diabetes was induced by intraperitoneal injection of streptozotocin. We found that knockout of AKAP150 reversed vascular remodelling and fibrosis in mice with diabetes and in AKAP150 −/− diabetic mice. Impaired Akt/GSK3β signalling contributed to decreased BK‐β 1 expression in aortas from diabetic mice, and the silencing of AKAP150 increased Akt phosphorylation and BK‐β 1 expression in MOVAS cells treated with HG medium. The inhibition of Akt activity caused a decrease in BK‐β 1 expression, and treatment with AKAP150 siRNA suppressed GSK3β expression in the nuclei of MOVAS cells treated with HG. Knockout of AKAP150 reverses impaired BK channel‐mediated vascular dysfunction through the Akt/GSK3β signalling pathway in diabetes mellitus.

Zhu, Yan‐Rong↗
DOE OSTI2020

Activated KCNQ1 channel promotes fibrogenic response in hereditary gingival fibromatosis via clustering and activation of Ras

Abstract Background and Objective Activated potassium channels were found to be strongly correlated with gingival overgrowth (GO) phenotype as we reviewed syndromic hereditary gingival fibromatosis (HGF). Nevertheless, the functional roles of potassium channels in gingival fibrosis or gingival overgrowth remained uncovered. The aim of the present study was to explore the pathogenic role of aberrantly activated potassium channel in Hereditary Gingival Fibromatosis (HGF). Methods Gingival tissues were collected from 9 HGF patients and 15 normal controls. Expression of KCNQ1 was detected by immunohistochemistry. Gingival fibroblasts were isolated, and outward K + currents were detected by whole‐cell patch‐clamp analysis, transmembrane potential was determined by flow cytometry. Normal human gingival fibroblasts (NHGFs) were transfected with KCNQ1 adenovirus or treated with KCNQ1 selective agonist ML277 and antagonist chromanol 293B. Accumulation of Extracellular Matrix (ECM) was measured by Western blotting and Sircol Soluble Collagen Assay. Content of secreted TGF‐β1 was measured by ELISA. Active RAS pull‐down assay and cell immunofluorescence were utilized to verify RAS activation. Results KCNQ1 was upregulated in gingival tissues derived from HGF patients and HGF gingival fibroblasts presented increased outward K + currents than NHGFs. Overexpression of KCNQ1, or KCNQ1 agonist ML277, promoted fibrotic responses of NHGFs. TGF‐β1 and KCNQ1 channels formed a positive feed‐back loop. ML277 generated lateral clustering and activation of Ras on plasma membrane, followed by augmented MAPK/AP‐1 signaling pathway output. JNK or ERK1/2 inhibitors suppressed ML277‐induced AP‐1 and ECM upregulation. Conclusion Activation of KCNQ1 potassium channel promoted fibrogenic responses in NHGFs via Ras/MAPK/AP‐1 signaling.

Gao, Qian↗
DOE OSTI2024

Applying a polysaccharide lyase from Stenotrophomonas maltophilia to disrupt alginate exopolysaccharide produced by Pseudomonas aeruginosa clinical isolates

Pseudomonas aeruginosa is considered one of the most challenging, drug-resistant, opportunistic pathogens partly due to its ability to synthesize robust biofilms. Biofilm is a mixture of extracellular polymeric substances (EPS) that encapsulates microbial cells, leading to immune evasion, antibiotic resistance, and thus higher risk of infection. In the cystic fibrosis lung environment, P. aeruginosa undergoes a mucoid transition, defined by overproduction of the exopolysaccharide alginate. Alginate encapsulation results in bacterial resistance to antibiotics and the host immune system. Given its role in airway inflammation and chronic infection, alginate is an obvious target to improve treatment for P. aeruginosa infection. Previously, we demonstrated polysaccharide lyase Smlt1473 from Stenotrophomonas maltophilia strain k279a can catalyze the degradation of multiple polyuronides in vitro, including D-mannuronic acid (poly-ManA). Poly-ManA is a major constituent of P. aeruginosa alginate, suggesting that Smlt1473 could have potential application against multidrug-resistant P. aeruginosa and perhaps other microbes with related biofilm composition. In this study, we demonstrate that Smlt1473 can inhibit and degrade alginate from P. aeruginosa. Additionally, we show that tested P. aeruginosa strains are dominant in acetylated alginate and that all but one have similar M-to-G ratios. These results indicate that variation in enzyme efficacy among the isolates is not primarily due to differences in total EPS or alginate chemical composition. Overall, these results demonstrate Smlt1473 can inhibit and degrade P. aeruginosa alginate and suggest that other factors including rate of EPS production, alginate sequence/chain length, or non-EPS components may explain differences in enzyme efficacy.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Bactericidal effectors of the Stenotrophomonas maltophilia type IV secretion system: functional definition of the nuclease TfdA and structural determination of TfcB

ABSTRACT Stenotrophomonas maltophilia expresses a type IV protein secretion system (T4SS) that promotes contact-dependent killing of other bacteria and does so partly by secreting the effector TfcB. Here, we report the structure of TfcB, comprising an N-terminal domain similar to the catalytic domain of glycosyl hydrolase (GH-19) chitinases and a C-terminal domain for recognition and translocation by the T4SS. Utilizing a two-hybrid assay to measure effector interactions with the T4SS coupling protein VirD4, we documented the existence of five more T4SS substrates. One of these was protein 20845, an annotated nuclease. A S. maltophilia mutant lacking the gene for 20845 was impaired for killing Escherichia coli , Klebsiella pneumoniae , and Pseudomonas aeruginosa . Moreover, the cloned 20845 gene conferred robust toxicity, with the recombinant E. coli being rescued when 20845 was co-expressed with its cognate immunity protein. The 20845 effector was an 899 amino-acid protein, comprised of a GHH-nuclease domain in its N-terminus, a large central region of indeterminant function, and a C-terminus for secretion. Engineered variants of the 20845 gene that had mutations in the predicted catalytic site did not impede E. coli , indicating that the antibacterial effect of 20845 involves its nuclease activity. Using flow cytometry with DNA staining, we determined that 20845, but not its mutant variants, confers a loss in DNA content of target bacteria. Database searches revealed that uncharacterized homologs of 20845 occur within a range of bacteria. These data indicate that the S. maltophilia T4SS promotes interbacterial competition through the action of multiple toxic effectors, including a potent, novel DNase. IMPORTANCE Stenotrophomonas maltophilia is a multi-drug-resistant, Gram-negative bacterium that is an emerging pathogen of humans. Patients with cystic fibrosis are particularly susceptible to S. maltophilia infection. In hospital water systems and various types of infections, S. maltophilia co-exists with other bacteria, including other pathogens such as Pseudomonas aeruginosa . We previously demonstrated that S. maltophilia has a functional VirB/D4 type VI protein secretion system (T4SS) that promotes contact-dependent killing of other bacteria. Since most work on antibacterial systems involves the type VI secretion system, this observation remains noteworthy. Moreover, S. maltophilia currently stands alone as a model for a human pathogen expressing an antibacterial T4SS. Using biochemical, genetic, and cell biological approaches, we now report both the discovery of a novel antibacterial nuclease (TfdA) and the first structural determination of a bactericidal T4SS effector (TfcB).

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Exosomes From Induced Pluripotent Stem Cell–Derived Cardiomyocytes Promote Autophagy for Myocardial Repair

Background. Induced pluripotent stem cells and their differentiated cardiomyocytes (iCMs) have tremendous potential as patient-specific therapy for ischemic cardiomyopathy following myocardial infarctions, but difficulties in viable transplantation limit clinical translation. Exosomes secreted from iCMs (iCM-Ex) can be robustly collected in vitro and injected in lieu of live iCMs as a cell-free therapy for myocardial infarction. Methods and Results. iCM-Ex were precipitated from iCM supernatant and characterized by protein marker expression, nanoparticle tracking analysis, and functionalized nanogold transmission electron microscopy. iCM-Ex were then used in in vitro and in vivo models of ischemic injuries. Cardiac function in vivo was evaluated by left ventricular ejection fraction and myocardial viability measurements by magnetic resonance imaging. Cardioprotective mechanisms were studied by JC-1 (tetraethylbenzimidazolylcarbocyanine iodide) assay, immunohistochemistry, quantitative real-time polymerase chain reaction, transmission electron microscopy, and immunoblotting. iCM-Ex measured ≈140 nm and expressed CD63 and CD9. iCM and iCM-Ex microRNA profiles had significant overlap, indicating that exosomal content was reflective of the parent cell. Mice treated with iCM-Ex demonstrated significant cardiac improvement post–myocardial infarction, with significantly reduced apoptosis and fibrosis. In vitro iCM apoptosis was significantly reduced by hypoxia and exosome biogenesis inhibition and restored by treatment with iCM-Ex or rapamycin. Autophagosome production and autophagy flux was upregulated in iCM-Ex groups in vivo and in vitro. Conclusions. iCM-Ex improve post–myocardial infarction cardiac function by regulating autophagy in hypoxic cardiomyoytes, enabling a cell-free, patient-specific therapy for ischemic cardiomyopathy.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Antibacterial activity of iron oxide, iron nitride, and tobramycin conjugated nanoparticles against Pseudomonas aeruginosa biofilms

Novel methods are necessary to reduce morbidity and mortality of patients suffering from infections with Pseudomonas aeruginosa. Being the most common infectious species of the Pseudomonas genus, P. aeruginosa is the primary Gram-negative etiology responsible for nosocomial infections. Due to the ubiquity and high adaptability of this species, an effective universal treatment method for P. aeruginosa infection still eludes investigators, despite the extensive research in this area. Results We report bacterial inhibition by iron-oxide (nominally magnetite) nanoparticles (NPs) alone, having a mean hydrodynamic diameter of ~ 16 nm, as well as alginate-capped iron-oxide NPs. Alginate capping increased the average hydrodynamic diameter to ~ 230 nm. We also investigated alginate-capped iron-oxide NP-drug conjugates, with a practically unchanged hydrodynamic diameter of ~ 232 nm. Susceptibility and minimum inhibitory concentration (MIC) of the NPs, NP-tobramycin conjugates, and tobramycin alone were determined in the PAO1 bacterial colonies. Investigations into susceptibility using the disk diffusion method were done after 3 days of biofilm growth and after 60 days of growth. MIC of all compounds of interest was determined after 60-days of growth, to ensure thorough establishment of biofilm colonies. Conclusions Positive inhibition is reported for uncapped and alginate-capped iron-oxide NPs, and the corresponding MICs are presented. We report zero susceptibility to iron-oxide NPs capped with polyethylene glycol, suggesting that the capping agent plays a major role in enabling bactericidal ability in of the nanocomposite. Our findings suggest that the alginate-coated nanocomposites investigated in this study have the potential to overcome the bacterial biofilm barrier. Magnetic field application increases the action, likely via enhanced diffusion of the iron-oxide NPs and NP-drug conjugates through mucin and alginate barriers, which are characteristic of cystic-fibrosis respiratory infections. We demonstrate that iron-oxide NPs coated with alginate, as well as alginate-coated magnetite–tobramycin conjugates inhibit P. aeruginosa growth and biofilm formation in established colonies. We have also determined that susceptibility to tobramycin decreases for longer culture times. However, susceptibility to the iron-oxide NP compounds did not demonstrate any comparable decrease with increasing culture time. These findings imply that iron-oxide NPs are promising lower-cost alternatives to silver NPs in antibacterial coatings, solutions, and drugs, as well as other applications in which microbial abolition or infestation prevention is sought.

Biotechnology & Applied Microbiology↗
DOE OSTI2022

A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program

The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n = 35) or hospitalization (n = 42) due to severe COVID-19 using genome-wide association summary data from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (n rs495828 = 53 and n rs505922 = 59); strongest association with venous embolism, odds ratio (OR rs495828 1.33 (p = 1.32 x 10 –199 ), and thrombosis OR rs505922 1.33, p = 2.2 x10 -265 . Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p = 4.12 × 10 –191 ; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p = 2.26× 10 –12 . The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p = 6.48 x10 -23 , lupus OR 0.84, p = 3.97 x 10 –06 . PheWAS stratified by ancestry demonstrated differences in genotype-phenotype associations. LMNA (rs581342) associated with neutropenia OR 1.29 p = 4.1 x 10 –13 among Veterans of African and Hispanic ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Cellular signaling within aged skeletal muscle reveals a dysregulated stress-induced remodeling response following volumetric muscle loss in female mice

Severe muscle trauma disrupts endogenous repair mechanisms, producing chronic functional deficits that are incompletely characterized in aged populations. This study investigated inflammatory, molecular, and physiological responses to volumetric muscle loss in young adult and aged female mice. Serum cytokine profiling revealed elevated baseline inflammation in aged animals and a blunted response to injury, with cytokines such as IL-6 increasing 4.4-fold in young versus 1.8-fold in aged mice at day 3 compared to baseline. By day 28 post-injury, histological analyses showed comparable reductions in muscle size and increases in fibrosis across ages. Despite these similar tissue-level outcomes, age-dependent differences emerged in downstream functional and molecular responses. Muscle functional testing demonstrated persistent force deficits independent of age but altered muscle relaxation kinetics in aged mouse muscles (p < 0.001), suggesting dysregulated excitation-contraction coupling. Additionally, mice displayed age-associated differences in post-injury limb loading. Global proteomic analyses further confirmed age-associated enrichment of complement and antigen-processing pathways alongside metabolic dysfunction (p < 0.05). Phosphoproteomic profiling revealed reduced basal kinase activity in the muscles of aged mice yet exaggerated injury-induced phosphorylation of Mapk1-associated phosphosites, indicating a dysregulated stress response. Collectively, these findings suggest that aged murine muscles function within a heightened inflammatory and perturbed kinase-signaling environment that may hinder the coordination of regenerative programs, underscoring the need for regenerative strategies that address age-specific molecular contexts to improve functional recovery across the lifespan.

Habing, Krista M.↗
DOE OSTI2024

Reduced ribonucleotide reductase RRM2 subunit expression increases DNA damage and mitochondria dysfunction in woody breast chickens

Abstract OBJECTIVE The aim of this study was to investigate the roles of ribonucleotide reductase subunit M2 (RRM2; subunit of ribonucleotide reductase) in severe woody breast (WB) and normal breast muscles. ANIMALS 40 8-week-old male Ross-708 broiler chickens. METHODS Quantitative PCR was performed to determine gene expression, and commercial ELISA/assay kits were used to obtain several enzymatic activities. RESULTS Results showed that RRM2 activity (P= .0002) and RRM2 (P= .05) and hydroxymethylbilane synthase expression (impaired oxygen transport and metabolism,P= .002) were reduced in WB, while caveolin-3 (defected membrane integrity,P= .09), endoglin (increased fibrosis,P= .06), and secreted protein acidic rich in cysteine (metabolic dysregulation,P= .09) expression tended to increase in WB. WB tended to have increased levels of homocysteine (P= .06), aspartate aminotransferase mitochondria (P= .02), pyruvate kinase (P= .04), DNA damage (P= .06), creatine kinase (P= .05), and triglyceride (P= .002) but decreased ATPase activity (P= .01), all indicating mitochondria dysfunction and tissue damage. CLINICAL RELEVANCE In this study, differences in various enzyme activities and increased DNA damage suggest that RRM2-mediated mitochondrial abnormalities may play a role in WB myopathy.

Veterinary Sciences↗
DOE OSTI2024

Rapid detection of mexX in Pseudomonas aeruginosa based on CRISPR-Cas13a coupled with recombinase polymerase amplification

The principal pathogen responsible for chronic urinary tract infections, immunocompromised hosts, and cystic fibrosis patients is Pseudomonas aeruginosa , which is difficult to eradicate. Due to the extensive use of antibiotics, multidrug-resistant P. aeruginosa has evolved, complicating clinical therapy. Therefore, a rapid and efficient approach for detecting P. aeruginosa strains and their resistance genes is necessary for early clinical diagnosis and appropriate treatment. This study combines recombinase polymerase amplification (RPA) and clustered regularly interspaced short palindromic repeats-association protein 13a (CRISPR-Cas13a) to establish a one-tube and two-step reaction systems for detecting the mexX gene in P. aeruginosa . The test times for one-tube and two-step RPA-Cas13a methods were 5 and 40 min (including a 30 min RPA amplification reaction), respectively. Both methods outperform Quantitative Real-time Polymerase Chain Reactions (qRT-PCR) and traditional PCR. The limit of detection (LoD) of P. aeruginosa genome in one-tube and two-step RPA-Cas13a is 10 aM and 1 aM, respectively. Meanwhile, the designed primers have a high specificity for P. aeruginosa mexX gene. These two methods were also verified with actual samples isolated from industrial settings and demonstrated great accuracy. Furthermore, the results of the two-step RPA-Cas13a assay could also be visualized using a commercial lateral flow dipstick with a LoD of 10 fM, which is a useful adjunt to the gold-standard qRT-PCR assay in field detection. Taken together, the procedure developed in this study using RPA and CRISPR-Cas13a provides a simple and fast way for detecting resistance genes.

Zhu, Xiao-Xuan↗
DOE OSTI2022

Fast Characterization of Inducible Regions of Atrial Fibrillation Models With Multi-Fidelity Gaussian Process Classification

Computational models of atrial fibrillation have successfully been used to predict optimal ablation sites. A critical step to assess the effect of an ablation pattern is to pace the model from different, potentially random, locations to determine whether arrhythmias can be induced in the atria. In this work, we propose to use multi-fidelity Gaussian process classification on Riemannian manifolds to efficiently determine the regions in the atria where arrhythmias are inducible. We build a probabilistic classifier that operates directly on the atrial surface. We take advantage of lower resolution models to explore the atrial surface and combine seamlessly with high-resolution models to identify regions of inducibility. We test our methodology in 9 different cases, with different levels of fibrosis and ablation treatments, totalling 1,800 high resolution and 900 low resolution simulations of atrial fibrillation. When trained with 40 samples, our multi-fidelity classifier that combines low and high resolution models, shows a balanced accuracy that is, on average, 5.7% higher than a nearest neighbor classifier. We hope that this new technique will allow faster and more precise clinical applications of computational models for atrial fibrillation. All data and code accompanying this manuscript will be made publicly available at: https://github.com/fsahli/AtrialMFclass.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

The safety of magnetic resonance imaging contrast agents

Gadolinium-based contrast agents are increasingly used in clinical practice. While these pharmaceuticals are verified causal agents in nephrogenic systemic fibrosis, there is a growing body of literature supporting their role as causal agents in symptoms associated with gadolinium exposure after intravenous use and encephalopathy following intrathecal administration. Gadolinium-based contrast agents are multidentate organic ligands that strongly bind the metal ion to reduce the toxicity of the metal. The notion that cationic gadolinium dissociates from these chelates and causes the disease is prevalent among patients and providers. We hypothesize that non-ligand-bound (soluble) gadolinium will be exceedingly low in patients. Soluble, ionic gadolinium is not likely to be the initial step in mediating any disease. The Kidney Institute of New Mexico was the first to identify gadolinium-rich nanoparticles in skin and kidney tissues from magnetic resonance imaging contrast agents in rodents. In 2023, they found similar nanoparticles in the kidney cells of humans with normal renal function, likely from contrast agents. We suspect these nanoparticles are the mediators of chronic toxicity from magnetic resonance imaging contrast agents. This article explores associations between gadolinium contrast and adverse health outcomes supported by clinical reports and rodent models.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Ultrastructural Location and Interactions of the Immunoglobulin Receptor Binding Sequence within Fibrillar Type I Collagen

Collagen type I is a major constituent of animal bodies. It is found in large quantities in tendon, bone, skin, cartilage, blood vessels, bronchi, and the lung interstitium. It is also produced and accumulates in large amounts in response to certain inflammations such as lung fibrosis. Our understanding of the molecular organization of fibrillar collagen and cellular interaction motifs, such as those involved with immune-associated molecules, continues to be refined. In this study, antibodies raised against type I collagen were used to label intact D-periodic type I collagen fibrils and observed with atomic force microscopy (AFM), and X-ray diffraction (XRD) and immunolabeling positions were observed with both methods. The antibodies bind close to the C-terminal telopeptide which verifies the location and accessibility of both the major histocompatibility complex (MHC) class I (MHCI) binding domain and C-terminal telopeptide on the outside of the collagen fibril. The close proximity of the C-telopeptide and the MHC1 domain of type I collagen to fibronectin, discoidin domain receptor (DDR), and collagenase cleavage domains likely facilitate the interaction of ligands and receptors related to cellular immunity and the collagen-based Extracellular Matrix.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Potential Role of Malassezia restricta in Pterygium Development

Pterygium is a condition affecting the ocular surface, marked by a triangular-shaped growth of fibrotic tissue extending from the nasal conjunctiva toward the corneal center, potentially causing visual impairment. While ultraviolet (UV )light exposure is the primary risk factor for pterygium, its underlying cause remains unclear. In order to better understand the true genesis of pterygium development, we investigated pterygium tissue and compared it with healthy conjunctiva controls. Given the eye’s direct environmental exposure, we analyzed the microbiota composition using metagenomic sequencing of pterygium tissue to identify microbes potentially associated with this condition. Metagenomic sequencing revealed a higher prevalence of the fungus Malassezia restricta in five pterygium samples, confirmed by in situ hybridization. The CHIT1 gene, which plays a role in antifungal defenses, displayed the highest expression in five pterygium tissue samples compared to healthy conjunctiva controls, suggesting the potential involvement of Malassezia restricta in pterygium development. Gene expression profiling of pterygium highlighted an IL-33 and IL-4 gene expression signature, along with an increased presence of M2 macrophages, emphasizing their role in promoting fibrosis—a hallmark feature of pterygium. The detection of Malassezia restricta in the pterygium samples and associated molecular changes provides novel insights into the ocular microbiome and raises the possibility of Malassezia’s involvement in pterygium pathology.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1973

The mammalian response to lunar particulates.

The response of germfree mice to subcutaneous and intraperitoneal injection of aqueous suspensions of lunar fine material (LFM) was evaluated. Both uninjected mice and mice injected with dry heat sterilized LFM were included as controls. After injection, the majority of mice were subjected to serial sacrifice to assess the time course of the tissue response. A smaller group of animals were held for lifespan studies. The observations suggest that LFM is relatively insoluble in tissue and that, while acting as a low grade irritant, it has little tendency to evoke reactive fibrosis.

Holland, J. M.↗
NASA NTRS1978

Continuous distributions of specific ventilation recovered from inert gas washout

A new technique is described for recovering continuous distributions of ventilation as a function of tidal ventilation/volume ratio from the nitrogen washout. The analysis yields a continuous distribution of ventilation as a function of tidal ventilation/volume ratio represented as fractional ventilations of 50 compartments plus dead space. The procedure was verified by recovering known distributions from data to which noise had been added. Using an apparatus to control the subject's tidal volume and FRC, mixed expired N2 data gave the following results: (a) the distributions of young, normal subjects were narrow and unimodal; (b) those of subjects over age 40 were broader with more poorly ventilated units; (c) patients with pulmonary disease of all descriptions showed enlarged dead space; (d) patients with cystic fibrosis showed multimodal distributions with the bulk of the ventilation going to overventilated units; and (e) patients with obstructive lung disease fell into several classes, three of which are illustrated.

Lewis, S. M.↗