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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 OSTI2021

miR-23b Ameliorates nonalcoholic steatohepatitis by targeting Acyl-CoA thioesterases 4

Non-alcoholic fatty liver disease (NAFLD) and its more advanced stages, Non-alcoholic steatohepatitis and Cirrhosis, are the most common liver diseases in the worldwide, especially in developing countries. NAFLD is distinguished by the accumulation of triglycerides within hepatocytes. An increasing body of evidence suggests that hepatic MicroRNAs play an important role in NAFLD by controlling lipid metabolism, inflammation, and fibrosis. However, the precise causative functions of miRNA in NAFLD remain unknown. Here, we discovered that mice lacking MicroRNA-23b developed NAFLD-like phenotypes such as increased serum triglyceride and lipid droplet accumulation. In db/db mice fed a high fat diet, MicroRNA-23b overexpression reduced liver weight and alleviated liver inflammation, apoptosis, and fibrosis. MicroRNA-23b regulates the acyl-CoA metabolic process via Acyl-CoA thioesterase 4 (Acot4), which interacts with Acetyl CoA Carboxylase (ACC), according to the RNA-seq analysis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Galectin-1 secreted by bone marrow-derived mesenchymal stem cells mediates anti-inflammatory responses in acute airway disease

The hallmarks of allergic airway disease (AAD) include infiltration of inflammatory cells into the bronchoalveolar space. Bone marrow derived mesenchymal stem cells (BMSCs) show anti-inflammatory properties in AAD. In addition, galectin-1 (Gal-1) is a lectin significantly upregulated upon inflammation and is also known to mediate potential anti-inflammatory responses. We hypothesized that BMSCs regulated inflammatory responses by secretion of Gal-1 during AAD pathogenesis. BMSCs were isolated from murine femurs and tibiae and adoptively transferred into an ovalbumin-induced AAD mouse model. Knockdown of Gal-1 in BMSCs was performed using shRNA. Flow cytometry, ELISAs, and immunohistology were performed to analyze inflammatory responses in mice, and a Transwell system was used to establish an in vitro co-culture system of lung epithelial cells (MLE-12) and BMSCs. Administration of BMSCs significantly upregulated Gal-1 expression upon inflammation and decreased infiltration of inflammatory cells and secretion of proinflammatory cytokines in vivo. In addition, we showed that this function was mediated by reduced activation of the MAPK p38 signaling pathway. Similar observations were found using an in vitro lipopolysaccharide-induced model when MLE-12 cells were co-cultured with BMSCs. Gal-1 secretion by BMSCs alleviated inflammatory responses observed in AAD and hence provides a promising therapeutic alternative to AAD patients insensitive to conventional drug treatments.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Proteomic assessment of serum biomarkers of longevity in older men

The biological bases of longevity are not well understood, and there are limited biomarkers for the prediction of long life. We used a high-throughput, discovery-based proteomics approach to identify serum peptides and proteins that were associated with the attainment of longevity in a longitudinal study of community-dwelling men age ≥65 years. Baseline serum in 1196 men were analyzed using liquid chromatography–ion mobility–mass spectrometry, and lifespan was determined during ~12 years of follow-up. Men who achieved longevity (≥90% expected survival) were compared to those who died earlier. Rigorous statistical methods that controlled for false positivity were utilized to identify 25 proteins that were associated with longevity. All these proteins were in lower abundance in long-lived men and included a variety involved in inflammation or complement activation. Lower levels of longevity-associated proteins were also associated with better health status, but as time to death shortened, levels of these proteins increased. Pathway analyses implicated a number of compounds as important upstream regulators of the proteins and implicated shared networks that underlie the observed associations with longevity. Overall, these results suggest that complex pathways, prominently including inflammation, are linked to the likelihood of attaining longevity. This work may serve to identify novel biomarkers for longevity and to understand the biology underlying lifespan.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Xanthohumol microbiome and signature in adults with Crohn’s disease (the XMaS trial): a protocol for a phase II triple-masked, placebo-controlled clinical trial

Xanthohumol (XN), a bioactive flavonoid from Humulus lupulus with anti-inflammatory properties, has potential benefits for patients with Crohn’s disease (CD), a type of inflammatory bowel disease. We recently completed and published results of a placebo-controlled phase I clinical trial demonstrating the safety and tolerability of 24 mg XN daily for 8 weeks. The present study aims to evaluate the safety and tolerability of the same dose of XN adults with clinically active CD in a placebo-controlled phase II clinical trial. Additional aims will assess the impact of XN on inflammatory biomarkers, platelet function, CD clinical activity, and stool microbial composition. The metabolism of XN will also be evaluated. This article provides a model protocol for consideration in investigations of XN or other natural products in disease states. A triple-masked, randomized, placebo-controlled trial will be conducted in adults with clinically active CD. Participants (n ≤ 32) will be randomized to either 24 mg encapsulated XN per day or placebo and followed for 8 weeks. Throughout the trial, participants will be queried for adverse events. Biomarkers of clinical safety, blood and stool markers of inflammation, platelet function, Crohn’s Disease Activity Index score, stool microbial composition, and XN metabolite profiles in blood, urine, and stool will be assessed every 2 weeks. We describe the protocol for a phase II clinical trial that evaluates the safety and tolerability of XN in adults with active CD, as well as evaluate metabolism and mechanisms that are relevant to CD and other diseases with underlying inflammation and/or gut permeability. The effects of XN on inflammatory biomarkers, platelet function, the microbiota, and multi-omics biomarkers measured in this phase II trial of adults with CD will be compared to the effects of XN in healthy adults in our previous phase I trial. The results of the study will advance the evidence guiding the use of XN in patients with CD.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Single Cell RNA-Seq and Machine Learning Reveal Novel Subpopulations in Low-Grade Inflammatory Monocytes With Unique Regulatory Circuits

Subclinical doses of LPS (SD-LPS) are known to cause low-grade inflammatory activation of monocytes, which could lead to inflammatory diseases including atherosclerosis and metabolic syndrome. Sodium 4-phenylbutyrate is a potential therapeutic compound which can reduce the inflammation caused by SD-LPS. To understand the gene regulatory networks of these processes, we have generated scRNA-seq data from mouse monocytes treated with these compounds and identified 11 novel cell clusters. We have developed a machine learning method to integrate scRNA-seq, ATAC-seq, and binding motifs to characterize gene regulatory networks underlying these cell clusters. Using guided regularized random forest and feature selection, our method achieved high performance and outperformed a traditional enrichment-based method in selecting candidate regulatory genes. Our method is particularly efficient in selecting a few candidate genes to explain observed expression pattern. In particular, among 531 candidate TFs, our method achieves an auROC of 0.961 with only 10 motifs. Finally, we found two novel subpopulations of monocyte cells in response to SD-LPS and we confirmed our analysis using independent flow cytometry experiments. Our results suggest that our new machine learning method can select candidate regulatory genes as potential targets for developing new therapeutics against low grade inflammation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Flaxseed oil ameliorates aging in d ‐galactose induced rats via altering gut microbiota and mitigating oxidative damage

Abstract BACKGROUND Aging causes decreased antioxidant capacity and chronic inflammation and may even elevate cancer risks. Previous studies reported that flaxseed oil (FO) can alleviate age‐related diseases, including improving alcoholic liver disease, atherosclerosis and diabetes. However, whether the intestinal microbiota accountable for this alleviation is still unknown. This study aims to study the antioxidant effects of FO in an aging rat model and the underlying mechanism between the intestinal microbiota and aging. RESULTS Our results presented that serum and liver antioxidant capacities in FO group were up‐regulated, and liver inflammation in FO group was reduced. The 16S rDNA sequencing showed that FO regulated the microbial community, including up‐regulation of four families of Lactobacillus and six families of Clostridium. In addition, FO had also adjusted the relative abundance of several genera such as Ruminococcaceae_UCG‐005 and Prevotella_9 , which may be the key bacteria associated with the aging process. Colonic transcriptome analysis showed that there were 1679 differentially expressed genes (DEGs) in the Model group and the FO group (134 up‐regulated and 1545 down‐regulated). Gene set enrichment analysis (GSEA) revealed FO down‐regulates the expression of the upstream genes Ptprc , Lck , Zap70 , Lat and Lcp2 in the T cell receptor signaling pathway. CONCLUSION In conclusion, FO improved antioxidant capacity and reduced intestinal microbial disturbances caused by aging damage, indicating that dietary FO has the potential to fight aging damage. This study provides a more comprehensive view of dietary intervention to improve aging. © 2022 Society of Chemical Industry.

Sun, Xiaoyan↗
DOE OSTI2023

Hierarchically Templated Synthesis of 3D‐Printed Crosslinked Cyclodextrins for Lycopene Harvesting

Abstract Plants produce a wide range of bioactive phytochemicals, such as antioxidants and vitamins, which play crucial roles in aging prevention, inflammation reduction, and reducing the risk of cancer. Selectively harvesting these phytochemicals, such as lycopene, from tomatoes through the adsorption method is cost‐effective and energy efficient. In this work, a templated synthesis of 3D‐printed crosslinked cyclodextrin polymers featuring nanotubular structures for highly selective lycopene harvesting is reported. Polypseudorotaxanes formed by triethoxysilane‐based telechelic polyethylene glycols and α‐cyclodextrins (α‐CDs) are designed as the template to (1) synthetically access urethane‐based nanotubular structures at the molecular level, and (2) construct 3D‐printed architectures with designed macroscale voids. The polypseudorotaxane hydrogels showed good rheological properties for direct ink writing, and the 3D‐printed hydrogels were converted to the desired α‐CD polymer network through a three‐step postprinting transformation. The obtained urethane‐crosslinked α‐CD monoliths possess nanotubular structures and 3D‐printed voids. They selectively adsorb lycopene from raw tomato juice, protecting lycopene from photo‐ or thermo‐degradations. This work highlights the hierarchically templated synthesis approach in developing functional 3D‐printing materials by connecting the bottom‐up molecular assembly and synthesis with the top‐down 3D architecture control and fabrication.

Chemistry↗
DOE OSTI2023

Cecropin P1 antimicrobial peptide modulates differential expression of immune relevant genes in rainbow trout ( Oncorhynchus mykiss ) gill cell line, RTgill-W1

Accumulated evidence indicates that antimicrobial peptides modulate immune activities in fish. In this study, we profiled the differential expression patterns of representative immune relevant genes in an epithelial-like cell line of rainbow trout gill, RTgill-W1, in response to exposure of cecropin P1 antimicrobial peptide. RTgill-W1 cells were treated with synthetic cecropin P1 over time (0, 2, 4 and 24 h) with or without the present of lipopolysaccharide (LPS) or polyinosinic polycytidylic acid (PolyI:C). The relative abundances of each mRNA were measured by real-time quantitative PCR. The dose-response study revealed significant perturbations of mRNA levels of genes related to pro-inflammation, acute phase, surface proteins and transcription factors at 30 μM of cecropin P1. In addition, cecropin P1 altered the differential expression patterns that were induced by LPS or PolyI:C, at different time points in RTgill-W1. Overall, our results indicate that cecropin P1 exhibits pro-inflammation activity, modulate cell-cell interaction and cytokine signal transduction in rainbow trout gill cell, and may suggest a potential application of this peptide as an immune adjuvant for disease control in aquaculture.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Apolipoprotein A5 reduces clearance of VLDL by altering apolipoprotein E content

Apolipoprotein A-V (APOA5) is a critical regulator of circulating triglyceride (TG) levels. Its deletion leads to elevated plasma TG concentrations by altering the metabolism of very low-density lipoprotein (VLDL) particles in vivo. One way APOA5 exerts its effects is through modulation of lipoprotein lipase (LPL) activity, specifically by disrupting inhibitory interactions between LPL and angiopoietin-like proteins (ANGPTLs). However, the impact of APOA5 on VLDL composition and its potential to alter VLDL metabolism in other ways remains poorly understood. To address this, we investigated the influence of APOA5 on the VLDL proteome, LPL activation, and hepatic remnant uptake. Using VLDL from Apoa5 knockout (KO) and wild-type (WT) mice, we found no evidence that APOA5 directly enhances LPL activity in purified or plasma systems. However, VLDL from Apoa5 K mice was cleared significantly more slowly by cultured hepatocytes. Proteomics experiments from two independent laboratories identified consistent depletion of 17 proteins involved in lipoprotein metabolism, inflammation, and immune response in Apoa5 KO VLDL, including APOE and serum amyloid A1 (SAA1). Remarkably, reintroduction of recombinant mouse APOA5 to the KO plasma partially restored the WT VLDL proteome, including APOE, and normalized VLDL uptake by hepatocytes without altering LPL lipolysis. These findings reveal that APOA5 influences hepatic clearance of VLDL remnants by modulating particle composition, particularly APOE content. This study expands the functional scope of APOA5 in TG metabolism and underscores its role in VLDL remodeling and remnant clearance, offering new insights with implications for understanding hypertriglyceridemia and its roles in inflammation and immune response.

LPL↗
DOE OSTI2024

Identification and characterization of small molecule inhibitors of the LINE-1 retrotransposon endonuclease

The long interspersed nuclear element-1 (LINE-1 or L1) retrotransposon is the only active autonomously replicating retrotransposon in the human genome. L1 harms the cell by inserting new copies, generating DNA damage, and triggering inflammation. Therefore, L1 inhibition could be used to treat many diseases associated with these processes. Previous research has focused on inhibition of the L1 reverse transcriptase due to the prevalence of well-characterized inhibitors of related viral enzymes. Here we present the L1 endonuclease as another target for reducing L1 activity. We characterize structurally diverse small molecule endonuclease inhibitors using computational, biochemical, and biophysical methods. We also show that these inhibitors reduce L1 retrotransposition, L1-induced DNA damage, and inflammation reinforced by L1 in senescent cells. These inhibitors could be used for further pharmacological development and as tools to better understand the life cycle of this element and its impact on disease processes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

ENPP1’s regulation of extracellular cGAMP is a ubiquitous mechanism of attenuating STING signaling

The metazoan innate immune second messenger 2'3'-cGAMP is present both inside and outside cells. However, only extracellular cGAMP can be negatively regulated by the extracellular hydrolase ENPP1. Here, we determine whether ENPP1’s regulation of extracellular cGAMP is a ubiquitous mechanism of attenuating stimulator of interferon genes (STING) signaling. We identified ENPP1 H362A , a point mutation that cannot degrade the 2'-5' linkage in cGAMP while maintaining otherwise normal function. The selectivity of this histidine is conserved down to bacterial nucleotide pyrophosphatase/phosphodiesterase (NPP), allowing structural analysis and suggesting an unexplored ancient history of 2'-5' cyclic dinucleotides. Enpp1 H362A mice demonstrated that extracellular cGAMP is not responsible for the devastating phenotype in ENPP1-null humans and mice but is responsible for antiviral immunity and systemic inflammation. Our data define extracellular cGAMP as a pivotal STING activator, identify an evolutionarily critical role for ENPP1 in regulating inflammation, and suggest a therapeutic strategy for viral and inflammatory conditions by manipulating ENPP1 activity.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Repeated exposure to eucalyptus wood smoke alters pulmonary gene and metabolic profiles in male Long-Evans rats

Abstract Exposure to wildfire smoke is associated with both acute and chronic cardiopulmonary illnesses, which are of special concern for wildland firefighters who experience repeated exposure to wood smoke. It is necessary to better understand the underlying pathophysiology by which wood smoke exposure increases pulmonary disease burdens in this population. We hypothesize that wood smoke exposure produces pulmonary dysfunction, lung inflammation, and gene expression profiles associated with future pulmonary complications. Male Long-Evans rats were intermittently exposed to smoldering eucalyptus wood smoke at 2 concentrations, low (11.0 ± 1.89 mg/m3) and high (23.7 ± 0.077 mg/m3), over a 2-week period. Whole-body plethysmography was measured intermittently throughout. Lung tissue and lavage fluid were collected 24 h after the final exposure for transcriptomics and metabolomics. Increasing smoke exposure upregulated neutrophils and select cytokines in the bronchoalveolar lavage fluid. In total, 3446 genes were differentially expressed in the lungs of rats in the high smoke exposure and only 1 gene in the low smoke exposure (Cd151). Genes altered in the high smoke group reflected changes to the Eukaryotic Initiation Factor 2 stress and oxidative stress responses, which mirrored metabolomics analyses. xMWAS-integrated analysis revealed that smoke exposure significantly altered pathways associated with oxidative stress, lung morphogenesis, and tumor proliferation pathways. These results indicate that intermittent, 2-week exposure to eucalyptus wood smoke leads to transcriptomic and metabolic changes in the lung that may predict future lung disease development. Collectively, these findings provide insight into cellular signaling pathways that may contribute to the chronic pulmonary conditions observed in wildland firefighters.

Toxicology↗
DOE OSTI2023

Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence

Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to age-related arterial dysfunction, in part, by promoting oxidative stress and inflammation, which reduce the bioavailability of the vasodilatory molecule nitric oxide (NO). In the present study, we assessed the efficacy of fisetin, a natural compound, as a senolytic to reduce vascular cell senescence and SASP factors and improve arterial function in old mice. We found that fisetin decreased cellular senescence in human endothelial cell culture. In old mice, vascular cell senescence and SASP-related inflammation were lower 1 week after the final dose of oral intermittent (1 week on—2 weeks off—1 weeks on dosing) fisetin supplementation. Old fisetin-supplemented mice had higher endothelial function. Leveraging old p16-3MR mice, a transgenic model allowing genetic clearance of p16 INK4A -positive senescent cells, we found that ex vivo removal of senescent cells from arteries isolated from vehicle- but not fisetin-treated mice increased endothelium-dependent dilation, demonstrating that fisetin improved endothelial function through senolysis. Enhanced endothelial function with fisetin was mediated by increased NO bioavailability and reduced cellular- and mitochondrial-related oxidative stress. Arterial stiffness was lower in fisetin-treated mice. Ex vivo genetic senolysis in aorta rings from p16-3MR mice did not further reduce mechanical wall stiffness in fisetin-treated mice, demonstrating lower arterial stiffness after fisetin was due to senolysis. Lower arterial stiffness with fisetin was accompanied by favorable arterial wall remodeling. The findings from this study identify fisetin as promising therapy for clinical translation to target excess cell senescence to treat age-related arterial dysfunction.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

NF-κB perturbation reveals unique immunomodulatory functions in Prx1 + fibroblasts that promote development of atopic dermatitis

Skin is composed of diverse cell populations that cooperatively maintain homeostasis. Up-regulation of the nuclear factor κB (NF-κB) pathway may lead to the development of chronic inflammatory disorders of the skin, but its role during the early events remains unclear. Here, through analysis of single-cell RNA sequencing data via iterative random forest leave one out prediction, an explainable artificial intelligence method, we identified an immunoregulatory role for a unique paired related homeobox-1 (Prx1) + fibroblast subpopulation. Disruption of Ikkb–NF-κB under homeostatic conditions in these fibroblasts paradoxically induced skin inflammation due to the overexpression of C-C motif chemokine ligand 11 (CCL11; or eotaxin-1) characterized by eosinophil infiltration and a subsequent T H 2 immune response. Because the inflammatory phenotype resembled that seen in human atopic dermatitis (AD), we examined human AD skin samples and found that human AD fibroblasts also overexpressed CCL11 and that perturbation of Ikkb–NF-κB in primary human dermal fibroblasts up-regulated CCL11. Monoclonal antibody treatment against CCL11 was effective in reducing the eosinophilia and T H 2 inflammation in a mouse model. Together, the murine model and human AD specimens point to dysregulated Prx1 + fibroblasts as a previously unrecognized etiologic factor that may contribute to the pathogenesis of AD and suggest that targeting CCL11 may be a way to treat AD-like skin lesions.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

A novel conjugative transposon carrying an autonomously amplified plasmid

Tetracyclines serve as broad-spectrum antibiotics to treat bacterial infections. The discovery of new tetracycline resistance genes has led to new questions about the underlying mechanisms of resistance, gene transfer, and their relevance to human health. We tracked changes in the abundance of a 55-kbp conjugative transposon (CTn214) carrying tetQ, a tetracycline resistance gene, within a Bacteroides fragilis metagenome-assembled genome derived from shotgun sequencing of microbial DNA extracted from the ileal pouch of a patient with ulcerative colitis. The mapping of metagenomic reads to CTn214 revealed the multi-copy nature of a 17,044-nt region containing tetQ in samples collected during inflammation and uninflamed visits. B. fragilis cultivars isolated from the same patient during periods of inflammation harbored CTn214 integrated into the chromosome or both a circular, multi-copy, extrachromosomal region of the CTn214 containing tetQ and the corresponding integrated form. The tetracycline-dependent mechanism for the transmission of CTn214 is nearly identical to a common conjugative transposon found in the genome of B. fragilis (CTnDOT), but the autonomously amplified nature of a circular 17,044-nt region of CTn214 that codes for tetQ and the integration of the same sequence in the linear chromosome within the same cell is a novel observation. Genome and transcriptome sequencing of B. fragilis cultivars grown under different concentrations of tetracycline and ciprofloxacin indicates that tetQ in strains containing the circular form remains actively expressed regardless of treatment, while the expression of tetQ in strains containing the linear form increases only in the presence of tetracycline.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Fecal microbiota transplantation ameliorates type 2 diabetes via metabolic remodeling of the gut microbiota in db/db mice

Gut microbiome (GM) deregulation has been implicated in major conditions such as obesity and type 2 diabetes (T2DM). Our previous prospective study indicated that fecal microbiota transplantation (FMT) successfully improved patients with T2DM. We hypothesized that FMT may be a potential therapeutic method for T2DM, but its precise mechanisms in T2DM remains to be elucidated. Eight db/m mice were FMT donors and control mice, and 16 genetically diabetic db/db mice were equally divided into two groups (db/db+phosphate-buffered saline (PBS) group, db/db+FMT group). The db/db+FMT group was administered fresh fecal suspension (0.2 mL/mice) daily for 4 weeks. Analysis of the GM and serum metabolome was carried out by 16S ribosomal RNA sequencing and liquid chromatogram-mass spectrometry, respectively. Effects of FMT on the gut barrier and pancreas were assessed using protein assays, messenger RNA, immunohistology and clinical indicators testing. Our results showed that FMT treatment of db/db mice relieves a series of clinical indicators, including fasting plasma glucose, serum insulin and oral glucose tolerance test among others. Compared with non-diabetic control mice, db/db+PBS mice exhibited decreased abundance of Ruminococaceae, Porphyromonadaceae and increased abundance of Rikenellaceae and Lactobacillaceae. FMT treatment reversed this effect on the microbiome. Eleven metabolites were changed between the db/db+PBS and db/db+FMT groups. Correlation analysis showed that the structural changes of the GM were correlated with host metabolite levels. We further showed that FMT treatment of db/db mice improved intestinal barrier function, reduced inflammation and caused an alteration in the number of circulating immune cells. FMT-mediated changes in the GM, serum metabolites, intestinal epithelial barrier, inflammation and circulating immune cells play an important role in the efficacy of FMT on T2DM disease progression.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Nested active learning for efficient model contextualization and parameterization: pathway to generating simulated populations using multi-scale computational models

There is increasing interest in the use of mechanism-based multi-scale computational models (such as agent-based models (ABMs)) to generate simulated clinical populations in order to discover and evaluate potential diagnostic and therapeutic modalities. The description of the environment in which a biomedical simulation operates (model context) and parameterization of internal model rules (model content) requires the optimization of a large number of free parameters. In this work, we utilize a nested active learning (AL) workflow to efficiently parameterize and contextualize an ABM of systemic inflammation used to examine sepsis. Contextual parameter space was examined using four parameters external to the model’s rule set. The model’s internal parameterization, which represents gene expression and associated cellular behaviors, was explored through the augmentation or inhibition of signaling pathways for 12 signaling mediators associated with inflammation and wound healing. We have implemented a nested AL approach in which the clinically relevant (CR) model environment space for a given internal model parameterization is mapped using a small Artificial Neural Network (ANN). The outer AL level workflow is a larger ANN that uses AL to efficiently regress the volume and centroid location of the CR space given by a single internal parameterization. We have reduced the number of simulations required to efficiently map the CR parameter space of this model by approximately 99%. In addition, we have shown that more complex models with a larger number of variables may expect further improvements in efficiency.

97 MATHEMATICS AND COMPUTING↗