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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 109 records · Page 6
All sourcesNASA NTRSDOE OSTI
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

Health Management Clinic Report FY18

The Health Management Clinic (HMC) is a worksite specialty clinic designed to provide an exceptional level of health care for Sandia employees with diabetes, cholesterol and blood pressure disorders, and for those employees that need help with smoking cessation, depression, anxiety, sleep disorders, or weight management. With a unified commitment to the best care practices available, the HMC is Sandia’s interface to workplace healthcare and health plan services. The HMC provides Sandia employees access to onsite screenings, health care exams, preventative health education, disease management education, care management, periodic laboratory testing, immunizations, podiatry services, and behavioral, fitness, and nutrition counseling/education. Our multidisciplinary team of health professionals consists of physicians, nurses, medical assistants, certified diabetes educators, dietitians, health educators, and exercise specialists. Services offered by the Health Management clinic have been designed to reduce further complications from disease states and promote healthy behavior changes for Sandia employees.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Alternative Splicing Events

Inclusion levels of alternative splicing (AS) events of five different varieties (i.e. skipped exon (SE), retained intron (RI), alternative 5’ splice site (A5SS), alternative 3’ splice site (A3SS), and mutually exclusive exons (MXE)) were measured in human blood samples from two separate cohorts of patients. Cohort 1 (Training Cohort): 12 healthy controls; 12 new onset type 1 diabetic (T1D) cases cases and controls matched on biological sex, age, and body mass index (BMI) 180 million reads Cohort 2 (Testing Cohort): 12 healthy controls; 12 new onset type 1 diabetic (T1D) cases cases and controls matched on biological sex and age. BMI not recorded. 150 million reads

Webb-Robertson, Bobbie-Jo M↗
DOE OSTI2023

Human Islet Research Network (HIRN): Alternative Splicing Events

Inclusion levels of alternative splicing (AS) events of five different varieties (i.e. skipped exon (SE), retained intron (RI), alternative 5’ splice site (A5SS), alternative 3’ splice site (A3SS), and mutually exclusive exons (MXE)) were measured in human blood samples from two separate cohorts of patients. Cohort 1 (Training Cohort): 12 healthy controls; 12 new onset type 1 diabetic (T1D) cases cases and controls matched on biological sex, age, and body mass index (BMI) 180 million reads Cohort 2 (Testing Cohort): 12 healthy controls; 12 new onset type 1 diabetic (T1D) cases cases and controls matched on biological sex and age. BMI not recorded. 150 million reads

Webb-Robertson, Bobbie-Jo M↗
DOE OSTI2023

Comparative Study of High-Resolution LysB29(Nε-myristoyl) des(B30) Insulin Structures Display Novel Dynamic Causal Interrelations in Monomeric-Dimeric Motions

The treatment of insulin-dependent diabetes mellitus is characterized by artificial supplementation of pancreatic β-cell ability to regulate sugar levels in the blood. Even though various insulin analogs are crucial for reasonable glycemic control, understanding the dynamic mechanism of the insulin analogs may help to improve the best-protracted insulin analog to assist people with type 1 diabetes (T1D) to live comfortably while maintaining tight glycemic control. Here, we present the high-resolution crystal structure of NN304, known as insulin detemir, to 1.7 Å resolution at cryogenic temperature. We computationally further investigated our crystal structure’s monomeric-dimeric conformation and dynamic profile by comparing it with a previously available detemir structure (PDB ID: 1XDA). Our structure (PDB ID: 8HGZ), obtained at elevated pH, provides electrostatically triggered minor movements in the equilibrium between alternate conformational substates compared to the previous structure, suggesting it might induce an intermediate state in the dissociation pathway of the insulin detemir’s hexamer:dihexamer equilibrium. Supplemented with orientational cross-correlation analysis by a Gaussian network model (GNM), this alternate oligomeric conformation offers the distinct cooperative motions originated by loose coupling of distant conformational substates of a protracted insulin analog that has not been previously observed.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Transcriptomic Analysis of Arachidonic Acid Pathway Genes Provides Mechanistic Insight into Multi-Organ Inflammatory and Vascular Diseases

Arachidonic acid (AA) metabolites have been associated with several diseases across various organ systems, including the cardiovascular, pulmonary, and renal systems. Lipid mediators generated from AA oxidation have been studied to control macrophages, T-cells, cytokines, and fibroblasts, and regulate inflammatory mediators that induce vascular remodeling and dysfunction. AA is metabolized by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) to generate anti-inflammatory, pro-inflammatory, and pro-resolutory oxidized lipids. As comorbid states such as diabetes, hypertension, and obesity become more prevalent in cardiovascular disease, studying the expression of AA pathway genes and their association with these diseases can provide unique pathophysiological insights. In addition, the AA pathway of oxidized lipids exhibits diverse functions across different organ systems, where a lipid can be both anti-inflammatory and pro-inflammatory depending on the location of metabolic activity. Therefore, we aimed to characterize the gene expression of these lipid enzymes and receptors throughout multi-organ diseases via a transcriptomic meta-analysis using the Gene Expression Omnibus (GEO) Database. In our study, we found that distinct AA pathways were expressed in various comorbid conditions, especially those with prominent inflammatory risk factors. Comorbidities, such as hypertension, diabetes, and obesity appeared to contribute to elevated expression of pro-inflammatory lipid mediator genes. Our results demonstrate that expression of inflammatory AA pathway genes may potentiate and attenuate disease; therefore, we suggest further exploration of these pathways as therapeutic targets to improve outcomes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Synchrotron fluorescence imaging of individual mouse beta-cells reveals changes in zinc, calcium, and iron in a model of low-grade inflammation

Pancreatic beta-cells synthesize and secrete insulin maintaining an organism's energy homeostasis. In humans, beta-cell dysfunction and death contribute to the pathogenesis of type 2 diabetes (T2D). Although the causes of beta-cell dysfunction are complex, obesity-induced low-grade systemic inflammation plays a role. For example, obese individuals exhibiting increased levels of proinflammatory cytokines IL-6 and IL-1beta have a higher risk of beta-cell dysfunction and T2D. Interestingly, obesity-induced inflammation changes the expression of several cellular metal regulating genes, prompting this study to examine changes in the beta-cell metallome after exposure to proinflammatory-cytokines. Here, primary mouse beta-cells were exposed to a combination of IL-6 and IL-1beta for 48 hours, were chemically fixed and imaged by synchrotron X-ray fluorescent microscopy. Quantitative analysis showed a surprising 2.4-fold decrease in the mean total cellular content of zinc from 158 ± 57.7 femtograms (fg) to 65.7 ± 29.7 fg; calcium decreased from 216 ± 67.4 to 154.3 ± 68.7 fg (control vs. cytokines, respectively). The mean total cellular iron content slightly increased from 30.4 ± 12.2 to 47.2 ± 36.4 fg after cytokine treatment; a sub-population of cells (38%) exhibited larger increases of iron density. Changes in the subcellular distributions of zinc and calcium were observed after cytokine exposure. Beta-cells contained numerous iron puncta that accumulated still more iron after exposure to cytokines. These findings provide evidence that exposure to low levels of cytokines is sufficient to cause changes in the total cellular content and/or subcellular distribution of several metals known to be critical for normal beta-cell function.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Characterization of Cytokine Treatment on Human Pancreatic Islets by Top‐Down Proteomics

Type 1 diabetes (T1D) results from autoimmune-mediated destruction of insulin-producing β cells in the pancreatic islet. This process is modulated by pro-inflammatory cytokine signaling, which has been previously shown to alter protein expression in ex vivo islets. Herein, we applied top-down proteomics to globally evaluate proteoforms from human islets treated with proinflammatory cytokines (interferon-γ and interleukin-1β). We measured 1636 unique proteoforms across six donors and two time points (control and 24 h post-treatment) and observed consistent changes in abundance across the glicentin-related pancreatic polypeptide (GRPP) and major proglucagon fragment regions of glucagon, as well as the LF-19/catestatin and vasostatin-1/2 region of chromogranin-A. We also observe several proteoforms that increase after cytokine-treatment or are exclusively observed after cytokine-treatment, including forms of beta-2 microglobulin (B2M), high-mobility group N2 protein (HMGN2), and chemokine (C-X-C motif) ligands (CXCL). Together, our quantitative results provide a baseline proteoform profile for human islets and identify several proteoforms that may serve as interesting candidate markers for T1D progression or therapeutic intervention.

glucagon↗
DOE OSTI2023

Pyridine-containing substrate analogs are restricted from accessing the human cytochrome P450 8B1 active site by tryptophan 281

The human oxysterol 12α-hydroxylase cytochrome P450 8B1 (CYP8B1) is a validated drug target for both type 2 diabetes and nonalcoholic fatty liver disease, but effective selective inhibitors are not yet available. Herein, steroidal substrate-mimicking compounds with a pyridine ring appended to the C12 site of metabolism were designed as inhibitors, synthesized, and evaluated in terms of their functional and structural interactions with CYP8B1. While the pyridine nitrogen was intended to coordinate the CYP8B1 active site heme iron, none of these compounds elicited shifts in the CYP8B1 Soret absorbance consistent with this type of interaction. However, when CYP8B1 was cocrystallized with the pyridine-containing compound with the 3-keto-Δ4 steroid backbone most similar to the endogenous substrate, it was apparent that this ligand was bound in a channel leading to the active site, instead of near the heme iron. Inspection of this structure suggested that tryptophan 281 directly above the heme might restrict active site binding of potential inhibitors with this design. This hypothesis was supported when a CYP8B1 W281F mutation did allow all three compounds to coordinate the heme iron as designed. These results indicated that the design of next-generation CYP8B1 inhibitors should be compatible with the low-ceiling tryptophan immediately above the heme iron.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Extracellular vesicles in β cell biology: Role of lipids in vesicle biogenesis, cargo, and intercellular signaling

Background: Type 1 diabetes (T1D) is a complex autoimmune disorder whose pathogenesis involves an intricate interplay between ß cells of the pancreatic islet, other islet cells, and cells of the immune system. Direct intercellular communication within the islet occurs via cell surface proteins and indirect intercellular communication has traditionally been as occurring via secreted proteins (e.g., endocrine hormones and cytokines). However, recent literature suggests that extracellular vesicles (EVs) secreted by ß cells constitute an additional and biologically important mechanism for transmitting signals to adjacent ß cells or immune cells. Scope of Review: This review summarizes the general mechanisms of EV formation, with a particular focus on how lipids and lipid signaling pathways influence their formation and cargo. We review the implications of EV release from ß cells for T1D pathogenesis, how EVs and their cargo might be leveraged as biomarkers of the early events leading to T1D, and how EVs might be engineered as a therapeutic candidate to counter T1D outcomes. Major Conclusions: Islet ß cells have been viewed as initiators and propagators of the cellular circuit giving rise to autoimmunity in T1D. In this context, emerging literature suggests that EVs may represent a conduit for communication that holds more comprehensive messaging about the ß cells from which they arise. As the field of EV biology advances, it opens the possibility that intervening with EV formation and cargo loading could be a novel disease-modifying approach in T1D.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2021

The human aortic endothelium undergoes dose-dependent DNA methylation in response to transient hyperglycemia

Glycemic control is a strong predictor of long-term cardiovascular risk in patients with diabetes mellitus, and poor glycemic control influences long-term risk of cardiovascular disease even decades after optimal medical management. This phenomenon, termed glycemic memory, has been proposed to occur due to stable programs of cardiac and endothelial cell gene expression. This transcriptional remodeling has been shown to occur in the vascular endothelium through a yet undefined mechanism of cellular reprogramming.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

An integrated multi-omics approach identifies the landscape of interferon-α-mediated responses of human pancreatic beta cells

Proinflammatory cytokines are important mediators of pancreatic beta cell dysfunction and demise in the early stages of type 1 diabetes (T1D). Interferon-a (IFNa), a type I interferon member, is expressed in the islets of T1D individuals and it is expression and signaling is regulated by both genetic (T1D risk variants) and environmental factors (viral infections) associated to T1D. We presently characterized human beta cells responses to IFNa by combining ATAC-seq, RNA-seq and proteomics assays. The initial beta cell response to IFNa was characterized by major chromatin remodeling, followed by marked changes in transcriptional and translational regulation. IFNa-induced changes in alternative splicing (AS) and first exon usage increased the diversity of transcripts expressed by beta cells. This, combined with changes observed on protein modification/degradation, ER stress and MHC class I, may significantly expand the peptide repertoire presented by beta cells to the immune system. On the other hand, beta cells up-regulated checkpoint proteins, such as PDL1 and HLA-E, that may protect them against the autoimmune assault. Data mining of the present multi-omics analysis led to the identification of two compound classes that revert IFNa effects on human beta cells and may be translated to clinical trials.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Artificial intelligence velocimetry and microaneurysm-on-a-chip for three-dimensional analysis of blood flow in physiology and disease

Significance Microfluidics is an important in vitro platform to gain insights into mechanics of blood flow and mechanisms of pathophysiology of human diseases. Extraction of 3D fields in microfluidics with dense cell suspensions remains a formidable challenge. We present artificial-intelligence velocimetry (AIV) as a general platform to determine 3D flow fields and a microaneurysm-on-a-chip to simulate blood flow in microaneurysms in patients with diabetic retinopathy. AIV is built on physics-informed neural networks that integrate seamlessly 2D images from microfluidic experiments or in vivo observations with physical laws to estimate full 3D velocity and stress fields. AIV could be integrated into imaging technologies to automatically infer key hemodynamic metrics from in vivo and in vitro biomedical images.

42 ENGINEERING↗
DOE OSTI2023

Top-Down Proteomics of Mouse Islets With Beta Cell CPE Deletion Reveals Molecular Details in Prohormone Processing

Altered prohormone processing, such as with proinsulin and pro-islet amyloid polypeptide (proIAPP), has been reported as an important feature of prediabetes and diabetes. Proinsulin processing includes removal of several C-terminal basic amino acids and is performed principally by the exopeptidase carboxypeptidase E (CPE), and mutations in CPE or other prohormone convertase enzymes (PC1/3 and PC2) result in hyperproinsulinemia. A comprehensive characterization of the forms and quantities of improperly processed insulin and other hormone products following Cpe deletion in pancreatic islets has yet to be attempted. In the present study we applied top-down proteomics to globally evaluate the numerous proteoforms of hormone processing intermediates in a β-cell-specific Cpe knockout mouse model. Increases in dibasic residue–containing proinsulin and other novel proteoforms of improperly processed proinsulin were found, and we could classify several processed proteoforms as novel substrates of CPE. Interestingly, some other known substrates of CPE remained unaffected despite its deletion, implying that paralogous processing enzymes such as carboxypeptidase D (CPD) can compensate for CPE loss and maintain near normal levels of hormone processing. In summary, our quantitative results from top-down proteomics of islets provide unique insights into the complexity of hormone processing products and the regulatory mechanisms.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Factors linked to participant attrition in a longitudinal occupational health surveillance program

For occupational medical screening programs focused on long-term health surveillance, participant attrition is a significant barrier to success. Here we investigate demographic, medical history, and clinical data from National Supplemental Screening Program (NSSP) examinees for association with likelihood of return for a second exam (rescreening). A total of 15,733 individuals completed at least one NSSP exam before December 31, 2016; of those, 4832 also completed a second exam on or before December 31, 2019. Stepwise logistic regression models were used to identify variables associated with whether a participant was rescreened in the NSSP. Individuals were less likely to return for rescreening if they had a history of any cancer; cardiovascular problems; diabetes or kidney disease; or if they used insulin. Age at time of first exam and job site category significantly influenced likelihood of return. Workers categorized as “guests” were more likely to return. Participants were less likely to return if they had an abnormal urinalysis, abnormal pulmonary function, pneumoconiosis, aortic atherosclerosis, or hearing loss at their initial exam. Participants who received a chest X-ray at their initial screening were more likely to return. The presence of health problems is strongly linked to screening program attrition. Participants who are older at the time of their initial screening exam are less likely to return. The discovery of several strong demographic, medical, and job associations reveals the importance for medical screening programs to understand and address factors that influence participant retention and, consequently, the effectiveness of long-term health surveillance activities.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Optimization of the autoclave preparation process for improving resistant starch content in rice grains

Abstract The autoclave preparation process to increase the content of resistant starch (RS) in rice grains was optimized, and the results showed that the optimal preparation process was obtained with a water content of 41.63%, a pH of 5.95, an autoclave time of 60.96 min, and a refrigeration time of 17.11 hr. Under these conditions, the theoretical value of RS content in rice grains reached 17.57%. After autoclaving, the estimated glycemic index (EGI) in rice grains was reduced from 78.35 to 66.08 measured after cooking, suggesting that autoclaving was capable of increasing the RS content in rice grains and reducing its EGI value. These results may help spark new concepts and methods for the development of specialized foods for specific populations, such as people with diabetes.

Zheng, Yunzhan↗
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 OSTI2020

Detection of a multi–disease biomarker in saliva with graphene field effect transistors

Human carbonic anhydrase 1 (CA1) has been suggested as a biomarker for identification of several diseases including cancers, pancreatitis, diabetes, and Sjogren’s syndrome. However, the lack of a rapid, cheap, accurate, and easy-to-use quantification technique has prevented widespread utilization of CA1 for practical clinical applications. To this end, we present a label-free electronic biosensor for detection of CA1 utilizing highly sensitive graphene field effect transistors (G-FETs) as a transducer and specific RNA aptamers as a probe. The binding of CA1 with aptamers resulted in a positive shift in Dirac voltage V D of the G-FETs, the magnitude of which depended on target concentration. These aptameric G-FET biosensors showed the binding affinity (K D ) of ~2.3 ng/ml (70 pM), which is four orders lower than that reported using a gel shift assay. This lower value of K D enabled us to achieve a detection range (10 pg/ml - 100 ng/ml) which is well in line with the clinically relevant range. These highly sensitive devices allowed us to further prove their clinical relevance by successfully detecting the presence of CA1 in human saliva samples. In conclusion, the utilization of this label-free biosensor could facilitate the early stage identification of various diseases associated with changes in concentration of CAs.

77 NANOSCIENCE AND NANOTECHNOLOGY↗