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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 667 records · Page 37
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

An asynchronous traversal engine for graph-based rich metadata management

Rich metadata in high-performance computing (HPC) systems contains extended information about users, jobs, data files, and their relationships. Property graphs are a promising data model to represent heterogeneous rich metadata flexibly. Specifically, a property graph can use vertices to represent different entities and edges to record the relationships between vertices with unique annotations. The high-volume HPC use case, with millions of entities and relationships, naturally requires an out-of-core distributed property graph database, which must support live updates (to ingest production information in real time), low-latency point queries (for frequent metadata operations such as permission checking), and large-scale traversals (for provenance data mining). Among these needs, large-scale property graph traversals are particularly challenging for distributed graph storage systems. Most existing graph systems implement a "level synchronous" breadth-first search algorithm that relies on global synchronization in each traversal step. This performs well in many problem domains; but a rich metadata management system is characterized by imbalanced graphs, long traversal lengths, and concurrent workloads, each of which has the potential to introduce or exacerbate stragglers (i.e., abnormally slow steps or servers in a graph traversal) that lead to low overall throughput for synchronous traversal algorithms. Previous research indicated that the straggler problem can be mitigated by using asynchronous traversal algorithms, and many graph-processing frameworks have successfully demonstrated this approach. Such systems require the graph to be loaded into a separate batch-processing framework instead of being iteratively accessed, however. In this work, we investigate a general asynchronous graph traversal engine that can operate atop a rich metadata graph in its native format. We outline a traversal-aware query language and key optimizations (traversal-affiliate caching and execution merging) necessary for efficient performance. We further explore the effect of different graph partitioning strategies on the traversal performance for both synchronous and asynchronous traversal engines. Our experiments show that the asynchronous graph traversal engine is more efficient than its synchronous counterpart in the case of HPC rich metadata processing, where more servers are involved and larger traversals are needed. Furthermore, the asynchronous traversal engine is more adaptive to different graph partitioning strategies.

96 KNOWLEDGE MANAGEMENT AND PRESERVATION↗
DOE OSTI2022

Metall: A persistent memory allocator for data-centric analytics

Data analytics applications transform raw input data into analytics-specific data structures before performing analytics. Unfortunately, such data ingestion steps are often more expensive than analytics. In addition, various types of NVRAM devices are already used in many HPC systems today. Such devices will be useful for storing and reusing data structures beyond a single process life cycle. We developed Metall, a persistent memory allocator built on top of the memory-mapped file mechanism. Metall enables applications to transparently allocate custom C++ data structures into various types of persistent memories. Metall incorporates a concise and high-performance memory management algorithm inspired by Supermalloc and the rich C++ interface developed by Boost.Interprocess library. On a dynamic graph construction workload, Metall achieved up to 11.7x and 48.3x performance improvements over Boost.Interprocess and memkind (PMEM kind), respectively. We also demonstrate Metall’s high adaptability by integrating Metall into a graph processing framework, GraphBLAS Template Library. Here this study’s outcomes indicate that Metall will be a strong tool for accelerating future large-scale data analytics by allowing applications to leverage persistent memory efficiently.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2022

The impact of multi-sensor land data assimilation on river discharge estimation

River discharge is one of the most critical renewable water resources. Accurately estimating river discharge with land surface models (LSMs) remains challenging due to the difficulty in estimating land water storages such as snow, soil moisture, and groundwater. While data assimilation (DA) ingesting optical, microwave, and gravity measurements from space can help constrain theses storage states, its impacts on runoff and eventually river discharge are not fully understood. In this study, by taking advantage of recently published land DA results that jointly assimilate eight different combinations of observations from the Moderate Resolution Imaging Spectroradiometer (MODIS), Gravity Recovery and Climate Experiment (GRACE), and Advanced Microwave Scanning Radiometer for EOS (AMSR-E), we quantify to what degree multi-sensor land DA improves the river discharge simulation skills over 40 global river basins, and investigate the complementary strengths of different satellite measurements on river discharge. To be more specific, river discharge is updated by feeding gridded runoff from the eight multi-sensor DA simulations into a vector-based river routing model named the Routing Application for Parallel computatIon of Discharge (RAPID). Our modeling results, including 7-year simulations at 177,458 river reaches globally, are used to study the seasonal to interannual variability of river discharge. It is found that assimilating GRACE has the greatest impact on global runoff patterns, leading to the most pronounced improvements in spatial river discharge in the middle and high latitudes with the R 2 increased by 0.16. The seasonal variation of spatial discharge is most skillful during the boreal summer. However, our evaluation also shows model and DA still struggle to generate reasonable variability and averaged discharge over permafrost regions. Finally, by assessing how different satellites add value to discharge forecasts, this study paves the way for more advanced multi-sensor satellite data assimilation to predict the terrestrial hydrological cycle.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2010

Speciation and distribution of vanadium in drinking water iron pipe corrosion by-products

Vanadium (V) when ingested from drinking water in high concentrations (> 15 {micro}g L{sup -1}) is a potential health risk and is on track to becoming a regulated contaminant. High concentrations of V have been documented in lead corrosion by-products as Pb{sub 5}(V{sup 5+}O{sub 4}){sub 3}Cl (vanadinite) which, in natural deposits is associated with iron oxides/oxyhydroxides, phases common in iron pipe corrosion by-products. The extent of potential reservoirs of V in iron corrosion by-products, its speciation, and mechanism of inclusion however are unknown. The aim of this study is to assess these parameters in iron corrosion by-products, implementing synchrotron-based {mu}-XRF mapping and {mu}-XANES along with traditional physiochemical characterization. The morphologies, mineralogies, and chemistry of the samples studied are superficially similar to typical iron corrosion by-products. However, we found V present as discrete grains of Pb{sub 5}(V{sup 5+}O{sub 4}){sub 3}Cl likely embedded in the surface regions of the iron corrosion by-products. Concentrations of V observed in bulk XRF analysis ranged from 35 to 899 mg kg{sup -1}. We calculate that even in pipes with iron corrosion by-products with low V concentration, 100 mg kg{sup -1}, as little as 0.0027% of a 0.1-cm thick X 100-cm long section of that corrosion by-product needs to be disturbed to increase V concentrations in the drinking water at the tap to levels well above the 15 {micro}g L{sup -1} notification level set by the State of California and could adversely impact human health. In addition, it is likely that large reservoirs of V are associated with iron corrosion by-products in unlined cast iron mains and service branches in numerous drinking water distribution systems.

36 MATERIALS SCIENCE↗
DOE OSTI2011

A biokinetic model for manganese for use in radiation protection

The ICRP is updating its recommendations regarding occupational exposure to radionuclides including the biokinetic models used to derive dose coefficients and assess bioassay data for internally deposited radionuclides. This report reviews biokinetic data for manganese and proposes a biokinetic model for systemic manganese consistent with the current database. The model provides a more detailed and biologically realistic description of the movement of absorbed manganese in the body than the model currently recommended by the International Commission on Radiological Protection (ICRP). The proposed model and current ICRP model yield broadly similar estimates of dose per unit activity of inhaled or ingested radio-manganese but differ substantially with regard to interpretation of bioassay data.

61 RADIATION PROTECTION AND DOSIMETRY↗
DOE OSTI2024

Analysis of biokinetic parameters reveals patterns in mercury accumulation across aquatic species

Mercury (Hg) is a potent neurotoxicant and poses a risk to human health through the ingestion of Hg-contaminated fish. Mercury, especially in its organic form methylmercury (MeHg), biomagnifies up food chains such that even small aqueous concentrations of Hg can result in significant concentrations of total Hg in fish. Understanding the ecological and human health risks associated with Hg and MeHg exposure requires an understanding of the factors that affect its bioaccumulation in aquatic species. We compiled estimates of three biokinetic parameters: uptake rate (k u ), assimilation efficiency (AE), and efflux rate (k e ). These parameters describe contaminant uptake from aqueous (k u ) and dietary (AE) exposure and the rate of excretion (k e ). We found parameter values for 38 and 34 different species of fish and aquatic invertebrates, respectively, and collected 502 parameter values in total. Here, we used a machine learning technique to establish the relationships between experimental and physiological variables and these parameter values. We found differences in which variables were associated with biokinetic parameter values for fish and aquatic invertebrates. The form of Hg was the most impactful variable, influencing values of all parameters except k u for invertebrates, for which aqueous exposure time was the only significant predicator variable. The parameter k e were the only values significantly influenced by more than one variable, with water type (freshwater, brackish, or marine), organism weight, and form of Hg significantly impacting parameter values for fish and/or invertebrates. To our knowledge, this study represents the most extensive review of biokinetic parameters of Hg and MeHg accumulation in aquatic organisms. Environmental parameters found to significantly impact Hg and MeHg bioaccumulation in past studies were not identified as important in our analyses across aquatic ecosystems and species. Our dataset and analysis reveal novel patterns that may help us better understand and manage Hg bioaccumulation.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2018

A Physics-based Smart Persistence model for Intra-hour forecasting of solar radiation (PSPI) using GHI measurements and a cloud retrieval technique

Short-term solar forecasting models based solely on global horizontal irradiance (GHI) measurements are often unable to discriminate the forecasting of the factors affecting GHI from those that can be precisely computed by atmospheric models. Here, we introduce a Physics-based Smart Persistence model for Intra-hour forecasting of solar radiation (PSPI) that decomposes the forecasting of GHI into the computation of extraterrestrial solar radiation and solar zenith angle and the forecasting of cloud albedo and cloud fraction. The extraterrestrial solar radiation and solar zenith angle are accurately computed by the Solar Position Algorithm (SPA) developed at the National Renewable Energy Laboratory (NREL). A cloud retrieval technique is used to estimate cloud albedo and cloud fraction from surface-based observations of GHI. With the assumption of persistent cloud structures, the cloud albedo and cloud fraction are predicted for future time steps using a two-stream approximation and a 5-min exponential weighted moving average, respectively. Our model evaluation using the long-term observations of GHI at NREL's Solar Radiation Research Laboratory (SRRL) shows that the PSPI has a better performance than the persistence and smart persistence models in all forecast time horizons between 5 and 60 min, which is more significant in cloudy-sky conditions. Finally, compared to the persistence and smart persistence models, the PSPI does not require additional observations of various atmospheric parameters but is customizable in that additional observations, if available, can be ingested to further improve the GHI forecast. An advanced technology of cloud forecast is also expected to improve the future performance of the PSPI.

14 SOLAR ENERGY↗
DOE OSTI2017

CMAS behavior of yttrium aluminum garnet (YAG) and yttria-stabilized zirconia (YSZ) thermal barrier coatings

Calcium magnesium aluminosilicate (CMAS) that is formed from the ingested deposits in gas turbines degrades thermal barrier coatings (TBCs), especially for the most widely used material; yttria-stabilized zirconia (YSZ). In the present work, we examine the behavior of yttrium aluminum garnet (YAG) as an alternative material for TBCs. CMAS interaction studies were conducted by making composite pellets of YAG-CMAS and YSZ-CMAS powders. These pellets, after being subjected to heat treatment between 1100 °C and 1500 °C were characterized by X-ray Diffraction (XRD), scanning electron microscopy (SEM) and Energy-dispersive X-ray spectroscopy (EDS), which showed YAG to be almost inert to CMAS whereas YSZ exhibited significant phase changes. To test the behavior of TBCs with YAG and 8YSZ as the topcoat material in a CMAS environment, cyclic furnace tests were conducted in which a controlled amount of CMAS was applied and then the samples were cycled to failure. In addition, to simulate the continuous accumulation of CMAS expected in service, a cyclic furnace test was devised in which a small dose of aqueous solution of CMAS was applied on TBC specimens at the start of every cycle until the samples were cycled to failure. In all these tests YAG TBCs outperformed YSZ in terms of durability. In conclusion, the mechanisms of CMAS attack are described and the relative resistance of YAG and YSZ is shown to be consistent with the Optical Basicity (OB) theory.

36 MATERIALS SCIENCE↗
DOE OSTI2010

Individual differences in arsenic metabolism and lung cancer in a case-control study in Cordoba, Argentina

In humans, ingested inorganic arsenic is metabolized to monomethylarsenic (MMA) then to dimethylarsenic (DMA), although in most people this process is not complete. Previous studies have identified associations between the proportion of urinary MMA (%MMA) and increased risks of several arsenic-related diseases, although none of these reported on lung cancer. In this study, urinary arsenic metabolites were assessed in 45 lung cancer cases and 75 controls from arsenic-exposed areas in Cordoba, Argentina. Folate has also been linked to arsenic-disease susceptibility, thus an exploratory assessment of associations between single nucleotide polymorphisms in folate metabolizing genes, arsenic methylation, and lung cancer was also conducted. In analyses limited to subjects with metabolite concentrations above detection limits, the mean %MMA was higher in cases than in controls (17.5% versus 14.3%, p = 0.01). The lung cancer odds ratio for subjects with %MMA in the upper tertile compared to those in the lowest tertile was 3.09 (95% CI, 1.08-8.81). Although the study size was too small for a definitive conclusion, there was an indication that lung cancer risks might be highest in those with a high %MMA who also carried cystathionine {beta}-synthase (CBS) rs234709 and rs4920037 variant alleles. This study is the first to report an association between individual differences in arsenic metabolism and lung cancer, a leading cause of arsenic-related mortality. These results add to the increasing body of evidence that variation in arsenic metabolism plays an important role in arsenic-disease susceptibility.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Elevated lactate dehydrogenase activity and increased cardiovascular mortality in the arsenic-endemic areas of southwestern Taiwan

Arsenic ingestion has been linked to increasing global prevalence of and mortality from cardiovascular disease (CVD); arsenic can be removed from drinking water to reduce related health effects. Lactate dehydrogenase (LDH) is used for the evaluation of acute arsenic toxicity in vivo and in vitro, but it is not validated for the evaluation of long-term, chronic arsenic exposure. The present study examined the long-term effect of chronic arsenic exposure on CVD and serum LDH levels, after consideration of arsenic metabolism capacity. A total of 380 subjects from an arseniasis-endemic area and 303 from a non-endemic area of southwestern Taiwan were recruited in 2002. Various urinary arsenic species were analyzed using high-performance liquid chromatography (HPLC) and hydride generation systems. Fasting serum was used for quantitative determination of the total LDH activity. A significant dose–response relationship was observed between arsenic exposure and LDH elevation, independent of urinary arsenic profiles (P < 0.001). Furthermore, abnormal LDH elevation was associated with CVD mortality after adjustment for Framingham risk scores for 10-year CVD and arsenic exposure (hazard ratio, 3.98; 95% confidence interval, 1.07–14.81). LDH was elevated in subjects with arsenic exposure in a dose-dependent manner. LDH is a marker of arsenic toxicity associated with CVD mortality. Results of this study have important implications for use in ascertaining long-term arsenic exposure risk of CVD. -- Highlights: ► We showed that arsenic exposure was correlated with LDH elevation. ► LDH elevation was related to arsenic methylation capacity. ► Abnormal LDH elevation can be a marker of susceptibility to CVD mortality.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Protective effects and mechanisms of curcumin on podophyllotoxin toxicity in vitro and in vivo

Podophyllotoxin (POD) is a naturally occurring lignan with pronounced antineoplastic and antiviral properties. POD binds to tubulin and prevents the formation of mitotic spindle. Although cases of overdose or accidental ingestion are quite often, no specific therapy is currently available to treat the POD intoxication. In the current investigation, the protective effects and mechanisms of curcumin (CUR) on podophyllotoxin toxicity were evaluated in vitro and in vivo. The results showed that CUR could protect POD-induced cytotoxicity by recovering the G2/M arrest and decrease the changes of membrane potential and microtubule structure in Vero cells. A significant decrease of mortality rates was observed in Swiss mice treated by intragastrical administration of POD + CUR as compared with POD alone. The POD + CUR group also exhibited decreases in plasma transaminases, alkaline phosphatase, lactate dehydrogenase, plasma urea, creatinine and malondialdehyde level but elevated superoxide dismutase and glutathione levels as compared to the POD group. Histological examination of the liver and kidney demonstrated less morphological changes in the treatment of POD + CUR as compared with POD alone. The mechanism of the protective effects might be due to the competitive binding of CUR with POD in the same colchicines binding site as revealed by the tubulin polymerization assay and the molecular docking analysis, and the antioxidant activity against the oxidative stress induced by POD. In summary, both in vitro and in vivo data indicated the promising role of CUR as a protective agent against the POD poisoning. Highlights: ► A potential antidote to treat the podophyllotoxin (POD) intoxication is found. ► Curcumin showed promising effects against POD poisoning in vitro and in vivo. ► The mechanisms lie in the antioxidant activity and competitive binding with tubulin.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Arsenic methylation and lung and bladder cancer in a case-control study in northern Chile

In humans, ingested inorganic arsenic is metabolized to monomethylarsenic (MMA) then to dimethylarsenic (DMA), although this process is not complete in most people. The trivalent form of MMA is highly toxic in vitro and previous studies have identified associations between the proportion of urinary arsenic as MMA (%MMA) and several arsenic-related diseases. To date, however, relatively little is known about its role in lung cancer, the most common cause of arsenic-related death, or about its impacts on people drinking water with lower arsenic concentrations (e.g., < 200 μg/L). In this study, urinary arsenic metabolites were measured in 94 lung and 117 bladder cancer cases and 347 population-based controls from areas in northern Chile with a wide range of drinking water arsenic concentrations. Lung cancer odds ratios adjusted for age, sex, and smoking by increasing tertiles of %MMA were 1.00, 1.91 (95% confidence interval (CI), 0.99–3.67), and 3.26 (1.76–6.04) (p-trend < 0.001). Corresponding odds ratios for bladder cancer were 1.00, 1.81 (1.06–3.11), and 2.02 (1.15–3.54) (p-trend < 0.001). In analyses confined to subjects only with arsenic water concentrations < 200 μg/L (median = 60 μg/L), lung and bladder cancer odds ratios for subjects in the upper tertile of %MMA compared to subjects in the lower two tertiles were 2.48 (1.08–5.68) and 2.37 (1.01–5.57), respectively. Overall, these findings provide evidence that inter-individual differences in arsenic metabolism may be an important risk factor for arsenic-related lung cancer, and may play a role in cancer risks among people exposed to relatively low arsenic water concentrations. - Highlights: • Urine arsenic metabolites were measured in cancer cases and controls from Chile. • Higher urine %MMA values were associated with increased lung and bladder cancer. • %MMA-cancer associations were seen at drinking water arsenic levels < 200 μg/L.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Hypoxia perturbs aryl hydrocarbon receptor signaling and CYP1A1 expression induced by PCB 126 in human skin and liver-derived cell lines

The aryl hydrocarbon receptor (AhR) is an important mediator of toxic responses after exposure to xenobiotics including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin-like polychlorinated biphenyls (PCBs). Activation of AhR responsive genes requires AhR dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT), a heterodimeric partner also shared by the hypoxia-inducible factor-1α (HIF-1α) protein. TCDD-stimulated AhR transcriptional activity can be influenced by hypoxia; however, it less well known whether hypoxia interferes with AhR transcriptional transactivation in the context of PCB-mediated AhR activation in human cells. Elucidation of this interaction is important in liver hepatocytes which extensively metabolize ingested PCBs and experience varying degrees of oxygen tension during normal physiologic function. This study was designed to assess the effect of hypoxia on AhR transcriptional responses after exposure to 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126). Exposure to 1% O{sub 2} prior to PCB 126 treatment significantly inhibited CYP1A1 mRNA and protein expression in human HepG2 and HaCaT cells. CYP1A1 transcriptional activation was significantly decreased upon PCB 126 stimulation under conditions of hypoxia. Additionally, hypoxia pre-treatment reduced PCB 126 induced AhR binding to CYP1 target gene promoters. Importantly, ARNT overexpression rescued cells from the inhibitory effect of hypoxia on XRE-luciferase reporter activity. Therefore, the mechanism of interference of the signaling crosstalk between the AhR and hypoxia pathways appears to be at least in part dependent on ARNT availability. Our results show that AhR activation and CYP1A1 expression induced by PCB 126 were significantly inhibited by hypoxia and hypoxia might therefore play an important role in PCB metabolism and toxicity. - Highlights: • Significant crosstalk exists between AhR and HIF-1α signaling. • Hypoxia perturbs PCB 126 induced AhR function and target gene expression. • PCB 126 mediated activation of AhR activity inhibits HIF-1α signaling. • AhR binding to CYP1A1 and CYP1B1 promoters is inhibited by hypoxia. • ARNT overexpression relieves hypoxic inhibition of AhR function.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Triclosan exacerbates the presence of {sup 14}C-bisphenol A in tissues of female and male mice

Current human generations are commonly exposed to both triclosan (TCS), an antimicrobial agent, and bisphenol A (BPA), the monomer of polycarbonate plastics and epoxies. Both are readily absorbed into circulation and found distributed among diverse tissues. Potential interactions between TCS and BPA are largely unstudied. We investigated whether TCS exposure affects the distribution of ingested {sup 14}C-BPA in select tissues. CF-1 mice were each subcutaneously injected with TCS then orally administered 50 μg/kg {sup 14}C-BPA. Females received 0, 0.2, 0.6, 1, 2, or 18 mg TCS (equivalent respectively to 0, 6.3, 16.9, 30.1, 60.5, and 558.9 mg/kg). Males received 0, 0.2, 2, or 18 mg TCS (equivalent respectively to 0, 5.3, 53.4, and 415.0 mg/kg). Levels of radioactivity were measured through liquid scintillation counting in blood serum and brain, reproductive, and other tissues. Significantly elevated levels of radioactivity were observed following combined TCS and {sup 14}C-BPA administration, with minimally effective TCS doses being tissue-dependent (Females: lungs, 0.6 mg; uterus, 1 mg; heart, muscle, ovaries, and serum, 18 mg. Males: serum, 0.2 mg; epididymides, 2 mg). Subsequently, we found that 2 or 6 mg TCS increased radioactivity in the ovaries and serum of females orally given only 5 μg/kg {sup 14}C-BPA. These data indicate that TCS can interact with BPA in vivo, magnifying its presence in certain tissues and serum. The data are consistent with evidence that TCS utilizes enzymes that are critical for metabolism and excretion of BPA. Further research should investigate the mechanisms through which these two chemicals interact at environmentally-relevant doses. - Highlights: • We examined whether triclosan exposure affects the distribution of oral {sup 14}C-BPA. • Radioactivity was elevated in select tissues of mice injected sc with triclosan. • In females, this effect was most pronounced in the uterus, ovaries, and lungs. • In males, this effect was most prominent in the blood serum and epididymides. • Our data accord with evidence that triclosan competes for enzymes conjugating BPA.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Protective effect of bioflavonoid myricetin enhances carbohydrate metabolic enzymes and insulin signaling molecules in streptozotocin–cadmium induced diabetic nephrotoxic rats

Diabetic nephropathy is the kidney disease that occurs as a result of diabetes. The present study was aimed to evaluate the therapeutic potential of myricetin by assaying the activities of key enzymes of carbohydrate metabolism, insulin signaling molecules and renal function markers in streptozotocin (STZ)–cadmium (Cd) induced diabetic nephrotoxic rats. After myricetin treatment schedule, blood and tissue samples were collected to determine plasma glucose, insulin, hemoglobin, glycosylated hemoglobin and renal function markers, carbohydrate metabolic enzymes in the liver and insulin signaling molecules in the pancreas and skeletal muscle. A significant increase of plasma glucose, glycosylated hemoglobin, urea, uric acid, creatinine, blood urea nitrogen (BUN), urinary albumin, glycogen phosphorylase, glucose-6-phosphatase, and fructose-1,6-bisphosphatase and a significant decrease of plasma insulin, hemoglobin, hexokinase, glucose-6-phosphate dehydrogenase, glycogen and glycogen synthase with insulin signaling molecule expression were found in the STZ–Cd induced diabetic nephrotoxic rats. The administration of myricetin significantly normalizes the carbohydrate metabolic products like glucose, glycated hemoglobin, glycogen phosphorylase and gluconeogenic enzymes and renal function markers with increase insulin, glycogen, glycogen synthase and insulin signaling molecule expression like glucose transporter-2 (GLUT-2), glucose transporter-4 (GLUT-4), insulin receptor-1 (IRS-1), insulin receptor-2 (IRS-2) and protein kinase B (PKB). Based on the data, the protective effect of myricetin was confirmed by its histological annotation of the pancreas, liver and kidney tissues. These findings suggest that myricetin improved carbohydrate metabolism which subsequently enhances glucose utilization and renal function in STZ–Cd induced diabetic nephrotoxic rats. - Highlights: • Diabetic rats are more susceptible to cadmium nephrotoxicity. • Cadmium plays as a cumulative nephrotoxicant whether ingested or inhaled. • Myricetin enhances insulin secretion from the damaged pancreatic β-cells. • Myricetin can eliminate metals and scavenge chemical induced free radicals. • Myricetin enhances the glucose uptake by regulating insulin signaling pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

The value of integrating pre-clinical data to predict nausea and vomiting risk in humans as illustrated by AZD3514, a novel androgen receptor modulator

Nausea and vomiting are components of a complex mechanism that signals food avoidance and protection of the body against the absorption of ingested toxins. This response can also be triggered by pharmaceuticals. Predicting clinical nausea and vomiting liability for pharmaceutical agents based on pre-clinical data can be problematic as no single animal model is a universal predictor. Moreover, efforts to improve models are hampered by the lack of translational animal and human data in the public domain. AZD3514 is a novel, orally-administered compound that inhibits androgen receptor signaling and down-regulates androgen receptor expression. Here we have explored the utility of integrating data from several pre-clinical models to predict nausea and vomiting in the clinic. Single and repeat doses of AZD3514 resulted in emesis, salivation and gastrointestinal disturbances in the dog, and inhibited gastric emptying in rats after a single dose. AZD3514, at clinically relevant exposures, induced dose-responsive “pica” behaviour in rats after single and multiple daily doses, and induced retching and vomiting behaviour in ferrets after a single dose. We compare these data with the clinical manifestation of nausea and vomiting encountered in patients with castration-resistant prostate cancer receiving AZD3514. Our data reveal a striking relationship between the pre-clinical observations described and the experience of nausea and vomiting in the clinic. In conclusion, the emetic nature of AZD3514 was predicted across a range of pre-clinical models, and the approach presented provides a valuable framework for predicition of clinical nausea and vomiting. - Highlights: • Integrated pre-clinical data can be used to predict clinical nausea and vomiting. • Data integrated from standard toxicology studies is sufficient to make a prediction. • The use of the nausea algorithm developed by Parkinson (2012) aids the prediction. • Additional pre-clinical studies can be used to confirm and quantify the risk.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Modulation of expression and activity of intestinal multidrug resistance-associated protein 2 by xenobiotics

The multidrug resistance-associated protein 2 (MRP2/ABCC2) is a transporter that belongs to the ATP-binding cassette (ABC) superfamily. In the intestine, it is localized to the apical membrane of the enterocyte and plays a key role in limiting the absorption of xenobiotics incorporated orally. MRP2 may also play a role in systemic clearance of xenobiotics available from the serosal side of the intestine. MRP2 transports a wide range of substrates, mainly organic anions conjugated with glucuronic acid, glutathione and sulfate and its expression can be modulated by xenobiotics at transcriptional- and post-transcriptional levels. Transcriptional regulation is usually mediated by a group of nuclear receptors. The pregnane X receptor (PXR) is a major member of this group. Relevant drugs described to up-regulate intestinal MRP2 via PXR are rifampicin, spironolactone and carbamazepine, among others. The constitutive androstane receptor (CAR, NR1I3) was also reported to modulate MRP2 expression, phenobarbital being a typical activator. Dietary compounds, including micronutrients and other natural products, are also capable of regulating intestinal MRP2 expression transcriptionally. We have given them particular attention since the composition of the food ingested daily is not necessarily supervised and may result in interactions with therapeutic drugs. Post-transcriptional regulation of MRP2 activity by xenobiotics, e.g. as a consequence of inhibitory actions, is also described in this review. Unfortunately, only few studies report on drug-drug or nutrient-drug interactions as a consequence of modulation of intestinal MRP2 activity by xenobiotics. Future clinical studies are expected to identify additional interactions resulting in changes in efficacy or safety of therapeutic drugs. - Highlights: • Intestinal MRP2 (ABCC2) expression and activity can be regulated by xenobiotics. • PXR and CAR are major MRP2 modulators through a transcriptional mechanism. • Rifampicin, spironolactone and carbamazepine among others up-regulate MRP2 via PXR. • MRP2 activity influences the availability and efficacy of drugs administered orally.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2017

Relationships among DNA hypomethylation, Cd, and Pb exposure and risk of cigarette smoking-related urothelial carcinoma

Cigarette smoking and environmental exposure to heavy metals are important global health issues, especially for urothelial carcinoma (UC). However, the effects of cadmium and lead exposure, as well as the levels of DNA hypomethylation, on UC risk are limited. We evaluated the possible exposure sources of Cd and Pb and the relationship among DNA hypomethylation, urinary Cd and Pb levels, and UC risk. We recruited 209 patients with UC and 417 control patients for a hospital-based case–control study between June 2011 and August 2014. We collected environmental exposure-related information with questionnaires. Blood and urine samples were analyzed to measure the Cd and Pb exposure and 5-methyl-2′-deoxycytidine levels as a proxy for DNA methylation. Multivariate logistic regression and 95% confidence intervals were applied to estimate the risk for UC. Study participants with high Cd and Pb exposure in blood or urine had significantly increased risk of UC, especially among the smokers. After adjusting for age and gender, the possible connections of individual cumulative cigarette smoking or herb medicine exposure with the increased levels of Cd and Pb were observed in the controls. Participants with 8.66%–12.39% of DNA hypomethylation had significantly increased risk of UC compared with those with ≥ 12.39% of DNA hypomethylation. Environmental factors including cigarette smoking and herb medicine may contribute to the internal dose of heavy metals levels. Repeat measurements of heavy metals with different study design, detailed dietary information, and types of herb medicine should be recommended for exploring UC carcinogenesis in future studies. - Highlights: • Smoking and herb medicine ingestion is associated with increased urinary Cd and Pb levels. • Urinary levels of Cd and Pb are associated with increased risk of UC. • UC carcinogenesis might have partially resulted from DNA hypomethylation.

60 APPLIED LIFE SCIENCES↗