Interaction of Natural Dietary and Herbal Anionic Compounds and Flavonoids with Human Organic Anion Transporters 1 (SLC22A6), 3 (SLC22A8), and 4 (SLC22A11)

Active components of complementary/alternative medicines and natural supplements are often anionic compounds and flavonoids. As such, organic anion transporters (OATs) may play a key role in their pharmacokinetic and pharmacological profiles, and represent sites for adverse drug-drug interactions. Therefore, we assessed the inhibitory effects of nine natural products, including flavonoids (catechin and epicatechin), chlorogenic acids (1,3- and 1,5-dicaffeoylquinic acid), phenolic acids (ginkgolic acids (13 : 0), (15 : 1), and (17 : 1)), and the organic acids ursolic acid and 18β-glycyrrhetinic acid, on the transport activity of the human OATs, hOAT1 (SLC22A6), hOAT3 (SLC22A8), and hOAT4 (SLC22A11). Four compounds, 1,3- and 1,5-dicaffeoylquinic acid, ginkgolic acid (17 : 1), and 18β-glycyrrhetinic acid, significantly inhibited hOAT1-mediated transport (50 μM inhibitor versus 1 μM substrate). Five compounds, 1,3- and 1,5-dicaffeoylquinic acid, ginkgolic acids (15 : 1) and (17 : 1), and epicatechin, significantly inhibited hOAT3 transport under similar conditions. Only catechin inhibited hOAT4. Dose-dependency studies were conducted for 1,3-dicaffeoylquinic acid and 18β-glycyrrhetinic acid on hOAT1, and IC50 values were estimated as 1.2 ± 0.4 μM and 2.7 ± 0.2 μM, respectively. These data suggest that 1,3-dicaffeoylquinic acid and 18β-glycyrrhetinic acid may cause significant hOAT1-mediated DDIs in vivo; potential should be considered for safety issues during use and in future drug development

Active Hydrophilic Components of the Medicinal Herb Salvia miltiorrhiza (Danshen) Potently Inhibit Organic Anion Transporters 1 (Slc22a6) and 3 (Slc22a8)

Many active components of herbal products are small organic anions, and organic anion transporters were previously demonstrated to be a potential site of drug-drug interactions. In this study, we assessed the inhibitory effects of six hydrophilic components of the herbal medicine Danshen, lithospermic acid, protocatechuic acid, rosmarinic acid, salvianolic acid A, salvianolic acid B, and tanshinol, on the function of the murine organic anion transporters, mOat1 and mOat3. All of Danshen components significantly inhibited mOat1- and mOat3-mediated substrate uptake () with lithospermic acid (LSA), protocatechuic acid, rosmarinic acid (RMA), and salvianolic acid A (SAA) producing virtually complete inhibition under test conditions. Kinetic analysis demonstrated that LSA, RMA, and SAA were competitive inhibitors. As such, values were estimated as  μM for LSA,  μM for RMA, and  μM for SAA on mOat1-mediated transport, and as  μM for LSA,  μM for RMA, and  μM for SAA on mOat3-mediated transport. These data suggest that herb-drug interactions may occur in vivo on the human orthologs of these transporters in situations of polypharmacy involving Danshen and clinical therapeutics known to be organic anion transporter substrates

On the exceptional damage-tolerance of gradient metallic materials

An experimental study is described on the fracture toughness and micro-mechanisms associated with the initiation and propagation of cracks in metallic nickel containing marked gradients in grain size, ranging from ∼30 nm to ∼4 μm. Specifically, cracks are grown in a gradient structured (GS) nickel with grain-size gradient ranging from the coarse macro-scale to nano-scale (CG → NG) and vice versa (NG → CG), with the measured crack-resistance R-curves compared to the corresponding behavior in uniform nano-grained (NG) and coarse-grained (CG) materials. It is found that the gradient structures display a much-improved combination of high strength and toughness compared to uniform grain-sized materials. However, based on J-integral measurements in the gradient materials, the crack-initiation toughness is far higher for cracks grown in the direction of the coarse-to-nano grained gradient than vice versa, a result which we ascribe primarily to excessive crack-tip blunting in the coarse-grained microstructure. Both gradient structures, however, display marked rising R-curve behavior with exceptional crack-growth toughnesses exceeding 200 MPa.m½

Outdoor performance of a reflective type 3D LCPV system under different climatic conditions

Concentrating sunlight and focusing on smaller solar cells increases the power output per unit solar cell area. In the present study, we highlight the design of a low concentrating photovoltaic (LCPV) system and its performance in different test conditions. The system essentially consists of a reflective type 3.6× cross compound parabolic concentrator (CCPC) designed for an acceptance angle of ± 30°, coupled with square shaped laser grooved buried contact (LGBC) silicon solar cells. A heat exchanger is also integrated with the PV system which extracts the thermal energy rejected by the solar cells whilst maintaining its temperature. Indoor characterization is carried out to evaluate the system performance under standard conditions. Results showed a power ratio of 3.12 and an optical efficiency of 73%. The system is placed under outdoor environment on a south facing roof at Penryn, UK with a fixed angular tilt of 50°. The high angular acceptance of the system allows collection of sunlight over a wider range. Results under different climatic conditions are presented and compared with a non-concentrating system under similar conditions. On an average, the LCPV system was found to collect an average of 2.54 times more solar energy than a system without the concentrator

Experimental characterization and multi-physics simulation of a triple-junction cell in a novel hybrid III:V concentrator photovoltaic–thermoelectric receiver design with secondary optical element

A lattice-matched monolithic triple-junction Concentrator Photovoltaic cell (InGa(0.495)P/GaIn(0.012)As/Ge) was electrically and thermally interfaced to a Thermoelectric Peltier module. A single optical design secondary lens was bonded to the CPV-TE receiver. The hybrid SILO-CPV-TE solar energy harvesting device was electrically, thermally and theoretically investigated. The electrical performance data for the cell under variable irradiance and cell temperature conditions were measured using the integrated thermoelectric module as both a temperature sensor and as a solid-state heat pump. The cell was electrically characterised under standard test conditions (1000 W/m2 irradiance, 25°C temperature and AM1.5G spectrum) for comparison with literature data. Transient multiphysics simulations in ANSYS CFX 15.0 were carried out to calculate cell temperatures and to determine the short circuit current and temperature coefficient in a scaling law. The optimization was used to determine 15 model parameters for the component sub-cells within the triple-junction cell at STC with a MATLAB scaling law. The root-mean-square error in electrical currents between measurement and simulations was 0.66%

Thermal performance of two heat exchangers for thermoelectric generators

Thermal performance of heat exchanger is important for potential application in integrated solar cell/module and thermoelectric generator (TEG) system. Usually, thermal performance of a heat exchanger for TEGs is analysed by using a 1D heat conduction theory which ignores the detailed phenomena associated with thermo-hydraulics. In this paper, thermal and mass transports in two different exchangers are simulated by means of a steady-state, 3D turbulent flow k -e model with a heat conduction module under various flow rates. In order to simulate an actual working situation of the heat exchangers, hot block with an electric heater is included in the model. TEG model is simplified by using a 1D heat conduction theory, so its thermal performance is equivalent to a real TEG. Natural convection effect on the outside surfaces of the computational model is considered. Computational models and methods used are validated under transient thermal and electrical experimental conditions of a TEG. It is turned out that the two heat exchangers designed have a better thermal performance compared with an existing heat exchanger for TEGs, and more importantly, the fin heat exchanger is more compact and has nearly half temperature rise compared with the tube heat exchanger

Cultured Bacteria Provide Insight into the Functional Potential of the Coral-Associated Microbiome

Improving the availability of representative isolates from the coral microbiome is essential for investigating symbiotic mechanisms and applying beneficial microorganisms to improve coral health. However, few studies have explored the diversity of bacteria which can be isolated from a single species. Here, we isolated a total of 395 bacterial strains affiliated with 49 families across nine classes from the coral Pocillopora damicornis. Identification results showed that most of the strains represent potential novel bacterial species or genera. We also sequenced and assembled the genomes of 118 of these isolates, and then the putative functions of these isolates were identified based on genetic signatures derived from the genomes and this information was combined with isolate-specific phenotypic data. Genomic information derived from the isolates identified putative functions including nitrification and denitrification, dimethylsulfoniopropionate transformation, and supply of fixed carbon, amino acids, and B vitamins which may support their eukaryotic partners. Furthermore, the isolates contained genes associated with chemotaxis, biofilm formation, quorum sensing, membrane transport, signal transduction, and eukaryote-like repeat-containing and cell-cell attachment proteins, all of which potentially help the bacterium establish association with the coral host. Our work expands on the existing culture collection of coral-associated bacteria and provides important information on the metabolic potential of these isolates which can be used to refine understanding of the role of bacteria in coral health and are now available to be applied to novel strategies aimed at improving coral resilience through microbiome manipulation. IMPORTANCE Microbes underpin the health of corals which are the building blocks of diverse and productive reef ecosystems. Studying the culturable fraction of coral-associated bacteria has received less attention in recent times than using culture-independent molecular methods. However, the genomic and phenotypic characterization of isolated strains allows assessment of their functional role in underpinning coral health and identification of beneficial microbes for microbiome manipulation. Here, we isolated 395 bacterial strains from tissues of Pocillopora damicornis with many representing potentially novel taxa and therefore providing a significant contribution to coral microbiology through greatly enlarging the existing cultured coral-associated bacterial bank Through analysis of the genomes obtained in this study for the coral-associated bacteria and coral host, we elucidate putative metabolic linkages and symbiotic establishment. The results of this study will help to elucidate the role of specific isolates in coral health and provide beneficial microbes for efforts aimed at improving coral health

A comparison of 3D particle, fluid and hybrid simulations for negative streamers

In the high field region at the head of a discharge streamer, the electron energy distribution develops a long tail. In negative streamers, these electrons can run away and contribute to energetic processes such as terrestrial gamma-ray and electron flashes. Moreover, electron density fluctuations can accelerate streamer branching. To track energies and locations of single electrons in relevant regions, we have developed a 3D hybrid model that couples a particle model in the region of high fields and low electron densities with a fluid model in the rest of the domain. Here we validate our 3D hybrid model on a 3D (super-)particle model for negative streamers in overvolted gaps, and we show that it almost reaches the computational efficiency of a 3D fluid model. We also show that the extended fluid model approximates the particle and the hybrid model well until stochastic fluctuations become important, while the classical fluid model underestimates velocities and ionization densities. We compare density fluctuations and the onset of branching between the models, and we compare the front velocities with an analytical approximation

Usefulness of gene expression profiling of bronchoalveolar lavage cells in acute lung allograft rejection.

BackgroundChronic lung allograft dysfunction (CLAD) is the main limitation to long-term survival after lung transplantation. Because effective therapies are lacking, early identification and mitigation of risk factors is a pragmatic approach to improve outcomes. Acute cellular rejection (ACR) is the most pervasive risk factor for CLAD, but diagnosis requires transbronchial biopsy, which carries risks. We hypothesized that gene expression in the bronchoalveolar lavage (BAL) cell pellet (CP) could replace biopsy and inform on mechanisms of CLAD.MethodsWe performed RNA sequencing on BAL CPs from 219 lung transplant recipients with A-grade ACR (n = 61), lymphocytic bronchiolitis (n = 58), infection (n = 41), or no rejection/infection (n = 59). Differential gene expression was based on absolute fold difference >2.0 and Benjamini-adjusted p-value ≤0.05. We used the Database for Annotation, Visualization and Integrated Discovery Bioinformatics Resource for pathway analyses. For classifier modeling, samples were randomly split into training (n = 154) and testing sets (n = 65). A logistic regression model using recursive feature elimination and 5-fold cross-validation was trained to optimize area under the curve (AUC).ResultsDifferential gene expression identified 72 genes. Enriched pathways included T-cell receptor signaling, natural killer cell-mediated cytotoxicity, and cytokine-cytokine receptor interaction. A 4-gene model (AUC = 0.72) and classification threshold defined in the training set exhibited fair performance in the testing set; accuracy was 76%, specificity 82%, and sensitivity 60%. In addition, classification as ACR was associated with worse CLAD-free survival (hazard ratio = 2.42; 95% confidence interval = 1.29-4.53).ConclusionsBAL CP gene expression during ACR is enriched for immune response pathways and shows promise as a diagnostic tool for ACR, especially ACR that is a precursor of CLAD