Expression of drug transporters and drug metabolizing enzymes in the bladder urothelium in man and affinity of the bladder spasmolytic trospium chloride to transporters likely involved in its pharmacokinetics.

The cationic, water-soluble quaternary trospium chloride (TC) is incompletely absorbed from the gut and undergoes wide distribution but does not pass the blood-brain barrier. It is secreted by the kidneys, liver, and intestine. To evaluate potential transport mechanisms for TC, we measured affinity of the drug to the human uptake and efflux transporters known to be of pharmacokinetic relevance. Affinity of TC to the uptake transporters OATP1A2, -1B1, -1B3, -2B1, OCT1, -2, -3, OCTN2, NTCP, and ASBT and the efflux carriers P-gp, MRP2 and MRP3 transfected in HEK293 and MDCK2 cells was measured. To identify relevant pharmacokinetic mechanisms in the bladder urothelium, mRNA expression of multidrug transporters, drug metabolizing enzymes, and nuclear receptors, and the uptake of TC into primary human bladder urothelium (HBU) cells were measured. TC was shown to be a substrate of OATP1A2 (Km = 6.9 ± 1.3 µmol/L; Vmax = 41.6 ± 1.8 pmol/mg·min), OCT1 (Km = 106 ± 16 µmol/L; Vmax = 269 ± 18 pmol/mg·min), and P-gp (Km = 34.9 ± 7.5 µmol/L; Vmax = 105 ± 9.1 pmol/mg·min, lipovesicle assay). The genetic OATP1A2 variants *2 and *3 were loss-of-function transporters for TC. The mRNA expression analysis identified the following transporter proteins in the human urothelium: ABCB1 (P-gp), ABCC1-5 (MRP1-5), ABCG2 (BCRP), SLCO2B1 (OATP2B1), SLCO4A1 (OATP4A1), SLC22A1 (OCT1), SLC22A3 (OCT3), SLC22A4 (OCTN1), SLC22A5 (OCTN2), and SLC47A1 (MATE1). Immuno-reactive P-gp and OATP1A2 were localized to the apical cell layers. Drug metabolizing enzymes CYP3A5, -2B6, -2B7 -2E1, SULT1A1-4, UGT1A1-10, and UGT2B15, and nuclear receptors NR1H3 and NR1H4 were also expressed on mRNA level. TC was taken up into HBU cells (Km = 18.5 ± 4.8 µmol/L; Vmax = 106 ± 11.3 pmol/mg·min) by mechanisms that could be synergistically inhibited by naringin (IC50 = 10.8 (8.4; 13.8) µmol/L) and verapamil (IC50 = 4.6 (2.8; 7.5) µmol/L), inhibitors of OATP1A2 and OCT1, respectively. Affinity of TC to OCT1 and P-glycoprotein may be the reason for incomplete oral absorption, wide distribution into liver and kidneys, and substantial intestinal and renal secretions. Absence of brain distribution may result from affinity to P-gp and a low affinity to OATP1A2. The human urothelium expresses many drug transporters and drug metabolizing enzymes that may interact with TC and other drugs eliminated into the urine.

From lab to field: biological control of the Japanese beetle with entomopathogenic fungi.

The Japanese beetle, Popillia japonica, is an invasive scarab and listed as quarantine organism in many countries worldwide. Native to Japan, it has invaded North America, the Azores, and recently mainland Europe. Adults are gregarious and cause agricultural and horticultural losses by feeding on leaves, fruits, and flowers of a wide range of crops and ornamental plants. Larvae feed belowground and damage grassland. To date, no efficient and environmentally friendly control measure is available. Larval populations of other scarab species such as Phyllopertha horticola and Melolontha melolontha are controlled by applying spores of the entomopathogenic fungi Metarhizium brunneum and Beauveria brongniartii to larval habitats. Here, we tested this control strategy against Japanese beetle larvae in grasslands, as well as spore spray applications against adults in crops. Using both, large-scale field experiments and inoculation experiments in the laboratory, we assess the efficacy of registered fungal strains against Japanese beetle larvae and adults. Metarhizium brunneum BIPESCO 5 established and persisted in the soil of larval habitats and on the leaves of adult's host plants after application. However, neither larval nor adult population sizes were reduced at the study sites. Laboratory experiments showed that larvae are not susceptible to M. brunneum ART 212, M. brunneum BIPESCO 5, and B. brongniartii BIPESCO 2. In contrast, adults were highly susceptible to all three strains. When blastospores were directly injected into the hemolymph, both adults and larvae showed elevated mortality rates, which suggests that the cuticle plays an important role in determining the difference in susceptibility of the two life stages. In conclusion, we do not see potential in adapting the state-of-the-art control strategy against native scarabs to Japanese beetle larvae. However, adults are susceptible to the tested entomopathogenic fungi in laboratory settings and BIPESCO 5 conidiospores survived for more than three weeks in the field despite UV-radiation and elevated temperatures. Hence, control of adults using fungi of the genera Beauveria or Metarhizium is more promising than larval control. Further research on efficient application methods and more virulent and locally adapted fungal strains will help to increase efficacy of fungal treatments for the control of P. japonica.

Role of percolation in the conductance of electrolyte-gated SrTiO3.

We study the electrolyte-gate-induced conductance at the surface of SrTiO(3)(001). We find two distinct transport regimes as a function of gate voltage. At high carrier densities, a percolative metallic state is induced in which, at low temperatures, clear signatures of a Kondo effect are observed. At lower carrier densities, the resistance diverges at low temperatures and can be well described by a 2D variable range hopping model. We postulate that this derives from nonpercolative transport due to inhomogeneous electric fields from imperfectly ordered ions at the electrolyte-oxide interface.

Efficient spin injector scheme based on Heusler materials.

We present a rational design scheme intended to provide stable high spin polarization at the interfaces of the magnetoresistive junctions by fulfilling the criteria of structural and chemical compatibilities at the interface. This can be realized by joining the semiconducting and half-metallic Heusler materials with similar structures. The present first-principles calculations verify that the interface remains half-metallic if the nearest interface layers effectively form a stable Heusler material with the properties intermediately between the surrounding bulk parts. This leads to a simple rule for selecting the proper combinations.

High-throughput screening of inorganic compounds for the discovery of novel dielectric and optical materials.

Dielectrics are an important class of materials that are ubiquitous in modern electronic applications. Even though their properties are important for the performance of devices, the number of compounds with known dielectric constant is on the order of a few hundred. Here, we use Density Functional Perturbation Theory as a way to screen for the dielectric constant and refractive index of materials in a fast and computationally efficient way. Our results constitute the largest dielectric tensors database to date, containing 1,056 compounds. Details regarding the computational methodology and technical validation are presented along with the format of our publicly available data. In addition, we integrate our dataset with the Materials Project allowing users easy access to material properties. Finally, we explain how our dataset and calculation methodology can be used in the search for novel dielectric compounds.

Suppression of metal-insulator transition in VO2 by electric field-induced oxygen vacancy formation.

Electrolyte gating with ionic liquids is a powerful tool for inducing novel conducting phases in correlated insulators. An archetypal correlated material is vanadium dioxide (VO(2)), which is insulating only at temperatures below a characteristic phase transition temperature. We show that electrolyte gating of epitaxial thin films of VO(2) suppresses the metal-to-insulator transition and stabilizes the metallic phase to temperatures below 5 kelvin, even after the ionic liquid is completely removed. We found that electrolyte gating of VO(2) leads not to electrostatically induced carriers but instead to the electric field-induced creation of oxygen vacancies, with consequent migration of oxygen from the oxide film into the ionic liquid. This mechanism should be taken into account in the interpretation of ionic liquid gating experiments.

Crystal-facet-dependent metallization in electrolyte-gated rutile TiO2 single crystals.

The electric-field-induced metallization of insulating oxides is a powerful means of exploring and creating exotic electronic states. Here we show by the use of ionic liquid gating that two distinct facets of rutile TiO2, namely, (101) and (001), show clear evidence of metallization, with a disorder-induced metal-insulator transition at low temperatures, whereas two other facets, (110) and (100), show no substantial effects. This facet-dependent metallization can be correlated with the surface energy of the respective crystal facet and, thus, is consistent with oxygen vacancy formation and diffusion that results from the electric fields generated within the electric double layers at the ionic liquid/TiO2 interface. These effects take place at even relatively modest gate voltages.

Anomalous transport properties of the half-metallic ferromagnets Co2TiSi, Co2TiGe and Co2TiSn.

In this work, the theoretical and experimental investigations of Co2TiZ (Z=Si, Ge or Sn) compounds are reported. Half-metallic ferromagnetism is predicted for all three compounds with only two bands crossing the Fermi energy in the majority channel. The magnetic moments fulfil the Slater-Pauling rule and the Curie temperatures are well above room temperature. All compounds show a metallic-like resistivity for low temperatures up to their Curie temperature, above the resistivity changes to semiconducting-like behaviour. A large negative magnetoresistance (MR) of 55 per cent is observed for Co2TiSn at room temperature in an applied magnetic field of µ(0)H=4T, which is comparable to the large negative MRs of the manganites. The Seebeck coefficients are negative for all three compounds and reach their maximum values at their respective Curie temperatures and stay almost constant up to 950 K. The highest value achieved is -52 µVK(-1) for Co2TiSn, which is large for a metal. The combination of half-metallicity and the constant large Seebeck coefficient over a wide temperature range makes these compounds interesting materials for thermoelectric applications and further spincaloric investigations.