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Fusarium head blight (FHB) threatens wheat production worldwide. Utilization of FHB resistant varieties is the most effective solution for disease control. Owing to the limited sources of FHB resistance, mining of novel resistance genes is crucial. Here, we report an FHB resistance gene from a wild wheat relative species, Roegneria ciliarisand developed FHB resistant germplasm containing this gene. Wheat-R. ciliarisdisomic addition line DA3Scshowed enhanced type II FHB resistance compared to its sister line 3Sc-Null without chromosome 3Sc, indicating that the resistance was contributed by the addition of 3Sc. The resistance gene on 3Scwas validated using F2and F2:3populations derived from the cross between DA3Scand susceptible Aikang 58 (a susceptible cultivar), demonstrating that the lines with 3Schad significantly enhanced FHB resistance compared to the individuals without 3Sc. This was the second resistance gene identified in R. ciliaris, designated FhbRc2. To transfer FhbRc2to common wheat, we produced a double-monosomic chromosome population by crossing DA3Scwith the Chinese Spring nulli-tetrasomic line N3DT3B. Eight alien chromosome lines containing 3Scwere identified using genomic/fluorescence in situhybridization and 3Sc-specific marker analysis. Only the lines carrying the long arm of 3Scconferred FHB resistance, further locating FhbRc2on 3ScL. A compensating wheat-R. ciliarisRobertsonian translocation line T3DS·3ScL harboring FhbRc2is developed and provides a potential genetic resource in wheat breeding for enhanced FHB resistance.

Giredestrant is a potent and selective small-molecule estrogen receptor degrader. The objectives of this study were to assess the absolute bioavailability (aBA) of giredestrant and to determine the mass balance, routes of elimination, and metabolite profile of [14C]giredestrant. In part 1 (mass balance), a single 30.8-mg oral dose of [14C]giredestrant (105 µCi) was administered to women of nonchildbearing potential (WNCBP; n= 6). The mean recovery of total radioactivity in excreta was 77.0%, with 68.0% of the dose excreted in feces and 9.04% excreted in urine over a 42-day sample collection period. The majority of the circulating radioactivity (56.8%) in plasma was associated with giredestrant. Giredestrant was extensively metabolized, with giredestrant representing only 20.0% and 1.90% of the dose in feces and urine, respectively. All metabolites in feces resulted from oxidative metabolism and represented 44.7% of the dose. In part 2 (aBA), WNCBP (n= 10) received an oral (30-mg capsule) or intravenous (30-mg solution) dose of giredestrant. The aBA of giredestrant after oral administration was 58.7%. Following the intravenous dose, giredestrant had a plasma clearance and volume of distribution of 5.31 L/h and 266 L, respectively. In summary, giredestrant was well tolerated, rapidly absorbed, and showed moderate oral bioavailability with low recovery of the dose as parent drug in excreta. Oxidative metabolism followed by excretion in feces was identified as the major route of elimination of giredestrant.

Taselisib (also known as GDC-0032) is a potent and selective phosphoinositide 3-kinase (PI3K) inhibitor that displays greater selectivity for mutant PI3Kαthan wild-type PI3Kα. To better understand the absorption, distribution, metabolism, and excretion properties of taselisib, mass balance studies were conducted following single oral doses of [14C]taselisib in rats, dogs, and humans. Absolute bioavailability (ABA) of taselisib in humans was determined by oral administration of taselisib at the therapeutic dose followed by intravenous dosing of [14C]taselisib as a microtracer. The ABA in humans was 57.4%. Absorption of taselisib was rapid in rats and dogs and moderately slow in humans. The recovery of radioactivity in excreta was high (>96%) in the three species where feces was the major route of excretion. Taselisib was the major circulating component in the three species with no metabolite accounting for >10% of the total drug-derived material. The fraction absorbed of taselisib was 35.9% in rats and 71.4% in dogs. In rats, absorbed drug underwent moderate to extensive metabolism and biliary excretion of taselisib was minor. In dog, biliary excretion and metabolism were major clearance pathways. In humans, 84.2% of the dose was recovered as the parent drug in excreta indicating that metabolism played a minor role in the drug’s clearance. Major metabolism pathways were oxidation and amide hydrolysis in the three species while methylation was another prominent metabolism pathway in dogs. The site of methylation was identified on the triazole moiety. In vitro experiments characterized that the N-methylation was dog-specific and likely mediated by a thiol methyltransferase.SIGNIFICANCE STATEMENTThis study provides a comprehensive description of the absorption, distribution, and metabolism and pharmacokinetic properties of taselisib in preclinical species and humans. This study demonstrated the importance of oral bioavailability results for understanding taselisib’s clearance pathways. The study also describes the identification and characterization of a unique dog-specific N-methylation metabolite of taselisib and the enzyme mediating N-methylation in vitro.

Significant wastage of the food deterioration in the food preserving process and residual liquid in a container has become a major concern for scientists and the whole society. In this study, an edible multifunctional film integrated superhydrophobicity and antioxidant ability is constructed by chitosan, tea polyphenol, carnauba wax material that is food and drug administration (FDA)-approved for food packaging. The formed edible packaging materials that exhibit great antioxidant property and extremely low water-absorbing quality, was thus proven to display excellent fresh beef preservation effect during storage of 14 days. Importantly, the formed edible multifunctional interface was also demonstrated to perform excellent superhydrophobicity due to the carnauba wax and exhibited large contact angles for various liquid foods, which could effectively reduce the liquid residue. Moreover, the formed edible multifunctional packaging materials showed good thermostability and biocompatibility, which has the potential to be applied as a functional packaging material.

Global plastics production increased over the past few decades, and some alternatives that have been developed to manage plastic wastes are recycling and the energy-recovery method. It is important to better understand the reaction mechanism and kinetic model of plastic waste pyrolysis. The pyrolysis kinetics and thermodynamic parameters of polyvinyl chloride (PVC) cable sheath were studied in detail. The Flynn–Wall–Ozawa (FWO) method was used to calculate the activation energy values, and the Coats–Redfern (CR) model-fitting method was used to determine the reaction mechanism. Three pyrolysis stages can be found in three temperature ranges. The first two stages correspond to the conversion rate of 0.10–0.60 and 0.60–0.85, respectively. The estimated activation energy values range from 132.78 to 149.5 kJ mol–1with a mean value of 141.54 kJ mol–1at the first stage, while they fall in between 193.85 and 266.44 kJ mol–1with a mean value of 235.37 kJ mol–1at the second stage. The contracting-area model and the fifth-order model are recommended to describe the pyrolysis reaction mechanisms of PVC cable sheath at the first two stages, respectively. The thermodynamic parameters were also calculated to prove the feasibility of plastic pyrolysis into energy and provide strong support for establishing the pyrolysis model and optimizing the actual reaction device.

For the problem that the satellite navigation signal is easily interfered, the anti-jamming technology of the traditional navigation receiver usually needs the direction of arrival (DOA) of the navigation signal. This paper proposes an anti-jamming method combining spatial projection and beamforming techniques. The method first constructs the orthogonal complement space of the interference subspace, and then projects the space-time signal vector receives by the antenna array onto it, and then uses the algorithm with strictly constrained minimum power sampling matrix gradient (CSMG) to project the output signal after beamforming in a fixed direction, and finally capture, locate, and solve the interference-free data obtained after beamforming. In this paper, the method is deduced theoretically and the relevant simulation experiments are completed. It shows that the anti-jamming algorithm not only can effectively suppress the interference signal, but also can better retain the desired signal.

Therapeutic biologics have become a fast-growing segment within the pharmaceutical industry during the past 3 decades. Although the metabolism of biologics is more predictable than small molecule drugs, biotransformation can significantly affect the activity of biologics. Unfortunately, there are only a limited number of published studies on the biotransformation of biologics, most of which are focused on one or a few types of modifications. In this study, an untargeted LC-MS–based differential analysis approach was developed to rapidly and precisely determine the universal biotransformation profile of biologics with the assistance of bioinformatic tools. A human monoclonal antibody (mAb) was treated with t-butyl hydroperoxide and compared with control mAb using a bottom-up proteomics approach. Thirty-seven types of post-translational modifications were identified, and 38 peptides were significantly changed. Moreover, although all modifications were screened and detected, only the ones related to the treatment process were revealed by differential analysis. Other modifications that coexist in both groups were filtered out. This novel analytical strategy can be effectively applied to study biotransformation-mediated protein modifications, which will streamline the process of biologic drug discovery and development.

For clarifying the combustion behavior of a circular ring thin-layer pool fire, a series of experiments with varying pool diameters were carried out. The equivalent pool area of 0.071 m2and an initial n-heptane thickness of 10 mm were fixed. An electronic balance, a digital camera, and K-type thermocouples were used to measure burning rate, flame height, and centerline temperature, respectively. The results show that more burning stages can appear with the increase of the inner and outer diameters of the circular ring pool. Fire merging can occur at any one of the stages of initial growth, quasi-steady burning with surface boiling, transition to bulk boiling, and bulk boiling burning; moreover, the maximum burning rate of fire merging is about 3.5 times that of the ordinary pool fire with the same area. The core hollow region plays an important role in decreasing the burning rate, flame height, fire merging time, etc. The evolutions of the characteristic parameters, e.g., burning rate, flame height, and centerline temperature, were analyzed. New correlations for predicting these parameters were also proposed.

Daclatasvir is a first-in-class, potent, and selective inhibitor of the hepatitis C virus nonstructural protein 5A replication complex. In support of nonclinical studies during discovery and exploratory development, liquid chromatography–tandem mass spectrometry and nuclear magnetic resonance were used in connection with synthetic and radiosynthetic approaches to investigate the biotransformation of daclatasvir in vitro and in cynomolgus monkeys, dogs, mice, and rats. The results of these studies indicated that disposition of daclatasvir was accomplished mainly by the release of unchanged daclatasvir into bile and feces and, secondarily, by oxidative metabolism. Cytochrome P450s were the main enzymes involved in the metabolism of daclatasvir. Oxidative pathways included δ-oxidation of the pyrrolidine moiety, resulting in ring opening to an aminoaldehyde intermediate followed by an intramolecular reaction between the aldehyde and the proximal imidazole nitrogen atom. Despite robust formation of the resulting metabolite in multiple systems, rates of covalent binding to protein associated with metabolism of daclatasvir were modest (55.2–67.8 pmol/mg/h) in nicotinamide adenine dinucleotide phosphate (reduced form)–supplemented liver microsomes (human, monkey, rat), suggesting that intramolecular rearrangement was favored over intermolecular binding in the formation of this metabolite. This biotransformation profile supported the continued development of daclatasvir, which is now marketed for the treatment of chronic hepatitis C virus infection.

The article presents a speech by Zhao Weiping, Chinese Consul General to Chicago, Illinois, delivered at the Opening Reception and Dinner of the "Has China Found a Unique Path of Modernization: The China Model Revisited" Conference, held on May 4, 2015. Topics of the speech include China's own model of development, concerns of the international community on this path of socialism with Chinese characteristics, and the relationship between China and the U.S.

Erbium-doped GaN (GaN:Er) epilayers were synthesized by metal organic chemical vapor deposition. GaN:Er waveguides were fabricated based on four different GaN:Er layer structures: GaN:Er/GaN/Al_2O_3, GaN:Er/GaN/AlN/Al_2O_3, GaN:Er/GaN/Al_0.75Ga_0.25N/AlN/Al_2O_3, and GaN/GaN:Er/GaN/Al_2O_3. Optical loss at 1.54 μm in these waveguide structures has been measured. It was found that the optical attenuation coefficient of the GaN:Er waveguide increases almost linearly with the GaN (002) x-ray rocking curve linewidth. The lowest measured loss was ∼6  dB/cm.

Organic anion–transporting polypeptides (OATP) 1B1, 1B3, and 2B1 can serve as the loci of drug–drug interactions (DDIs). In the present work, the cynomolgus monkey was evaluated as a potential model for studying OATP-mediated DDIs. Three cynomolgus monkey OATPs (cOATPs), with a high degree of amino acid sequence identity (91.9, 93.5, and 96.6% for OATP1B1, 1B3, and 2B1, respectively) to their human counterparts, were cloned, expressed, and characterized. The cOATPs were stably transfected in human embryonic kidney cells and were functionally similar to the corresponding human OATPs (hOATPs), as evident from the similar uptake rate of typical substrates (estradiol-17β-d-glucuronide, cholecystokinin octapeptide, and estrone-3-sulfate). Moreover, six known hOATP inhibitors exhibited similar IC50values against cOATPs. To further evaluate the appropriateness of the cynomolgus monkey as a model, a known hOATP substrate [rosuvastatin (RSV)]-inhibitor [rifampicin (RIF)] pair was examined in vitro; the monkey-derived parameters (RSV Kmand RIF IC50) were similar (within 3.5-fold) to those obtained with hOATPs and human primary hepatocytes. In vivo, the area under the plasma concentration-time curve of RSV (3 mg/kg, oral) given 1 hour after a single RIF dose (15 mg/kg, oral) was increased 2.9-fold in cynomolgus monkeys, consistent with the value (3.0-fold) reported in humans. A number of in vitro–in vivo extrapolation approaches, considering the fraction of the pathways affected and free versus total inhibitor concentrations, were also explored. It is concluded that the cynomolgus monkey has the potential to serve as a useful model for the assessment of OATP-mediated DDIs in a nonclinical setting.

Vandetanib was evaluated as an inhibitor of human organic anion transporter 1 (OAT1), OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion (MATE1 and MATE2K) transfected (individually) into human embryonic kidney 293 cells (HEK293). Although no inhibition of OAT1 and OAT3 was observed, inhibition of OCT2-mediated uptake of 1-methyl-4-phenylpyridinium (MPP+) and metformin was evident (IC50of 73.4 ± 14.8 and 8.8 ± 1.9 µM, respectively). However, vandetanib was an even more potent inhibitor of MATE1- and MATE2K-mediated uptake of MPP+(IC50of 1.23 ± 0.05 and 1.26 ± 0.06 µM, respectively) and metformin (IC50of 0.16 ± 0.05 and 0.30 ± 0.09 µM, respectively). Subsequent cytotoxicity studies demonstrated that transport inhibition by vandetanib (2.5 µM) significantly decreased the sensitivity [right shift in concentration of cisplatin giving rise to 50% cell death; IC50(CN)] of MATE1-HEK and MATE2K-HEK cells to cisplatin [IC50(CN)of 1.12 ± 0.13 versus 2.39 ± 0.44 µM; 0.85 ± 0.09 versus 1.99 ± 0.16 µM; P< 0.05), but not OCT2-HEK cells (1.36 ± 0.19 versus 1.47 ± 0.24 µM) versus vandetanib untreated cells and Mock-HEK cells [IC50(CN)of 2.34 ± 0.31 µM]. In summary, the results show that vandetanib is a potent inhibitor of MATE1 and MATE2K (versus OCT2). Inhibition of the two transporters may explain why there are reports of decreased creatinine clearance, and increased cisplatin nephrotoxicity (reduced cisplatin clearance), in some subjects receiving vandetanib therapy.

This study evaluated the reproducibility, sensitivity, accuracy, and precision of stop-flow liquid radiochromatographic detection (RFD). Stop-flow RFD was about 10-fold more sensitive compared with traditional RFD and had a good reproducibility for quantification and HPLC retention time. Stop-flow RFD was applied to determine enzyme kinetics of radiolabeled drugs. The enzyme kinetic parameters of muraglitazar glucuronidation determined by stop-flow RFD were comparable with those determined by microplate scintillation counting (MSC).

An improved mass defect filter (MDF) method employing both drug and core structure filter templates was applied to the processing of high resolution liquid chromatography/mass spectrometry (LC/MS) data for the detection and structural characterization of oxidative metabolites with mass defects similar to or significantly different from those of the parent drugs. The effectiveness of this approach was investigated using nefazodone as a model compound, which is known to undergo multiple common and uncommon oxidative reactions. Through the selective removal of all ions that fall outside of the preset filter windows, the MDF process facilitated the detection of all 14 nefazodone metabolites presented in human liver microsomes in the MDF-filtered chromatograms. The capability of the MDF approach to remove endogenous interferences from more complex biological matrices was examined by analyzing omeprazole metabolites in human plasma. The unprocessed mass chromatogram showed no distinct indication of metabolite peaks; however, after MDF processing, the metabolite peaks were easily identified in the chromatogram. Compared with precursor ion scan and neutral loss scan techniques, the MDF approach was shown to be more effective for the detection of metabolites in a complex matrix. The comprehensive metabolite detection capability of the MDF approach, together with accurate mass determination, makes high resolution LC/MS a useful tool for the screening and identification of both common and uncommon drug metabolites.

This study was carried out to determine the metabolic pathways of buspirone and cytochrome P450 (P450) isoform(s) responsible for buspirone metabolism in human liver microsomes (HLMs). Buspirone mainly underwent N-dealkylation to 1-pyrimidinylpiperazine (1-PP), N-oxidation on the piperazine ring to buspirone N-oxide (Bu N-oxide), and hydroxylation to 3'-hydroxybuspirone (3'-OH-Bu), 5-hydroxybuspirone (5-OH-Bu), and 6'-hydroxybuspirone (6'-OH-Bu) in HLMs. The apparent Km values for buspirone metabolite formation in pooled HLMs were 8.7 (1-PP), 34.0 (Bu N-oxide), 4.3 (3'-OH-Bu), 11.4/514 (5-OH-Bu), and 8.8 µM (6'-OH-Bu). CYP3A inhibitor ketoconazole (1 µM) completely inhibited the formation of all major metabolites in HLMs (0-16% of control), whereas the chemical inhibitor selective to other P450 isoforms had little or no inhibitory effect. Recombinant CYP3A4, CYP3A5, and CYP2D6 exhibited buspirone oxidation activities among nine P450 isoforms tested. The overall metabolism rate of 5 µM buspirone by CYP3A4 was 18-fold greater than that by CYP2D6 and 35-fold greater than that by CYP3A5. In a panel of HLMs from 16 donors, buspirone metabolism correlated well CYP3A activity (r2 = 0.85-0.96, ρ < 0.0005), but not the activities of other P450 isoforms. The metabolism rates of buspirone in CYP2D6 poor-metabolizer genotype HLMs were comparable to those in pooled HLMs. Taken together, these data suggest that CYP3A, mostly likely CYP3A4, is primarily responsible for the metabolism of buspirone in HLMs.

Erbium-doped GaN (Er:GaN) possesses superior optical, mechanical and thermal properties and is a very promising material as a gain medium for solid-state high-energy lasers. We report here the optical properties of GaN/Er:GaN/GaN core-cladding planar waveguides (PWGs). Optical confinement in the core layer has been investigated. The measured optical loss coefficients of Er:GaN PWGs at 1.54 ?m are 1.0 cm?1for the TE polarization mode and 1.2 cm?1for the TM polarization mode. Approaches to further reduce optical loss and the optimal configuration for resonantly pumped GaN/Er:GaN/GaN PWGs for achieving amplification near 1.5 ?m have been identified.