Pd/Cu-catalyzed cascade Heck-type reactions of alkenyl halides with terminal alkynes toward substituted pyrrolidine analogues.

Pd/Cu-catalyzed cascade Heck-type reactions of alkenyl halides with terminal alkynes have been developed. This research provides an efficient atom-economical approach to access a variety of highly substituted pyrrolidines in moderate to good yields. This protocol features readily available substrates, broad substrate scope, easy scale-up, high selectivities and versatile transformations.

Evaluation of the diagnostic performance of thyroid-stimulating immunoglobulin and thyrotropin receptor antibodies for Graves' disease.

OBJECTIVE: To evaluate thyroid-stimulating immunoglobulin (TSI) and thyrotropin receptor antibodies (TRAb) diagnostic performance for Graves' disease (GD) and determine clinical cut-off value for diagnosing GD. METHODS: Of 1369 retrospectively enrolled subjects, 1364 had a definitive diagnosis of untreated GD (GD-UT, n = 87); treated GD (GD-T, n = 206); autoimmune thyroid disease (AIT, n = 241); thyroid nodules (TN, n = 677); subacute thyroiditis (ST, n = 28); healthy subjects (HS, n = 125); other diseases with serological hyperthyroidism (n = 5) and were grouped into the following: UT-GD and control groups (AIT, TN, ST, and HS); and UT-GD and non-GD hyperthyroidism groups. Diagnostic performance of TSI and TRAb was evaluated using area under the curve (AUC) of receiver-operating characteristic (ROC) curve, and optimal clinical cut-off value was determined using maximization of Youden index. RESULTS: TRAb AUC and clinical cut-off value for diagnosing GD were 0.981 and 1.245 IU/L (sensitivity, 96.6%; specificity, 97.1%; positive predictive value [PPV], 71.8%; negative predictive value [NPV], 99.9%; positive likelihood ratio [PLR], 33.31; negative likelihood ratio [NLR, 0.035), respectively, for the GD-UT and control groups. Those for TSI were 0.992 and 0.467 IU/L (sensitivity 98.8%; specificity, 96.4%; PPV, 68.8%; NPV, 99.9%; PLR, 27.472; NLR, 0.011). Those for TRAb in GD-UT and non-GD hyperthyroidism groups were 0.923 and 1.78 IU/L (sensitivity, 92.0%; specificity, 89.1%; PPV, 93%; NPV, 87.5%; PLR, 8.44; NLR, 0.089), respectively. For TSI, these were 0.92 and 0.545 IU/L (sensitivity, 97.7%; specificity, 83.6%; PPV, 90.4%; NPV, 95.8%; PLR27.472, NLR, 0.011), respectively. CONCLUSION: TSI diagnostic performance for GD was excellent and had better sensitivity than TRAb.

Enantioselective Synthesis of Dihydropyrazoles by Palladium/Xu-Phos-Catalyzed Alleneamination of ß,γ-Unsaturated Hydrazones with Propargylic Acetates.

The palladium-catalyzed asymmetric carboamination reaction is one of the most significant transformations in organic chemistry. Herein, we report the first palladium-catalyzed asymmetric alleneamination of ß,γ-unsaturated hydrazones with propargylic acetates. This protocol enables the efficient installation of various multisubstituted allene groups onto dihydropyrazoles in good yields with excellent enantioselectivities. The chiral sulfinamide phosphine ligand Xu-5 exhibits highly efficient stereoselective control in this protocol. The salient features of this reaction include the readily available starting materials, a broad substrate scope, an easy scale-up, mild reaction conditions and versatile transformations.

Triazole resistance in Aspergillus fumigatus exposed to new chiral fungicide mefentrifluconazole.

BACKGROUND: Triazole resistance in the human fungal pathogen Aspergillus fumigatus has been a growing challenge in clinic treatment with triazole drugs such as itraconazole. The fast evolvement of triazole resistance in A. fumigatus in the ecosystem has drawn great attention, and there has been a possible link between the application of triazole fungicides in agriculture and triazole resistance in A. fumigatus. The change in susceptibility of A. fumigatus exposed to the new chiral triazole fungicide mefentrifluconazole was investigated in this study. RESULTS: The results indicated that triazole resistance in A. fumigatus was acquired with exposure to mefentrifluconazole at a level of greater than or equal to 2 mg L-1 in liquid medium and soil (not at 0.4 nor 1 mg L-1 ). Interestingly, stereoselectivity was found in the acquisition of triazole resistance in A. fumigatus when exposed to mefentrifluconazole. R-mefentrifluconazole, which is very active on plant pathogens, exhibited stronger possibility in the development of the resistance in A. fumigatus than its antipode. Overexpression of cyp51A, AtrF, AfuMDR1 and AfuMDR4 were associated with the acquired resistance in A. fumigatus with hereditary stability. CONCLUSION: The results suggest that triazole resistance in A. fumigatus could be resulted from the selection of mefentrifluconazole at concentrations larger than 2 mg L-1 . Mefentrifluconazole should be applied within the dosage recommended by good agricultural practice to avoid the resistance in A. fumigatus in soil. This also may be applicable to other triazole fungicides. © 2022 Society of Chemical Industry.

Follicular fluid steroid and gonadotropic hormone levels and mitochondrial function from exosomes predict embryonic development.

Purpose: Human follicular fluid (FF) is a complex biological fluid that contributes to the micro-environment of oocyte development. The aim of this study was to evaluate the role of steroid and gonadotropic hormones levels and mitochondrial function in embryo development during in vitro fertilization cycles. Methods: This was a cohort study of 138 women receiving IVF/ICSI, including 136 FF samples from 109 infertile women. FF steroid and gonadotropic hormones levels were tested by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and immunoassays. The mRNA expression levels of mitochondrial electron transport chain (ETC) complex genes from FF exosomes were detected by qPCR. Results: Analysis of these individual FF concentrations revealed that LH and FSH concentrations were higher in follicles in which the oocyte developed into a top quality (TQ) blastocyst (LH: 9.44 ± 2.32mIU/ml, FSH: 9.32 ± 1.01mIU/ml) than those in which there was a failure of fertilization (LH: 5.30 ± 0.84mIU/ml, FSH: 6.91 ± 0.62mIU/ml). In contrast, follicular cortisone concentrations were lower for oocytes that resulted in a TQ blastocyst (12.20 ± 0.82mIU/ml). The receiver operating characteristic analysis showed that FF LH and FSH levels predicted TQ blastocyst with excellent AUC value of 0.711 and 0.747. Mitochondrial ETC complex I and III mRNA levels were increased in the FF exosomes of TQ blastocyst. Correlation analysis showed that mRNA levels of ETC complex I was positively correlated with LH and FSH levels in FF. Conclusion: The levels of FF steroid and gonadotropic hormones from single follicle can predetermine subsequent embryo development to some extent. Furthermore, impaired exosome mitochondrial dysfunction is a potiential event that causes hormone change in embryo development.

Interfacial Bi-S bonds modulate band alignment for efficient solar water oxidation.

Introducing suitable interfacial chemical bonds into heterojunctions can increase the charge carrier density, propel the charge separation, and facilitate interfacial charge extraction in photoanodes for photoelectrochemical (PEC) water oxidation. However, tuning chemical bonds at heterojunction interfaces and elucidating their influences on band alignment and the associated evolution of PEC performance remain elusive. Herein, Bi-S bonds were introduced into the interface of a CdIn2S4 (CIS)/Bi2WO6 (BWO) heterojunction. In situ irradiated X-ray photoelectron spectroscopy and electron spin resonance signals confirm that the Bi-S bond transforms the band alignment from type II to the direct Z-scheme, significantly enhancing the carrier separation efficiency. Theoretical calculations show that the Bi-S bond not only acts as an atomic-level charge transfer channel, but also changes the migration pathway and distance within the heterojunction. As a result, the optimized CIS/BWO photoanode exhibits a relatively high PEC performance of 4.25 mA cm-2 at 1.23 V vs. RHE (VRHE) and a low onset potential of 0.30 VRHE. This work presents a new avenue to construct comprehensively improved photoanodes by tuning the interfacial structures at the atomic level.

Uptake, Accumulation, and translocation of azoxystrobin by Vegetable plants in soils: influence of soil characteristics and plant species.

Although azoxystrobin has been widely applied on various crops, little is known about the bioavailability of azoxystrobin in the soil-vegetable system. In this study, the uptake, accumulation and translocation of azoxystrobin as affected by soil characteristics and plant species were respectively investigated. The accumulation amount of azoxystrobin in pakchoi increased as soil adsorption decreased and was positively associated with its concentration in pore water (Cpw), which was mainly affected by soil organic matter content. Therefore, Cpw could be a candidate for the estimation of azoxystrobin accumulation in pakchoi. In all the tested vegetables, azoxystrobin was mainly accumulated in roots, and its upward translocation was limited. Root lipid content was a major factor affecting the uptake and translocation of azoxystrobin in different vegetables.

Enhanced Intramuscular Bioavailability of Cannabidiol Using Nanocrystals: Formulation, In Vitro Appraisal, and Pharmacokinetics.

Cannabidiol (CBD) has poor water solubility and is subjected to extensive first-pass metabolism. These absorption obstacles are responsible for low and variable oral bioavailability of CBD. This study endeavored to improve CBD bioavailability by intramuscular (IM) injection of CBD nanocrystals (CBD-NC). The nanocrystals were prepared by antisolvent precipitation method and were characterized in terms of the particle size, polydispersity index (PDI), zeta potential, morphology, and crystalline status. CBD-NC displayed a particle size of 141.7±1.5 nm, a PDI of 0.18±0.01, and a zeta potential of -25.73 mV. CBD-NC freeze-dried powder using bovine serum albumin (BSA) as cryoprotectant had good redispersibility, and the average particle size was 139.1±1.4 nm after reconstitution. Moreover, these freeze-dried powders were characterized for drug loading and pH and were evaluated for in vitro dissolution and in vivo studies in a rat model. The in vivo results showed that AUC0-24 h and Cmax of CBD by IM injection of CBD nanocrystals increased significantly compared with that of oral (P.O) administration of CBD nanocrystals and CBD oil solution. This underlines the nano-sized CBD could be suggested as a practical and simple nanosystem for IM delivery with improved bioavailability. More importantly, these results pave the way for future development of CBD-NC retentive dosage forms. Graphical abstract.

Enantioselectivity of new chiral triazole fungicide mefentrifluconazole: Bioactivity against phytopathogen, and acute toxicity and bioaccumulation in earthworm (Eisenia fetida).

Elaborating the environmental behavior of mefentrifluconazole, a novel triazole fungicide, in stereoselective level is of paramount importance for the application of the pesticide in agriculture. In this study, the enantioselective bioactivity, acute toxicity and stereoselective bioaccumulation of mefentrifluconazole in earthworm (Eisenia fetida) were investigated. Bioactivity tests against four pathogens revealed that R-(-)-mefentrifluconazole exhibited approximately 11-113 times higher bioactivity than its S-(+)-mefentrifluconazole. However, the LC50 of S-(+)-, rac- and R-(-)-mefentrifluconazole to earthworm was measured to be 4.1, 11.4 and 7.3 µg/cm2, respectively, indicating active ingredient R-(-)-mefentrifluconazole is less toxic than its racemate and S-form. Accumulation of mefentrifluconazole in earthworms was non-enantioselective and negatively related to its adsorption onto soils. The concentration of mefentrifluconazole in in situ pore water (CIPW) and CaCl2 extraction (CCaCl2) was closely related to its accumulation in earthworms, suggesting that CIPW and CCaCl2 could be appropriate indicators for estimation of the bioavailability of mefentrifluconazole in soil. Conclusively, our study provides necessary information for the risk assessment of mefentrifluconazole in agriculture.

Characterization, genome functional analysis, and detoxification of atrazine by Arthrobacter sp. C2.

Residual injury of atrazine to the succeeding crops has been frequently reported. It is necessary to find a solution for the detoxification of atrazine contaminated soil. A high-efficient bacterial strain Arthrobacter sp. C2 for atrazine degradation was isolated in this study. The genomic information of the isolate C2, and its degradation characteristics and potential application in detoxification of atrazine contaminated soil were investigated. The results indicated that the isolate C2 genome contained 4,305,216 bp nucleotides, three plasmids, and 4705 coding genes. The degradation rates of atrazine at levels of 1, 10, 100 mg/L by the isolate C2 were 0.34, 1.94, 18.64 mg/L/d, respectively. The optimum temperature and pH for the isolate C2 to degrade atrazine were 30 °C and 7.0-9.0. Based on the metabolites detected by UPLC-TOF-MS/MS and genome annotation of the isolate C2, a common metabolic pathway of atrazine was proposed as that atrazine is firstly dechlorinated into hydroxyatrazine, and subsequently to N-isopropylammelide via dealkylation, and ultimately deaminated to cyanuric acid. Introduction of the isolate C2 into soil can enhance degradation of atrazine and thus eliminate the toxic effect of this herbicide on wheat growth. Our results indicate that the strain C2 could be a potential bioresource for bioremediation of atrazine contaminated soil.

Root Uptake of Imidacloprid and Propiconazole Is Affected by Root Composition and Soil Characteristics.

Residual pesticides in soil may be taken up by crops and negatively affect food safety. The uptake mechanism of imidacloprid and propiconazole was studied using wheat roots. The factors affecting root uptake were also studied with different crops and in different soils. Imidacloprid and propiconazole were taken up by wheat roots mainly through the symplastic and apoplastic pathways, respectively. Root protein and lipid contents were the main factors affecting the uptake and accumulation of imidacloprid and propiconazole by different crop roots, respectively. The uptake of imidacloprid and propiconazole in soil by wheat plants was linearly correlated with their concentrations in soil pore water, which were governed by soil characteristics. These results are helpful for understanding and estimating crop uptake of residual pesticides in soils.

Triazole resistance in Aspergillus fumigatus in crop plant soil after tebuconazole applications.

Aspergillus fumigatus is the primary agent of invasive aspergillosis (IA) causing high morbidity and mortality in immunocompromised patients. Triazole resistance in A. fumigatus and its sources have gained wide attention. For several years, environmental fungicides use has been proposed as the major cause for triazole resistance in A. fumigatus. However, there are few studies on azole-resistant A. fumigatus (ARAF) selected by triazole fungicides in agricultural systems. We studied the possible emergence of ARAF in the field after exposure to triazole fungicide tebuconazole. Our results showed that exposure to tebuconazole in soil selects for resistance to triazoles in A. fumigatus. The probability of ARAF developing in soils depends upon the concentrations of tebuconazole after application. We suggest that tebuconazole applications should be minimized to reduce selective pressure for the generation of ARAFs.

Five-Year Survey (2014 to 2018) of Azole Resistance in Environmental Aspergillus fumigatus Isolates from China.

A total of 191 soil samples from Hangzhou, China, were submitted to detect non-wild-type (non-WT) Aspergillus fumigatus and its associated mechanisms. There were 2 (4.7%), 13 (12.4%), and 31 (23.1%) isolates identified as non-WT in 2014, 2016, and 2018, respectively. The resistant mutations of TR34/L98H, TR46/Y121F/T289A, and TR34/L98H/S297T/F495I were found in 3, 5, and 5 non-WT isolates. The G448S mutation, previously only found in clinical settings, was detected in A. fumigatus from soil samples.

Increased triazole-resistance and cyp51A mutations in Aspergillus fumigatus after selection with a combination of the triazole fungicides difenoconazole and propiconazole.

Triazole-resistance in Aspergillus fumigatus is widespread. We evaluated whether triazole-resistance in A. fumigatus and its related cyp51A mutations, induced by a combination of the triazole fungicides difenoconazole and propiconazole, differs from resistance induced by the individual fungicides. Both difenoconazole and propiconazole can induce triazole-resistance in A. fumigatus. Resistance is much easier induced by formulated fungicides or a combination of these two fungicides compared with standard fungicides or individual fungicides, respectively. Six different mutations (G138S, G138D, H147Y, I246M, M263I and D430N) were identified in the induced resistant strains. The H147Y, I246M and M263I mutations were associated with triazole-resistance. This implies that the application of a combination of difenoconazole and propiconazole may result in higher triazole-resistance in A. fumigatus and more mutations in the cyp51A gene.

Subcellular distribution governing accumulation and translocation of pesticides in wheat (Triticum aestivum L.).

Root uptake, translocation, and subcellular distribution of six pesticides (dinotefuran, thiamethoxam, imidacloprid, imazethapyr, propiconazole, and chlorpyrifos) with Kow ranging from -0.549 to 4.7 were investigated in wheat to study transportation and accumulation of pesticides. The root bioconcentration factor (RCF) of pesticides decreased with water solubility (R2 = 0.6121) and increased with hydrophobicity (when the pH-adjusted log Kow > 2, R2 = 0.925), respectively. The translocation of neutral pesticides from roots to shoots increased positively with water solubility (R2 > 0.6484) but decreased with hydrophobicity (R2 > 0.8039). The subcellular fraction concentration factor (SFCF) increased linearly with hydrophobicity of the tested pesticides (R2 > 0.958). The log RCF was positively correlated with log SFCF in root cell walls (R2 = 0.9894) and organelles (R2 = 0.9786). Transportation of the pesticides from roots to stems and stems to leaves was adversely affected by the log SFCF of cell walls and organelles of roots (R2 > 0.7997) and stems (R2 > 0.6666), respectively. Hydrophobicity-dependent SFCF is a factor governing accumulation of pesticides in roots after uptake and their subsequent upward translocation.

Upward translocation of acetochlor and atrazine in wheat plants depends on their distribution in roots.

Residual acetochlor and atrazine in soils, resulting from their extensive application to maize plants, may affect product safety of the ultimate wheat crop. To determine the potential uptake and accumulation of acetochlor and atrazine by wheat plants, the uptake mechanism, translocation, and subcellular distribution of these two herbicides were studied through hydroponic experiments (10 mg L-1). The results indicated that acetochlor can be taken up through the apoplastic pathway and can accumulate in wheat roots with little upward translocation. However, atrazine could be taken up by roots through the symplastic pathway and subsequently transported to the stems and leaves. Little upward translocation of acetochlor in wheat plants was due to its preferential distribution into root organelles with higher lipid contents. Conversely, the low bioconcentration of atrazine in root organelles and cell walls after uptake led to its easy upward translocation. Uptake of acetochlor and atrazine by wheat roots and the distribution of atrazine to the stems and leaves were predicted well by using the partition-limited model. The obtained results indicated that residual atrazine in soil may be taken up by wheat roots and acropetally translocated, thereby posing a threat to product safety of wheat.

Mechanism of the effect of pH and biochar on the phytotoxicity of the weak acid herbicides imazethapyr and 2,4-D in soil to rice (Oryza sativa) and estimation by chemical methods.

The existing form of an ionizable organic compound can simultaneously affect its soil adsorption and plant bioactivity. In this experiment, the adsorption and bioactivity of two weak acid herbicides (WAHs), imazethapyr and 2,4-D, were studied to explore the predominant mechanism by which the soil pH and the addition of biochar can influence the phytotoxicity of WAHs in soil. Then, the WAH concentration extracted by hollow fiber-based liquid-phase microextraction (CHF-LPME), the in situ pore water concentration (CIPW) and the added concentration (CAC) were employed to estimate the phytotoxicity. The results showed that with increased pH from 5.5 to 8.5, the phytotoxicity of the WAHs to rice increased about 1-fold in the soil, but decreased in aqueous solutions, the IC50 values for imazethapyr and 2,4-D at pH 5.0 were 3- and 2-fold higher than that at pH 8.0. In addition, the soil adsorption decreased, indicating that the adsorption process was the dominant factor for the variation of the phytotoxicity of the WAHs in the tested soil instead of the decreasing bioactivity. The concentration that inhibits plant growth by 50% (IC50) calculated by the CAC in different pH and biochar soils ranged from 0.619 to 3.826 mg/kg for imazethapyr and 1.871-72.83 mg/kg for 2,4-D. The coefficient of variation (CV) of the IC50 values reached 65.61% for imazethapyr and 130.0% for 2,4-D. However, when IC50 was calculated by CIPW and CHF-LPME, the CVs of the IC50 values decreased to 23.51% and 36.23% for imazethapyr and 40.21% and 50.93% for 2,4-D, respectively. These results suggested that CIPW and CHF-LPME may be more appropriate than CAC for estimating the phytotoxicity of WAHs.

Estimation of the toxicity of sulfadiazine to Daphnia magna using negligible depletion hollow-fiber liquid-phase microextraction independent of ambient pH.

The toxicity of ionizable organic compounds to organisms depends on the pH, which therefore affects risk assessments of these compounds. However, there is not a direct chemical method to predict the toxicity of ionizable organic compounds. To determine whether hollow-fiber liquid-phase microextraction (HF-LPME) is applicable for this purpose, a three-phase HF-LPME was used to measure sulfadiazine and estimate its toxicity to Daphnia magna in solutions of different pH. The result indicated that the sulfadiazine concentrations measured by HF-LPME decreased with increasing pH, which is consistent with the decreased toxicity. The concentration immobilize 50% of the daphnids (EC50) in 48 h calculated from nominal concentrations increased from 11.93 to 273.5 mg L-1 as the pH increased from 6.0 to 8.5, and the coefficient of variation (CV) of the EC50 values reached 104.6%. When calculated from the concentrations measured by HF-LPME (pH 12 acceptor phase), the EC50 ranged from 223.4 to 394.6 mg L-1, and the CV decreased to 27.60%, suggesting that the concentrations measured by HF-LPME can be used to estimate the toxicity of sulfadiazine irrespective of the solution pH.