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1.For the first time, a systemic in vivo investigation was employed to evaluate the potential effects of m-nisoldipine on activities of rat cytochrome P450 enzymes (CYP1A2, CYP2C11, CYP2D1 and CYP3A1) by both cocktail probe drugs and the quantitative real-time reverse-transcription polymerase chain reaction (RT-qPCR). 2.m-Nisoldipine-treated and blank control groups were respectively administered m-nisoldipine at the dosage of 2.5, 5 and 12.5 mg/kg and CMC-Na solution for 15 days consecutively, then they were given the probe drugs of caffeine, diclofenac, dextromethorphan and midazolam (all probes were 5 mg/kg) by p.o. The blood samples were collected at different times for liquid chromatography coupled with mass spectrometry (LC-MS) analysis. The corresponding pharmacokinetic parameters were applied to evaluate the effects of m-nisoldipine on the four CYP isoforms in vivo. In addition, RT-qPCR was performed to determine the effects of m-nisoldipine on the mRNA expression of CYPs in rat liver. Results indicated that high dose and middle dose of m-nisoldipine showed significant effects on all four CYPs and CYP2C11, respectively. Moreover, for CYP2D1 and CYP1A2, there were no significant effects found at either low or middle dose of m-nisoldipine. 3.This study could provide not only experimental evidence for potential clinical application of m-nisoldipine but also a practical strategy for assessing CYP-mediated drug-drug interactions. [ABSTRACT FROM AUTHOR]

Abstract: Farfarae Flos, the dried flower buds of Tussilago farfara L., is usually used to treat coughs, bronchitic and asthmatic conditions as an important traditional Chinese medicine. Tussilagone and methl butyric acid tussilagin ester are seen as representatives of two kinds of active substances. In addition, the pyrrolizidine alkaloids, mainly senkirkine and senecionine, present in the herb can be hepatoxic. In this study, a rapid and sensitive ultra‐high‐performance liquid chromatography coupled with hybrid triple quadrupole time‐of‐flight mass spectrometry method was successfully applied to identify the metabolites of tussilagone, methl butyric acid tussilagin ester, senkirkine and senecionine. A total of 35, 37, 18 and nine metabolites of tussilagone, methl butyric acid tussilagin ester, senkirkine and senecionine in rats were tentatively identified. Hydrolysis, oxidation, reduction and demethylation were the major metabolic reactions for tussilagone and methl butyric acid tussilagin ester. The main biotransformation routes of senkirkine and senecionine were identified as demethylation, N‐methylation, oxidation and reduction. This study is the first reported analysis and characterization of the metabolites and the proposed metabolic pathways might provide further understanding of the metabolic fate of the chemical constituents after oral administration of Farfarae Flos extract in vivo. [ABSTRACT FROM AUTHOR]

m-Nisoldipine, as a novel 1,4-dihydropyridine calcium ion antagonist, was presented as a couple of enantiomers [(−), (+)- m-nisoldipine]. In this report, the in vitro metabolism of m-nisoldipine enantiomers was investigated in rat liver microsomes (RLM) by the combination of two liquid chromatography mass spectrometric techniques for the first time. The metabolites were separated and assayed by ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry and further identified by comparison of their mass and chromatographic behaviors with reference substances. A total of 18 metabolites of (−)- m-nisoldipine and 16 metabolites of (+)- m-nisoldipine were detected, respectively, which demonstrated that (+)- m-nisoldipine is more metabolically stable than (−)- m-nisoldipine. In addition, the identified metabolic pathways of m-nisoldipine enantiomers were involved in dehydrogenation, oxidation and ester hydrolysis . Afterwards, based on high-performance liquid chromatography coupled to triple quadrupole linear ion trap mass spectrometry, various selective cytochrome P450 (CYP) enzyme inhibitors were employed to evaluate CYP isoforms. The results indicated that the inhibitors of CYP1A1/2, CYP2B1/2, 2D and 2C11 had no obvious inhibitory effects, yet the inhibitor of CYP 3A had a significant inhibitory effect on metabolism of m-nisoldipine enantiomers. This showed that CYP 3A might primarily metabolize m-nisoldipine in RLM. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Relation extraction task aims at detecting the semantic relation between a pair of entities in a given target sentence. However, previous methods lack the description of the relation definition, thus needing to model the implication of relations during training. To tackle this issue, we propose a natural language inference method for relation extraction. Given a premise and a hypothesis, the natural language inference task refers to predicting whether the facts in the premise necessarily imply the facts in the hypothesis. Specifically, for each relation type, we construct a relation description. These relation descriptions are the definition of relation, containing prior knowledge that helps model understand the meaning of relation. The given target sentence is viewed as the premise, and these descriptions are viewed as the hypotheses. Then model infers whether these hypotheses can be concluded from the premise. Based on the inference results, our model selects the relation corresponding to the most confident hypothesis as the prediction. Substantial experiments on SemEval2010 Task8 dataset demonstrate that the proposed method achieves state-of-the-art performance. • We propose a natural language inference method for relation extraction. • Our model is enhanced using prior relation knowledge without extra pre-training. • We design a joint inference and classification loss. • Our model achieves state-of-the-art results on SemEval2010 Task8 and TACRED. [ABSTRACT FROM AUTHOR]

Titelbild: Single-Cell Imaging of m6A Modified RNA Using m6A-Specific In Situ Hybridization Mediated Proximity Ligation Assay (m6AISH-PLA) (Angew. In ihrer Zuschrift auf S. 22828 postulieren Jinghong Li et al. eine leistungsstarke In-situ-Imaging-Methode, die als "m SP 6 sp A-specific in situ hybridization mediated proximity ligation assay" (m SP 6 sp AISH-PLA) bezeichnet wird und die Identifizierung von m SP 6 sp A-Modifikationen an spezifischen Stellen in RNA und die Bildgebung von m SP 6 sp A-RNA mit Einzelzell- und Einzelmolekül-Auflösung ermöglicht. In ihrer Zuschrift auf S. 22828 postulieren Jinghong Li et al. eine leistungsstarke In-situ-Imaging-Methode, die als "m SP 6 sp A-specific in situ hybridization mediated proximity ligation assay" (m SP 6 sp AISH-PLA) bezeichnet wird und die Identifizierung von m SP 6 sp A-Modifikationen an spezifischen Stellen in RNA und die Bildgebung von m SP 6 sp A-RNA mit Einzelzell- und Einzelmolekül-Auflösung ermöglicht. [Extracted from the article]

In their Communication on page 22646, Jinghong Li et al. propose a powerful in situ imaging method, termed m SP 6 sp A-specific in situ hybridization mediated proximity ligation assay (m SP 6 sp AISH-PLA), that enables the identification of m SP 6 sp A modifications at a specific location in RNAs and the imaging of m SP 6 sp A RNA with single-cell and single-molecule resolution. Keywords: in situ imaging; m6A; proximity ligation; single-molecule; spatiotemporal information EN in situ imaging m6A proximity ligation single-molecule spatiotemporal information 22589 22589 1 10/06/21 20211011 NES 211011 B N b SP B 6 b sp B -methyladenosine b (m SP 6 sp A)-modified RNA analysis is limited at the bulk-population level, thus not giving access to spatiotemporal and cell-to-cell variability information. Cover Picture: Single-Cell Imaging of m6A Modified RNA Using m6A-Specific In Situ Hybridization Mediated Proximity Ligation Assay (m6AISH-PLA) (Angew. [Extracted from the article]

To understand the effects and related potential mechanism of H2O2 on pigment metabolism in postharvest broccoli, an integrated analysis of transcriptome and metabolome was performed. Results suggested that 65 differentially expressed genes and 26 differentially accumulated metabolites involved in chlorophyll, carotenoid, and flavonoid metabolism were identified. H2O2 treatment delayed the decrease of chlorophyll content by upregulating the expressions of chlorophyll synthetic genes, thylakoid synthetic genes, and 15 light‐harvesting complex genes compared with the control and diphenylene iodonium treatments. H2O2 treatment decreased the accumulation of 11 flavonoids and 5 flavonols by downregulating the flavonoid synthetic genes. In addition, H2O2 treatment promoted carotenoid biosynthesis to eliminate reactive oxygen species in thylakoids, thereby protecting chlorophyll molecules from degradation. The inhibition of flavonoids and flavonols accumulation and chlorophyll decrease was the crucial reason for the delayed yellowing in H2O2 treatment. This study provides a new method and theoretical support for delaying the yellowing process in postharvest broccoli. [ABSTRACT FROM AUTHOR]

Although farrerol, a characteristically bioactive constituent of Rhododendron dauricum L., exhibits extensive biological and pharmacological activities (e.g., anti-oxidant, anti-immunogenic, and anti-angiogenic) as well as a high drug development potential, its metabolism remains underexplored. Herein, we employed ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry coupled with multiple data post-processing techniques to rapidly identify farrerol metabolites produced in vivo (in rat blood, bile, urine and feces) and in vitro (in rat liver microsomes). As a result, 42 in vivo metabolites and 15 in vitro metabolites were detected, and farrerol shown to mainly undergo oxidation, reduction, (de)methylation, glucose conjugation, glucuronide conjugation, sulfate conjugation, N-acetylation and N-acetylcysteine conjugation. Thus, this work elaborates the metabolic pathways of farrerol and reveals the potential pharmacodynamics forms of farrerol. [ABSTRACT FROM AUTHOR]

• Transcriptomics revealed the wound-healing mechanism of broccoli stems during SAS. • The promoted PPP produced large amounts of NADPH. • NADPH enhancement activated the shikimate and phenylpropane pathway. • The wound-healing process of broccoli stems was promoted by the enhancement of NADPH. • PPP is the crucial driving force for wound healing in cut harvest broccoli stems. Wound healing is a crucial metabolic process that occurs in fruit and vegetables within a short time after harvest, especially in cut-harvest ones. To reveal wound healing mechanisms in cut-harvest broccoli stems during the self-adaptive stage (SAS, 12 h after harvest), tissue samples from the stems at the incision were analyzed at the transcriptome level. With the extension of time, the expression levels of six differentially expressed genes (DEGs) in the pentose phosphate pathway (PPP) significantly increased in the stems after cut-harvest. Among the genes, the expression levels of PGLS and PGD , which are directly involved in nicotinamide adenine dinucleotide phosphate (NADPH) generation, were 2.62 and 5.82 times higher in the 12 h vs 0 h comparison group, respectively. The shikimate and phenylpropanoid pathways were significantly activated in the broccoli stems during SAS. Genes involved in NADPH degradation through the aforementioned two pathways, including DHQ-SDH1 (106323466), aroC1 (106295042), and PAL3 (106300639), were significantly upregulated. These findings certified that wound healing of cut-harvest broccoli stems was promoted by enhancing NADPH levels. Interestingly, glycolysis (EMP) was a non-significant change during SAS after cut-harvest that contributed to maintaining organic matter by suppressing respiration and acclimatizing the postharvest broccoli to become an independent unit. These results indicate that the focus should be on NADPH levels for promoting wound healing of fruit and vegetables during storage. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • MLR affects channel stability by changing crosslinking effect between nanosheets. • 2D channel effectively limited via nanosheet edge and interface layer regulation. • Strong interaction between nanosheet achieved by formation of disulfide bond. • Regulation of membrane hydration and wetting by constructing the interface layer. • Superior Li+/Mg2+ separation benefited from the synergies between these strategies. The novel two-dimensional (2D) channel membranes have great potential for effective Li+/Mg2+ separation due to the rapid ion transport and precise adjustment of their channels. However, the solution composition greatly affects the control of channel height, resulting in an unsatisfactory selectivity performance. Herein, the 2D montmorillonite membranes are used to understand the causes of channel instability and explore the effective solutions. It is found that the changes in solution component can enlarge the channel height by changing the cross-linking constraint of Fe3+ between MMT nanosheets, thus leading to a weak sieving effect. To improve the channel constraint and its Li+/Mg2+ separation, the end face and interfacial layer constraint of nanosheets are proposed. As an effective strategy to strengthen the constraint effect, glutathione can modify the end faces of nanosheets and enhance the mutual binding force between them through its oxidative transformation. Besides, the construction of an interfacial layer can also limit channel swelling by altering the membrane hydration and wetting. These strategies will also form a synergistic regulatory effect. Consequently, a superior membrane is obtained and presents an improved selectivity of 8.89 at 100:1 Mg2+/Li+ ratio. These innovative approaches offer a valuable framework for creating high-performance 2D channel membranes, which can also support their wider application in the Li+/Mg2+ separation. [ABSTRACT FROM AUTHOR]

Currently, millions of people suffer from undiagnosed chronic hepatitis B (CHB) infection each year, which leads to high mortality rates attributed to cirrhosis and hepatocellular carcinoma. Previously reported assays, such as PCR-based assays, have limitations in terms of convenient for CHB screening in high-burden regions and resource-limited settings. Recently, diagnosis based on CRISPR/Cas, which has been considered as a potential method of point-of-care test (POCT) in resource-limited settings, offers a significant advantage in terms of high sensitivity and specificity. Therefore, there is an urgent need for the hepatitis B virus (HBV) detection utilizing CRISPR/Cas system. We have proposed a one-pot of one-step method for CRISPR/Cas12b assisted loop-mediated isothermal amplification (LAMP) to facilitate the quick, sensitive, and precise quantification of HBV DNA. This method is designed for point-of-care testing following genomic extraction or sample heat treatment. We have optimized several critical factors, such as the reaction buffer, AapCas12b-gRNA concentration, reporter and its concentration, reaction temperature, and chemical additives, to significantly enhance the performance of the one-pot assay for HBV. Importantly, it exhibited no cross-reactivity between HBV and blood-borne pathogens. Moreover, the assay is capable of quantifying HBV DNA within 1 h with a limit of detection (LOD) of 25 copies per milliliter. Additionally, when tested on 236 clinical samples, the assay demonstrated a sensitivity of 99.00 % (198/200) and a specificity of 100.00 % (36/36) at the 99 % confidence level compared to real-time quantitative PCR. The utilization of convenient and reliable point-of-care diagnostic methods is crucial for reducing the burden of CHB globally. The assay we developed was helpful to improve the ability of HBV diagnosis for practical clinical translation, especially in high-burden regions and resource-limited settings. It has great advantages for rapid screening of CHB as well as evaluation of therapeutic efficacy as a companion diagnostic method. [Display omitted] • HBV HOMLESv2 assay was established for easy, rapid, sensitive, and specific HBV quantification. • The assay demonstrated 99.00 % sensitivity and 100.00 % specificity based on 236 clinical samples. • It is good for rapid screening of chronic hepatitis B as well as evaluating therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Energy status is a vital factor in the physiology of postharvest vegetables. An integration profiling of transcriptome and metabolome was used to examine the effects of hydrogen peroxide treatment on carbohydrate and energy metabolism in broccoli at 20 ℃ for 4 d. The results showed that hydrogen peroxide (H 2 O 2) treatment maintained higher levels of ATP and energy charge during storage. The integration profiling of transcriptome and metabolome revealed that H 2 O 2 treatment promoted the degradation of 1,3-β-glucan to D-glucose and inhibited sucrose, D-raffinose, maltose, and cellulose degradation, thereby maintaining a long-term and stable supply of glucose for glycolysis (EMP) and pentose phosphate pathway (PPP)·H 2 O 2 treatment enhanced the EMP and PPP by upregulating the expression of related genes. Enhancing the tricarboxylic acid cycle and inhibiting alcohol fermentation in H 2 O 2 treatment promoted energy production. Therefore, the long-term and stable energy supply might be crucial for the delayed senescence of postharvest broccoli via H 2 O 2 treatment. [Display omitted] • H 2 O 2 treatment maintains a long-term and stable supply of glucose in broccoli. • H 2 O 2 treatment enhances the glycolysis and oxidative phosphorylation. • H 2 O 2 treatment enhances the TCA cycle and inhibits alcohol fermentation. • Stable energy supply is key reason for the delayed senescence of broccoli by H 2 O 2. [ABSTRACT FROM AUTHOR]

An integrated transcriptome and metabolome profiling was used to investigate how exogenous H2O2 affects amino acid metabolism and its underlying regulatory mechanism involved in post-harvest broccoli’s yellowing and senescence processes. This approach found 86 differentially expressed genes (DEGs) and 28 differentially accumulated metabolites (DAMs) associated with amino acid metabolism during broccoli storage in the Control, H2O2, and DPI (diphenylene iodonium, an H2O2 inhibitor) treatments on 2 or 4 d. Furthermore, H2O2 treatment promoted the biosynthesis and accumulation of amino acids (e.g., tryptophan, valine, isoleucine, arginine, lysine, histidine, and glutamate) while inhibiting the degradation of seven amino acids (e.g., tyrosine, valine, leucine, isoleucine, β-alanine, glutamate, and proline) into tricarboxylic acid (TCA) cycle precursor (pyruvate) and intermediates (fumarate, acetyl-CoA, and 2-oxoglutarate). This inhibition alleviated metabolic disorders and ammonium-induced toxicity of post-harvest broccoli. Additionally, H2O2 treatment promoted the NH3 conversion into glutamine and the urea cycle, further mitigating ammonium-induced toxicity. H2O2 treatment also down-regulated the expressions of S-adenosylmethionine synthases (SAM), 1-aminocyclopropane-1-carboxylate synthases (ACS), and 1-aminocyclopropane-1-carboxylate oxidases (ACO), which reduced the S-adenosyl-L-methionine content, thereby inhibiting ethylene biosynthesis from methionine. Therefore, this study provides insights into the role and potential underlying regulatory mechanism of H2O2 on amino acid metabolism during broccoli senescence, thus offering a theoretical basis for delaying senescence in post-harvest horticultural products by regulating their amino acid metabolism. [ABSTRACT FROM AUTHOR]

To investigate the effects and potential mechanism of exogenous H 2 O 2 on antioxidant metabolism and yellowing in postharvest broccoli, the transcriptome and metabolome integrated analysis were performed. A total of 61 differentially expressed genes and 6 differentially accumulated metabolites identified among of H 2 O 2 and diphenylene iodonium (DPI) treatments on 2 and 4 d. Exogenous H 2 O 2 promoted the accumulation of endogenous H 2 O 2 within 1 d by activating RBOHs expressions·H 2 O 2 treatment up-regulated the expressions of SOD , CAT and peroxiredoxin (Prx) genes and APX , DHAR and GPX genes involved in ascorbic acid-glutathione (AsA-GSH) cycle, thereby promoting the scavenging of O 2 -. and H 2 O 2 and alleviating the oxidative damage. Additionally, H 2 O 2 treatment promoted the biosynthesis of AsA and GSH, and increased the content of AsA, GSH, oxidized glutathione, and γ-glutamylcysteine·H 2 O 2 treatment also promoted glucosinolate biosynthesis, the accumulation of 3-(6′-methylthio)hexylmalic acid, and the production of sulforaphane by up-regulating MYS expression, thereby enhancing the health-care function of postharvest broccoli. This study provided the new insights into regulatory mechanism of H 2 O 2 on antioxidant system. [Display omitted] • Multi-omics revealed the regulatory mechanism of H 2 O 2 on antioxidant metabolism. • Exogenous H 2 O 2 promoted H 2 O 2 accumulation of broccoli in 1 d by activating RBOHs. • H 2 O 2 up-regulated SOD , CAT and Prx expression and enhanced the AsA-GSH cycle. • H 2 O 2 promoted the biosynthesis and accumulation of AsA and GSH. • H 2 O 2 promoted sulforaphane production by up-regulating MYS , and GSL biosynthesis. [ABSTRACT FROM AUTHOR]