Design, Synthesis, and Biological Evaluation of 2-Substituted Aniline Pyrimidine Derivatives as Potent Dual Mer/c-Met Inhibitors.

Mer and c-Met kinases, which are commonly overexpressed in various tumors, are ideal targets for the development of antitumor drugs. This study focuses on the design, synthesis, and evaluation of several 2-substituted aniline pyrimidine derivatives as highly potent dual inhibitors of Mer and c-Met kinases for effective tumor treatment. Compound 18c emerged as a standout candidate, demonstrating robust inhibitory activity against Mer and c-Met kinases, with IC50 values of 18.5 ± 2.3 nM and 33.6 ± 4.3 nM, respectively. Additionally, compound 18c displayed good antiproliferative activities on HepG2, MDA-MB-231, and HCT116 cancer cells, along with favorable safety profiles in hERG testing. Notably, it exhibited exceptional liver microsomal stability in vitro, with a half-life of 53.1 min in human liver microsome. Compound 18c also exhibited dose-dependent cytotoxicity and hindered migration of HCT116 cancer cells, as demonstrated in apoptosis and migration assays. These findings collectively suggest that compound 18c holds promise as a dual Mer/c-Met agent for cancer treatment.

Analysis of the microbial community structure and flavor components succession during salt-reducing pickling process of zhacai (preserved mustard tuber).

The salt-reducing pickling method has been applied to the industrial production of zhacai. In order to reveal the succession of the microbial community structure and flavor components during the pickling process, this study used PacBio Sequel to sequence the full length of 16S rRNA (bacteria, 1400 bp) and ITS (fungi, 1200 bp) genes, and detected flavor components simultaneously, including organic acids, volatile flavor components (VFC), monosaccharides, and amino acids. Eleven phyla and 148 genera were identified in the bacterial community, and 2 phyla and 60 genera in the fungal community. During the four stages of pickling, the dominant bacterial genera were Leuconostoc, Lactobacillus, Leuconostoc, and Lactobacillus, while the dominant fungal genera were Aspergillus, Kazachstania, Debaryomyces, and Debaryomyces, respectively. There were 32 main flavor components (5 organic acids, 19 VFCs, 3 monosaccharides, and 5 amino acids). Correlation heat mapping and bidirectional orthogonal partial least squares (O2PLS) analysis showed that the flora having close relation to flavor components included 14 genera of bacteria (Leuconostoc, Clostridium, Devosia, Lactococcus, Pectobacterium, Sphingobacterium, Serratia, Stenotrophomonas, Halanaerobium, Tetragenococcus, Chromohalobacter, Klebsiella, Acidovorax, and Acinetobacter) and 3 genera of fungi (Filobasidium, Malassezia, and Aspergillus). This study provides detailed data regarding the microbial community and flavor components during the salt-reducing pickling process of zhacai, which can be used as a reference for the development and improvement of salt-reducing pickling methods.

COVID-19 impact on the Chinese top academic libraries: Libraries' response to space, collection and services.

In 2020, the COVID-19 pandemic was a major public health emergency on a global scale. The literature regarding the pandemic and its impact on academic libraries is still rising. This article examines the two-year process of developing a flexible service scenario and the broader picture by analyzing data on Chinese top university libraries' programmes and outreach initiatives prior to, during, and the normal COVID-19 pandemic (Sept. 2019-Sept. 2021). COVID-19 is found to have a significant impact on the physical space, collection development, and service of the library, demonstrating the characteristics of space access restricted by security measures, collection digitization, and online service. This research also examines the previous year's initiatives and programmes and discusses the next phase of "new normal" procedures. Hopefully, this study will give insight on how Chinese libraries responded to the recent pandemic, informing libraries' outreach and efforts to be better prepared to take imperative, swift, and decisive action in the post-COVID-19 era and beyond.

Pharmacophore modeling and 3D-QSAR study for the design of novel α-synuclein aggregation inhibitors.

Alpha-synuclein (α-syn), as a highly soluble presynaptic protein expressed in the brain, plays an important role in recycling synaptic vesicles and regulating the synthesis, storage, and release of neurotransmitters. Accumulation of α-syn in Lewy bodies and Lewy neurites is the pathological hallmark of Parkinson's disease (PD), so inhibition of α-syn aggregation may provide a novel approach for treating PD. In this study, the 3D structure of α-syn was downloaded from Protein Data Bank (PDB ID: 2N0A). A ligand-based pharmacophore model was conducted on a set of 43 diverse α-syn ligands, and the results suggested that two hydrogen-bond acceptors, one hydrophobic group, and two aromatic rings were significant to the inhibition of α-syn aggregation. A ligand-based 3D-QSAR model was also established with good statistical significance (R2 = 0.920) and excellent predictive ability (Q2 = 0.752). Novel indolinone derivatives were designed and synthesized based on the pharmacophore model. Subsequently, the 3D-QSAR model was used to predict the inhibitory activities towards α-syn aggregation, and the actual inhibitory activities were evaluated by thioflavin-T assay in vitro with the best inhibitory activity reaching 45.08%. The fitting results indicated that the built pharmacophore and 3D-QSAR models provided better reliability and accuracy for compound modification and prediction of the activity thereof. A ligand-based pharmacophore modeling and 3D-QSAR study have been performed on a set of 43 diverse ligands for α-synuclein for the first time. Based on the best pharmacophore modeling, novel indolinone derivatives were designed and synthesized, and the inhibitory activities for α-synuclein aggregation were evaluated by thioflavin-T assay in vitro, which preliminary indicated that five pharmacophore sites (two hydrogen bond acceptors (A), a hydrophobic group (H), and two aromatic rings (R)) in compounds contribute to the inhibitory activities. In the study, the built pharmacophore modeling and 3D-QSAR provided better reliability and accuracy for compound modification and prediction of the activity thereof.

Structure-guided design and development of novel N-phenylpyrimidin-2-amine derivatives as potential c-Met inhibitors.

The HGF/Met signaling pathway is over-expressed in many types of cancers and closely related to oncogenesis and metastasis. Thus, we developed novel N-phenylpyrimidin-2-amine derivatives to test their inhibitory activities towards c-Met kinase, and most of the compounds (15a-i, 15o-r, 20 and 34a-c) could inhibit the target with IC50 values from 550.8 nM to 15.0 nM. Subsequently, compound 15b, 15d, 15f, 15i, 15o, 15r, 20, 34a and 34b also showed high antiproliferative activities in c-Met sensitive tumor cell lines (PC-3, Panc-1, HepG2, HCT116 and Caki-1) with IC50 values from 0.53 to 1.37 µM. The lead compound 34a displayed outstanding c-Met inhibitory activity (IC50: 15.0 nM) and antiproliferative activities. Furthermore, 34a also performed favorable pharmacokinetic properties in mice (F%: 59.3) and an acceptable safety profile in preclinical studies. Further docking studies showed a common interaction of 34a with c-Met at the ATP-binding site, which indicated that 34a could be a potential candidate for c-Met inhibitors.

Metabolic Study of Stable Isotope Labeled Indolinone Derivative in Hepatocyte Cell by UPLC/Q TOF MS.

The aggregation process of α-synuclein (α-syn) is substantial in the pathogenesis of Parkinson's disease. Indolinone derivatives are inhibitors of α-syn aggregates and can be used as PET-based radiotracers for imaging α-syn fibrils. However, no investigations on the metabolism of indolinone derivatives have been reported until now. In the present research, a 13C and 15N isotope labeling strategy was developed to synthesize compound [13C2,15N]-(Z)-1-(4-aminobenzyl)-3-((E)-(3-phenyl)allylidene)indolin-2-one (M0'), which was then used in a study of metabolism in hepatocytes. The metabolites were characterized using accurate mass and characteristic ion measurements. In the metabolic system, compound M0' was the main component (accounting for 97.5% of compound-related components) after incubation in hepatocytes for 3 h, which indicated that compound M0' possessed great metabolic stability. Seven metabolites have been successfully verified by UPLC/Q TOF MS in metabolic studies, including hydroxyl M0' (M1'), hydroxyl and methylated M0' (M2'), N-acetylated M0' (M3'), sulfate of hydroxyl M0' (M4'), the glucose conjugate of M0' (M5'), glucuronide conjugate of M0' (M6'), and glucuronide conjugate of hydroxyl M0' (M7'). The study on metabolism provides the important information to develop effective α-syn aggregate inhibitors and new PET-tracer-related indolinone derivatives.

Metagenomic analysis of microbial community succession during the pickling process of Zhacai (preserved mustard tuber) and its correlation with Zhacai biochemical indices.

BACKGROUND: Industrial Fuling Zhacai is pickled by a method summarized as 'three times pickled and pressed', in which raw mustard tubers are subjected to three stages of pickling in different salt concentrations, with a pressing operation at the end of each stage to remove brine. This study used Illumina MiSeq technology and multivariate statistical analyses to investigate microbial community succession during the pickling process and its correlation with Zhacai biochemical indices. RESULTS: A total of 19 phyla, 208 genera, and 295 species of bacteria were identified. Lactobacillus was the dominant genus of bacteria in all three stages and Lactobacillus sakei was the dominant species in the first and second stages. A total of six phyla, 200 genera and 301 species of fungi were also identified. According to a PICRUSt2 prediction, the main functions of the bacterial and fungal communities were carbohydrate and protein metabolism, while alcohol metabolism was also a function of fungi. Nine bacterial genera closely correlated with Zhacai biochemical indices: Acinetobacter, Pseudomonas, Pedobacter, Erwinia, Lactobacillus, Chryseobacterium, Flavobacterium, Duganella, and Paenarthrobacter. Six genera of fungi correlated closely: Penicillium, Cystobasidium, Cladosporium, Plenodomus, Aspergillus, and Simplicillium. All these genera probably originated from the surface microorganisms of raw mustard tuber. CONCLUSION: This study reveals the succession patterns of microbial community structures during the pickling process of industrial Zhacai and infers the core functional flora, providing reference data for Zhacai pickling process control. © 2020 Society of Chemical Industry.

Synthesis of [13 C2,15 N]-1,3-2H-1-benzyl-(Z)-3-(benzylidene)indolin-2-one.

Parkinson disease (PD) is a neurodegenerative disorder characterized by the accumulation of α-synuclein into Lewy bodies. 3-Benzylidine-indolin-2-one represents a class of compounds, which are known to inhibit the accumulation of α-synuclein. In this paper, we report the synthesis of [13 C] and [15 N] labelled 1-benzyl-(Z)-3-(benzylidene)indolin-2-one from commercially available [13 C2 ]-chloroacetic acid and [15 N]-aniline in five steps. The product will be used to study its metabolites in human liver microsomes by liquid chromatography-tandem mass spectrometry.

Emotion regulation in the context of customer mistreatment and felt affect: An event-based profile approach.

Variable-centered views of emotional labor suggest that high customer incivility and employee-felt negative affect should co-occur with high employee emotion regulation. Similarly, low customer incivility and employee positive affect should be accompanied by low emotion regulation. We theorize that these theory-based configurations of emotional labor variables represent only a subset of the possible ways that emotional labor events unfold. We propose that there are distinct subpopulations of emotional labor events, some of which conform to this standard view of emotional labor and some of which deviate from this model and that these distinct configurations suggest different underlying theoretical processes with implications for employee well-being. To investigate these ideas, we adopt an event-centered view (i.e., event-level profiles) that seeks to identify distinct configurations of emotional labor events. In a sample of 246 call center employees who provided ratings of 7,331 customer service interactions, results from multilevel latent profile analysis (MLPA) revealed 8 distinct event-level profiles, some of which align with variable-centered approaches and some of which suggest new ways to think about such events. We then linked these profiles to the event-level well-being outcomes of emotional exhaustion and psychological vitality, showing both longitudinal and concurrent effects. Finally, supplemental analyses detailed how this event-level profile approach differed from standard variable-centered analyses. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Bacterial diversity and community structure in Chongqing radish paocai brines revealed using PacBio single-molecule real-time sequencing technology.

BACKGROUND: Traditional Chongqing radish paocai fermented with aged brine is considered to have the most intense flavor and authentic taste. Eight 'Yanzhi' (red, RRPB group) and 'Chunbulao' (white, WRPB) radish paocai brine samples were collected from Chongqing peasant households, and the diversity and community structures of bacteria present in these brines were determined using PacBio single-molecule real-time sequencing of their full-length 16S rRNA genes. RESULTS: In total, 30 phyla, 218 genera, and 306 species were identified from the RRPB group, with 20 phyla, 261 genera, and 420 species present in the WRPB group. Obvious differences in bacterial profiles between the RRPB and WRPB groups were found, with the bacterial diversity of the WRPB group shown to be greater than that of the RRPB group. This study revealed several characteristics of the bacteria composition, including the predominance of heterofermentative lactic acid bacteria, the species diversity of genus Pseudomonas, and the presence of three opportunistic pathogenic species. CONCLUSION: This study provides detailed information on the bacterial diversity and community structure of Chongqing radish paocai brine samples, and suggests it may be necessary to analyze paocai brine for potential sources of bacterial contamination and take appropriate measures to exclude any pathogenic species. © 2018 Society of Chemical Industry.

Service workers' chain reactions to daily customer mistreatment: Behavioral linkages, mechanisms, and boundary conditions.

Drawing on the stressor-emotion model, we examine how customer mistreatment can evoke service workers' passive forms of deviant behaviors (i.e., work withdrawal behavior [WWB]) and negative impacts on their home life (i.e., work-family conflict [WFC]), and whether individuals' core self-evaluations and customer service training can buffer the negative effects of customer mistreatment. Using the experience sampling method, we collect daily data from 77 customer service employees for 10 consecutive working days, yielding 546 valid daily responses. The results show that daily customer mistreatment increases service workers' daily WWB and WFC through negative emotions. Furthermore, employees with high core self-evaluations and employees who received customer service training are less likely to experience negative emotions when faced with customer mistreatment, and thus are less likely to engage in WWB or provoke WFC. (PsycINFO Database Record

Four-factor justice and daily job satisfaction: a multilevel investigation.

This study examined the differential effects of 4 types of organizational justice on daily job satisfaction at between- and within-individual levels. Specifically, the authors predicted that interpersonal justice and informational justice would exhibit meaningful daily variations and would have direct impacts on individuals' job satisfaction on a daily basis. They further theorized that distributive justice and procedural justice at a between-person level would moderate the within-person relationships. The authors used hierarchical linear modeling to test their hypotheses with a sample of 231 full-time employees in Hong Kong over the course of 25 working days. The results showed that both daily interpersonal and informational justice were positively related to daily job satisfaction. As hypothesized, between-individual distributive justice moderated the relationship between daily interpersonal justice and daily job satisfaction, and between-individual procedural justice moderated the relationship between daily informational justice and daily job satisfaction.

Procedural justice climate and group power distance: an examination of cross-level interaction effects.

In this article, the authors extend research on the cross-level effects of procedural justice climate by theorizing and testing its interaction with group power distance. The results indicated that group power distance moderated the relationships between procedural justice climate and individual-level outcomes (organizational commitment and organization-directed citizenship behavior). More specifically, a larger group power distance was found to attenuate the positive cross-level effects of procedural justice climate. Implications for procedural justice climate research are discussed.

[Studies on extracellular virulent factors produced by potential pathogenic bacteria isolated from abalone postlarvae and biofilms].

To find out the potential pathogen(s) that caused massive death of abalone postlarvae( Haliotis diversicolor supertesta ) in Southern China, 105 bacterial strains were isolated from the water, whitened postlarvae and their biofilms of an abalone farm in Guangdong Province. Extra-cellular protease, gelatinase, lipase as well as haemolysis tests were performed on them. Lysophospholipase (Tlh)-targeted PCR was also carried out in order to reveal if the haemolysis caused by bacterial strains were related to Tlh. Results showed that 35 out of 105 strains possessed extra-cellular enzymatic abilities and strains 1, 2, 3, 5, 9 and 16 were the most powerful ones of all. Among these 35 strains, 85.6% strains (30/35) possessed haemolytic activities on goat blood agar and specific PCR revealed that 16 strains were PCR positive, indicating that they contained Tlh genes. In order to identify these strains, API 20 E strips were employed and results indicated that 50% were vibrios, among them Vibrio alginolyticus composed 70% of the vibrio population. In conclusion, compared to other strains, 6 Vibrio alginolyticus (strain 1, 2, 3, 5, 13, and 16 ) and 2 Vibrio parahaemolyticus (strain 9 and 21) which all were isolated from whitened abalone postlarvae, warrant further studies due to their better abilities in extra-cellular enzyme(s) production and/or haemolytic activities.