A series of MnI complexes containing lutidine‐based chiral pincer ligands with modular and tunable structures has been developed. The complex shows unprecedentedly high activities (up to 9800 TON; ...TON=turnover number), broad substrate scope (81 examples), good functional‐group tolerance, and excellent enantioselectivities (85–98 % ee) in the hydrogenation of various ketones. These aspects are rare in earth‐abundant metal catalyzed hydrogenations. The utility of the protocol have been demonstrated in the asymmetric synthesis of a variety of key intermediates for chiral drugs. Preliminary mechanistic investigations indicate that an outer‐sphere mode of substrate–catalyst interactions probably dominates the catalysis.
Broad spectrum: Chiral PNN/Mn catalysts for the asymmetric hydrogenation of a broad spectrum of ketones have been developed. The utility of the protocol was demonstrated in the asymmetric synthesis of a variety of key intermediates for chiral drugs. Preliminary mechanistic investigations indicate that an outer‐sphere substrate–catalyst interaction dominates the catalysis.
Activation of the serine-threonine kinase Akt promotes the survival and proliferation of various cancers. Hypoxia promotes the resistance of tumor cells to specific therapies. We therefore explored a ...possible link between hypoxia and Akt activity. We found that Akt was prolyl-hydroxylated by the oxygen-dependent hydroxylase EglN1. The von Hippel-Lindau protein (pVHL) bound directly to hydroxylated Akt and inhibited Akt activity. In cells lacking oxygen or functional pVHL, Akt was activated to promote cell survival and tumorigenesis. We also identified cancer-associated Akt mutations that impair Akt hydroxylation and subsequent recognition by pVHL, thus leading to Akt hyperactivation. Our results show that microenvironmental changes, such as hypoxia, can affect tumor behaviors by altering Akt activation, which has a critical role in tumor growth and therapeutic resistance.
Liancheng white duck is a typical local duck breed in Fujian Province famous for its meat traits. To better understand how meat quality varies with breed, the chemical composition of breast meats of ...Liancheng white ducks (LD) and Cherry Valley ducks (CD) were examined using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS).The correlation between meat quality and the differential metabolites was further analyzed. The results showed that the effects of breed on duck breast meat were significant for pH, color, cooking loss, and shear force. Liancheng white duck breast meat exhibited a higher shear force and pH, and lower cooking loss and lightness (L*24), redness (a*24), and yellowness (b*24) than CD. Metabolomic analysis revealed significant differences between the meat extracts from the 2 duck breeds. A total of 49 and 57 significantly different metabolites were identified in positive and negative ion modes, respectively. These differentially accumulated metabolites (DAMs) could be divided into 28 classes, of which the 4 main categories were carbohydrates, amino acids, fatty acids, and eicosanoids. Liancheng white duck might have better nutritional and medicinal value considering the higher content of (4Z,7Z,10Z,13Z,16Z,19Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), eicosapentaenoic acid (EPA), and prostaglandinF3α (PGF3α), having anti-inflammatory orantioxidant effects. Carbohydrate concentration negatively correlated with pH24. The 4 metabolites positively correlated with the shear force. These results provide an overall perspective for bridging the gap between variation of duck meat quality and metabolites with respect to breed.
The aim of the study was to explore the regulatory mechanism of differences in embryonic gonadal development between intergeneric distance hybrid offspring Mulard ducks and parent ducks. The ...morphological differences gonadal tissues of Muscovy ducks, Pekin ducks and Mulard ducks at 12.5-day embryonic age were observed by sectioning and hematoxylin-eosin (HE) staining. Then followed by transcriptome sequencing to screen for gonadal development-related differentially expressed circRNAs and mRNAs to construct a competitive endogenous RNA (ceRNA) regulatory network. Finally, qRT-PCR and luciferase reporter system were used to verify the sequencing data and targeting relationship of ceRNA pairs. The results showed that the seminiferous tubule lumen of Mulard ducks was not obvious, while there were obvious seminiferous tubules and tubular structures in testis of Pekin ducks and Muscovy ducks, with number and shape indicating maturity. There were 18 upregulated circRNAs and 16 downregulated circRNAs in Mulard ducks and Pekin ducks, respectively, and 39 upregulated circRNAs and 1 downregulated circRNA in Mulard ducks and Muscovy ducks, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis found that genes involves in dorso-ventral axis formation, for example, neurogenic locus notch homolog protein 1 (NOTCH1), were significantly enriched (P < 0.05). The novel_circ_0002265-gga-miR-122-5p-PAFAH1B2 regulatory network was constructed. The qRT-PCR results showed that the sequencing results were reliable. The dual-luciferase reporter assay showed that gga-miR-122-5p exists binding site of circ_0002265 and PAFAH1B2, indicating circ_0002265-gga-miR-122-5p-PAFAH1B2 targeting relationship. In summary, the embryonic gonadal development of intergeneric hybrid Mulard ducks may be regulated by differentially expressed circRNAs and genes, such as novel_circ_0000519, novel_circ_0003537, NOTCH1, FGFR2, PAFAH1B1, and PAFAH1B2, among which circ_0002265-gga-miR-122-5p-PAFAH1B2 may participate in the targeted regulation of gonadal development in Mulard ducks. The findings of this study are helpful for analyzing the mechanism of embryonic gonadal development differences in avians.
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•LGSP suppress the production of NO and pro-inflammatory cytokines in macrophages.•LGSP inhibit the activation of MAPKs and NF-κB signaling pathways.•LGSP reduce the recruitment of ...neutrophils at the amputation site in zebrafish.•LGSP present better anti-inflammatory effect than GSP in vitro and in vivo.
Grape seed proanthocyanidin (GSP), a major polyphenol in grape seed, has several remarkable physiological activities beneficial to human health. However, the hydrophilicity of GSP hampers its cellular absorption and thus limits the bio-efficiency in vivo. In order to enhance the lipophilicity of GSP for improved bio-efficiency, lipophilic grape seed proanthocyanidin (LGSP) was synthesized by enzymatic esterification of GSP. The anti-inflammatory activity of LGSP was evaluated in lipopolysaccharides-stimulated RAW 264.7 cells in vitro and a zebrafish tail-amputated model in vivo. LGSP exhibited strong inhibitory effects on the production of NO and pro-inflammatory cytokines TNF-α, IL-6 and IL-1β in RAW 264.7 cells. Further mechanistic studies showed that LGSP achieved the aforementioned effects by inhibiting the activation of MAPKs and NF-κB signaling pathways. In the zebrafish model, LGSP effectively suppressed the aggregation of neutrophils. Our findings suggest that LGSP may be effective as a complementary agent for the prevention/treatment of inflammation-mediated diseases.
Copper plays pivotal roles in metabolic homoeostasis, but its potential role in human tumorigenesis is not well defined. Here, it is revealed that copper activates the phosphoinositide 3‐kinase ...(PI3K)‐protein kinase B (PKB, also termed AKT) oncogenic signaling pathway to facilitate tumorigenesis. Mechanistically, copper binds 3‐phosphoinositide dependent protein kinase 1 (PDK1), in turn promotes PDK1 binding and subsequently activates its downstream substrate AKT to facilitate tumorigenesis. Blocking the copper transporter 1 (CTR1)‐copper axis by either depleting CTR1 or through the use of copper chelators diminishes the AKT signaling and reduces tumorigenesis. In support of an oncogenic role for CTR1, the authors find that CTR1 is abnormally elevated in breast cancer, and is subjected by NEDD4 like E3 ubiquitin protein ligase (Nedd4l)‐mediated negative regulation through ubiquitination and subsequent degradation. Accordingly, Nedd4l displays a tumor suppressive function by suppressing the CTR1‐AKT signaling. Thus, the findings identify a novel regulatory crosstalk between the Nedd4l‐CTR1‐copper axis and the PDK1‐AKT oncogenic signaling, and highlight the therapeutic relevance of targeting the CTR1‐copper node for the treatment of hyperactive AKT‐driven cancers.
Besides playing pivotal roles in metabolic homoeostasis, copper also binds PDK1 to activate its downstream AKT kinase, which in turn facilitates tumorigenesis. Meanwhile, the copper transporter 1 (CTR1) is negatively regulated by Nedd4l‐mediated ubiquitination and subsequent degradation, indicating a novel regulatory crosstalk between the Nedd4l‐CTR1‐copper axis and the PDK1‐AKT oncogenic signaling to govern tumorigenesis.
In order to address severe climate change, land occupation and excessive consumption of resources, China as a giant developing country is relentlessly promoting the utilization of basic oxygen ...furnace slag byproduct. The concerns referred to its large scale reutilization include deleterious potential, and possible problems in aggregate heating. Regarding the concerns, we elaborated a series of tests including toxicity characteristic leaching procedure and differential scanning calorimeter as complements of established researches in literature. The leaching results are consistent with peers' studies that the leachate of slag meets the requirements of laws and regulations in many countries. However toxic metal was detected from in-field waste water in slag aggregate making processor. It indicates the bulk slag in soils should be treated much carefully as it could be a giant pollution to shadow or ground water. The Differential Scanning Calorimeter results show that the enthalpy changes of slag samples from ambient temperature to 200 °C are comparable or less than that of dolerite. Water evaporation and decomposition of gypsum and carbonates contribute to the changes in heat flow. It grants the reliability that slag is a physical stable material in drying drum of asphalt mixture plant. Heating rate tests show that the slag samples with various water contents that are kept in hot oven show negligible discrepancy in the rate of temperature increase in comparison to dolerite. Based on the laboratory test results, an 8-km highway surface layer with basic oxygen furnace slag has been constructed and presents good performance. All the work completed in laboratory and in-place construction indicates that basic oxygen furnace slag is an environment-friendly aggregate if it is well treated. What's more, the bulk slag with less than 3% water content can be used in routine production. The slag based asphalt mixture is able to hold a warmer temperature, and hence granting a longer haul distance than when using dolerite.
•There is barium (Ba) in drained water in BOF making processor.•BOF is a physical stable aggregate.•Water infiltrated BOF is heated quicker than dolerite in oven.•BOF asphalt mixture provides longer haul distance than dolerite.
Thirty phenolic ether derivatives of scopoletin modified at the 7-hydroxy position were synthesized, and their structures were confirmed by IR, ¹H-NMR,
C-NMR, MS and elemental analysis. Preliminary ...acaricidal activities of these compounds against female adults of
(Boisduval) were evaluated using the slide-dip method. The results indicated that some of these compounds exhibit more pronounced acaricidal activity than scopoletin, especially compounds
,
,
,
and
which exhibited about 8.41-, 7.32-, 7.23-, 6.76-, and 6.65-fold higher acaricidal potency. Compound
possessed the the most promising acaricidal activity and exhibited about 1.45-fold higher acaricidal potency against
than propargite. Statistically significant 2D-QSAR model supports the observed acaricidal activities and reveals that polarizability (HATS5p) was the most important parameter controlling bioactivity. 3D-QSAR (CoMFA: q² = 0.802, r² = 0.993; CoMSIA: q² = 0.735, r² = 0.965) results show that bulky substituents at R₄, R₁, R₂ and R₅ (C₆, C₃, C₄, and C₇) positions, electron positive groups at R₅ (C₇) position, hydrophobic groups at R₁ (C₃) and R₂ (C₄), H-bond donors groups at R₁ (C₃) and R₄ (C₆) will increase their acaricidal activity, which provide a good insight into the molecular features relevant to the acaricidal activity for further designing novel acaricidal agents. Molecular docking demonstrates that these selected derivatives display different bide modes with
from lead compound and they interact with more key amino acid residues than scopoletin. In silico ADME properties of scopoletin and its phenolic ether derivatives were also analyzed and showed potential to develop as good acaricidal candidates.
To explore the differential regulation mechanism of heat stress on the egg production performance and egg quality of Jinding ducks, 200 Jinding ducks (360-day-old) in good health and with similar ...body weights and a normal appetite were selected and randomly divided into a control (normal temperature NT) group (20°C-25°C) and a heat stress (HS) group (32°C-36°C), with 4 replicates in each group and 25 ducks in each replicate. The pretrial period was 1 wk, and the formal trial period was 4 wk. At the end of the 4th wk, 12 duck eggs were collected from each replicate to determine egg quality. Pituitary and ovarian tissues of Jinding ducks were collected, transcriptome sequencing was performed to screen differentially expressed miRNAs and mRNAs related to high temperature and heat stress, and a competitive endogenous RNA regulatory network was constructed. The sequencing data were verified by qRT‒PCR method. The following results were obtained: (1) Compared with the NT group, the HS group had a significantly lower laying rate, total egg weight, average egg weight, total feed intake, and feed intake per duck (P < 0.01), an extremely significantly higher feed-to-egg ratio (P < 0.01), and a higher mortality rate. (2) Compared with the NT group, the HS group had an extremely significantly lower egg weight, egg yolk weight, eggshell weight, and eggshell strength (P < 0.01) and an extremely significantly lower yolk ratio and eggshell thickness (P < 0.01, P < 0.05); however, there was no significant difference in the egg shape index, Haugh unit or protein height (P > 0.05). (3) A total of 1,974 and 1,202 genes were identified in the pituitary and ovary, respectively, and there were 5 significantly differentially expressed miRNAs. The differentially expressed genes were involved in the arginine and proline metabolism pathways, ether lipid metabolism pathway, and drug metabolism-cytochrome P450 pathway, which are speculated to be related to the egg production performance of Jingding ducks under high-temperature heat stress. (4) Novel_221 may target the PRPS1 gene to participate in egg production performance; novel_168 and novel_289 may target PIGW; novel_289 may target Q3MUY2; and novel_289 and novel_208 may target PIGN or genes that may be related to high-temperature heat stress. (5) In pituitary tissue, upregulated novel_141 (center of the network) formed a regulatory network with HSPB1 and HSP30A, and downregulated novel_366 (center of the network) formed a regulatory network with the JIP1 gene. In ovarian tissue, downregulated novel_289 (center of the network) formed a regulatory network with the ZSWM7, ABI3, and K1C23 genes, novel_221 formed a regulatory network with the IGF1, BCL7B, SMC6, APOA4, and FARP2 genes, and upregulated novel_40 formed a regulatory network with the HA1FF10 gene. In summary, heat stress affects the production performance and egg quality of Jinding ducks by regulating the secretion of endocrine-related hormones and the release of neurotransmitters as well as the expression of miRNAs and mRNAs in pituitary and ovarian tissues. The miRNA‒mRNA regulatory network provides a theoretical basis for the molecular mechanism that regulates the stress response in pituitary and ovarian tissues, egg quality, and production performance under heat stress.
Various classes of plant pathogenesis-related proteins have been identified in the past several decades. PR-Q, a member of the PR3 family encoding chitinases, has played an important role in ...regulating plant resistance and preventing pathogen infection. In this paper, we functionally characterized
in tobacco plants and found that the overexpression of
in tobacco Yunyan87 resulted in higher resistance to
inoculation. Surprisingly, overexpression of
led to the activation of many defense-related genes, such as salicylic acid (SA)-responsive genes
,
and
, JA-responsive gene
and ET production-associated genes
and
. Consistent with the role of
in multiple stress responses,
transcripts were induced by the exogenous hormones SA, ethylene and methyl jasmonate, which could enhance the resistance of tobacco to
. Collectively, our results suggested that
overexpression led to the up-regulation of defense-related genes and enhanced plant resistance to
infection.
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