The catalytic asymmetric construction of N−N atropisomeric biaryls remains a formidable challenge. Studies of them lag far behind studies of the more classical carbon‐carbon biaryl atropisomers, ...hampering meaningful development. Herein, the first palladium‐catalyzed enantioselective C−H activation of pyrroles for the synthesis of N−N atropisomers is presented. Structurally diverse indole‐pyrrole atropisomers possessing a chiral N−N axis were produced with good yields and high enantioselectivities by alkenylation, alkynylation, allylation, or arylation reactions. Furthermore, the kinetic resolution of trisubstituted N−N heterobiaryls with more sterically demanding substituents was also achieved. Importantly, this versatile C−H functionalization strategy enables iterative functionalization of pyrroles with exquisite selectivity, expediting the formation of valuable, complex, N−N atropisomers.
Enantioselective synthesis of N−N indole‐pyrrole and bisindole atropisomers was achieved by a palladium‐catalyzed TDG‐enabled C−H functionalization. A wide variety of the N−N atropisomers were produced in good yields with excellent enantioselectivities by C−H alkenylation, alkynylation, allylation or arylation reactions.
Dielectric polymer nanocomposites by integration of high‐E
b polymer matrix and high‐D(εr) ceramic fillers have shown great potential for dielectric and energy storage applications in modern ...electronic and electrical systems. Interface between ceramic fillers and polymer matrix is considered as a predominant factor to determine the dielectric performances of the nanocomposites. This review analyzes the influence of the interface on dielectric responses and breakdown strength in the nanocomposites, and discusses the viability of current interface engineering strategies in improving their energy storage capabilities. Two scopes of current interface modification approaches are focused from both structural and functional considerations in the dielectric ceramics/polymer nanocomposites: first, the organic/inorganic interface compatibility can be modified to generate homogeneous dispersion of ceramic nanoparticles in polymer matrix, which is the premise of fully realizing the synergistic combination of advantages of polymer and ceramic fillers; second, regulated local electrical and dielectric behaviors in interface region enable the enhancement of dielectric properties (both high dielectric constant and high breakdown strength) in resultant nanocomposites. In the last part, some present challenges and future perspectives are proposed to utilize the interface strategy for developing high energy density ceramics/polymer nanocomposites for dielectric and energy storage applications.
The influence of interface on dielectric responses and breakdown strength in ceramics/polymer nanocomposites is analyzed and the viability of current interface engineering strategies in improving their energy storage capabilities is discussed. Interface modification leads not only to homogeneous dispersion of ceramic nanofillers, but also improves dielectric and energy storage performances in resultant nanocomposites from regulated local interfacial electrical and dielectric behaviors.
Abstract
To clarify the phytogeography of
Prunus armeniaca
L., two chloroplast DNA fragments (
trn
L-
trn
F and
ycf
1) and the nuclear ribosomal DNA internal transcribed spacer (ITS) were employed to ...assess genetic variation across 12
P. armeniaca
populations. The results of cpDNA and ITS sequence data analysis showed a high the level of genetic diversity (cpDNA:
H
T
= 0.499; ITS:
H
T
= 0.876) and a low level of genetic differentiation (cpDNA:
F
ST
= 0.1628; ITS:
F
ST
= 0.0297) in
P. armeniaca
. Analysis of molecular variance (AMOVA) revealed that most of the genetic variation in
P. armeniaca
occurred among individuals within populations. The value of interpopulation differentiation (
N
ST
) was significantly higher than the number of substitution types (
G
ST
), indicating genealogical structure in
P. armeniaca
.
P. armeniaca
shared genotypes with related species and may be associated with them through continuous and extensive gene flow. The haplotypes/genotypes of cultivated apricot populations in Xinjiang, North China, and foreign apricot populations were mixed with large numbers of haplotypes/genotypes of wild apricot populations from the Ili River Valley. The wild apricot populations in the Ili River Valley contained the ancestral haplotypes/genotypes with the highest genetic diversity and were located in an area considered a potential glacial refugium for
P. armeniaca
. Since population expansion occurred 16.53 kyr ago, the area has provided a suitable climate for the population and protected the genetic diversity of
P. armeniaca
.
The poor prognosis of patients with ovarian cancer is mainly due to cancer progression. γ-Synuclein (SNCG) has reported as a critical player in cancer metastasis. However, its biological roles and ...mechanism are yet incompletely understood in ovarian cancer, especially in high-grade serous ovarian cancer (HGSOC).
This is a retrospective study of 312 patients with ovarian cancer at a single center between 2006 and 2016. Ovarian cancer tissues were stained by immunohistochemistry to analyze the relationship between SNCG expression and clinicopathologic factors. The clinical outcomes versus SNCG expression level were evaluated by Kaplan-Meier method and multiple Cox regression analysis. Next, systematical functional experiments were given to examine the proliferation and metastatic abilities of SNCG both in vitro and in vivo using loss- and gain- of function approaches. Furthermore, the mechanisms of SNCG overexpression were examined by human phospho-kinase array kit and western blot analysis.
Clinically, the expression of SNCG was significantly upregulated in ovarian cancer compared with the borderline and benign tumor, normal ovary, and fallopian tube. Notably, the high level of SNCG correlated with high-risk clinicopathologic features and showed poor survival for patients with HGSOC, indicating an independent prognostic factor for these patients. Functionally, we observed that overexpression of SNCG promoted cell proliferation, tumor formation, migration, and invasion both in vitro and in vivo. Mechanistically, we identified that SNCG promoted cancer cell metastasis through activating the PI3K/AKT signaling pathway.
Our results reveal SNCG up-regulation contributes to the poor clinical outcome of patients with HGSOC and highlight the metastasis-promoting function of SNCG via activating the PI3K/Akt signaling pathway in HGSOC.
Alzheimer's disease (AD) is the most common type of neurodegenerative disease in the contemporary era, and it is still clinically incurable. Eriodictyol, a natural flavonoid compound that is mainly ...present in citrus fruits and some Chinese herbal medicines, has been reported to exert anti-inflammatory, antioxidant, anticancer and neuroprotective effects. However, few studies have examined the anti-AD effect and molecular mechanism of eriodictyol.
APP/PS1 mice were treated with eriodictyol and the cognitive function of mice was assessed using behavioral tests. The level of amyloid-β (Aβ) aggregation and hyperphosphorylation of Tau in the mouse brain were detected by preforming a histological analysis and Western blotting. HT-22 cells induced by amyloid-β peptide (1-42) (Aβ
) oligomers were treated with eriodictyol, after which cell viability was determined and the production of p-Tau was tested using Western blotting. Then, the characteristics of ferroptosis, including iron aggregation, lipid peroxidation and the expression of glutathione peroxidase type 4 (GPX4), were determined both in vivo and in vitro using Fe straining, Western blotting and qPCR assays. Additionally, the expression level of vitamin D receptor (VDR) and the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) signaling pathway were tested using Western blotting and qPCR assays. Afterward, HT-22 cells with VDR knockout were used to explore the potential mechanisms, and the relationship between VDR and Nrf2 was further assessed by performing a coimmunoprecipitation assay and bioinformatics analysis.
Eriodictyol obviously ameliorated cognitive deficits in APP/PS1 mice, and suppressed Aβ aggregation and Tau phosphorylation in the brains of APP/PS1 mice. Moreover, eriodictyol inhibited Tau hyperphosphorylation and neurotoxicity in HT-22 cells induced by Aβ
oligomer. Furthermore, eriodictyol exerted an antiferroptosis effect both in vivo and in vitro, and its mechanism may be associated with the activation of the Nrf2/HO-1 signaling pathway. Additionally, further experiments explained that the activation of Nrf2/HO-1 signaling pathway by eriodictyol treatment mediated by VDR.
Eriodictyol alleviated memory impairment and AD-like pathological changes by activating the Nrf2/HO-1 signaling pathway through a mechanism mediated by VDR, which provides a new possibility for the treatment of AD.
AbstractObjectiveTo assess the effects of Helicobacter pylori treatment, vitamin supplementation, and garlic supplementation in the prevention of gastric cancer.DesignBlinded randomized placebo ...controlled trial.SettingLinqu County, Shandong province, China.Participants3365 residents of a high risk region for gastric cancer. 2258 participants seropositive for antibodies to H pylori were randomly assigned to H pylori treatment, vitamin supplementation, garlic supplementation, or their placebos in a 2×2×2 factorial design, and 1107 H pylori seronegative participants were randomly assigned to vitamin supplementation, garlic supplementation, or their placebos in a 2×2 factorial design.InterventionsH pylori treatment with amoxicillin and omeprazole for two weeks; vitamin (C, E, and selenium) and garlic (extract and oil) supplementation for 7.3 years (1995-2003).Main outcome measuresPrimary outcomes were cumulative incidence of gastric cancer identified through scheduled gastroscopies and active clinical follow-up through 2017, and deaths due to gastric cancer ascertained from death certificates and hospital records. Secondary outcomes were associations with other cause specific deaths, including cancers or cardiovascular disease.Results151 incident cases of gastric cancer and 94 deaths from gastric cancer were identified during 1995-2017. A protective effect of H pylori treatment on gastric cancer incidence persisted 22 years post-intervention (odds ratio 0.48, 95% confidence interval 0.32 to 0.71). Incidence decreased significantly with vitamin supplementation but not with garlic supplementation (0.64, 0.46 to 0.91 and 0.81, 0.57 to 1.13, respectively). All three interventions showed significant reductions in gastric cancer mortality: fully adjusted hazard ratio for H pylori treatment was 0.62 (95% confidence interval 0.39 to 0.99), for vitamin supplementation was 0.48 (0.31 to 0.75), and for garlic supplementation was 0.66 (0.43 to 1.00). Effects of H pylori treatment on both gastric cancer incidence and mortality and of vitamin supplementation on gastric cancer mortality appeared early, but the effects of vitamin supplementation on gastric cancer incidence and of garlic supplementation only appeared later. No statistically significant associations were found between interventions and other cancers or cardiovascular disease.ConclusionsH pylori treatment for two weeks and vitamin or garlic supplementation for seven years were associated with a statistically significant reduced risk of death due to gastric cancer for more than 22 years. H pylori treatment and vitamin supplementation were also associated with a statistically significantly reduced incidence of gastric cancer.Trial registrationClinicalTrials.gov NCT00339768.
Abstract
With the growth of the global population and the increasing frequency of natural disasters, crop yields must be steadily increased to enhance human adaptability to risks. Pre-harvest ...sprouting (PHS), a term mainly used to describe the phenomenon in which grains germinate on the mother plant directly before harvest, is a serious global problem for agricultural production. After domestication, the dormancy level of cultivated crops was generally lower than that of their wild ancestors. Although the shortened dormancy period likely improved the industrial performance of cereals such as wheat, barley, rice, and maize, the excessive germination rate has caused frequent PHS in areas with higher rainfall, resulting in great economic losses. Here, we systematically review the causes of PHS and its consequences, the major indicators and methods for PHS assessment, and emphasize the biological significance of PHS in crop production. Wheat quantitative trait loci functioning in the control of PHS are also comprehensively summarized in a meta-analysis. Finally, we use Arabidopsis as a model plant to develop more complete PHS regulatory networks for wheat. The integration of this information is conducive to the development of custom-made cultivated lines suitable for different demands and regions, and is of great significance for improving crop yields and economic benefits.
Pre-harvest sprouting has a negative effect on cereal yield and quality, and understanding the genetic and regulatory mechanisms underlying it is of great agricultural and economic significance.
Abnormal activation of the extrasynaptic N‐methyl‐d‐aspartate receptor (NMDAR) contributes to the pathogenesis of Alzheimer's disease (AD). Ceftriaxone (Cef) can improve cognitive impairment by ...upregulating glutamate transporter‐1 and promoting the glutamate–glutamine cycle in an AD mouse model. This study aimed to investigate the effects of Cef on synaptic plasticity and cognitive‐behavioral impairment and to unravel the associated underlying mechanisms. We used an APPswe/PS1dE9 (APP/PS1) mouse model of AD in this study. Extrasynaptic components from hippocampal tissue homogenates were isolated using density gradient centrifugation. Western blot was performed to evaluate the expressions of extrasynaptic NMDAR and its downstream elements. Intracerebroventricular injections of adeno‐associated virus (AAV)‐striatal enriched tyrosine phosphatase 61 (STEP61) and AAV‐STEP61‐shRNA were used to modulate the expressions of STEP61 and extrasynaptic NMDAR. Long‐term potentiation (LTP) and Morris water maze (MWM) tests were performed to evaluate the synaptic plasticity and cognitive function. The results showed that the expressions of GluN2B and GluN2BTyr1472 in the extrasynaptic fraction were upregulated in AD mice. Cef treatment effectively prevented the upregulation of GluN2B and GluN2BTyr1472 expressions. It also prevented changes in the downstream signals of extrasynaptic NMDAR, including increased expressions of m‐calpain and phosphorylated p38 MAPK in AD mice. Furthermore, STEP61 upregulation enhanced, whereas STEP61 downregulation reduced the Cef‐induced inhibition of the expressions of GluN2B, GluN2BTyr1472, and p38 MAPK in the AD mice. Similarly, STEP61 modulation affected Cef‐induced improvements in induction of LTP and performance in MWM tests. In conclusion, Cef improved synaptic plasticity and cognitive behavioral impairment in APP/PS1 AD mice by inhibiting the overactivation of extrasynaptic NMDAR and STEP61 cleavage due to extrasynaptic NMDAR activation.
Glutamate receptor GLT‐1 damage leads to increased perisynaptic glutamate concentration in Alzheimer's disease (AD), which activates extrasynaptic N‐methyl‐d‐aspartate receptor (eNMDAR) and its downstream signaling and causes impairment of synaptic plasticity and cognition. The results showed that ceftriaxone downregulated eNMDAR expression, inhibited eNMDAR‐STEP61 and p38 MAPK signaling, and improved impairments of long‐term potentiation (LTP) and Morris water maze in AD mice. The STEP61‐mediated modulation of eNMDAR confirmed the hypothesis that ceftriaxone exerts anti‐AD effects by improving GLT‐1 impairment and inhibiting the activation of eNMDAR and its downstream signals.
PDF
