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A new iridoid glycoside, named 6'-O-trans-feruloyl-8-epiloganic acid, together with fifteen known compounds were isolated from the twigs and leaves of Callicarpa nudiflora, a traditional Chinese medicine to treat inflammatory-related diseases. Their structures were identified by comprehensive spectroscopic analysis and comparison with reported data. Bioassay results revealed that twelve of the isolates could obviously inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW 264.7 cell lines with IC

The presence of apoptosis inhibition proteins renders the cancer cells resistant to apoptosis, severely compromising the antitumor efficacy of sonodynamic therapy (SDT). Here, an intelligent anticancer nanoplatform based on an Aza-boron-dipyrromethene dye (denoted as Aza-BDY) is elaborately established for ferroptosis augmented SDT through cysteine (Cys) starvation. After endocytosis by tumor cells, Aza-BDY serves as both a ferroptosis inducing agent and a sonosensitizer for tumor treatment. The specific Cys response facilitates the disruption of redox homeostasis and initiation of cellular ferroptosis. Meanwhile, the released sonosensitizer causes efficient SDT and augments ferroptosis under ultrasound irradiation. Detailed in vitro and in vivo investigations demonstrate that the synergistic effect of Cys depletion and singlet oxygen (1 O2 ) generation significantly induces cancer-cell death and suppresses tumor proliferation with a high inhibition rate of 97.5 %. Agency for Science, Technology and Research (A*STAR) National Research Foundation (NRF) We greatly acknowledge the financial support from the National Natural Science Foundation of China (32171391 and 51902336), the Shanghai Science and Technology Program (21010500100), the Basic Research Program of Shanghai Municipal Government (21JC1406002), the Shanghai Rising-Star Program (22QA1403600), the Singapore National Research Foundation Investigatorship (NRF-NRFI2018-03), and the Singapore Agency for Science, Technology and Research (A*STAR) AME IRG grant (A20E5c0081).

Machine‐induced soil disturbance may negatively impact the sustainability of a smallholder farming system. On‐farm studies at 143 fields were conducted over three crop seasons with the goal of quantifying the effect of soil disturbance on rice (Oryza sativa L.) paddy productivity induced by small harvesters (i.e., power

BACKGROUND: Although sex disparities in hepatocellular carcinoma (HCC) incidence have been well described, there are limited data examining sex disparities in HCC prognosis. AIM: To characterize sex differences in HCC presentation and prognosis METHODS: We performed a retrospective study of consecutive patients (n=1110, 23.5% women) diagnosed with HCC between 2008–2017 at two U.S. health systems. We used Cox proportional hazard and multivariable logistic regression models to identify factors associated with overall survival, early tumor detection, and response to HCC treatment (per the modified Response Evaluation Criteria in Solid Tumors [mRECIST] criteria). RESULTS: Women were older at HCC diagnosis (mean 62.5 vs 59.2 years, p

More than two-thirds of patients with hepatocellular carcinoma (HCC) cannot receive curative therapy and have poor survival due to late diagnosis and few prognostic directions. In our study, nontargeted and targeted metabolomics analyses were conducted by liquid chromatography-mass spectrometry to characterize metabolic features of HCC and identify diagnostic and prognostic biomarker candidate incorporating liver tissue and serum metabolites. A total of 552 subjects, including 432 with liver tissue and 120 with serum specimens, were recruited in China. In the discovery cohort, a series of 138 metabolites were identified to discriminate HCC tissues from matched nontumor tissues. Retinol presented with the highest area under the curve (AUC) of 0.991 and associated with Edmondson grade. In the validation cohort, all metabolites in retinol metabolism pathway were examined and the levels of retinol and retinal in tumor tissue and serum decreased in the order of normal to cirrhosis to HCC of Edmondson Grades I to IV. Retinol and retinal levels could also differentiate between HCC and cirrhosis, with AUCs of 0.996 and 0.994, respectively, in tissue and 0.812 and 0.744, respectively, in serum. The AUC of the combined retinol and retinal panel in serum was 0.852. Univariate and multivariate Cox regression identified this panel as an independent predictor for HCC and showed that low expression of retinol and retinal correlated with decreased survival time. In conclusion, the retinol metabolic signature had considerable diagnostic and prognostic value for identifying HCC patients who would benefit from prompt therapy and optimal prognostic direction.

Male patients with multiple morphological abnormalities of the sperm flagella (MMAF) are infertile and exhibit absent, short, coiled, bent and/or irregular sperm flagella. Mutations in the SPEF2 gene reduce sperm motility and cause sperm tail defects in animal models and humans. In the present study, we performed a genetic analysis on an MMAF patient and identified novel biallelic mutations in the SPEF2 gene. The biallelic mutations were confirmed by Sanger sequencing and in silico analysis revealed that, these variations were deleterious. The expression of truncated SPEF2 protein was reduced significantly in the patient's spermatozoa. The spermatozoa harbored biallelic mutations and showed severe ultrastructural defects in the axoneme and mitochondrial sheath. Our data suggest that biallelic mutations in SPEF2 can cause severe sperm flagellum defects, thus providing a novel candidate genetic pathogen for the human MMAF phenotype.

A series of novel aminopyrimidine and diaminopyrimidine derivatives were designed and optimized to improve their potency and permeability relative to lead compound 1 (IC50 = 37.4 μM), which was discovered in a previous virtual screening. The potency of the optimized compound, 13g (IC50 = 1.4 μM), was 26-fold greater than that of 1 based on a fluorescence resonance energy transfer assay, and a parallel artificial membrane permeability assay suggested that it could pass through the blood-brain barrier. Additionally, several compounds containing selenium showed good potencies and deserve further investigation as anti-Alzheimer's agents.

So far, most techniques for modifying perovskite solar cells (PSCs) focus on either the perovskite or electron transport layer (ETL). For the sake of comprehensively improving device performance, a dual‐functional method of simultaneously passivating trap defects in both the perovskite and ETL films is proposed that utilizes guidable transfer of Eu3+ in SnO2 to perovskite. Europium ions are distributed throughout the SnO2 film during the formation process of SnO2, and they can diffuse directionally through the SnO2/perovskite interface into the perovskite, while most of the europium ions remain at the interface. Under the synergistic effect of distributed Eu3+ in the SnO2 and aggregated Eu3+ at the interface, the electron mobilities of ETLs are evidently improved. Meanwhile, diffused Eu3+ ions passivate the perovskite to reduce trap densities at the grain boundaries, which can dramatically elevate the open‐circuit voltage (V oc) of PSCs. Finally, the mainly PSCs coated on SnO2:Eu3+ ETL achieve a power conversion efficiency of 20.14%. Moreover, an unsealed device degrades by only 13% after exposure to ambient atmosphere for 84 days., A dual‐functional method of simultaneously passivating trap defects in both perovskite and electron transport layer (ETL) films is proposed. Europium ions distribute throughout SnO2 film and diffuse into perovskite, while most of Eu3+ remain at the interface. Under the synergistic effect of distributed Eu3+, the electron mobility of ETL is improved and the trap density of perovskite is also reduced.

Nanocomposites, multiphase solid materials with at least one nanoscaled component, have been attracting ever-increasing attention because of their unique properties. Graphene is an ideal filler for high-performance multifunctional nanocomposites in light of its superior mechanical, electrical, thermal, and optical properties. However, the 2D nature of graphene usually gives rise to highly anisotropic features, which brings new opportunities to tailor nanocomposites by making full use of its excellent in-plane properties. Here, recent progress on graphene/polymer nanocomposites is summarized with emphasis on strengthening/toughening, electrical conduction, thermal transportation, and photothermal energy conversion. The influence of the graphene configuration, including layer number, defects, and lateral size, on its intrinsic properties and the properties of graphene/polymer nanocomposites is systematically analyzed. Meanwhile, the role of the interfacial interaction between graphene and polymer in affecting the properties of nanocomposites is also explored. The correlation between the graphene distribution in the matrix and the properties of the nanocomposite is discussed in detail. The key challenges and possible solutions are also addressed. This review may provide a constructive guidance for preparing high-performance graphene/polymer nanocomposite in the future.

A ruthenium-catalyzed switchable N–H/C–H alkenylation reaction of 6-phenyl-(dihydro)pyridazin-3(2H)-ones triggered by a nitrogen/oxygen atmosphere was developed. To achieve switchable modification of the two important sites of the widely used pharmacophore, a simple and efficient procedure containing two optimized ruthenium catalytic systems was utilized, which afforded excellent activity, high selectivity, and good tolerance of a wide range of functional groups.

There is widespread interest in the application, optimization, and evolution of the transition-metal-catalyzed arylation of N-heteroarenes to discover full-color tunable fluorescent core frameworks. Inspired by the versatile roles of pyridazinone in organic synthesis and medicinal chemistry, herein, we report a simple and efficient copper-catalyzed cross-coupling reaction for the N-functionalization of pyridazinones in neat water. To achieve the efficient conversion of pyridazinones and organic halides in aqueous phase, a series of copper-salen complexes composed of different Schiff base ligands were investigated by rational design. A final choice of fine-tuned hydrophilicity balanced with lipophilicity among the candidates was confirmed, which affords excellent activity towards the reaction of a wide range of pyridazinones and organic halides. More importantly, the products as N-substituted pyridazinones were synthesized rationally by this methodology as full-color tunable fluorescent agents (426-612 nm). The N2 position of pyridazinones was modified by different aryl group such as benzothiazole, N,N-dimethylaniline, 3-quinoline, 4-isoquinoline and 2-thiophene, resulting in a series of full-color tunable fluorescent reagents. Meanwhile, the effects of electron-donating and electron-withdrawing groups of the 6-substituted phenyl ring have also been investigated to optimize the fluorescent properties. These fluorescent core frameworks were studied in several cell lines as fluorescent dyes. Different colors from blue to red were observed by using fluorescence microscopy and confocal microscopy.

A simple and efficient procedure for the synthesis of pyridazin-3(2H)-ones through copper-catalyzed dehydrogenation of a single C–C bond of 4,5-dihydropyridazin-3(2H)-ones to a C=C bond with oxygen as the terminal oxidant is described. Functional groups including hydroxy, carboxylic, bromo, chloro, cyano, nitro and alkoxy were all tolerated under the reaction conditions. Moreover, this methodology was applied to the preparation of a series of structurally similar N-substituted 6-phenylpyridazinone compounds containing fluorine. The dehydrogenation reactions exhibit good yields and selectivity.

A copper-catalyzed cascade dehydrogena- tive and dehalogenative reaction of halogenated 6- phenyl-4,5-dihydropyridazin-3(2H)-ones to 6-phe- nylpyridazin-3(2H)-ones has been developed. More- over, the catalytic system consisting of copper(II) acetate/sodium carbonate/pyridine exhibits high re- activity and selectivity with oxygen as the terminal oxidant.

Cardiovascular disease prevalence and mortality are both increased by insulin resistance, hypertension, and atherosclerosis. The large-conductance Ca(2+)-activated K(+) channel (BK(Ca)) plays a pivotal role in the diastolic function of vascular smooth muscle cells. However, the role of this channel in insulin resistance remains unknown. Male Sprague-Dawley rats were randomly divided into an insulin resistant group and control group. We investigated the BK(Ca) current and subunit expression in myocytes from aortas and mesenteric arteries by Western blot, real-time PCR and the whole-cell patch-clamp methods. BK(Ca) current was decreased in smooth muscle cells in insulin resistant rats, compared with that in control group. Peak BK(Ca) current at + 60 mV was significantly decreased after iberiotoxin (IBTX) perfusion at 100 nmol/L (64.2 ± 4.7 versus 20.3 ± 3.5% in thoracic aortas and 65.6 ± 6.2 versus 29.3 ± 3.9% in mesenteric arteries, both p < 0.01). However, there was no significant difference in BK(Ca) alpha subunit between the two groups, both at the level of mRNA and protein. BK(Ca) beta 1 subunit expression in aortas and mesenteric arteries from the insulin resistant group was lower than in those from control group. The plasma level of nitric oxide was higher in the insulin resistant group than in the control group. Our results demonstrated that the BK(Ca) channel is decreased both in macrovessels and microvessels in insulin resistant rats. These impairments may be related to the down-regulation of β1 subunit expression and compensatory increase in plasma nitric oxide levels.

Recently, inorganic CsPbI2Br perovskite is attracting ever-increasing attention for its outstanding optoelectronic properties and ambient phase stability. Here, an efficient CsPbI2Br perovskite solar cell (PSC) is developed by: 1) using a dimension-grading heterojunction based on a quantum dots (QDs)/bulk film structure, and 2) post-treatment of the CsPbI2Br QDs/film with organic iodine salt to form an ultrathin iodine-ion-enriched perovskite layer on the top of the perovskite film. It is found that the above procedures generate proper band edge bending for improved carrier collection, resulting in effectively decreased recombination loss and improved hole extraction efficiency. Meanwhile, the organic capping layer from the iodine salt also surrounds the QDs and tunes the surface chemistry for further improved charge transport at the interface. As a result, the champion device achieves long-term stabilized power conversion efficiency beyond 14%.

We have developed a new protocol in- volving the "copper(II) chloride-cesium carbonate" system for the aerobic oxidation of primary alco- hols. Cesium carbonates and the solvents such as toluene and 1,2-dichloroethane play important roles to form a catalytically active intermediate contain- ing a m-hydroxyl-bridged trinuclear copper moiety (complex 1). From the X-ray crystal structure of complex 1, an electrostatic interaction between chloride anions and cesium cations was observed, which stimulated us to understand the roles of cesium carbonate in this reaction as a base, stabiliz- ing and "solvating" intermediates in toluene and 1,2-dichloroethane.

To demonstrate protein modulation of metal-cofactor reactivity through noncovalent interactions, pH-dependent sulfoxidation and 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) oxidation reactivity of a designed myoglobin (Mb) containing non-native Mn-salen complex (1) was investigated using H2O2 as the oxidant. Incorporation of 1 inside the Mb resulted in an increase in the turnover numbers through exclusion of water from the metal complex and prevention of Mn-salen dimer formation. Interestingly, the presence of protein in itself is not enough to confer the increase activity as mutation of the distal His64 in Mb to Phe to remove hydrogen-bonding interactions resulted in no increase in the turnover numbers, while mutation His64 to Arg, another residue with ability to hydrogen-bond interactions, resulted in an increase in reactivity. These results strongly suggest that the distal ligand His64, through its hydrogen-bonding interaction, plays important roles in enhancing and fine-tuning reactivity of the Mn-salen complex. Nonlinear least-squares fitting of rate versus pH plots demonstrates that 1.Mb(H64X) (X=H, R and F) and the control Mn-salen 1 exhibit pKa values varying from pH 6.4 to 8.3, and that the lower pKa of the distal ligand in 1.Mb(H64X), the higher the reactivity it achieves. Moreover, in addition to the pKa at high pH, 1.Mb displays another pKa at low pH, with pKa of 5.0+/-0.08. A comparison of the effect of different pH on sulfoxidation and ABTS oxidation indicates that, while the intermediate produced at low pH conditions could only perform sulfoxidation, the intermediate at high pH could oxidize both sulfoxides and ABTS. Such a fine-control of reactivity through hydrogen-bonding interactions by the distal ligand to bind, orient and activate H2O2 is very important for designing artificial enzymes with dramatic different and tunable reactivity from catalysts without protein scaffolds.

6-Aryl(dihydro)pyridazinones (I) react with alkynes to give N-alkenylation products under nitrogen atmosphere, while C-alkenylation products are obtained under oxygen atmosphere.

A broad scope of different functionalized purine-fused compounds is obtained in high yields by the presented process.

Continuous ethanol fermentation using polyvinyl alcohol (PVA), immobilized yeast, and sugarcane molasses (22 and 35°Bx) with 8 g/L urea was run in a combined bioreactor system consisting of three-stage tubular bioreactors in series. The effect of the dilution rate (D) at 0.0037, 0.0075, 0.0117, 0.0145, 0.018, and 0.0282 H(-1) on continuous ethanol fermentation was investigated in this study. The results showed that D had a significant effect on fermentation efficiency, sugar-utilized rate, ethanol yield, and ethanol productivity in this designed continuous fermentation system. The D had a linear relationship with residual sugar and ethanol production under certain conditions. The highest fermentation efficiency of 83.26%, ethanol yield of 0.44 g/g, and the lowest residual sugar content of 6.50 g/L were achieved at 0.0037 H(-1) in the fermentation of 22°Bx molasses, indicating that the immobilization of cells using PVA, sugarcane pieces, and cotton towel is feasible and the established continuous system performs well.

There is widespread interest in the application, optimization, and evolution of the transition-metal-catalyzed arylation of N-heteroarenes to discover full-color tunable fluorescent core frameworks. Inspired by the versatile roles of pyridazinone in organic synthesis and medicinal chemistry, herein, we report a simple and efficient copper-catalyzed cross-coupling reaction for the N-functionalization of pyridazinones in neat water. To achieve the efficient conversion of pyridazinones and organic halides in aqueous phase, a series of copper-salen complexes composed of different Schiff base ligands were investigated by rational design. A final choice of fine-tuned hydrophilicity balanced with lipophilicity among the candidates was confirmed, which affords excellent activity towards the reaction of a wide range of pyridazinones and organic halides. More importantly, the products as N-substituted pyridazinones were synthesized rationally by this methodology as full-color tunable fluorescent agents (426–612 nm). The N2 position of pyridazinones was modified by different aryl group such as benzothiazole, N,N-dimethylaniline, 3-quinoline, 4-isoquinoline and 2-thiophene, resulting in a series of full-color tunable fluorescent reagents. Meanwhile, the effects of electron-donating and electron-withdrawing groups of the 6-substituted phenyl ring have also been investigated to optimize the fluorescent properties. These fluorescent core frameworks were studied in several cell lines as fluorescent dyes. Different colors from blue to red were observed by using fluorescence microscopy and confocal microscopy.

A simple and efficient procedure for the synthesis of pyridazin-3(2H)-ones through copper-catalyzed dehydrogenation of a single C–C bond of 4,5-dihydropyridazin-3(2H)-ones to a C=C bond with oxygen as the terminal oxidant is described. Functional groups including hydroxy, carboxylic, bromo, chloro, cyano, nitro and alkoxy were all tolerated under the reaction conditions. Moreover, this methodology was applied to the preparation of a series of structurally similar N-substituted 6-phenylpyridazinone compounds containing fluorine. The dehydrogenation reactions exhibit good yields and selectivity.

A Cu-catalyzed tandem dehydrogenation/dehalogenation sequential reaction along with N-arylation has been developed for the synthesis of pyridazinone derivatives in an aerobic and aqueous environment. To achieve the transformation of three chemical bonds in a one-pot reaction, a multifunctional copper catalyst was used which afforded excellent activity, high selectivity, and recyclability. The catalytic system consists of a water-soluble Cusalen complex and Na2CO3 in neat water and an air atmosphere.

of halogenated 6-aryl-4,5-dihydropyridazinones using a catalytic system consisting of Cu(OAc)2/Na2CO3/pyridine with oxygen as the terminal oxidant

A direct C(sp2)—H activation/intramolecular amination reaction of 6-anilinopurine derivatives using PhI(OAc)2 as oxidant in AcOH/Ac2O as solvent affords the title fused purines.

An efficient method for the synthesis of 6-alkyl or 6-aryl purines (nucleosides) was developed vianickel-catalyzed Negishi cross-couplings of 6-chloropurines and organozinc halides. The ligand-free process gave good to excellent isolated yields at room temperature.

Regioselective diarylation of 9-allyl-9H-purine (I) proceeds via chelation-assisted Heck reaction.

The reaction proceeds selectively as a monoarylation in ortho position even with an excess of aryl iodides.

N-arylation of imidazoles with aryl halides catalyzed by a combination of copper(II) sulfate and 1,2-bis(2-pyridyl)-ethane-N,N'-dioxide in water afforded up to 95% yield.

A new heavy rare-earth-based Dy 36 Ho 20 Al 24 Co 20 bulk metallic glass (BMG) with high thermal stability and excellent magnetocaloric properties has been prepared by a copper mold casting. Compared with the other known rare-earth-based BMGs, this BMG alloy possess higher glass transition temperature and crystallization temperature, larger effective activation energy for glass transition and crystallization. Under a modest magnetic field, this BMG alloy exhibits a comparable or even larger magnetocaloric effect than that the previously reported RE-based BMGs and crystalline compounds. The high thermal stability and the excellent magnetocaloric effect together with other merits of the BMGs make this BMG alloy suitable candidate for use as magnetic refrigerant in a temperature range below 50 K.