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Dapagliflozin (DAPA) exerts cardioprotective effects in non-diabetic patients. Nonetheless, the protective mechanism remains unknown. This study aims to evaluate the performance of DAPA on cardiac function and remodeling as well as its potential mechanism in mice with myocardial infarction (MI). Here, a MI mice model was established. One week after MI, mice were treated with saline or DAPA (1.5 mg/kg/day) for 4 weeks. At the end of this study, echocardiography was performed to assess cardiac structure and function. Myocardial apoptosis was analyzed by Western blot and immunofluorescence. Inflammatory cytokines and cardiac fibrosis were analyzed by real-time PCR and Masson's trichrome stain, respectively. Results showed that DAPA improved cardiac structure and function, attenuated cardiac fibrosis, and inhibited inflammatory cytokines and myocardial apoptosis. Moreover, the inhibition of PI3K/AKT/mTOR pathway might be related to the cardioprotective role of DAPA. These findings reveal that dapagliflozin is a potential therapeutic agent for MI patients without diabetes.

The development of an improved kilogram-scale synthesis of the JAK1 inhibitor GDC-4379 for the treatment of asthma is described. The new process is highlighted by a step-economical construction of ...

Nanomaterials are threatening the environment and human health, but there has been little discussion about the stability and mobility of nanoparticles (NPs) in saturated porous media at environmentally relevant concentrations of surfactants, which is a knowledge gap in exploring the fate of engineered NPs in groundwater. Therefore, the influences of the anionic surfactant (sodium dodecylbenzene sulfonate, SDBS), the cationic surfactant (cetyltrimethylammonium bromide, CTAB), and the nonionic surfactant (Tween-80) with environmentally relevant concentrations of 0, 5, 10, and 20 mg/L on nano-TiO2 (nTiO2, negatively charged) and nano-CeO2 (nCeO2, positively charged) transport through saturated porous media were examined by column experiments. On the whole, with increasing SDBS concentration from 0 to 20 mg/L, the concentration peak of nTiO2 and nCeO2 in effluents increased by approximately 0.2 and 0.3 (dimensionless concentration, C/C0), respectively, because of enhanced stability and reduced aggregate size resulting from enhanced electrostatic and steric repulsions. By contrast, the transportability of NPs significantly decreased with increasing CTAB concentration due to the attachment of positive charges, which was opposite to the charge on the medium surface and facilitated the NP deposition. On the other hand, the addition of Tween-80 had no significant influence on the stability and mobility of nTiO2 and nCeO2. The results were also demonstrated by the colloid filtration theory (CFT) modeling and the Derjaguin-Landau-Verwey-Overbeek (DLVO) interaction calculations; it might promote the assessment and remediation of NP pollution in subsurface environments.

Three Gracilariopsis lemaneiformis strains, including wild type and high-temperature-resistant cultivars 981 and 2007, were studied with the changes in their photosynthetic pigment contents and related gene transcription levels under different light intensities (10, 60, 100, and 200 µmol m−2 s−1). The three G. lemaneiformis strains had the following photosynthetic pigments with high-to-low contents: phycoerythrin (PE), phycocyanin (PC), allophycocyanin (APC), and chlorophyll a (Chl a). Among the three strains, cultivar 981 had the highest PE content, followed by cultivar 2007. The PC and APC contents were similar among the three strains, but they were higher in cultivars 981 and 2007 than in the wild type. The Chl a contents in the three G. lemaneiformis strains were equal. A low light intensity (10 µmol m−2 s−1) promoted photosynthetic pigment accumulation in G. lemaneiformis and improved the relative PE gene transcription (peA and peB) in a short period (≤ 6 d). A high light intensity decreased the PE content. PebA and PebB, which catalyzed phycoerythrobilin synthesis, showed no compensatory upregulation at a low light intensity among the strains except for the wild type. At a high light intensity, transcription levels of pebA and pebB in the three strains were upregulated. This study provided an experimental basis for elucidating the photosynthesis of G. lemaneiformis. As key genes of algal growth, photosynthesis-related genes served as useful gene markers for screening elite varieties with good traits in breeding. Cultivar 2007 was superior to cultivar 981 in terms of maintaining high pigment levels in a wide range of light intensities, which is the most suitable for aquaculture.

A facile and green approach to the preparation of peroxidase-like nanozymes by reducing and functionalizing graphene oxide (rGO) with Ganoderma polysaccharide (GP) has been achieved in this work. Our results showed that the as-fabricated nanozyme, namely rGO-GP, possessed the excellent property of simulating peroxidase with higher catalytic activity compared with GO or rGO obtained by using chitosan, which may be due to the better dispersion of rGO-GP in the solution. Steady-state kinetics studies further showed that the catalytic process conformed to Michaelis-Menten equation and ping-pong mechanism. Benefiting from the excellent peroxidase property of rGO-GP, we have also successfully established a highly sensitive and selective colorimetric detection approach to trace detection of L-cysteine (L-Cys). The limit of detection (LOD) of L-cysteine is 0.1 μM and the linear detection range is 2-30 μM. Furthermore, the nanozyme was successfully applied for detecting L-cysteine in serum. This work therefore demonstrates the advantages of rGO-GP as an effective nanozyme in both its green synthesis and detecting application.

Bufadienolides are the main active ingredients of Venenum Bufonis, which is a widely used traditional Chinese medicine secreted from parotoid gland and skin glands of Bufo bufo gargarizans. According to the transcriptome analysis, “cholesterol-bile acid-bufadienolidies pathway” was proposed as animal-derived bufadienolides biosynthesis pathway by us previously. In this pathway 3β-hydroxysteroid dehydrogenase (3βHSD) and steroid 5β-reductase (SRD5β) might be the key enzymes to convert the A/B ring to cis-configuration. Therefore, as the second report of our group, here we report the cloning of the full length of SRD5β cDNA of B. bufo gargarizans (Bbg-SRD5β) from the parotoid gland of B. bufo gargarizans for the first time, and site-directed mutagenesis was used to explored the character of Bbg-SRD5β. Bbg-SRD5β had an open reading frame of 981 bp and encoded 326 amino acids residues. The expression conditions of the recombinant Bbg-SRD5β in E. coli BL21 (DE3) harbored with pCold-Bbg-SRD5β was optimized as induction for 10 h at 15 °C with 0.1 mM IPTG. With NADPH as a cofactor, Bbg-SRD5β can reduce the Δ4,5 double bonds of progesterone to generate dihydroprogesterone owithout substrate inhibition effect. The catalytic rate of mutant type Bbg-SRD5β-Y132G was 1.8 times higher than that of wild type Bbg-SRD5β. Although Bbg-SRD5β was almost unable to reduce the progesterone to dihydroprogesterone after mutation of V309, the affinity of enzyme with NADPH changed significantly. Bbg-SRD5β is the key enzymes to convert the A/B ring of steroid to cis-configuration, and V309 is a key site affecting the binding affinity of enzyme with NADPH, and the mutation of Y132 can adjust the catalytic rate of Bbg-SRD5β.

Cu–ZnO catalysts are widely studied for the direct hydrogenation of CO2 to methanol for high activity. However, despite the widespread research, promoting the intrinsic activity of active sites rem...

An efficient copper-catalyzed addition of arylboronic esters to (Boc)2O was developed. The reaction can be conducted under exceedingly mild conditions and is compatible with a variety of synthetically relevant functional groups. It therefore represents a useful alternative route for the synthesis of methyl arylcarboxylates. A preliminary mechanistic study indicated the involvement of an addition–elimination mechanism.

Renin-angiotensin system (RAS) signaling has been implicated in the development of cancer. The new RAS ACE2/Ang-(1-7)/Mas axis antagonizes the classical ACE/Ang II/AT1R axis. Ang-(1-7) has pleiotropic roles in lung cancer including suppressing proliferation, angiogenesis, and metastasis. This research was designed to investigate the effect of Ang-(1-7) on tumor-associated angiogenesis in DDP-resistant lung cancer cell lines. We first established acquired DDP-resistant cell lines A549 (A549-DDP) and LLC (LLC-DDP). We next performed RT-qPCR, western blot, ELISA, tube formation, microvessel density detection, immunohistochemistry, and tumor formation assays. The results showed that the mRNA and protein levels of RAS components and vascular endothelial growth factor A (VEGFa) were lessened in the A549/LLC-DDP+Ang-(1-7) group compared with the A549/LLC-DDP group. This effect could be blocked by the MAS receptor antagonist A779. The data revealed that Ang-(1-7) could perform its antiangiogenic function by PI3K/AKT and MAPK pathways. Furthermore, the impact of Ang-(1-7) on tumor-associated angiogenesis has been confirmed in lung cancer xenograft model with acquired DDP resistance. These results provide a theoretical basis for designing therapeutic strategies for targeting Ang-(1-7) in the treatment of NSCLC.

Metallic oxide based catalysts have received much attention in CO2 hydrogenation to methanol because of their high methanol selectivity and long-term stability. But the relatively weak hydrogenation ability leads to low methanol activity. Here, we introduce a small amount of Cu (molar fraction

Transition metals have been considered as potential catalysts for ammonia decomposition to produce COx-free hydrogen for fuel cells. However, the facile synthesis of transition metal catalysts with small size active species, high porosity and good structural stability is still a challenge in catalytic NH3 decomposition. Herein, mesoporous Co/Al2O3 catalysts with various cobalt contents were synthesized by a facile modified sol–gel method. The catalyst 15CoAl with 15 at% cobalt content realizes the optimal catalytic NH3 decomposition performance. 92% NH3 conversion at 600 °C is achieved with a gaseous hourly space velocity (GHSV) of 24 000 cm3 gcat−1 h−1 and a hydrogen formation rate of 33.9 mmol gcat−1 min−1 at 600 °C is maintained after a 120 h long-duration stability test. Uniform small cobalt particles with high dispersion are well embedded into the skeleton of the mesoporous Al2O3 matrix. The aggregation of active cobalt species during the high temperature reaction can be effectively prevented by the mesoporous Al2O3 matrix due to the strong interaction between them, thus ensuring a good catalytic performance for ammonia decomposition.

It is imminent to develop a new type of rapid COVID-19 detection method with high sensitivity. Here, we used novel red emission-enhanced carbon dot (CD)-based silica (RCS) spheres as the signals of lateral flow immunochromatography (LFI) to ultrasensitively detect novel severe acute respiratory syndrome coronavirus 2 nucleocapsid proteins (SARS-CoV-2 NPs). The red emission of CDs can be enhanced and enriched in silica spheres by a simple way. The amino ends of the N-β-(aminoethyl)-γ-aminopropyltrimethoxy anchor carboxyl-rich CDs and enhance the red emission, while the other end is embedded in the silica carrier. Then, the composite silica spheres werecoated with 3-(triethylsilyl) propylamine to protect the CDs, promote bioconjugation and obtain RCS spheres. The optimal emission peaks of the aqueous solution and the solid state of RCS spheres were at 634 nm and 638 nm, respectively, with quantum yields (QYs) of 48.5% and 35.7%, respectively. Their red emission has a wide excitation range (from the ultraviolet region to the red region), and the best excitation wavelength is about 580 nm. Two fluorescence detection modes of the RCS-LFI technology for the SARS-CoV-2 NP assay are available: the simple mode of observation under ultraviolet light has a sensitivity of 100 pg mL-1; the advanced mode of detection under a fluorescence microscope has a sensitivity of 10 pg mL-1. This assay also exhibits the advantages of fast detection speed, high specificity, and simple operation. In addition, the feasibility of this method in actual sample detection was verified in human serum by the standard-addition method, and the results show that the method has excellent practicability. We believe that this method will be a valuable supplement for the diagnosis of COVID-19.

Background: Some literature has studied the relationship between lignans intake and its metabolite, enterolactone, and breast cancer survival, but the results are far from consistent and conclusive. Therefore, we conducted a systematic review and meta-analysis in this situation. Methods: From its inception to August 2020, we conducted a comprehensive search of PubMed, Embase, Web of Science, and Cochrane Library databases. This study reported the correlation between lignans intake and serum enterolactone concentrations and prognosis of breast carcinoma. The total hazard ratios (HRs) and 95% confidence interval (95% CI) were estimated, comparing the highest versus the lowest category of lignans intake and serum enterolactone concentrations, using a fixed or random-effects effect model. Results: A total of 6 articles were included in reporting the all-cause mortality (ACM), breast cancer-specific mortality (BCSM), and recurrence of 2668, 1516, and 474 breast cancer patients in 18053 breast cancer patients. In postmenopausal women with breast cancer, lignans intake or enterolactone concentrations were associated with a reduced risk of all-cause mortality (maximum and minimum) (pooled HR = 0.73, 95% CI, 0.58-0.91), as was the association with breast cancer-specific mortality (maximum and minimum) (pooled HR = 0.72, 95% CI, 0.60, 0.87). Stratified analysis showed that exposure type and diagnosis time might be the sources of heterogeneity. In premenopausal women, the relationship seemed to be the opposite, showing an increased risk of all-cause mortality (maximum and minimum) in breast cancer patients (pooled HR = 1.57, 95% CI, 1.11-2.23). No significant association was found between lignans intake or enterolactone concentrations and breast cancer recurrence (pooled HR = 0.91, 95% CI, 0.69, 1.20). Conclusion: This study provides limited evidence that lignans intake and higher serum enterolactone concentrations in postmenopausal women are beneficial to breast cancer patients' prognosis. In premenopausal women, however, the relationship may be reversed.

Ginseng is usually consumed as a dietary supplement for health care in the normal state or prescribed as a herbal medicine in pathologic conditions. Although metabolic studies of ginseng are commonly performed on healthy organisms, the metabolic characteristics in pathologic organisms remain unexplored. This study aimed to uncover the difference in intestinal metabolism of ginseng between normal and cyclophosphamide-induced immunosuppressed rats and further discuss the potential mechanisms involved. Twelve Sprague-Dawley rats (6–8 weeks old) were randomly divided into two groups: the normal group (NG) and immunosuppressed group (ISG). Rats in the NG and ISG groups were intraperitoneally administered normal saline and cyclophosphamide injections (40 mg/kg) on the 1st, 2nd, 3rd and 10th days; on the 12th day, all rats were intragastrically administered ginseng water extract (900 mg/kg). The difference in intestinal metabolism of ginseng was compared using an ultra-high-performance liquid chromatography coupled with quadruple time-of-flight mass spectrometry-based metabolomics approach, and the diversities of gut microbiota were analyzed by 16S rRNA gene sequencing between the two groups. The intestinal metabolomic characteristics of ginseng were significantly different between the normal and immunosuppressed rats, with the ginsenoside F2 (F2), 20S-ginsenoside Rg3 (20(S)-Rg3), pseudo-ginsenoside Rt5 (Pseudo-Rt5), ginsenoside Rd (Rd), ginsenoside Rh1 (Rh1), 20S-ginsenoside Rg1 (20(S)-Rg1), ginsenoside compound K (CK), ginsenoside Rg2 (Rg2) and 20S-panaxatriol (S-PPT) more abundant in immunosuppressed ones (P

Resistance-nodulation-division (RND) efflux pumps are important determinants of multidrug resistance in Gram-negative bacteria. As one of the typical members of the RND superfamily, Escherichia coli OqxAB multidrug efflux pump confers resistance to antimicrobial agents, such as olaquindox and fluoroquinolone. In the present study, site-directed mutagenesis and antimicrobial susceptibility measurement assay were applied to identify the crucial residues within OqxB, the transporter component of the OqxAB efflux pump system. It was found that alanine substitution of proton translocation pathway residues D410, D411, and R976 resulted in a complete loss of the transport function. Further studies revealed that the charge property of these residues is important for proper function of OqxB. Alanine replacement of residues involved in substrate-binding domains, including V141, F180, Y330, and F626, exhibited different responses toward different antimicrobial agents. Conservative replacement of Y330, F626, and F180 with amino acids having similar aromatic ring structure resulted in full or partial recovery of the efflux function. Molecular docking analysis demonstrated that olaquindox may form hydrogen bonds with F626, Y330, and V141, whereas only Y330 and F180 may interact with ciprofloxacin, implicating the different roles played by these residues when transporting different kinds of substrates. Graphical Abstract [Figure: see text].

Development of low-cost and eco-friendly approaches to fight bacterial pathogens is especially needed in aquaculture. We previously showed that exogenous malate reprograms zebrafish’s metabolome to potentiate zebrafish survival against Vibrio alginolyticus infection. However, the underlying mechanism is unknown. Here, we use GC-MS based metabolomics to identify the malate-triggered metabolic shift. An activated TCA cycle and elevated taurine are identified as the key metabolic pathways and the most crucial biomarker of the reprogrammed metabolome, respectively. Taurine elevation is attributed to the activated TCA cycle, which is further supported by the increased expression of genes in the metabolic pathway of taurine biosynthesis from the isocitrate of the TCA cycle to taurine. Exogenous taurine increases the survival of zebrafish against V. alginolyticus infection as malate did. Moreover, exogenous taurine and malate regulate the expression of innate immunity genes and promote the generation of reactive oxygen species and nitrogen oxide in a similar way. The two metabolites can alleviate the excessive immune response to bacterial challenge, which protects fish from bacterial infection. These results indicate that malate enhances the survival of zebrafish to V. alginolyticus infection via taurine. Thus, our study highlights a metabolic approach to enhance a host’s ability to fight bacterial infection.

Higher alcohol (C2+) synthesis (HAS) from direct CO2 hydrogenation is a promising way to realize the fixation of CO2 to high-value chemicals; however, the identification of active catalysts to give...

The diphosphine ligand N,N-bis(diphenylphosphanylmethyl)-aniline (bdppma) and PdCl2 afforded a Suzuki–Miyaura catalyst [(bdppma­)PdCl2] that was highly efficient at an ultralow catalyst loading (0.001 mol%) in 20:1 H2O–EtOH. This low catalyst loading in an aqueous solvent system permitted simple product separation by direct filtration without the need for chromatography. The ligand bdppma imparted surprisingly better reactivity than that achieved with other bidentate diphosphine ligands, but the catalytic system had a slightly narrower substrate scope than some similar Pd catalysts reported previously.

The nitrile groups in the tetrafluoroterephthalonitrile-crosslinked β-cyclodextrin (β-CD) were modified by (1) the reaction with the diethanolamine resulting in the hydroxyalkylaminoalkylamide groups or the hydroxyalkylaminoimide groups (2) the reduction of the borane-tetrahydrofuran complex resulting in the amide groups to form two novel β-CD based polymers (CDPs), namely the CDP-DEA and the CDP-NH2, correspondingly. Furthermore, the dye adsorption abilities of these two CDPs in the aqueous solution were investigated using the anionic dyes including the Congo red (CR) and the orange G (OG). For both the CDP-DEA and the CDP-NH2, the pseudo second-order model fitted well with their adsorption dynamics and their equilibrium adsorption process followed the Langmuir isotherm model. The maximum adsorption capacities of the CDP-DEA for CR at pH = 5 and OG at pH = 3 were 813 mg/g and 442 mg/g, respectively, while the corresponding values of the CDP-NH2 were 40 mg/g and 446 mg/g, respectively. It was found that the electrostatic attraction played an important role in the anionic dye adsorption of the CDP-DEA and the CDP-NH2.

Rhubarb is a widely used herbal medicine. To achieve different effects, rhubarb is usually steamed with rice wine (steamed rhubarb). This steaming treatment increases the blood-activating and stasis-removing effects of rhubarb. A specific and accurate ultra high performance liquid chromatography with tandem mass spectrometry method was established for simultaneous determination of anthraquinone glycosides, aglycones, and glucuronic acid metabolites in plasma and tissues after administration of raw rhubarb and steamed rhubarb in blood stasis rats. Chromatographic separation was performed on ACQUITY UPLC BEH Shield RP 18 column using the mobile phase consisting of water and acetonitrile both containing 0.1% formic acid. Satisfactory linearity, precision, accuracy, extraction recovery, and matrix effect have been achieved. From pharmacokinetic study, it showed that glucuronic acid metabolites were found abundantly in plasma as bioactive components. The lower area under concentration-time curve, maximum concentration, and higher apparent volume of distribution (P

Approximately 10% of bone fractures do not heal satisfactorily, leading to significant clinical and socioeconomic implications. Recently, the role of macrophages in regulating bone marrow stem cell (BMSC) differentiation through the osteogenic pathway during fracture healing has attracted much attention. Methods: The tibial monocortical defect model was employed to determine the critical role of macrophage scavenger receptor 1 (MSR1) during intramembranous ossification (IO) in vivo. The potential functions and mechanisms of MSR1 were explored in a co-culture system of bone marrow-derived macrophages (BMDMs), RAW264.7 cells, and BMSCs using qPCR, Western blotting, immunofluorescence, and RNA sequencing. Results: In this study, using the tibial monocortical defect model, we observed delayed IO in MSR1 knockout (KO) mice compared to MSR1 wild-type (WT) mice. Furthermore, macrophage MSR1 mediated PI3K/AKT/GSK3β/β-catenin signaling increased ability to promote osteogenic differentiation of BMSCs in the co-culture system. We also identified proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) as the target gene for macrophage MSR1-activated PI3K/AKT/GSK3β/β-catenin pathway in the co-culture system that facilitated M2-like polarization by enhancing mitochondrial oxidative phosphorylation. Conclusion: Our findings revealed a previously unrecognized function of MSR1 in macrophages during fracture repair. Targeting MSR1 might, therefore, be a new therapeutic strategy for fracture repair.

Tea consumption has been found to be associated with low incidence of inflammatory bowel disease in Asian countries. However, there is very limited knowledge of such potential protection and its underlying mechanism. Ripened Pu-erh tea (RPT) belongs to the variety of microbial fermented tea, but its function regarding anti-inflammation remains unclear. In the present study, we investigated the effects of RPT on dextran sulfate sodium (DSS)-induced colitis in mice. The results demonstrated that RPT significantly relieved the loss of body weight, disease severity and shortening of colon length, and remarkably inhibited the secretion of pro-inflammatory cytokines by lessening the infiltration of inflammatory cells. Furthermore, we found that RPT suppressed the activation of the NF-κB pathway and down-regulated the expression of HIF-1α. Thus, it was concluded that RPT attenuated the progress of colitis via suppressing the HIF-1α/NF-κB signaling pathways thus reducing inflammation. This suggests that RPT may be a potential anti-inflammatory nutraceutical for the prevention and treatment of colonic colitis.

International audience; Dielectric nanomaterials offer great promise for diverse technological applications such as capacitors, actuators, and sensors. Unfortunately, the exploitation of desirable dielectric properties in polymer nanocomposites is a great challenge due to lack of efficient routes to achieve uniform dispersion of nanoparticles and good compatibility of interfaces at high nanoparticle loadings. A dilemma between the nanofiller loading and dispersion as well as interfacial compatibility makes it impossible to fully exploit the intrinsic polarization of the nanoparticles. Herein, we solve such a dilemma and fabricate highly filled barium titanate/silicone rubber (BT/SR) nanocomposites through chemically bonding BT nanoparticles with SR by “thiol–ene click” and isostatic pressing techniques. BT loading varies from 88 wt% to 97 wt% without compromising the uniform dispersion quality and good interfacial adhesion with the SR matrix. The 90 wt% BT nanocomposite shows an optimum dielectric constant as high as 55, while its loss tangent can be kept as low as 0.019 at 103 Hz. Meanwhile, it displays good stability of dielectric properties from room temperature up to 100 °C. In addition, the breakdown strength just decreases slightly compared to neat SR (97 MV m−1) but is still beyond 75 MV m−1. The present work provides a facile strategy towards superior dielectric polymer nanocomposites.

In the present study, the hypoglycemic effects of glucomannan (AGM) and its enzyme-degraded products from Amorphophallus albus were investigated. Four degraded products were prepared through ultrafiltration of β-glucanase-degraded products of AGM. The hypoglycemic activities were evaluated in HFD-STZ-induced type 2 diabetes mellitus (T2DM) mice, and the diversity of gut bacteria was analyzed by 16S rRNA gene sequencing; the fecal short chain fatty acids (SCFAs) and endogenous metabolites were determined by UPLC-QTOF-MS/MS. It was found that AGM and its enzyme-degraded products, though with different molecular weights, had similar β-glycosidic bonds and monosaccharide compositions, exerted similar strength of hypoglycemic effects, and reinstated with a similar extent the disordered gut microbiota and the contents of SCFAs and endogenous metabolites. It was speculated that the hypoglycemic activity of AGM is decided by not the molecular weight but the glycosidic bonds/monosaccharide composition of AGM, which might be structurally specific to the gut bacteria, and thus certain SCFAs and endogenous metabolites that are related to the occurrence and therapy of T2DM. This study provides a scientific basis for using AGM as potential prebiotics beneficial for prevention or therapeutic treatment of T2DM.

Sensitive detection of severe fever with thrombocytopenia syndrome virus (SFTSV) by a point-of-care assay is of great significance for promoting clinical diagnosis. In this work, ultrasensitive det...

Lysosomes are organelles containing many hydrolytic enzymes responsible for degrading macromolecules. Abnormal lysosomal pH changes are known to associate with dysfunction of cells linking to various diseases such as cancer and neurodegenerative disorders. Thus, it is of paramount importance to monitor lysosomal pH changes in order to investigate the pathological conditions. We report herein two novel, highly sensitive and fast responsive bis-chromophoric ratiometric two-photon fluorescent probes with different emission wavelengths, namely VP and VL for acidic pH sensing in live cells. Importantly, by adopting bis-chromophoric approach, the VP and VL probes bearing pyridyl and quinolyl as acid sensing sites exhibit pKa values of 4.62 and 5.26, respectively, which are ideal for quantitative analysis of lysosomal pH changes in live cells. These two biocompatible probes are not only highly lysosomal targeting, sensitive towards pH change with distinct emission color shifting but also highly two-photon active in cells with excellent photostability and reversibility. These probes were successfully applied to ratiometrically track and image pH fluctuation in lysosomes of HeLa cells by one- and two-photon excited fluorescence microscopy. For the first time, we have demonstrated here that the bis-chromophoric strategy is a useful tool to effectively modify and tune the pKa of a fluorescent probe.

Glycogen synthase (GS) and glycogen phosphorylase (GP) are two key enzymes in the glycogen synthesis pathway, which catalyze trehalose and glucose transformation in insects. GS and GP can be regulated by trehalose metabolism, which plays an important role in insect growth. However, it is not known whether these genes can be targeted for pest control through regulation of chitin metabolism. We studied the function of Nilaparvata lugens GS and GP (NLGS and NLGP, respectively) using RNA interference, and reported that trehalose and the chitin biosynthesis pathways are regulated by GP and GS, especially TPS3, TRE1-1, and G6PI1, which decreased following knockdown of these two genes. The expression levels of TPS1, TPS2, and several chitin synthesis pathway family genes were significantly increased following dsNlGP injection. Additionally, despite there being no apparent change to the chitin content, an abnormal molting phenotype and wing deformity appeared, and close to 25% insects died. These results demonstrate that silencing of NLGP or NLGS can lead to molting deformities and an elevated mortality rate through the regulation of chitin pathway genes and chitinase genes. NLGP may play a key role in chitin synthesis due to the number of genes regulated, and higher deformity and mortality rates resulting from its knockdown.

A highly regioselective Mg-catalyzed alkylation of 3-substituted pyrazoles has been developed to provide N2-alkylated regioisomers. Using α-bromoacetates and acetamides as alkylating agents, this new method was applied to a variety of 3-substituted and 3,4-disubstituted pyrazoles to produce the N2-alkylated products with high regioselectivities ranging from 76:24 to 99:1 and 44–90% yields.

An early and rapid diagnosis of acute myocardial infraction (MI) by serum biomarker quantification is vital for boosting up treatment efficacy and survival rate; however, it still remains challenging due to ultralow biomarkers content and the emergent nature of the disease. In view of these challenges, a single-step target capturing method for cardiac Troponin I (cTnI), the major cardiac biomarker of MI, was developed. The detection of target cTnI was performed by coupling the capture antibody modified magnetic silica nanoparticle (mSiO2) and an aptamer-based DNA nanostructure produced by hybridization chain reaction (aptHCR). cTnI in sample was first directly captured by mSiO2 and aptHCR in 30 min. The as formed nanocomplex was then labelled by a customized DNA turn on fluorescent dye SPM. By reading the strengthened fluorescent signal using total internal reflection fluorescence microscope (TIRFM), the detection platform has accomplished an impressive LOD of 8.5 fM with high specificity towards cTnI. The advantages of the short immunoreaction time (30 min) and the pre-treatment free property of the method have addressed the urgent diagnostic requirements of MI. The detection platform offers a potential solution to tackle insufficient sensitivity and tedious turnaround time of clinically approved assays for cTnI detection.

Radial oxygen loss (ROL) for macrophytes is intimately involved in their survival and growth, thus detailed characterizations of ROL and its implication for geochemical processes are of particular interest. We experimentally investigated ROL patterns from the submerged macrophyte species Potamogeton crispus and determined how light, temperature and O2 content in overlying water regulate O2 micro-distributions in the rhizosphere. Planar optodes were firstly used for non-destructive imaging of the O2 micro-distributions around single roots of P. crispus planted in rhizotrons containing sediment. The dynamic changes in below-ground O2 concentrations and oxygenation expansion at different light intensities (0–216 μmol photons m−2), temperatures (14 and 25 °C) and O2 content in overlying waters (0–256 μmoL−1) were quantified. P. crispus-mediated ROL is predominantly localized to the root apices with an average rate of 168.1 ± 21.4 nmol m−2 s−1 under nearly natural conditions (light, saturated overlying water at 14 °C), maintaining a visible oxygenated rhizosphere zone with a radius of 1.33 ± 0.21 mm. ROL is closely correlated with light intensity, suggesting photosynthetic O2 evolution. In darkness, the rhizosphere O2 availability is significantly reduced and strongly affected by the O2 content in overlying water, which passively diffuses into the plant leaves. Elevated temperatures lead to diminished ROL as a result of increased O2 demand of the surrounding sediment. A high O2 microheterogeneity around P. crispus root apices is firstly demonstrated, and we provide direct empirical evidences that ROL are regulated dynamically by the shifting light, temperature and O2 content in overlying water.

Sugars provide a source of energy; they also function as signaling molecules that regulate gene expression, affect metabolism, and alter growth in plants. Rapid responses to sugar signaling and metabolism are essential for optimal growth and fitness, but the regulatory mechanisms underlying these are largely unknown. In this study, we found that the rapid induction of sugar responses in Arabidopsis (Arabidopsis thaliana) requires the W-box cis-elements in the promoter region of GLC 6-PHOSPHATE/PHOSPHATE TRANSLOCATOR2, a well-studied sugar response marker gene. The transcription factors WRKY18 and WRKY53 directly bind to the W-Box cis-elements in the promoter region of sugar response genes and activate their expression. In addition, HISTONE ACETYLTRANSFERASE 1 (HAC1) is recruited to the WRKY18 and WRKY53 complex that resides on the promoters. In this complex, HAC1 facilitates the acetylation of histone 3 Lys 27 (H3K27ac) on the sugar-responsive genes. Taken together, our findings demonstrate a mechanism by which sugar regulates chromatin modification and gene expression, thus helping plants to adjust their growth in response to environmental changes.

Better understanding on the photosynthetic regulation of yield will be useful to improve agricultural water use efficiency under straw mulching. The yield, photosynthetic parameters and related leaf traits were measured and compared between straw mulching (SM) and non-mulching (NM) treatments in a maize field of North China Plain in 2013–2015. Total aboveground biomass of the SM treatment increased by 7.1%, 11.2% and 14.7%, and grain yield increased by 11.5%, 6.8% and 12.1%, respectively for the three years, comparing to those of the NM treatment. Such increases were related to higher leaf area index (LAI) and leaf area duration, photosynthetic capacity per unit of area (Amax) and the apparent quantum efficiency (α) for the SM treatment. Maximum LAI of the SM treatment were 17.2%, 19.2% and 20% higher than those of the NM treatment, respectively, for the three years. Amax and α of the SM treatment were 7.9%–36.8% and 7.7%–16.7% higher than those of the NM treatment during different growth stages in the three years. Amax and α were linearly correlated to leaf nitrogen content on mass basis (Nmass). Liner regressions between Amax and Nmass, and between α and Nmass were affected by straw mulching treatment, under which the slopes were similar but the intercepts were higher. With no significant increase of Nmass in most measurements, the results suggested that the SM treatment improved N-use efficiency, which may be due to lower leakiness of the bundle-sheath cells to CO2 (L) under the SM treatment. Collectively, the results help understanding the physiological basis of positive effect of the straw mulching on yield and quantified the photosynthetic parameters of summer maize in this area.

Water deficit is one of the main limiting factors for apple growth and production. Root architecture plays an important role in drought tolerance of plants. However, little is known about the molecular basis of root system in apple trees under drought. In this study, we compared root morphology of two widely used rootstocks of apple (R3 and Malus sieversii) under drought. Our results suggested that M. sieversii is more tolerant to drought than R3, since M. sieversii had a higher ratio of root to shoot as well as root hydraulic conductivity under long-term drought conditions. We then performed whole-genome transcriptomic analysis to figure out the molecular basis of root responses in M. sieversii under drought. It was found that genes involved in transcription regulation, signaling or biosynthesis of hormones, and oxidative stress were differentially expressed under drought. Consistent with the gene expression profile, roots of M. sieversii had higher activities of peroxidase (POD) and superoxide dismutase (SOD) under drought, as well as higher content of abscisic acid (ABA) and lower content of auxin. Taken together, our results revealed the physiological and transcriptomic analyses of M. sieversii roots in response to drought.

Corona and chemical treatment worked cooperatively for increasing and stabilizing the polyethylene film surface energy. Gentle and varied corona discharge treatment conditions were applied for each polyethylene film to reach 40 dynes/cm. A rather low blending amount of additive could stabilize the film surface energy obviously. Compared with neat PE film, of which the surface energy decreased to 36 dynes/cm at the 12th day, films blended with 1000 ppm A7-OH or PE-PEG4k-PE showed stable surface energy (36–38 dynes/cm) over 150 days. The influence of industrial applied slipping agent was investigated as well. Morphological and chemical changes were studied by X-ray photoelectron spectroscopy (XPS) and Atomic Force Microscope (AFM). The surface energy was determined by the dyne pens. Mechanism investigation of hydrophilization and hydrophobic recovery processes showed that proper crystallization behavior and enough C O groups on the film surface guarantee satisfactory stability of the surface energy.

Water kefir is a fermented beverage, which is traditionally prepared from sucrose, kefir grains, dried or fresh fruits, and water. L. hordei and S. cerevisiae are isolated as predominant and stable species of lactic acid bacteria and yeasts, respectively. In this study we demonstrate that label free quantitative proteomics is useful to study microbial interaction along the response of co-cultivated L. hordei TMW 1.1822 in the presence of S. cerevisiae TMW 3.221 as compared with their single cultures in a water kefir model. It is shown and L. hordei responds to S. cerevisiae in many respects revealing a mutualistic relationship. The data suggest that L. hordei responds to the presence of S. cerevisiae with adjustment of intracellular redox reactions controlled of proteins, which are part of Rex regulons and proteins involved in the glycolytic pathway and energy fermentation. An NADH, H+-driven metabolic switch to preferential production of butanediol instead of acetate or lactate, and up-regulation of arginine deiminase, alleviated acid stress and concomitantly protected S. cerevisiae against an acidic environment, which L. hordei generated in single culture. Moreover, the data suggest that the presence of S. cerevisiae in the nitrogen and fatty acids limited environment of the water kefir facilitated and improved the growth of L. hordei by delivering gluconate, fructose, amino acids, fatty acids or substrates for their biosynthesis. Up-regulation of the OppABCDF peptide transport and enzymes involved in amino acid metabolism indicates enhanced peptide uptake, as well as cross-feeding of L. hordei by glutamine, glutamate, histidine, tryptophan, methionine, proline, tryptophan delivered by S. cerevisiae.

Materials with micro-nano hierarchical structure have shown excellent electrochemical performance for lithium ion batteries because of the favorable electron/ionic transportation provided by the unique geometrical structure. In this work, hierarchical LiNi0.4Co0.2Mn0.4O2 hollow microsphere is synthesized by a template-sacrificial route using porous CoMn2O4 template, which is prepared by pyrolysis of solvothermal synthesized Co1/3Mn2/3CO3 precursor. The influence of synthesis parameters in solvothermal reaction and high temperature calcining on the morphology of particles is systematically investigated. Benefiting from the desired micro-nano hierarchical porous hollow structure and well-ordered crystal structure, the LiNi0.4Co0.2Mn0.4O2 hollow microsphere exhibits excellent electrochemical performance and favorable Li+ extraction/insertion kinetics.

One of the major challenges in treating Alzheimer's disease (AD) is its early diagnosis. Increasing data from clinical and animal research indicate that the retina may facilitate an early diagnosis of AD. However, a previous study on the 5xFAD (a fast AD model), showing retinal changes before those in the brain, has been questioned because of the involvement of the retinal degeneration allele Pde6brd1. Here, we tested in parallel, at 4 and 6 months of age, both the retinal and the brain structure and function in a 5xFAD mouse line that carries no mutation of rd1. In the three tested regions of the 5xFAD brain (hippocampus, visual cortex, and olfactory bulb), the Aβ plaques were more numerous than in wild-type (WT) littermates already at 4 months, but deterioration in the cognitive behavioral test and long-term potentiation (LTP) lagged behind, showing significant deterioration only at 6 months. Similarly in the retina, structural changes preceded functional decay. At 4 months, the retina was generally normal except for a thicker outer nuclear layer in the middle region than WT. At 6 months, the visual behavior (as seen by an optomotor test) was clearly impaired. While the full-field and pattern electroretinogram (ERG) responses were relatively normal, the light responses of the retinal ganglion cells (measured with multielectrode-array recording) were decreased. Structurally, the retina became abnormally thick with few more Aβ plaques and activated glia cells. In conclusion, the timeline of the degenerative processes in the retina and the brain is similar, supporting the use of non-invasive methods to test the retinal structure and function to reflect changes in the brain for early AD diagnosis.

The present study hypothesized that fumaric acid and succinic acid may exhibit therapeutic effects on gestational hypertension. During pregnancy, estrogen upregulates ten-eleven translocation 1 (TET1) expression, which subsequently increases calcium-activated potassium channel subunit β1 (KCNMB1) expression. KCNMB1 is associated with hypertension. Fumaric acid and succinic acid are understood to inhibit TET. Therefore, the present study investigated whether fumaric acid and succinic acid exhibit therapeutic effects on gestational hypertension and whether these effects are mediated by TET1 and KCNMB1. Nω-Nitro-L-arginine methyl ester hydrochloride was injected into rats to establish a gestational hypertension model. Dimethyl fumarate (DMF) and succinic acid were administrated into rats to treat gestational hypertension. Rats were divided into five groups: i) Control; ii) model; iii) DMF; iv) succinic acid; and v) DMF + succinic acid. Blood pressure was monitored by a noninvasive meter and urinary protein was determined using a urinary protein kit. Placenta pathology was examined by hematoxylin-eosin staining. Compared with the control group, urinary protein and blood pressure in the model group increased significantly. The placental cells in the control group were arranged orderly. However, in the model group, decidual cellular edema of placenta and vacuolar degeneration were observed, and the intervascular membrane was markedly thicker with plenty of fibrin deposition. These results indicate successful establishment of a gestational hypertension model. However, compared with the model group, urinary protein, blood pressure, edema, vacuoles and fibrin deposition were markedly reduced in the DMF, succinic acid and DMF + succinic acid groups. mRNA and protein levels of TET1 and KCNMB1 in placenta were evaluated by immunohistochemical analysis, reverse transcription-quantitative polymerase chain reaction and western blotting. The TET1 and KCNMB1 levels in the model group were markedly increased compared with those in the control group. However, compared with the model group, the expression levels were markedly downregulated in the DMF, succinic acid and DMF + succinic acid groups. In conclusion, fumaric acid and succinic acid may treat gestational hypertension by downregulating the expression of KCNMB1 and TET1.

The separation and chemical analysis of mixtures in an emergency situation represent major challenges, especially in remote or poverty-stricken areas. A novel method was developed for the rapid separation and detection of multiple components via paper centrifugal chromatography, which costs as little as $2.26 US. The method was realized based on the combination of portable paper centrifugal chromatography and surface-enhanced Raman scattering (SERS) detection. This coupled technique was successfully implemented for the separation and qualitative analysis of a rhodamine 6G-crystal violet mixture and a colorless aniline-pyrocatechol-benzidine mixture. A chromatographic mobile phase was collected using absorbent cotton, which was demonstrated to have no effect on the SERS results. The optimized device achieved rapid and effective separation of the colorless aniline-pyrocatechol-benzidine mixture with a high centrifugal force (0.3303π2 N). The newly developed method involving multicomponent paper centrifugal chromatography-SERS detection will be of great value for emergency-related substance separation and analysis in remote and poor areas.

Summary Converting the greenhouse gas CO2 into higher alcohols (HAs) via hydrogenation reaction requires more attention in C1 chemistry because the C2+ alcoholic products are value-added chemicals as fuel additives, reaction solvents, and intermediates. However, the chemical inertness of CO2, complexity in various reaction routes, and uncontrollability of C–C coupling from untamed surface moieties in higher alcohol synthesis (HAS) make this approach very challenging to achieve. In this review, we summarize and analyze the recent advances in catalytic HAS from direct CO2 hydrogenation. The first section highlights the potential promising catalyst families, including a noble-metal class of catalysts, modified Co-based catalysts, modified Cu-based catalysts, and Mo-based catalysts with the roles of promoters and supports specified in each case. The second section reviews the possible reaction mechanisms based on previous experimental results. The rational design of ideal catalyst systems for this reaction is discussed in the third section.

The therapeutic effects of water extract of ginseng (WEG) on exercise-induced fatigue (EF) have been reported in several previous studies, but the molecular mechanisms involved remain unexplored. In this study, the anti-EF effects of WEG were studied, and the potential mechanisms were discussed. We characterized the chemical components of WEG by ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometry (UHPLC-QqQ-MS/MS) and high performance liquid chromatography coupled with evaporative light scattering detection (HPLC-ELSD), and then examined the anti-EF effects of WEG on a rat model of weight-loaded swimming with a focus on endogenous metabolism and gut microbiota. WEG contains abundant (90.15%, w/w) saccharides and ginsenosides with structurally diverse glycosyls. WEG taken orally showed strong anti-EF effects by ameliorating energy metabolism abnormality, oxidative stress, lipid peroxidation, inflammatory response, disorders in the metabolism of bile acid, amino acid, fatty acid and lipid, as well as the gut microbiota dysbiosis. Given that gut microbiota is significantly associated with energy expenditure, systemic inflammation and host metabolism, these findings suggest a potential central role of the gut microbiota in mediating the anti-EF effect of WEG. That is, the saccharides and ginsenosides in WEG serve as energy substrates for specific intestinal bacteria, thereby beneficially regulating the gut microbiota, and the reshaped gut microbial ecosystem then triggers several molecular and cellular signaling pathways (e.g. butyrate or TGR5 signals) to achieve the therapeutic effects on EF. The outcomes highlighted here enable deeper insight into how WEG overcomes EF.

We use coarse grained Molecular Dynamics simulations to determine the effect of diblock copolymers and inorganic sheet like compatibilizers at polymer blend interfaces. Previous studies have shown that the interfacial region is prone to slip if an external shear force is applied to the polymer blend. While a number of theoretical and computational studies have examined the effect of copolymer compatibilizers, the effect of adding sheet-like compatilibilizers (for e.g. nanoclay) has not been investigated computationally. Thus, while experiments have shown that sheet-like filler are effective, the exact mechanisms are unknown. Our results indicate that sheet like fillers that have equal affinity to either polymer in a binary blend can produce a larger reduction of interfacial tension when compared to diblock copolymers at equal volume fractions. However, the localization of sheet fillers at the interface can be a possible limiting factor. We also show that sheet fillers reduce slip, thus providing for improved stress transfer across the interface, leading to a stronger blend.

Glutamine:fructose-6-phosphate aminotransferase (GFAT) and phosphofructokinase (PFK) are enzymes related to chitin metabolism. RNA interference (RNAi) technology was used to explore the role of these two enzyme genes in chitin metabolism. In this study, we found that GFAT and PFK were highly expressed in the wing bud of Nilaparvata lugens and were increased significantly during molting. RNAi of GFAT and PFK both caused severe malformation rates and mortality rates in N. lugens. GFAT inhibition also downregulated GFAT, GNPNA, PGM1, PGM2, UAP, CHS1, CHS1a, CHS1b, Cht1-10, and ENGase. PFK inhibition significantly downregulated GFAT; upregulated GNPNA, PGM2, UAP, Cht2-4, Cht6-7 at 48 h and then downregulated them at 72 h; upregulated Cht5, Cht8, Cht10, and ENGase; downregulated Cht9 at 48 h and then upregulated it at 72 h; and upregulated CHS1, CHS1a, and CHS1b. In conclusion, GFAT and PFK regulated chitin degradation and remodeling by regulating the expression of genes related to the chitin metabolism and exert opposite effects on these genes. These results may be beneficial to develop new chitin synthesis inhibitors for pest control.

Psoriasis is a common inflammatory dermatology disease. Strongly expressed serum amyloid A (SAA) promotes psoriasis exacerbation through inducing IL-17 secretion. What's more, SAA can stimulate the release of cathepsin B. The current work was performed to demonstrate the specific effects of cathepsin B silencing on inflammatory response, proliferation, and differentiation of IL-17A and SAA-induced keratinocytes and to report the precise role of cathepsin B in psoriasis-like lesion. HaCaT keratinocytes received treatment with IL-17A (0, 10, 50, 100 ng/ml) or SAA (0, 1, 5, 10, 20 μg/ml) for 24 h to establish psoriasis-like keratinocytes model. HaCaT keratinocytes were transfected with small interfering RNA (siRNA)-cathepsin B for the functional experiments. Cathepsin B mRNA and protein levels were separately assessed by performing RT-qPCR and Western blot analysis. Then, CCK-8 for detection of cell proliferative capacity and Western blot assay for detection of Ki67 and PCNA expression were adopted to evaluate the influence of silenced cathepsin B on proliferation of IL-17A/SAA-induced HaCaT keratinocytes. Furthermore, IL-6, IL-1β, TNF-α, and p-NF-κB p65 were detected to assess the effects of cathepsin B knockdown on inflammatory response in IL-17A/SAA-induced HaCaT keratinocytes. In addition, assessment of KRT10, FLG, and LOR levels were applied to analyze the function of cathepsin B silencing on differentiation of IL-17A/SAA-induced HaCaT keratinocytes. Cathepsin B expression is distinctly elevated in IL-17A/SAA-induced HaCaT keratinocytes. IL-17A or SAA treatment enhanced proliferation, promoted the release of inflammatory factors, and arrested differentiation in HaCaT keratinocytes. Furthermore, downregulation of cathepsin B reduced proliferation, suppressed inflammatory response, and boosted differentiation in IL-17A/SAA-induced HaCaT keratinocytes. To sum up, cathepsin B silencing rescued excessive proliferation and inflammatory response and scarce differentiation in HaCaT keratinocytes induced by IL-17A and SAA. These findings prompted that cathepsin B might be a promising therapeutic target for psoriasis-like lesion, which helps to develop an anti-psoriatic agent.

Background and aims Limited data is available on the efficacy of direct acting anti-viral drugs on hepatitis C in drug users. The aim of this meta-analysis was to comprehensively analyze the efficacy and safety of LDV/SOF in drug users infected with the hepatitis C virus (HCV). Methods The PubMed, Cochrane library, Embase and Web of Science databases were searched for articles published till April 2021 on HCV-positive drug users who were treated with ledipasvir/sofosbuvir (LDV/SOF). The primary endpoint was pooled sustained virological response at 12 weeks (SVR12) with 95% confidence interval (95% CI). Funnel plots and Egger’s test were used to assess the publication bias. Results A total of 12 studies and 711 subjects treated with LDV/SOF-based regimen for HCV were included, and the pooled SVR12 rate was 89.8% (95% CI 85.9–92.7). The pooled SVR12 rate of genotype 1 drug users was 92.4% (95% CI 88.6–95.0). Subgroup analysis showed that pooled SVR12 rates of patients treated with LDV/SOF and LDV/SOF ± RBV were 89.2% (95% CI 83.4–93.1), 90.4% (95% CI 83.6–94.5) respectively. In addition, the SVR12 rates were 88% (95% CI 70.7–95.7) for 8 weeks, 89.9% (95% CI 81.0–94.9) for 12 weeks and 82.2% (95% CI 24.9–98.5) for 24 weeks of treatment. Conclusion LDV/SOF is a safe and relatively effective treatment for hepatitis C in drug users.