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The metabolite profiles and distributions of procyanidin B2 were qualitatively described using UPLC-DAD-ESI-IT-TOF-MSn without help of reference standards, and a possible metabolic pathway was proposed in the present study. Summarily, 53 metabolites (24 new metabolites) were detected as metabolites of procyanidin B2, and 45 of them were tentatively identified. Twenty seven metabolites were assigned as similar metabolites of (−)-epicatechin by scission of the flavanol interflavanic bond C4–C8, including 16 aromatic metabolites, 5 conjugated metabolites, 3 ring-cleavage metabolites, and 2 phenylvalerolactone metabolites. Additionally, 14 metabolites were conjugates of free procyanidin B2, comprising 9 methylation metabolites, 8 sulfation metabolites, 5 hydration metabolites, 2 hydroxylation metabolites, 1 hydrogenation metabolites, and 1 glucuronidation metabolites. The results of metabolite distributions in organs indicated that the conjugated reaction of free procyanidin B2 mainly occurred in liver and diversified metabolites forms were observed in small intestine. The metabolic components of procyanidin B2 identified in mice provided useful information for further study of the bioactivity and mechanism of its action.

Pyruvate dehydrogenase kinase 1 (PDK1) is overexpressed in ovarian cancer and thus is a promising anticancer therapeutic target. Our previous work suggests that coumarin compounds are potential inhibitors of PDKs. In this study, we used the ovarian cancer cell line SKOV3 as the model system and examined whether dicumarol (DIC), a coumarin compound, could inhibit ovarian cancer through targeting PDK1. We showed that DIC potently inhibited the kinase activity of PDK1, shifted the glucose metabolism from aerobic glycolysis to oxidative phosphorylation, generated a higher level of reactive oxygen species (ROS), attenuated the mitochondrial membrane potential (MMP), induced apoptosis, and reduced cell viability in vitro. The same phenotypes induced by DIC also were translated in vivo, leading to significant suppression of xenograft growth. This study not only identifies a novel inhibitor for PDK1, but it also reveals novel anticancer mechanisms of DIC and provides a promising anticancer therapy that targets the Warburg effect.

An efficient one-pot tandem cyclization/[3 + 2] cycloaddition reaction of N’-(2-alkynylbenzylidene)hydrazides with ethyl 4,4,4-trifluorobut-2-ynoate under silver triflate-catalyzed or electrophile-mediated conditions is described. Various trifluoromethylated pyrazolo[5,1-a]isoquinolines were afforded in moderate to excellent yield by this developed method.

Lytic polysaccharide monooxygenases (LPMOs) are key enzymes in both the natural carbon cycle and the biorefinery industry. Understanding the molecular basis of LPMOs acting on polysaccharide substrates is helpful for improving industrial cellulase cocktails. Here we analyzed the sequences, structures, and substrate binding modes of LPMOs to uncover the factors that influence substrate specificity and regioselectivity. Our results showed that the different compositions of a motif located on L2 affect the electrostatic potentials of substrate binding surfaces, which in turn affect substrate specificities of AA10 LPMOs. A conserved Asn at a distance of 7 Å from the active center Cu might, together with the conserved Ser immediately before the second catalytic His, determine the localization of LPMOs on substrate, and thus contribute to C4-oxidizing regioselectivity. The findings in this work provide an insight into the molecular basis of substrate specificity and regioselectivity of LPMOs.

Self-assembly growth of alloyed NiPt nanocrystals with holothuria-like wire shape has been achieved via a facile and moderate hydrothermal process at 120 °C for 1 h from the reaction of nickel nitrate and chloroplatinic acid in alkaline solution in the presence of ethanediamine and hydrazine hydrate. The holothuria-like alloyed NiPt wires are Ni-rich in composition (Ni23.6Pt) and uniform in diameter with many tiny tips outstretched from the wires surface. The holothuria-like wires are assembled from granular subunits with the assistance of capping molecular of ethanediamine and the wires display an improved oxygen evolution reaction catalytic activity.

Radar coincidence imaging (RCI) is a high-resolution staring imaging technique without the limitation of the target relative motion. To achieve better imaging performance, sparse reconstruction is commonly used. While its performance is based on the assumption that the scatterers are located at the prediscretized grid-cell centers, otherwise, off-grid emerges and the performance of RCI degrades significantly. In this paper, RCI using frequency-hopping (FH) waveforms is considered. The off-grid effects are analyzed, and the corresponding constrained Cramér-Rao bound (CCRB) is derived based on the mean square error (MSE) of the “oracle” estimator. For off-grid RCI, the process is composed of two stages: grid matching and off-grid error (OGE) calibration, where two-dimension (2D) band-excluded locally optimized orthogonal matching pursuit (BLOOMP) and alternating iteration minimization (AIM) algorithms are proposed, respectively. Unlike traditional sparse recovery methods, BLOOMP realizes the recovery in the refinement grids by overwhelming the shortages of coherent dictionary and is robust to noise and OGE. AIM calibration algorithm adaptively adjusts the OGE and, meanwhile, seeks the optimal target reconstruction result.

The two-dimensional angular resolution limit (ARL) of elevation and azimuth for MIMO radar with ultrawideband (UWB) noise waveforms is investigated using statistical resolution theory. First, the signal model of monostatic UWB MIMO noise radar is established in a 3D reference frame. Then, the statistical angular resolution limits (SARLs) of two closely spaced targets are derived using the detection-theoretic and estimation-theoretic approaches, respectively. The detection-theoretic approach is based on the generalized likelihood ratio test (GLRT) with given probabilities of false alarm and detection, while the estimation-theoretic approach is based on Smith’s criterion which involves the Cramér-Rao lower bound (CRLB). Furthermore, the relationship between the two approaches is presented, and the factors affecting the SARL, that is, detection parameters, transmit waveforms, array geometry, signal-to-noise ratio (SNR), and parameters of target (i.e., radar cross section (RCS) and direction), are analyzed. Compared with the conventional radar resolution theory defined by the ambiguity function, the SARL reflects the practical resolution ability of radar and can provide an optimization criterion for radar system design.

Serine protease inhibitors (serpins) are native inhibitors of serine proteases, constituting a large protein family with members spread over eukaryotes and prokaryotes. However, only very few prokaryotic serpins, especially from extremophiles, have been characterized to date. In this study, Pnserpin, a putative serine protease inhibitor from the thermophile Pyrobaculum neutrophilum, was overexpressed in Escherichia coli for purification and characterization. It irreversibly inhibits chymotrypsin-, trypsin-, elastase-, and subtilisin-like proteases in a temperature range from 20 to 100 °C in a concentration-dependent manner. The stoichiometry of inhibition (SI) of Pnserpin for proteases decreases as the temperature increases, indicating that the inhibitory activity of Pnserpin increases with the temperature. SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis) showed that Pnserpin inhibits proteases by forming a SDS-resistant covalent complex. Homology modeling and molecular dynamic simulations predicted that Pnserpin can form a stable common serpin fold. Results of the present work will help in understanding the structural and functional characteristics of thermophilic serpin and will broaden the current knowledge about serpins from extremophiles.

BackgroundThe Chinese population has undergone rapid transition to a high-fat diet. Furthermore, monosodium L-glutamate (MSG) is widely used as a daily food additive in China. Little information is available on the effects of oral MSG and dietary fat supplementation on the amino acid balance in tissues. The present study aimed to determine the effects of both dietary fat and MSG on amino acid metabolism in growing pigs, and to assess any possible interactions between these two nutrients.Methods and resultsFour iso-nitrogenous and iso-caloric diets (basal diet, high fat diet, basal diet with 3% MSG and high fat diet with 3% MSG) were provided to growing pigs. The dietary supplementation with fat and MSG used alone and in combination were found to modify circulating and tissue amino acid pools in growing pigs. Both dietary fat and MSG modified the expression of gene related to amino acid transport in jejunum.ConclusionsBoth dietary fat and MSG clearly influenced amino acid content in tissues but in different ways. Both dietary fat and MSG enhance the absorption of amino acids in jejunum. However, there was little interaction between the effects of dietary fat and MSG.

Objective. Rab27b is reported to correlate with cancer development and progression. However, the association between Rab27b expression and the clinical characteristics of colorectal cancer (CRC) is barely investigated. Methods. One-step quantitative reverse transcription-polymerase chain reaction (qPCR) test with 18 fresh-frozen CRC samples and immunohistochemistry (IHC) analysis in 113 CRC cases were performed to explore the relationship between Rab27b expression and the clinicopathological features of CRC. Cox regression and Kaplan-Meier survival analyses were executed to evaluate the prognosis of CRC. Results. The results demonstrated that the expression levels of Rab27b mRNA and protein were significantly higher in CRC tissues than that in matched noncancerous tissues (P

Nature Communications 7: Article number: 11146 (2016); Published: 31 March 2016; Updated: 26 April 2016 In Fig. 3 of this Article, data in panel ‘a’ were inadvertently partially obscured during the production process. The correct version of Fig. 3 now appears in the PDF and HTML versions of the Article.

Pyruvate dehydrogenase kinases (PDKs) are key enzymes in glucose metabolism, negatively regulating pyruvate dehyrogenase complex (PDC) activity through phosphorylation. Inhibiting PDKs could upregulate PDC activity and drive cells into more aerobic metabolism. Therefore, PDKs are potential targets for metabolism related diseases, such as cancers and diabetes. In this study, a series of computer-aided virtual screening techniques were utilized to discover potential inhibitors of PDKs. Structure-based screening using Libdock was carried out following by ADME (adsorption, distribution, metabolism, excretion) and toxicity prediction. Molecular docking was used to analyze the binding mechanism between these compounds and PDKs. Molecular dynamic simulation was utilized to confirm the stability of potential compound binding. From the computational results, two novel natural coumarins compounds (ZINC12296427 and ZINC12389251) from the ZINC database were found binding to PDKs with favorable interaction energy and predicted to be non-toxic. Our study provide valuable information of PDK-coumarins binding mechanisms in PDK inhibitor-based drug discovery.

The complex molecule of the title compound, [Mn(C13H10N4O8)(H2O)2] or [Mn(H4pbidc)(H2O)2] (H6pbidc = 2,2′-(propane-1,3-diyl)bis(1H-imidazole-4,5-dicarboxylic acid), has 2 symmetry with the twofold rotation axis running through the Mn2+ cation and the central C atom of the propanediyl unit. The cation is six-coordinated by two N atoms and two O atoms from one H4pbidc2− anion and two water O atoms in a considerably distorted octahedral coordination. In the crystal, adjacent molecules are linked through O—H...O and N—H...O hydrogen bonds into a three-dimensional network.