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As one of the most induced genes in activated macrophages, immune-responsive gene 1 (IRG1) encodes a mitochondrial metabolic enzyme catalysing the production of itaconic acid (ITA). Although ITA has an anti-inflammatory property, the underlying mechanisms are not fully understood. Here we show that ITA is a potent inhibitor of the TET-family DNA dioxygenases. ITA binds to the same site on TET2 as the co-substrate α-ketoglutarate, inhibiting TET2 catalytic activity. Lipopolysaccharide treatment, which induces Irg1 expression and ITA accumulation, inhibits Tet activity in macrophages. Transcriptome analysis reveals that TET2 is a major target of ITA in suppressing lipopolysaccharide-induced genes, including those regulated by the NF-κB and STAT signalling pathways. In vivo, ITA decreases the levels of 5-hydroxymethylcytosine, reduces lipopolysaccharide-induced acute pulmonary oedema as well as lung and liver injury, and protects mice against lethal endotoxaemia, depending on the catalytic activity of Tet2. Our study thus identifies ITA as an immune modulatory metabolite that selectively inhibits TET enzymes to dampen the inflammatory responses.

In the title complex, [Cu(C16H11Cl2NO4)(C3H7NO)] , the CuII atom is coordinated by two O atoms and one N atom from the tridentate ligand L2− {LH2 = (2S)-[2-(3,5-dichloro-2-hydroxybenzylidene)imino]-3-(4-hydroxyphenyl)propionic acid} and one O atom from a dimethylformamide molecule, resulting in a slightly distorted square-planar geometry. The structure forms a one-dimensional chain through weak coordination bonds [Cu...O 3.080 (1), Cu...Cl 3.269 (1) Å] and a three-dimensional network through O—H...O and C—H...O hydrogen bonds.

In the title complex, [Cu(C16H11Br2NO4)(C3H7NO)]2, there are two unique molecules in the asymmetric unit. Each CuII atom is coordinated by two O atoms and one N atom from the tridentate ligand L2− [LH2 = (E)-2-(3,5-dibromo-2-hydroxybenzylideneamino)-2-(4-hydroxyphenyl)acetic acid] and the O atom of a dimethylformamide molecule to give a slightly distorted square-planar geometry. The two unique molecules form a dimer through weak C—H...O hydrogen bonds. In the dimer, the Cu...Cu distance is 3.712 (1) Å. In the crystal structure, molecules form a one-dimensional chain through C—H...O hydrogen bonds. These are further aggregated into a three-dimensional network by O—H...O and C—H...O hydrogen bonds.

Silicone rubber composites have attracted wide attention due to their excellent thermal stability and climate resistance. However, it is still a challenge to synthesize these composites with high tensile property without external stimulation. Meanwhile, incorporation of superparamagnetic iron oxide nanoparticles to fabricate magnetic nanocomposites have a broad application prospect. In the present work, aiming to improve the mechanical and magnetic properties of the silicone rubber composite, fumed silica and different content of oleic acid‐modified Fe3O4 nanoparticles are well dispersed in the silicone rubber matrix. The synthesized nanocomposites exhibit excellent thermal stability, superelasticity, superparamagnetic property, and sensitive magnetic response. In particular, a high elongation at break of 1931%, a low storage modulus of 0.56 MPa and a deflection of 27 mm under an applied magnetic field of 1.31 Oe are obtained in the silicone rubber nanocomposite. The present work provides a feasible way to prepare silicone rubber matrix nanocomposites with excellent mechanical and magnetic performance. [ABSTRACT FROM AUTHOR]

B-cell acute lymphocytic leukemia (B-ALL) is a malignant blood cancer that develops in children and adults and leads to high mortality. THZ1, a covalent cyclin-dependent kinase 7 (CDK7) inhibitor, shows anti-tumor effects in various cancers by inhibiting cell proliferation and inducing apoptosis. However, whether THZ1 has an inhibitory effect on B-ALL cells and the underlying mechanism remains obscure. In this study, we showed that THZ1 arrested the cell cycle of B-ALL cells in vitro in a low concentration, while inducing the apoptosis of B-ALL cells in vitro in a high concentration by activating the apoptotic pathways. In addition, RNA-SEQ results revealed that THZ1 disrupted the cellular metabolic pathways of B-ALL cells. Moreover, THZ1 suppressed the cellular metabolism and blocked the production of cellular metabolic intermediates in B-ALL cells. Mechanistically, THZ1 inhibited the cellular metabolism of B-ALL by downregulating the expression of c-MYC-mediated metabolic enzymes. However, THZ1 treatment enhanced cell apoptosis in over-expressed c-MYC B-ALL cells, which was involved in the upregulation of p53 expression. Collectively, our data demonstrated that CDK7 inhibitor THZ1 induced the apoptosis of B-ALL cells by perturbing c-MYC-mediated cellular metabolism, thereby providing a novel treatment option for B-ALL. [ABSTRACT FROM AUTHOR]

Summary: Severe acquired aplastic anaemia (AA) is a serious disease characterised by autoreactive T cells attacking haematopoietic stem cells, leading to marrow hypoplasia and pancytopenia. Immunosuppressive therapy combined with antithymocyte globulin and ciclosporin can rescue most patients with AA. However, the relapse after ciclosporin withdrawal and the severe side effects of long‐term ciclosporin administration remain unresolved. As such, new strategies should be developed to supplement current therapeutics and treat AA. In this study, the possibility of all‐trans‐retinoic acid (ATRA) as an alternative AA treatment was tested by using an immune‐mediated mouse model of AA. Results revealed that ATRA inhibited T‐cell proliferation, activation and effector function. It also restrained the Fas/Fasl pathway, shifted Th1 towards Th2 cell development, rebalanced T‐cell subsets at a relatively high level and corrected the Th1/Th2 ratio by targeting NFAT1 signalling. In addition, ATRA inhibited Th17 cell differentiation and promoted regulatory T‐cell development. Therefore, ATRA was an effective agent to improve AA treatment outcomes. [ABSTRACT FROM AUTHOR]

Simple and rapid high-performance liquid chromatography methods were developed for the determination of berberine (BB) in various rat tissues so as to evaluate a P-gp inhibitor, glycyrrhetinic acid (GA), on BB's oral bioavailability. Acetonitrile was used to extract BB from tissues and showed different extraction recoveries in diverse tissues. The intra- and interday precision and accuracy were less than 10%. Long-term stability, pre (post) -preparative stability, and freeze-thaw stability were evaluated, and the results showed it could meet the need of this study. The proposed methods were subsequently applied to investigate the possible drug-drug interaction of GA and BB in vivo from the aspect of tissue distribution. The results showed that no significant difference was found between the group of low dose and high dose at the same time point. The tissue distributions show a saturated model, i.e., the content of BB in tissue tends to be constant while its dose is more than 200 mg/kg. Besides, the contents of BB ranged from high to low according to the order of the liver, kidney, and spleen. The BB content in the liver is especially high as compared to other tissues. [ABSTRACT FROM AUTHOR]

To combine homomorphic public key encryption with reversible data hiding, a reversible data hiding scheme in homomorphic encrypted image based on EC-EG is proposed. Firstly, the cover image is segmented. The square grid pixel group randomly selected by the image owner has one reference pixel and eight target pixels. The n least significant bits (LSBs) of the reference pixel and all bits of target pixel are self-embedded into other parts of the image by a method of predictive error expansion (PEE). To avoid overflowing when embedding data, the n LSBs of the reference pixel are reset to zero before encryption. Then, the pixel values of the image are encrypted after being encoded onto the points of the elliptic curve. The encrypted reference pixel replaces the encrypted target pixels surrounding it, thereby constructing the mirroring central ciphertext (MCC). In a set of MCC, the data hider embeds the encrypted additional data into the n LSBs of the target pixels by homomorphic addition in ciphertexts, while the reference pixel remains unchanged. The receiver can directly extract additional data by homomorphic subtraction in ciphertexts between the target pixels and the corresponding reference pixel; extract the additional data by subtraction in plaintexts with the directly decrypted image; and restore the cover image without loss. The experimental results show that the proposed scheme has higher security than the similar algorithms, and the average embedding rate of the scheme is 0.25 bpp under the premise of ensuring the quality of the directly decrypted image. [ABSTRACT FROM AUTHOR]

Since waves fluctuate continuously, the forecast of the wave energy is very important for the operation of the power system integrated with large-scale wave energy generations. Waves are driven by wind, so that the relationship between wind and wave is very useful in wave energy forecast. Hence, a wave energy forecast method based on the wind–wave coupling model is proposed in this paper. The wave is first divided into wind waves and swells. The correlation between wind and wind wave is analyzed, and a wind–wave coupling model is established using copula function. Based on the coupling model and the forecasted wind speed, the average wave height of the wind wave can be forecasted, while the time series method is used to forecast the average wave height of the swell. Combining the wind wave and the swell, the average wave height of the integrated wave is obtained and the wave energy can be forecasted. Using the measured wind and wave data from a real ocean, the day-ahead wave energy is forecasted by the proposed method. The forecast result is close to the measured data and the effectiveness of the proposed wave energy forecast method is validated. [ABSTRACT FROM AUTHOR]

As a representative paradigm of evolutionary algorithms, particle swarm optimization (PSO) has been combined with partial least square (PLS) (called PSO-PLS) to select informative descriptors in quantitative structure-activity/property relationship (QSAR/QSPR). However, one of the main limitations of PSO-PLS is that it ignores PLS model information. In this paper, by incorporating the PLS model information into PSO-PLS, we present a novel weighted sampling method (called WS-PSO-PLS) to choose the optimal descriptor subset. Due to the fact that the regression coefficients of the PLS model reflect the importance of descriptors in the model development, we firstly obtain the normalized regression coefficients by establishing the PLS model with all the descriptors. Afterward, weighted sampling is used to generate some individuals according to the aforementioned normalized regression coefficients. Finally, we employ some dimensions of the generated individuals to replace the corresponding dimensions of the individuals with poor quality in the population at each generation. WS-PSO-PLS has been assessed through three QSAR/QSPR datasets and the experimental results suggest that WS-PSO-PLS has the capability to effectively guide the search process by introducing the PLS model coefficients into PSO during the evolution and, therefore, performs better than PSO-PLS. WS-PSO-PLS could be considered as a general and promising mechanism to introduce extra information to improve the performance of PSO for descriptor selection in QSAR/QSPR. [ABSTRACT FROM AUTHOR]

This paper describes Picat's planner, its implementation, and planning models for several domains used in International Planning Competition (IPC) 2014. Picat's planner is implemented by use of tabling. During search, every state encountered is tabled, and tabled states are used to effectively perform resource-bounded search. In Picat, structured data can be used to avoid enumerating all possible permutations of objects, and term sharing is used to avoid duplication of common state data. This paper presents several modeling techniques through the example models, ranging from designing state representations to facilitate data sharing and symmetry breaking, encoding actions with operations for efficient precondition checking and state updating, to incorporating domain knowledge and heuristics. Broadly, this paper demonstrates the effectiveness of tabled logic programming for planning, and argues the importance of modeling despite recent significant progress in domain-independent PDDL planners. [ABSTRACT FROM AUTHOR]

Tabling has been used for some time to improve efficiency of Prolog programs by memorizing answered queries. The same idea can be naturally used to memorize visited states during search for planning. In this paper we present a planner developed in the Picat language to solve the Petrobras planning problem. Picat is a novel Prolog-like language that provides pattern matching, deterministic and non-deterministic rules, and tabling as its core modelling and solving features. We demonstrate these capabilities using the Petrobras problem, where the goal is to plan transport of cargo items from ports to platforms using vessels with limited capacity. Monte Carlo Tree Search has been so far the best technique to tackle this problem and we will show that by using tabling we can achieve much better runtime efficiency and better plan quality. [ABSTRACT FROM AUTHOR]

Hydrazonyl radicals are known for their π-electronic structures; however, their σ-electronic structures have not been reported as yet. Herein, we show that readily accessible β,γ- and γ,δ-unsaturated N-trichloroacetyl and N-trifluoroacetyl hydrazones can be conveniently converted into hydrazonyl σ radicals, which subsequently undergo 5- exo-trig radical cyclization at the N1 or N2 atom to form pyrazolines and azomethine imines, respectively. [ABSTRACT FROM AUTHOR]

This paper presents our program in B-Prolog submitted to the third ASP solver competition for the Sokoban problem. This program, based on dynamic programming, treats Sokoban as a generalized shortest path problem. It divides a problem into independent subproblems and uses mode-directed tabling to store subproblems and their answers. This program is very simple but quite efficient. Without use of any sophisticated domain knowledge, it easily solves 14 of the 15 instances used in the competition. We show that the approach can be easily applied to other optimization planning problems. [ABSTRACT FROM AUTHOR]

Current tabling systems suffer from an increase in space complexity, time complexity or both when dealing with sequences due to the use of data structures for tabled subgoals and answers and the need to copy terms into and from the table area. This symptom can be seen in not only B-Prolog, which uses hash tables, but also systems that use tries such as XSB and YAP. In this paper, we apply hash-consing to tabling structured data in B-Prolog. While hash-consing can reduce the space consumption when sharing is effective, it does not change the time complexity. We enhance hash-consing with two techniques, called input sharing and hash code memoization, for reducing the time complexity by avoiding computing hash codes for certain terms. The improved system is able to eliminate the extra linear factor in the old system for processing sequences, thus significantly enhancing the scalability of applications such as language parsing and bio-sequence analysis applications. We confirm this improvement with experimental results. [ABSTRACT FROM AUTHOR]

A new method based on chemical vapor generation (CVG) coupled with flame atomic absorption spectrometry (FAAS) was developed for the determination of iron, cobalt and nickel in environmental and biological samples. Room temperature ionic liquids (RTIL) combined with ammonium pyrroldinedithiocarbamate (APDC) were used to synergetically enhance the CVG of iron, cobalt and nickel. The addition of RTIL leads to 2.5, 3.2, 3.0 times improvement in the CVG efficiencies of Fe, Co and Ni, respectively. The efficiencies for the CVG of Fe, Co and Ni in the presence of RTIL and APDC were 42%, 61% and 54%, respectively. Volatile species of iron, cobalt and nickel were effectively generated through reduction of acidified analyte solutions with KBH4 in the presence of 0.02% or 0.01% (m/v) APDC and 0.1% or 0.2% (m/v) 1-butyl-3-methylimidazolium hexafluorophosphate ([C4MIM]PF6). Some parameters that influenced CVG and subsequent determination were evaluated in detail, such as the concentrations of RTIL, APDC, nitric acid (HNO3) and KBH4; flow rates of carrier gas, lengths of reaction tube and transfer tube, as well as interferences. Under optimized conditions, the detection limits (LODs) for Fe, Co and Ni were 18, 14 and 11 ng mL−1, respectively. Relative standard deviations for five replicate determinations of the standard solution containing 500 ng mL−1 Fe, Co and Ni were 5.3%, 4.6% and 4.3%, respectively. The proposed method was successfully applied to the determination of iron, cobalt and nickel in certified environmental and biological reference materials with satisfactory results. [ABSTRACT FROM AUTHOR]

B-Prolog is a high-performance implementation of the standard Prolog language with several extensions including matching clauses, action rules for event handling, finite-domain constraint solving, arrays and hash tables, declarative loop constructs, and tabling. The B-Prolog system is based on the Tree-Oriented Abstract Machine (TOAM) architecture which differs from the Warren Abstract Machine (WAM) mainly in that (1) arguments are passed old fashionedly through the stack, (2) only one frame is used for each predicate call, and (3) instructions are provided for encoding matching trees. The most recent architecture, called TOAM Jr., departs further from the WAM in that it employs no registers for arguments or temporary variables, and provides variable-size instructions for encoding predicate calls. This paper gives an overview of the language features and a detailed description of the TOAM Jr. architecture, including architectural support for action rules and tabling. [ABSTRACT FROM PUBLISHER]

A rapid, simple, and specific liquid chromatography-electrospray ionization-mass spectrometric method has been developed and validated for the determination of fluoxetine in human plasma. The method was validated with a linear range of 0.5-100 ng mL-1, and the lowest limits of quantification were 0.5 ng mL-1 for fluoxetine. The extraction efficiencies were about 65% and recoveries of method were in the range of 94.0-97.5%. The intraday relative standard deviation (RSD) was less than 11% and interday RSD was within 12%. The method has been successfully applied to the evaluation of pharmacokinetics and bioequivalence of fluoxetine. [ABSTRACT FROM AUTHOR]

A rapid, simple, and specific liquid chromatography–electrospray ionization mass spectrometry (LC–ESI-MS) method has been developed and validated for the determination of lisinopril in human plasma. Enalaprilat was used as the internal standard (IS). Sample preparation of the serum involved deproteination with methanol twice, repeatedly. Samples were separated using a Thermo Hypersil-HyPURITY C18 reversed-phase column (150 × 2.1 mm i.d., 5 µm). Mobile phase consisted of formic acid solution (pH 2.9)–methanol–acetonitrile (58:25:17, v/v). Lisinopril and its internal standard were measured by electrospray ion source in positive selected ion monitoring mode. The method was validated with a linear range of 2.5–320 ng/mL and the lowest limits of quantitation were 2.5 ng/mL for lisinopril. The extraction efficiencies were approximately 80% and recoveries of method were in range of 94.4–98.2%. The intra-day relative standard deviation (RSD) was less than 8.8% and inter-day RSD was within 10.3%. QC samples were stable when kept at ambient temperature for 24 h, at –20°C for 30 days and after four freeze/thaw cycles. The method has been successfully applied to the evaluation of pharmacokinetics and bioequivalence of 2 lisinopril formulations in 18 healthy Chinese volunteers after an oral dose of 20 mg. [ABSTRACT FROM AUTHOR]

Licorice is the most widely used crude drug in traditional Chinese medicine. Glycyrrhetinic acid (GA) is the metabolite of glycyrrhizic acid, which is the main bioactive ingredient of licorice. In this work, capillary electrophoresis-frontal analysis (CE-FA) was applied to study the binding of bovine serum albumin with GA and two diuretics: furosemide (FU) and hydrochlorothiazide (HZ). The binding parameters of GA were determined by Scatchard analysis, which showed that there are two kinds of binding sites in bovine serum albumin for GA. However, the results showed that the CE-FA method was not suitable for the interaction study of FU and HZ. Therefore, utracentrifugation-CE was used to probe the binding characteristic of these two drugs and the results showed only one kind of binding site for them under the studied conditions. Displacement interactions between these drugs were also investigated by utracentrifugation-CE method and the results showed that GA hardly displaces HZ while it can slightly displace FU and FU can slightly displace HZ. For comparison, the binding of these drugs was also studied by the fluorescence quenching method and the data were processed by the Stern-Volmer quenching equation. Results showed that the binding constants were basically consistent for two methods for all drugs studied. The number of binding sites on one protein molecule was well consistent for FU and HZ while it was quite different for GA. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Mode information (directional information concerning the arguments of predicates) is important in improving the speed of the execution of logic programs. This paper proposes a bi-directional inference algorithm for inferring precise mode information. Compared with the conventional inference algorithms, the proposed algorithm has the following two features: (1) the algorithm utilizes not only the modes of the predicates at the top level but also the modes of the built-in predicates used in the program; and (2) by propagating the modes of the top level predicates top-down and that of the built-in predicates bottom-up, more precise mode information can be inferred. [ABSTRACT FROM AUTHOR]

Hydrazonyl radicals, generally possessing π-electronic structures, can be tuned to σ radicals by attaching a trifluoroacetyl or trichloroacetyl group to the N-1 atom. [ABSTRACT FROM AUTHOR]

Leucine-rich repeat containing G-protein-coupled receptor 6 (LGR6) is a member of the rhodopsin-like 7-transmembrane domain receptor superfamily and has high homology to LGR4 and LGR5. LGR6 is highly expressed in osteoblastic progenitors, and LGR6-deficient mice show nail and bone regeneration defect. However, the effect of LGR6 on the osteogenic differentiation of osteoblastic progenitors and its underlying mechanisms are largely unknown. In this study, we overexpressed and knockdown LGR6 with lentivirus in the preosteoblastic cell MC3T3-E1 to observe the effect of LGR6 on osteogenic differentiation and explore its possible molecular mechanism. LGR6 overexpression promoted osteogenic differentiation and mineralization by stabilizing β-catenin to potentiate the Wnt/β-catenin signaling pathway in MC3T3-E1 cells. Conversely, LGR6 knockdown inhibited osteogenic differentiation and mineralization by enhancing β-catenin degradation to inactivate the Wnt/β-catenin signaling pathway. These results reveal that LGR6 is highly expressed in osteoblastic progenitors, and promotes osteogenesis by enhancing β-catenin stability to strengthen the Wnt signaling pathway. This study provides an important reference into the exact mechanisms of osteogenic differentiation. • LGR6 expression is remarkably increased during osteogenic differentiation in MC3T3-E1. • LGR6 overexpression promotes the osteogenic differentiation of MC3T3-E1. • LGR6 overexpression activates the Wnt pathway by stabilizing β-catenin. • LGR6 knockdown inhibits osteogenic differentiation by suppressing the Wnt pathway. [ABSTRACT FROM AUTHOR]

Aplastic anemia (AA) is a serious blood system disease that threatens human health. At present, the main cause of this disease is believed to be immune hyperfunction. However, the specific metabolic mode involved in the occurrence of lymphocytes in AA is still unknown. In addition, whether rapamycin, a specific blocker of the mTOR signaling pathway, plays a therapeutic role by inhibiting lymphocyte metabolism remains unclear. We induced an AA mouse model through the classical immune-mediated pathway and simultaneously administered rapamycin intervention therapy. First, the AA-associated phenotypic changes and the efficacy of rapamycin in the treatment of AA were discussed. Second, the proliferation and metabolic pathway of bone marrow (BM) lymphocytes in AA and the effect of rapamycin on this process were determined. Finally, the expression levels of mTOR pathway-related proteins were analyzed. By inhibiting the mTOR signaling pathway, rapamycin could ameliorate the phenotype of the immune-mediated AA model and inhibit the proliferation of T cells by preventing cell cycle transition from G0 to G1 phase. Moreover, we found that mitochondrial oxidative phosphorylation is involved in the metabolic reprogramming of T cells in AA and that rapamycin can inhibit this process. We confirmed that mitochondrial oxidative phosphorylation is involved in the metabolic reprogramming of T cells in AA and further extended the mechanism of rapamycin in treating AA by inhibiting the mTOR signaling pathway. This viewpoint may provide a new therapeutic idea for clinical applications. • Rapamycin could ameliorate the phenotype of the immune-mediated AA model. • Rapamycin inhibits the proliferation of T cells by preventing cell cycle transition. • Rapamycin inhibits the mitochondrial metabolism of T cells in vivo. • Rapamycin exerts its function by inhibiting the mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Action planning deals with the problem of finding a sequence of actions transferring the world from a given state to a desired (goal) state. This problem is important in various areas such as robotics, manufacturing, transportation, autonomic computing, computer games, etc. Action planning is a form of a reachability problem in a huge state space so it is critical to efficiently represent world states and actions (transitions between states). In this paper we present a modeling framework for planning problems based on tabled logic programming that exploits a planner module in the Picat language. In particular, we suggest techniques for structured representation of states and for including control knowledge in the description of actions. We demonstrate these techniques using the complex planning domain Cave Diving from the International Planning Competition. Experimentally, we show properties of the model for different search approaches and we compare the performance of the proposed approach with state-of-the-art automated planners. The focus of this paper is on providing guidelines for manual modeling of planning domains rather than on automated reformulation of models. [ABSTRACT FROM AUTHOR]