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Metal nitrides are usually prepared by high temperature nitridation with metal oxide precursors under an NH3 atmosphere. However, owing to the differences in crystal structures between oxide precursors and nitride products, the preparation of oriented nitride nanostructures is difficult and challenging. Our previous work has demonstrated that a [100]-oriented TaON film can be fabricated by using a (012)-LiTaO3 single crystal substrate through an endotaxial transformation process. However, details about the endotaxial growth mechanism are still unclear. In this work, we systematically investigated the endotaxial growth process of TaON from the LiTaO3 single crystal substrate, and proposed a plausible growth mechanism. This work could be helpful to deepen the understanding of the unique endotaxial growth process and facilitate the fabrication of other oriented nitride nanostructures. [ABSTRACT FROM AUTHOR]

For tunnelling in urban areas, the current sequential excavation (SE) method usually increases the number of temporary drifts to achieve better control of surface settlements, which may prolong construction duration. In this case study, a four-drift SE method, termed the suspension-type centre cross diaphragm (S-CRD) method, was proposed and applied to the construction of a large cross-section tunnel in soft ground, where normally the six-drift double-side drift (DSD) method would be adopted. Field monitoring results and statistical data indicated that, in comparison with the six-drift DSD method, the four-drift S-CRD method achieved better control of the surface settlements while improving the efficiency of construction by 30%. The advantages of the S-CRD method, i.e., safe and rapid construction, were eminently clear. [ABSTRACT FROM AUTHOR]

The construction of protective forests in Nursultan is key to reducing near-surface wind speeds and snowstorm effects in urban areas. This study analyzed the effects of the number of plant rows and spacing of the shelterbelts on the flow field around protective forests to evaluate the wind protection benefits of the existing configuration of the shelterbelt in Nursultan and guide the construction of protective forests. We measured the airflow fields of four shelterbelts with different numbers of rows, seven double pure shelterbelts, and double mixed shelterbelts of arbors and shrubs with different spacings. The results showed that the airflow field around the shelterbelts can be divided into five characteristic regions based on shelter efficiency: a deceleration region before the shelterbelt, acceleration region above the canopy, strong deceleration region in the canopy layer, deceleration region behind the shelterbelt, and recovery region behind the shelterbelt. In terms of windproof ability, the wind protection benefits of a shelterbelt with six rows are the best in a single shelterbelt. Behind the shelterbelt, the wind protection benefits of double pure shelterbelts are greater than that of double mixed shelterbelts of arbor and shrub. On the contrary, the windbreak benefits of the latter are stronger than those of the former between the two shelterbelts. [ABSTRACT FROM AUTHOR]

The fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) signaling pathways play critical roles in a variety of cancers, such as hepatocellular carcinoma (HCC). FGFR4 is recognized as a promising target to treat HCC. Currently, all FGFR covalent inhibitors target one of the two cysteines (Cys477 and Cys552). Here, we designed and synthesized a dual-warhead covalent FGFR4 inhibitor, CXF-009, targeting Cys477 and Cys552 of FGFR4. We report the cocrystal structure of FGFR4 with CXF-009, which exhibits a dual-warhead covalent binding mode. CXF-009 exhibited stronger selectivity for FGFR4 than FGFR1-3 and other kinases. CXF-009 can also potently inhibit the single cystine mutants, FGFR4(C477A) and FGFR4(C552A), of FGFR4. In summary, our study provides a dual-warhead covalent FGFR4 inhibitor that can covalently target two cysteines of FGFR4. CXF-009, to our knowledge, is the first reported inhibitor that forms dual-warhead covalent bonds with two cysteine residues in FGFR4. CXF-009 also has the potential to overcome drug induced resistant FGFR4 mutations and might serve as a lead compound for future anticancer drug discovery. Fibroblast growth factor receptor 4 (FGFR4) is a promising target for the treatment of hepatocellular carcinoma, but current FGFR4 covalent inhibitors target only one of the two cysteine residues (Cys477 or Cys552) that provide FGFR4-specificity. Here, a dual-warhead covalent FGFR4 inhibitor that can covalently target both cysteine residues of FGFR4 is reported, and strong selectivity for FGFR4 is observed. [ABSTRACT FROM AUTHOR]

The fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) signaling pathways play critical roles in a variety of cancers, such as hepatocellular carcinoma (HCC). FGFR4 is recognized as a promising target to treat HCC. Currently, all FGFR covalent inhibitors target one of the two cysteines (Cys477 and Cys552). Here, we designed and synthesized a dual-warhead covalent FGFR4 inhibitor, CXF-009, targeting Cys477 and Cys552 of FGFR4. We report the cocrystal structure of FGFR4 with CXF-009, which exhibits a dual-warhead covalent binding mode. CXF-009 exhibited stronger selectivity for FGFR4 than FGFR1-3 and other kinases. CXF-009 can also potently inhibit the single cystine mutants, FGFR4(C477A) and FGFR4(C552A), of FGFR4. In summary, our study provides a dual-warhead covalent FGFR4 inhibitor that can covalently target two cysteines of FGFR4. CXF-009, to our knowledge, is the first reported inhibitor that forms dual-warhead covalent bonds with two cysteine residues in FGFR4. CXF-009 also has the potential to overcome drug induced resistant FGFR4 mutations and might serve as a lead compound for future anticancer drug discovery. Fibroblast growth factor receptor 4 (FGFR4) is a promising target for the treatment of hepatocellular carcinoma, but current FGFR4 covalent inhibitors target only one of the two cysteine residues (Cys477 or Cys552) that provide FGFR4-specificity. Here, a dual-warhead covalent FGFR4 inhibitor that can covalently target both cysteine residues of FGFR4 is reported, and strong selectivity for FGFR4 is observed. [ABSTRACT FROM AUTHOR]

Aberrant signaling via fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) has been identified as a driver of tumorigenesis and the development of many solid tumors, making FGFR4 is a promising target for anticancer therapy. Herein, we designed and synthesized a series of bis-acrylamide covalent FGFR4 inhibitors and evaluated their inhibitory activity against FGFRs, FGFR4 mutants, and their antitumor activity. CXF-007 , verified by mass spectrometry and crystal structures to form covalent bonds with Cys552 of FGFR4 and Cys488 of FGFR1, exhibited stronger selectivity and potent inhibitory activity for FGFR4 and FGFR4 cysteine mutants. Moreover, CXF-007 exhibited significant antitumor activity in hepatocellular carcinoma cell lines and breast cancer cell lines through sustained inhibition of the FGFR4 signaling pathway. In summary, our study highlights a novel covalent FGFR4 inhibitor, CXF-007 , which has the potential to overcome drug-induced FGFR4 mutations and might provide a new strategy for future anticancer drug discovery. [Display omitted] • The covalent inhibitor CXF-007 demonstrated the greatest potency against FGFR4. • CXF-007 has the potential to overcome acquired FGFR4 cysteine mutants. • CXF-007 selectively inhibits and interacts more with FGFR4. • CXF-007 potently inhibits proliferation and FGFR4 signaling in cancer cell lines. [ABSTRACT FROM AUTHOR]

[Display omitted] • Deep bulk K doped carbon nitride was realized by adapted ionothermal treatment. • Electron transfer bridge facilitates the bulk carrier transfer to the surface. • The utilization of penetrated light and bulk carrier was enhanced. • 139 times improved H 2 O 2 production rate was obtained. The incorporation of potassium (K) ions into polymerized carbon nitride has been experimentally proven to be an efficient strategy for enhancing photocatalytic performance. However, the diffusion doping in the traditional ionothermal post-treatment of pre-polymerized precursor results in only surface-level K doping. This limitation hinders the effective utilization of the incident light and photogenerated electrons in the deeper bulk, especially the mismatched zone between the depth of light absorption and carrier diffusion length. In this study, K dopants were successfully introduced into the deep bulk of carbon nitride while maintaining the integrity of heptazine skeleton structure by treating exfoliated nanosheets. Compared to the superficially doped counterpart, both experiments and theoretical calculations indicate the deeper K dopants not only activate the bulk light harvest and facilitate carrier separation, but also fabricate an efficient electron transfer bridge. This bridge is responsible for extracting the electrons to the surface, thus facilitating the O 2 reduction reaction. Consequently, a 139-fold enhancement in the H 2 O 2 production rate over pristine carbon nitride was achieved, surpassing the performance of most recently reported photocatalysts. This study would deepen the understanding of the role of bulk doping and stimulate the development of doping beyond the superficial zone. [ABSTRACT FROM AUTHOR]

• CCl 4 assisted method was firstly applied to construct free-standing g-C 3 N 4 films. • Metal cations can be in-situ extracted from the substrates and serve as nucleate sites. • The physicochemical properties of the g-C 3 N 4 films can be easily adjusted. • The g-C 3 N 4 film exhibited an excellent visible-light hydrogen evolution rate of 74.98 μmol g−1 h−1. Developing a simple and general method to fabricate graphitic carbon nitride (g-CN) film is crucial for the application of devices. Herein, we report a CCl 4 -assisted method for the fabrication of continuous g-CN films on various substrates with in-situ extracted metal cations as nucleate sites. The g-CN film exhibits continuous wrinkles-like graphene structure, and can be completely exfoliated as a free-standing film. In the g-CN film, the metallic cations are bonded with the electron-rich nitrogen as the nucleate sites for connecting molecular structure. By changing the synthesis temperature and the flow rate of CCl 4 , the thickness and the band structure of the g-CN films can be successfully adjusted. Under visible light illumination, the g-CN films exhibit efficient hydrogen evolution with a rate of 74.98 μmol g−1 h−1. We believe that the precise controlled free-standing g-CN film will shed light on many opportunities in the utilization of graphitic carbon nitride for catalysis, sensor, electronic and energy-related applications. This method may open a new avenue to fabricate other two-dimensional films on different substrates. [ABSTRACT FROM AUTHOR]

Graphitic carbon nitride tetragonal hollow prism (GCN-THP) with nitrogen vacancies was prepared by a simple two-step calcination method. Based on the characterizations of the as-prepared GCN-THP and the intermediate precursor, a possible mechanism was proposed for the formation of GCN-THP. The as-prepared GCN-THP exhibits superior activity and excellent stability during photocatalytic hydrogen evolution under visible light irradiation. The photocatalytic hydrogen evolution rate of GCN-THP was measured to be 1990 μmol g−1 h−1, which is 6.2 times as that of GCN. The enhanced photocatalytic activity could be attributed to unique 1D tetragonal hollow prism morphology and the presence of nitrogen vacancies in the as-prepared GCN-THP, which could increase the surface area, expand the visible light absorption, and promote the charge separation during photocatalytic hydrogen evolution. Our work could provide a new route to synthesize highly efficient photocatalysts with 1D hollow structures. Image 1 • g-C 3 N 4 tetragonal hollow prism was prepared by a two-step calcination method. • Low polymerized melamine serves as the template. • The g-C 3 N 4 hollow prism exhibits a superior HER rate of 1990 μmol g−1 h−1. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Melon with inter-triazine N-vacancies was fabricated in CCl 4 atmosphere for the first time. • Defect state is localized around the atoms adjacent to the vacancy. • Singly-occupied defect state acts as a trap for photogenerated electrons. • The vacancy site acts as the 2H+ → H 2 reduction site. • Melon with inter-triazine N-vacancies exhibits 8 times that of one without N-vacancies in photocatalytic H 2 evolution. Abstract We developed a new method to introduce N-vacancies of graphitic carbon nitride (GCN, typically in the Melon structure) at the inter-triazine sites and investigated how the visible-light photocatalytic H 2 evolution of GCN is affected by the N-vacancies at the intra- and inter-triazine sites of GCN. Theoretical and experimental results show that these N-vacancies of GCN create singly-occupied defect states within the band gap acting as a trap for photogenerated electrons and act as the reaction sites for H+ reduction. Compared with the intra-triazine N-vacancy, the inter-triazine N-vacancy exhibits stronger electron localization leading to a more efficient H 2 evolution. The photocatalytic reaction rate of GCN with inter-triazine N-vacancies is 9 times higher than that of "defect free" GCN, and 2.2 times higher normalized reaction rates than GCN with intra-triazine N-vacancies. The catalysis mechanism and the method to prepare melon with inter-triazine N-vacancies can be extended to explore new photocatalysts with high activities. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • NaYF 4 :Yb3+,Tm3+@NaYF 4 :Yb3+,Nd3+@TiO 2 core@shell photocatalysts are fabricated. • The higher activity can be based on the absorption in visible-NIR region of Nd3+. • The enhanced activity can be attributed to the unique core@shell nanostructure. • The mechanism of photocatalyst for near-infrared light is proposed in detail. • The work provides a route to improve the near-infrared photocatalytic activity. Abstract In this work, we fabricated NaYF 4 :Yb3+,Tm3+@NaYF 4 :Yb3+,Nd3+@TiO 2 (Tm@Nd@TiO 2) core@shell nanoparticles and investigated their near-infrared (NIR) photocatalytic activities. Comparing to traditional TiO 2 based upconversion (UC) photocatalysts (i.e., NaYF 4 :Yb3+,Tm3+@TiO 2 , named Tm@TiO 2), Tm@Nd@TiO 2 exhibits enhanced photocatalytic activity under NIR light irradiation. The photocatalytic activity of Tm@Nd@TiO 2 under 980, 808, and 980 + 808 nm laser irradiation is 4.40, 5.84, and 9.83 times as high as that of Tm@TiO 2 under only 980 nm irradiation, respectively. The ethylene degradation rate of Tm@Nd@TiO 2 under 980 + 808 nm laser irradiation is 6.4 times as that of Tm@TiO 2. The photocatalytic activity of Tm@Nd@TiO 2 under visible + NIR irradiation is even comparable with (∼2/3) that under UV light irradiation during Rhodamine B (RhB) degradation. The enhanced photocatalytic activity of Tm@Nd@TiO 2 can be attributed to the stronger light absorption in NIR region ascribed to Nd3+, lower water absorption and the enhanced UC emission of Tm@Nd with unique core@shell nanostructures. This work can provide a possible route to improve the NIR photocatalytic activity and stimulate the applications in many other fields. [ABSTRACT FROM AUTHOR]

In this work, we developed a simple method to fabricate BiVO 4 photoanode consisted of mesoporous nanoparticles (meso-BVO) by using P123 as a pore maker. Owing to the unique mesoporous nanostructure, meso-BVO exhibits higher BET surface areas, shorter hole transit distance and higher electrical conductivity than does pristine BiVO 4 photoanode (BVO) consisted of solid nanoparticles. As a result, the charge separation efficiency and PEC performances of meso-BVO have been greatly improved. Meso-BVO yields a photocurrent of 2.19 mA/cm 2 (1.23 V vs RHE) and IPCE of 39% (420 nm), which is 2.52 and 2 times as high as that of pristine BVO. With the assistance of Mo 6+ ions doping and Co-Pi, the PEC performances could be further improved by addressing the inefficient electron transport and slow water oxidation kinetics. Co-Pi/Mo:meso-BVO yields a photocurrent of 4.57 mA/cm 2 (1.23 V vs RHE) and IPCE value of 65% (420 nm). The enhanced PEC performance can be mainly ascribed to the perfect charge separation in the bulk of Co-Pi/Mo:meso-BVO photoanode. Our work provides a simple method to fabricate high efficient BiVO 4 photoanodes consisted of mesoporous nanoparticles with enhanced bulk charge separation efficiencies. [ABSTRACT FROM AUTHOR]

Carbon bridged graphitic carbon nitride (g-C 3 N 4 ) was prepared by a facile supramolecular self-assembly method. Experimental results and theoretical calculations indicate C atoms were introduced into the g-C 3 N 4 lattice by substituting the bridged N atoms. As a result, the delocalized big π bonds can be formed among the adjacent heptazine rings, which could both enhance the light absorption and promote the charge separation. Beneficial from the efficient charge separation and enhanced light absorption, the carbon bridged g-C 3 N 4 exhibits high efficient photocatalytic activity, where the H 2 evolution rate is about 7 times as high as that of pristine g-C 3 N 4 . This work demonstrates carbon bridged C 3 N 4 can be fabricated by a simple supramolecular self-assembly process, which could be useful for the further development of high efficient g-C 3 N 4 photocatalysts. [ABSTRACT FROM AUTHOR]

Myelin is a specialized subcellular structure that evolved uniquely in vertebrates. A myelinated axon conducts action potentials many times faster than an unmyelinated axon of the same diameter; for the same conduction speed, the unmyelinated axon would need a much larger diameter and volume than its myelinated counterpart. Hence myelin speeds information transfer and saves space, allowing the evolution of a powerful yet portable brain. Myelination in the central nervous system (CNS) is controlled by a gene regulatory program that features a number of master transcriptional regulators including Olig1, Olig2 and Myrf. Olig family genes evolved from a single ancestral gene in non-chordates. Olig2, which executes multiple functions with regard to oligodendrocyte identity and development in vertebrates, might have evolved functional versatility through post-translational modification, especially phosphorylation, as illustrated by its evolutionarily conserved serine/threonine phospho-acceptor sites and its accumulation of serine residues during more recent stages of vertebrate evolution. Olig1 , derived from a duplicated copy of Olig2 in early bony fish, is involved in oligodendrocyte development and is critical to remyelination in bony vertebrates, but is lost in birds. The origin of Myrf orthologs might be the result of DNA integration between an invading phage or bacterium and an early protist, producing a fusion protein capable of self-cleavage and DNA binding. Myrf seems to have adopted new functions in early vertebrates – initiation of the CNS myelination program as well as the maintenance of mature oligodendrocyte identity and myelin structure – by developing new ways to interact with DNA motifs specific to myelin genes. This article is part of a Special Issue entitled SI: Myelin Evolution . [ABSTRACT FROM AUTHOR]

Two Al based MOFs (MIL-53(Al) and MIL-53-NH 2 (Al)) were synthesized, and their photoelectrical, photophysical and photocatalytic properties towards oxygen evolution from water were investigated. Different from the ligand to metal charge transfer process previously reported, we proposes a new photocatalytic mechanism based on electron tunneling according to the results of theoretical calculation, steady state and time resolved fluorescence spectra. The organic linkers absorb photons, giving rise to electrons and holes. Then, the photogenerated electrons tunnel through the AlO 6 -octahedra, which not only inhibit the recombination of photogenerated charge carriers, but also is a key factor to the photocatalytic activity of Al based MOFs. [ABSTRACT FROM AUTHOR]

Summary: A fundamental feature of central nervous system development is that neurons are generated before glia. In the embryonic spinal cord, for example, a group of neuroepithelial stem cells (NSCs) generates motor neurons (MNs), before switching abruptly to oligodendrocyte precursors (OLPs). We asked how transcription factor OLIG2 participates in this MN-OLP fate switch. We found that Serine 147 in the helix-loop-helix domain of OLIG2 was phosphorylated during MN production and dephosphorylated at the onset of OLP genesis. Mutating Serine 147 to Alanine (S147A) abolished MN production without preventing OLP production in transgenic mice, chicks, or cultured P19 cells. We conclude that S147 phosphorylation, possibly by protein kinase A, is required for MN but not OLP genesis and propose that dephosphorylation triggers the MN-OLP switch. Wild-type OLIG2 forms stable homodimers, whereas mutant (unphosphorylated) OLIG2S147A prefers to form heterodimers with Neurogenin 2 or other bHLH partners, suggesting a molecular basis for the switch. [ABSTRACT FROM AUTHOR]

Oligodendrocytes (OLs) are the myelin-forming cells of the central nervous system (CNS). They differentiate from proliferative OL precursor cells that migrate from the embryonic neuroepithelium throughout the developing CNS before associating with axons and elaborating myelin. Recent research into the regulation of OL differentiation has uncovered a two-stage mechanism of transcriptional control that combines epigenetic repression of transcriptional inhibitors with direct transcriptional activation of myelin genes. This ‘two-pronged’ approach creates a fail-safe system of genetic control to ensure orderly and unambiguous expression of the myelination program during development and during repair of demyelinated lesions. [Copyright &y& Elsevier]

Two new thiazinediones along with five known compounds were isolated from the fruits of Xanthium strumarium L. The structures of the two new compounds were determined to be 7-hydroxymethyl-8,8-dimethyl-4,8-dihydrobenzol[1,4]thiazine-3,5-dione-11- O-β-D-glucopyranoside (1) and 2-hydroxy-7-hydroxymethyl-8,8-dimethyl-4,8-dihydrobenzol[1,4]thiazine-3,5-dione-11- O-β-D-glucopyranoside (2). The five known compounds were identified as xanthiazone (3), chlorogenic acid (4), ferulic acid (5), formononetin (6), and ononin (7), respectively. [ABSTRACT FROM AUTHOR]

Abstract: Myelin is the multi-layered glial sheath around axons in the vertebrate nervous system. Myelinating glia develop and function in intimate association with neurons and neuron–glial interactions control much of the life history of these cells. However, many of the factors that regulate key aspects of myelin development and maintenance remain unknown. To discover new molecules that are important for glial development and myelination, we undertook a screen of zebrafish mutants with previously characterized neural defects. We screened for myelin basic protein (mbp) mRNA by in situ hybridization and identified four mutants (neckless, motionless, iguana and doc) that lacked mbp expression in parts of the peripheral and central nervous systems (PNS or CNS), despite the presence of axons. In all four mutants electron microscopy revealed that myelin-forming glia were present and had formed loose wraps around axons but did not form compact myelin. We found that addition of exogenous retinoic acid (RA) rescued mbp expression in neckless mutant embryos, which lack endogenous RA synthesis. Timed application of the RA synthesis inhibitor DEAB to wild type embryos showed that RA signalling is required at least 48 h before the onset of myelin protein synthesis in both CNS and PNS. [Copyright &y& Elsevier]

A novel dynamin-like GTPase gene, Pfdyn1, was cloned from an asexual stage cDNA library of Plasmodium falciparum Dd2 strain. Pfdyn1 contains a highly conserved N-terminal tripartite GTPase domain, a coiled-coil region, and a C-terminal 129 aa unknown function domain. Like yeast Vps1p, it lacks pleckstrin homology domain and proline-rich region. Western blot analysis showed that Pfdyn1 is a Triton X-100 insoluble protein expressed only in the mature sub-stage. Morphological studies indicated that Pfdyn1 is partly co-localized with PfGRP, a known ER-resident protein, and localizes diffusely with several membrane structures and a 60–100 nm vesicle both inside and on surface of the parasites and also in the cytoplasm of infected erythrocytes. The dsRNA originated by C-terminus fragment of Pfdyn1 inhibits markedly the growth of P. falciparum parasite at the erythrocyte stage. Those data showed that Pfdyn1 is a conservative, membrane related protein and plays an essential role for the survival of Plasmodium parasite. [Copyright &y& Elsevier]

The TiO 2 /Ti 3 C 2 composites performed excellent conversion efficiency and product selectivity. The enhanced photocatalytic activity could be ascribed to the existence of Ti 3 C 2 , which could improve charge separation, facilitate the O 2 activation to generate more O2− active species and lower the VB level of TiO 2 in the TiO 2 /Ti 3 C 2 composites to avoid the over oxidation of BAD. • The TiO 2 /Ti 3 C 2 composite exhibits higher conversion efficiency and product selectivity than TiO 2. • The presence of Ti 3 C 2 could stabilize the oxygen vacancies and Ti3+ to promote the production of active intermediates. • The presence of Ti 3 C 2 could lower the VB level to avoid the over oxidation. Photocatalytic selective oxidation of alcohols into corresponding aldehydes has received enormous attention. However, it remains a great challenge to explore photocatalysts with high conversion efficiency and selectivity. Herein, we developed a composite consisted of TiO 2 and Ti 3 C 2 through a simple calcination of Ti 3 C 2 nanosheets. It was found that Ti 3 C 2 could stabilize the oxygen vacancies and Ti3+ species in the TiO 2 /Ti 3 C 2 composite, which could subsequent promote the production of active intermediates during the photocatalytic oxidation of benzyl alcohol (BA) to benzaldehyde (BAD). Additionally, the valence band of TiO 2 in the composites was found to be up-shifted, which would avoid the further oxidation of BAD and enhance selectivity. As a result, the optimal composite exhibits the BA conversion efficiency of 97 % and BAD selectivity of 98 %, which is 2.8 and 1.2 folds higher than that of pristine TiO 2. Our work may provide insights for designing efficient photocatalysts for selective oxidation of alcohols. [ABSTRACT FROM AUTHOR]

Three novel process related impurities (impurity I-III) in empagliflozin bulk drug were isolated, identified and characterized using modern analytical tool. The possible formation mechanism of these impurities was discussed in this report. [Display omitted] • Isolation, identification and characterization of process related impurities in empagliflozin. • Structural conformation of process impurities has been confirmed by HRMS, 1D-NMR and 2D-NMR techniques. • The possible pathway for the formation of the impurities has been discussed. Empagliflozin is an effective sodium glucose cotransporter-2 (SGLT2) inhibitor to improve glycemic control in adults with type 2 diabetes. During the manufacture of empagliflozin, three unknown impurities were discovered in pilot batches ranging from 0.05 % to 0.15 % by LC analysis. These unknown impurities were isolated from the crystallization mother liquor by column chromatography and semi-preparative LC, and their structures were elucidated by comprehensive analysis of HRMS, 1D-NMR (1H, 13C) and 2D-NMR (1H-1H COSY, HSQC, HMBC) spectroscopy data. The plausible mechanistic pathways to the formation of these three impurities were also discussed. [ABSTRACT FROM AUTHOR]

Background: The role of adjuvant transcatheter arterial chemoembolization (TACE) following repeated resection/ablation for recurrent hepatocellular carcinoma (HCC) remains uncertain. The aim of this study was to assess the effectiveness of adjuvant TACE following repeated resection or ablation in patients with early recurrent HCC. Methods: Information for patients who underwent repeated surgery or radiofrequency ablation (RFA) for early recurrent HCCs (< 2 years) at our institution from January 2017 to December 2020 were collected. Patients were divided into adjuvant TACE and observation groups according to whether they received adjuvant TACE or not. The recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups before and after propensity score matching (PSM). Results: Of the 225 patients enrolled, the median time of HCC recurrence was 11 months (IQR, 6–16 months). After repeated surgery or radiofrequency ablation (RFA) for recurrent tumors, 45 patients (20%) received adjuvant TACE while the remaining 180 (80%) didn't. There were no significant differences in RFS (P = 0.325) and OS (P = 0.072) between adjuvant TACE and observation groups before PSM. There were also no significant differences in RFS (P = 0.897) and OS (P = 0.090) between the two groups after PSM. Multivariable analysis suggested that multiple tumors, liver cirrhosis, and RFA were independent risk factors for the re-recurrence of HCC. Conclusion: Adjuvant TACE after repeated resection or ablation for early recurrent HCCs was not associated with a long-term survival benefit in this single-center cohort. [ABSTRACT FROM AUTHOR]

Background: The role of adjuvant transcatheter arterial chemoembolization (TACE) following repeated resection/ablation for recurrent hepatocellular carcinoma (HCC) remains uncertain. The aim of this study was to assess the effectiveness of adjuvant TACE following repeated resection or ablation in patients with early recurrent HCC. Methods: Information for patients who underwent repeated surgery or radiofrequency ablation (RFA) for early recurrent HCCs (< 2 years) at our institution from January 2017 to December 2020 were collected. Patients were divided into adjuvant TACE and observation groups according to whether they received adjuvant TACE or not. The recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups before and after propensity score matching (PSM). Results: Of the 225 patients enrolled, the median time of HCC recurrence was 11 months (IQR, 6–16 months). After repeated surgery or radiofrequency ablation (RFA) for recurrent tumors, 45 patients (20%) received adjuvant TACE while the remaining 180 (80%) didn't. There were no significant differences in RFS (P = 0.325) and OS (P = 0.072) between adjuvant TACE and observation groups before PSM. There were also no significant differences in RFS (P = 0.897) and OS (P = 0.090) between the two groups after PSM. Multivariable analysis suggested that multiple tumors, liver cirrhosis, and RFA were independent risk factors for the re-recurrence of HCC. Conclusion: Adjuvant TACE after repeated resection or ablation for early recurrent HCCs was not associated with a long-term survival benefit in this single-center cohort. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • An integrated strategy was developed for screening and identifying of constituents from biological samples. • The method of UPLC-QTOF/MS combined with UNIFI software and data-mining technique OPLS-DA was applied. • Comprehensive metabolic profile of DZT was proposed for the first time. • 51 prototypes and 119 metabolites of DZT in rat plasma and cerebrospinal fluid were identified. • Some prototypes and metabolites originated from animal-oriented medicines were firstly detected and identified in vivo. Abstract Metabolites derived from traditional Chinese medicine (TCM) are becoming active substances of pharmacologically as well as promising sources for discovering new drugs. However, detection and identification of constituents in vivo remains a challenge for TCM, due to massive endogenous interference and low abundance of metabolites in biological matrix. Traditional Chinese medicine formula Dan Zhi Tablet (DZT), a well-established TCM formula developed based on years of clinical experiences, was widely used to treat cerebral infraction disease. In this study, an integrated strategy based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) was adopted to comprehensively identify the prototype and metabolite constituents of DZT. The potential constituents were screened by cross orthogonal partial least-squares discriminant analysis (OPLS-DA). Automatic matching analysis was performed on UNIFI platform based on the function of predicting metabolites. Using this strategy, a total of 170 compounds, including 51 prototype constituents and 119 metabolites were unambiguously or tentatively identified in rat plasma. Furthermore, 31 compounds have also been detected in rat cerebrospinal fluid. The metabolism reactions included phase I reactions (hydroxylation, hydrolysis, deglycosylation, hydrogenation, demethylation and dehydroxylation) and phase II reactions (conjugation with glutatione, cysteine, acetylcysteine, glucuronide, sulfate). It is the first systematic metabolic study of DZT in vivo and some metabolites were also reported for the first time, which could provide a scientific basis for explaining the multiple functions of DZT. More importantly, the integrated strategy also shows promising perspectives in the identification of the metabolites in TCM from a complicated biological matrix. [ABSTRACT FROM AUTHOR]

Isocitrate dehydrogenase (IDH) mutation, a known pathologic classifier, initiates metabolic reprogramming in glioma cells and has been linked to the reaction status of glioma‐associated microglia/macrophages (GAMs). However, it remains unclear how IDH genotypes contribute to GAM phenotypes. Here, it is demonstrated that gliomas expressing mutant IDH determine M1‐like polarization of GAMs, while archetypal IDH induces M2‐like polarization. Intriguingly, IDH‐mutant gliomas secrete excess cholesterol, resulting in cholesterol‐rich, pro‐inflammatory GAMs without altering their cholesterol biosynthesis, and simultaneously exhibiting low levels of tumoral cholesterol due to expression remodeling of cholesterol transport molecules, particularly upregulation of ABCA1 and downregulation of LDLR. Mechanistically, a miR‐19a/LDLR axis‐mediated novel post‐transcriptional regulation of cholesterol uptake is identified, modulated by IDH mutation, and influencing tumor cell proliferation and invasion. IDH mutation‐induced PERK activation enhances cholesterol export from glioma cells via the miR‐19a/LDLR axis and ABCA1/APOE upregulation. Further, a synthetic PERK activator, CCT020312 is introduced, which markedly stimulates cholesterol efflux from IDH wild‐type glioma cells, induces M1‐like polarization of GAMs, and consequently suppresses glioma cell invasion. The findings reveal an essential role of the PERK/miR‐19a/LDLR signaling pathway in orchestrating gliomal cholesterol transport and the subsequent phenotypes of GAMs, thereby highlighting a novel potential target pathway for glioma therapy. [ABSTRACT FROM AUTHOR]

Background: Sensitivity to ethanol provides an index of the predisposition to recover from unconsciousness induced by a dose of ethanol. The role of the G protein‐coupled receptor 158 (GPR158) in modulating sensitivity to the sedative‐hypnotic effect of ethanol has not been investigated. Methods: Loss of righting reflex (LORR) is a behavioral indicator of hypnosis in rodents. In this study, Gpr158−/− mice and wild‐type (WT) littermates (n = 8/genotype) were tested using LORR induced by a dose of 3.5 g/kg ethanol, an open‐field test (OFT), and a measure of blood ethanol concentration. The OFT was used to examine the role of GPR158 in the ethanol effect on motor activity in Gpr158−/− mice (n = 6/genotype). We also tested CamK2A‐Cre;Gpr158fl/fl (n = 9) and Vgat‐Cre;Gpr158fl/fl mice (n = 10) using the LORR test and OFT to compare with controls (n = 9 and 8, respectively). Results: Gpr158 deficiency prolonged the LORR duration by 110.6%, t(14) = −5.241, p = 0.0001, without altering spontaneous activity, t(14) = −0.718, p = 0.485, or ethanol metabolism, F(1, 8) = 0.259, p = 0.625. Gpr158 knockout did not change the ethanol effect on locomotion, F(1, 10) = 0.262, p = 0.62. The LORR duration increased by 69% in the conditional knockouts of Gpr158 within calcium/calmodulin‐dependent protein kinase II alpha‐positive (CamK2A+) neurons, t(16) = −2.914, p = 0.01, and by 92% in the vesicular GABA transporter‐positive (Vgat+) neurons, t(9.802) = −2.519, p = 0.023. Locomotion was not altered in Camk2A‐Cre;Gpr158fl/fl, t(16) = 0.49, p = 0.631 or Vgat‐Cre;Gpr158fl/fl mice, t(16) = 0.035, p = 0.972. Conclusions: This study reveals the key role of neuronal GPR158 in shaping sensitivity to the sedative‐hypnotic effect of ethanol. These findings contribute to our understanding of the neurobiology of ethanol intoxication. [ABSTRACT FROM AUTHOR]

An operationally simple domino approach for the ruthenium-catalyzed synthesis of (E)-2,3′-bi(3H-indol)-3-oneO-alkyl oximes by the region- and stereoselective three-component, four-molecule reactions of indoles with sodium nitrite and alkyl bromides under mild reaction condition in dimethylformamide is described. Remarkably, multiple bonds including C‒C, C=N, and C‒O bonds were conveniently formed in one pot. The reaction is tolerant to air and is atom economical, in accordance with the concept of modern green chemistry. [ABSTRACT FROM AUTHOR]

GREMLIN1 (GREM1) is a secreted protein that antagonizes bone morphogenetic proteins (BMPs). While abnormal GREM1 expression has been reported to cause behavioral defects in postpartum mice, the spatial and cellular distribution of GREM1 in the brain and the influence of the GREM1-secreting cells on brain function and behavior remain unclear. To address this, we designed a genetic cassette incorporating a 3×Flag-TeV-HA-T2A-tdTomato sequence, resulting in the creation of a novel Grem1Tag mouse model, expressing an epitope tag (3×Flag-TeV-HA-T2A) followed by a fluorescent reporter (tdTomato) under the control of the endogenous Grem1 promoter. This design facilitated precise tracking of the cell origin and distribution of GREM1 in the brain using tdTomato and Flag (or HA) markers, respectively. We confirmed that the Grem1Tag mouse exhibited normal motor, cognitive, and social behaviors at postnatal 60 days (P60), compared with C57BL/6J controls. Through immunofluorescence staining, we comprehensively mapped the distribution of GREM1-secreting cells across the central nervous system. Pervasive GREM1 expression was observed in the cerebral cortex (Cx), medulla, pons, and cerebellum, with the highest levels in the Cx region. Notably, within the Cx, GREM1 was predominantly secreted by excitatory neurons, particularly those expressing calcium/calmodulin-dependent protein kinase II alpha (Camk2a), while inhibitory neurons (parvalbumin-positive, PV+) and glial cells (oligodendrocytes, astrocytes, and microglia) showed little or no GREM1 expression. To delineate the functional significance of GREM1-secreting cells, a selective ablation at P42 using a diphtheria toxin A (DTA) system resulted in increased anxiety-like behavior and impaired memory in mice. Altogether, our study harnessing the Grem1Tag mouse model reveals the spatial and cellular localization of GREM1 in the mouse brain, shedding light on the involvement of GREM1-secreting cells in modulating brain function and behavior. Our Grem1Tag mouse serves as a valuable tool for further exploring the precise role of GREM1 in brain development and disease. • Construction of a Grem1Tag mouse for tracking GREM1 molecules and the cell of origin. • The distribution pattern and intensity of GREM1 molecules in various brain regions using the Grem1Tag mouse. • GREM1 is secreted mainly by excitatory neurons, and to a much lesser extent by microglia. • Partial removal of GREM1-secreting-cells induced phenomenal behavioral abnormalities in Grem1-CreERT2 : DTA mouse. [ABSTRACT FROM AUTHOR]

[Display omitted] • Calcined Ge-UTL encountered structural degradation under pure water solution at RT. • A simply ultrasonic treatment caused random arrangement of the formed cfi layers. • The stacking faults of cfi layers generated abundant intracrystal mesopores. • An excellent styrene epoxidation activity (TOF = 403 h−1) is achieved on Co-Meso-UTL. Co-zeolites with hierarchical porous are significantly desirable for the liquid-phase selective epoxidation of styrene that required relatively open reaction spaces. A typical UTL germanosilicate with the absence of organic structure-directing agent molecules inside pore channels suffered from severe structural collapse after ultrasonic treatment under pure water medium, originating from the unstable germanium-rich double four ring subunits. The simple strategy cleaved the weak linkage Ge-O bands and caused the irregular location of silicon-rich cfi layers. Subsequently, Co activity centers was incorporated into the framework through reacting with the abundant silanol groups located in the hydroxyl nests at room temperature. The random arrangement of mono- or multi- cfi layers induced the stacking faults and generated a large amount of intracrystal mesopores after calcination. The resultant Co-Meso-UTL catalysts favored the molecules diffusion of large-sized styrene and target products, improving the accessibility of Co active sites and exhibiting excellent catalytic performance in the styrene epoxidation reaction with single hydrogen peroxide (H 2 O 2) oxidant. Especially, high styrene oxide product selectivity was also obtained through controlling appropriate H 2 O 2 -added content as well as reaction time, which possessed a highest turnover frequency value of 403 h−1 among the reported catalysts. [ABSTRACT FROM AUTHOR]

Robust PN H N pincer complex Ru1 provides an efficient catalytic system for the hydrogenation of a broad range of carbamates and their derivatives with highly efficiency and selectivity. [Display omitted] • Ruthenium-promoted efficient hydrogenation of a broad spectrum of arylcarbamates and their derivatives is reported. • This protocol provides a green approach for the hydrogenation of carbamates to the amines and alcohols or diols. • Computations indicate an outer-sphere mechanism and support the cleavage of the C N bond in H(CO)NHPh likely being the rate-determining step. The [ fac -PNN]RuH(PPh 3)(CO) complex (Ru1) has been identified as a highly efficient catalyst for the hydrogenation of a broad spectrum of arylcarbamates and their derivatives (49 examples). The hydrogenation reaction occurs smoothly via C N bond cleavage, affording the desired amines and alcohols or diols at a low catalyst loading of 0.25 mol% in tert -amyl alcohol. Most importantly, this catalytic system offers a promising route for the sustainable depolymerization and recycling of polyurethanes (PUs). Moreover, a detailed mechanism for the hydrogenation of carbamates has been established through combined DFT calculations and control experiments, which suggests that Ru-hydride pathways involve three cycles, with the rate-determining step most likely being the dissociation of the C N bond in the key intermediate H(CO)NHPh. These results have far-reaching implications for the development of more effective and eco-friendly catalytic systems for carbamate transformation and their potential industrial application on a large scale. [ABSTRACT FROM AUTHOR]

Hierarchical structure designs can maximize the application of structural materials on multi-dimensional scale from a limited choice. Mimicking this performance is a great challenge, especially in optical structures. Here, a hierarchical structural-colored film with highly ordered periodic layers and amorphous array layers was designed by a simple one-step confined self-assembly procedure based on hydrophobic substrates, which shows an excellent optical effect. The highly ordered periodic layers could act as a specific wavelength mirror-like reflectance, which enhanced the coherent scattering of light in the amorphous arrays, resulting in higher color visibility. The intricate interaction of light over hierarchical structures at different length scales has profound significance for the application of complex optical assemblies. [Display omitted] • Order and disorder structure is realized on one film. • Superhydrophobic is the key to transformation from order to disorder structure. • The structure displays brilliant noniridescent structural color. [ABSTRACT FROM AUTHOR]

This new decade has started with a global pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), precipitating a worldwide health crisis and economic downturn. Scientists and clinicians have been racing against time to find therapies for COVID-19. Repurposing approved drugs, developing vaccines and employing passive immunization are three major therapeutic approaches to fighting COVID-19. Chicken immunoglobulin Y (IgY) has the potential to be used as neutralizing antibody against respiratory infections, and its advantages include high avidity, low risk of adverse immune responses, and easy local delivery by intranasal administration. In this study, we raised antibody against the spike (S) protein of SARS-CoV-2 in chickens and extracted IgY (called IgY-S) from egg yolk. IgY-S exhibited high immunoreactivity against SARS-CoV-2 S, and by epitope mapping, we found five linear epitopes of IgY-S in SARS-CoV-2 S, two of which are cross-reactive with SARS-CoV S. Notably, epitope SIIAYTMSL, one of the identified epitopes, partially overlaps the S1/S2 cleavage region in SARS-CoV-2 S and is located on the surface of S trimer in 3D structure, close to the S1/S2 cleavage site. Thus, antibody binding at this location could physically block the access of proteolytic enzymes to S1/S2 cleavage site and thereby impede S1/S2 proteolytic cleavage, which is crucial to subsequent virus-cell membrane fusion and viral cell entry. Therefore, the feasibility of using IgY-S or epitope SIIAYTMS-specific IgY as neutralizing antibody for preventing or treating SARS-CoV-2 infection is worth exploring. [ABSTRACT FROM AUTHOR]

Given the growing evidence of a link between gut microbiota (GM) dysbiosis and multiple sclerosis (MS), fecal microbiota transplantation (FMT), aimed at rebuilding GM, has been proposed as a new therapeutic approach to MS treatment. To evaluate the viability of FMT for MS treatment and its impact on MS pathology, we tested FMT in mice with experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We provide evidence that FMT can rectify altered GM to some extent with a therapeutic effect on EAE. We also found that FMT led to reduced activation of microglia and astrocytes and conferred protection on the blood-brain barrier (BBB), myelin, and axons in EAE. Taken together, our data suggest that FMT, as a GM-based therapy, has the potential to be an effective treatment for MS. [ABSTRACT FROM AUTHOR]

[Display omitted] • The metal–organic complex (IANF) is evenly coated on BiVO 4 via chemical bonding. • The IANF could relieve the photocorrosion of BiVO 4 and promote water oxidation. • The interfacial bonding could greatly accelerate charge separation and transfer. • An excellent PEC activity with long-term stability is achieved on BiVO 4 /IANF. Photoelectrochemical (PEC) water splitting is a promising strategy for solar energy conversion, while the sluggish water oxidation kinetics and poor stability seriously restrict its practical applications. Herein, we demonstrated a facile hydrothermal method to in situ self-assemble metal–organic coordination networks on BiVO 4 for significantly improving the PEC water oxidation activity and stability. Specifically, the 4,5-Imidazoledicarboxylic acid (IA) containing rich O/N atoms readily cross-links multiple Ni/Fe ions to form IA-NiFe (IANF) coordination networks with strong coordination capacity, which could uniformly attach on BiVO 4 through chemical bonding. Systematic characterizations and theoretical calculations reveal that the uniformly coated and chemically linked IANF on BiVO 4 not only effectively minimizes interfacial kinetic barriers and facilitates hole transfer, but prevents BiVO 4 from photocorrosion. What's more, IANF catalysts could provide plentiful active sites to decrease the OER overpotential and accelerate reaction kinetics. As expected, the BiVO 4 /IANF photoanode shows an outstanding photocurrent density of 5.25 mA cm−2 at 1.23 V RHE and long-term stability. This work offers a potential pathway for building highly efficient and stable PEC water splitting systems. [ABSTRACT FROM AUTHOR]

B Tumor Microenvironment b Cholesterol is the essential structural and functional component for glioma cells to maintain their biological aggressiveness. PERK-Mediated Cholesterol Excretion from IDH Mutant Glioma Determines Anti-Tumoral Polarization of Microglia (Adv. Sci. 20/2023) In article number 2205949, Yulong He, Yonggao Mou, Ningning Li, and co-workers identify that excessive cholesterol excreted from IDH-mutant glioma cells, as a metabolic messenger, determines M1-like polarization of glioma-associated microglia/macrophage (GAMs). [Extracted from the article]

Hepatocellular carcinoma (HCC) is known for high mortality and limited available treatments. Aberrant activation of the Wnt and Notch signaling pathways is critical to liver carcinogenesis and progression. Here, we identified a small molecule, bruceine D (BD), as a Notch inhibitor, using an RBP-Jκ-dependent luciferase-reporter system. BD significantly inhibited liver tumor growth and enhanced the therapeutic effects of sorafenib in various murine HCC models. Mechanistically, BD promotes proteasomal degradation of β-catenin and the depletion of its nuclear accumulation, which in turn disrupts the Wnt/β-catenin-dependent transcription of the Notch ligand Jagged1 in HCC. Our findings provide important information about a novel Wnt/Notch crosstalk inhibitor that is synergistic with sorafenib for treatment of HCC, and therefore have high clinical impact. [ABSTRACT FROM AUTHOR]

[Display omitted] • Photocharged carbon nitride was fabricated by CCl 4 -assisted molten salt treatment. • Strong local electron accumulation was obtained at the edge nitrogen vacancy sites. • The electron lifetime extends to days by forming electron storage equivalents. • Round-the-clock H 2 O 2 evolution akin to natural photosynthesis was realized. Prolonging the lifetime of photogenerated electrons is crucial not only for improving surface photocatalytic reactions under light irradiation, but also for developing round-the-clock applications to overcome solar intermittency. Herein, edge nitrogen vacancies were introduced into K-doped polymeric carbon nitride through a CCl 4 assisted molten salt calcination method. The electron lifetime was successfully extended to days by forming photocharged active electron storage equivalents akin to natural photosynthesis. This timescale is far beyond the requirement for surface photocatalytic O 2 reduction to H 2 O 2 , therefore, an unprecedented photocatalytic H 2 O 2 production rate of 10.02 mmol L-1 h−1 was achieved under visible light, which is 176 times that of pristine carbon nitride and significantly higher than those of the state-of-the-art photocatalysts. Meantime, the stored electrons endow the photocatalyst with a delayed photocatalytic H 2 O 2 evolution ability, allowing the novel prototype of round-the-clock H 2 O 2 evolution to be realized. This intriguing character is ascribed to the strong local electron accumulation at the edge nitrogen vacancies, which realizes the photocharging effect and enhances electron transfer to chemisorbed O 2. This work would deepen the understanding and pave the way for designing efficient photocatalysts for round-the-clock applications. [ABSTRACT FROM AUTHOR]

• A novel sequential excavation method (S-CRD) was implemented in practice. • Field monitoring was carried out. The monitoring data were provided in detail. • A theoretical model was proposed for analysing the performance of the S-CRD method. Sequential excavation (SE) methods involve the division of a tunnel passage into drifts to limit ground settlement. However, an increase in the number of tunnel drifts may prolong the construction duration. In this case study, a 4-drift centre cross diaphragm (CRD) method with a suspension system at the ground surface, termed the suspension-type CRD (S-CRD) method, was proposed and applied to the construction of a large-cross-section tunnel in soft ground. A theoretical settlement prediction model based on Mindlin's elastic equations was established to predict the ground settlement induced by the excavation of an S-CRD tunnel. The proposed theoretical model was validated to have satisfactory performance, as the predicted ground settlement agrees well with the field monitoring results. The effects of three crucial design parameters (the prestress F a , spacing S a , and diameter D a of the prestressed anchors) were analysed and compared using this theoretical model. It was found that the spacing of the prestressed anchors is more effective than the prestress and diameter in limiting the ground settlement. [ABSTRACT FROM AUTHOR]

Abstract: A new thiazinedione was isolated from the fruit of Xanthium strumarium. Its structure was elucidated by a combination of spectral methods. [Copyright &y& Elsevier]

(E)-2,3′-bi(3H-indol)-3-one O-alkyl oximes (III), (V) are regio- and stereoselectively obtained. [ABSTRACT FROM AUTHOR]

Merrilliadione ( 1), a new diterpene with a unique isopropyl (13→11)- abeo-9,11- seco-abietane skeleton, and two new abietane diterpenoids ( 2 and 3) were isolated from Illicium merrillianum. This is the first report of an isopropyl (13→11)- abeo-9,11- seco abietane diterpenoid. The structures of 1- 3 were established by comprehensive spectroscopic analysis, single-crystal X-ray diffraction, and quantum chemical computation of electronic circular dichroism (ECD) spectra. [ABSTRACT FROM AUTHOR]

Abstract: A novel and sensitive HPLC-UV method has been developed for the simultaneous determination of five major flavonoids in Hypericum japonicum hydroalcoholic extract. The chemical profile of five flavonoids, including taxfolin-7-O-α-l-rhamnoside (1), isoquercitrin (2), quercitrin (3), quercetin-7-O-α-l-rhamnoside (4) and quercetin (5) was acquired by using high-performance liquid chromatography-diode array detector coupled to an electrospray tandem mass spectrometer (HPLC-DAD–ESI/MS). The analysis was performed on a ZORBAX SB-C18 analytical column (5μm, 250mm×4.6mm, i.d.) with a gradient solvent system of acetonitrile-0.5% aqueous formic acid. The validation was carried out and the linearities (r 2 >0.9997) and recoveries (ranged from 98.4% to 99.8%) were acceptable. The limits of detection (LOD) of these flavonoids ranged from 0.5 to 7.5ng. The results indicated that the contents of investigated flavonoids in H. japonicum varied significantly from habitat to habitat with contents ranging from 2.00 to 34.18mg/g. The proposed method is simple, effective and suitable for the quality control of this traditional Chinese medicine (TCM). [Copyright &y& Elsevier]

Abstract: Astragaloside IV is a novel cardioprotective agent extracted from the Chinese medical herb Astragalus membranaceus (Fisch) Bge. This agent is being developed for treatment for cardiovascular disease. Further development of Astragaloside IV will require detailed pharmacokinetic studies in preclinical animal models. Therefore, we established a sensitive and accurate high performance liquid chromatography (HPLC) coupled with tandem mass spectrometry (LC/MS/MS) quantitative detection method for measurement of Astragaloside IV levels in plasma, urine as well as other biological samples including bile fluid, feces and various tissues. Extraction of Astragaloside IV from plasma and other biological samples was performed by Waters OASIS™ solid phase extraction column by washing with water and eluting with methanol, respectively. An aliquot of extracted residues was injected into LC/MS/MS system with separation by a Cosmosil C18 (5μm, 150mm×2.0mm) column. Acetonitrile:water containing 5μM NaAc (40:60, v/v) was used as a mobile phase. The eluted compounds were detected by tandem mass spectrometry. The average extraction recoveries were greater than 89% for Astragaloside IV and digoxin from plasma, while extraction recovery of Astragaloside IV and digoxin from tissues, bile fluid, urine and fece ranged from 61 to 85%, respectively. Good linearity (R 2 >0.9999) was observed throughout the range of 10–5000ng/ml in 0.5ml rat plasma and 5–5000ng/ml in 0.5ml dog plasma. In addition, good linearity (R 2 >0.9999) was also observed in urine, bile fluid, feces samples and various tissue samples. The overall accuracy of this method was 93–110% for both rat plasma and dog plasma. Intra-assay and inter-assay variabilities were less than 15.03% in plasma. The lowest quantitation limit of Astragaloside IV was 10ng/ml in 0.5ml rat plasma and 5ng/ml in 0.5ml dog plasma, respectively. Practical utility of this new LC/MS/MS method was confirmed in pilot pharmacokinetic studies in both rats and dogs following intravenous administration. [Copyright &y& Elsevier]

This study presents a design method for the advanced support of subway tunnels for different water content conditions in the silty clay layer. The influence of particle size distribution and water content on the mechanical properties of silty clay is studied through laboratory tests. In addition to the actual construction of the Harbin subway with a silty clay layer, a numerical calculation model is established to study the surface settlement, crown settlement, and supporting structure internal force during the tunnel excavation and support process under different working conditions. Furthermore, the mechanism of action of the advanced small pipe support is clearly defined, and a stability analysis model of the top and bench excavation in a silty clay layer is proposed to evaluate the stability of the tunnel face. The necessity and rationality of the pre-support is quantitatively analysed using the stability coefficient. The laboratory tests illustrate that within a certain range of clay content, the shear strength of silty clay decreases with an increase in water content. The silty clay was further divided into subgrades. The pre-support transfers the loose soil load to the initial support, which improves the early utilization of the lining structure. The advanced small pipe grouting increases the range of the bearing arch, shortens the interval distance of the supporting arch feet, and reduces the vertical load acting on the tunnel face. For the condition of subgrade V in silty clay strata, the stability of the tunnel face can be maintained without the advanced small pipe support. For the condition of subgrade VI 1 , the advanced small pipe support must be applied to ensure the stability of the tunnel face, but the grouting reinforcement measures are not required. For the condition of subgrade VI 2 , the advanced small pipe support and grouting reinforcement must be used simultaneously to ensure the stability of the tunnel face. [ABSTRACT FROM AUTHOR]

Backgroud Aquilaria sinensis (Lour.) Spreng is one of the important plant resources involved in the production of agarwood in China. The agarwood resin collected from wounded Aquilaria trees has been used in Asia for aromatic or medicinal purposes from ancient times, although the mechanism underlying the formation of agarwood still remains poorly understood owing to a lack of accurate and high-quality genetic information. Findings We report the genomic architecture of A. sinensis by using an integrated strategy combining Nanopore, Illumina, and Hi-C sequencing. The final genome was ∼726.5 Mb in size, which reached a high level of continuity and a contig N50 of 1.1 Mb. We combined Hi-C data with the genome assembly to generate chromosome-level scaffolds. Eight super-scaffolds corresponding to the 8 chromosomes were assembled to a final size of 716.6 Mb, with a scaffold N50 of 88.78 Mb using 1,862 contigs. BUSCO evaluation reveals that the genome completeness reached 95.27%. The repeat sequences accounted for 59.13%, and 29,203 protein-coding genes were annotated in the genome. According to phylogenetic analysis using single-copy orthologous genes, we found that A. sinensis is closely related to Gossypium hirsutum and Theobroma cacao from the Malvales order, and A. sinensis diverged from their common ancestor ∼53.18–84.37 million years ago. Conclusions Here, we present the first chromosome-level genome assembly and gene annotation of A. sinensis. This study should contribute to valuable genetic resources for further research on the agarwood formation mechanism, genome-assisted improvement, and conservation biology of Aquilaria species. [ABSTRACT FROM AUTHOR]

In the effort to identify natural products that regulate immunity and inflammation, we found that nitidine chloride (NC), an alkaloid from herb Zanthoxylum nitidum, enhanced IL-10 production in lipopolysaccharide (LPS)-stimulated myeloid cells. While NC was shown to be capable of inhibiting topoisomerase I (TOP1), NC analogs that could not inhibit TOP1 failed to increase IL-10 production. Moreover, medicinal TOP1 inhibitors TPT and SN-38 also augmented IL-10 production significantly, whereas knockdown of TOP1 prevented NC, TPT, and SN-38 from enhancing IL-10 expression. Thus, NC promoted IL-10 production by inhibiting TOP1. In LPS-induced endotoxemic mice, NC and TOP1 inhibitors increased IL-10 production, suppressed inflammatory responses, and reduced mortality remarkably. The anti-inflammatory activities of TOP1 inhibition were markedly reduced by IL-10-neutralizing antibody and largely absent in IL-10-deficient mice. In LPS-stimulated RAW264.7 cells and in peritoneal macrophages from endotoxemic mice, NC and TOP1 inhibitors significantly enhanced the activation of Akt, a critical signal transducer for IL-10 production, and inhibition of Akt prevented these compounds from enhancing IL-10 production and ameliorating endotoxemia. These data indicated that NC and TOP1 inhibitors are able to exert anti-inflammatory action through enhancing Akt-mediated IL-10 production and may assist with the treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Abstract: The isolation of a new flavan, 5,7,4′-trihydroxy-8-ethoxycarbonylflavan (1), from the root of Daphne odora var. atrocaulis is reported. [Copyright &y& Elsevier]