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Supplementary Tables S1-S6 and Supplementary Figures S1-S2. Table S1: Data collection and refinement statistics, related to Figure 1B; Table S2: Summary of cell line related information; Table S3: BGB-283 is a reversible B-RAF inhibitor; Table S4. Kinase inhibition profile of BGB-283. BGB-283 selectively inhibited multiple kinases at concentration of 10 μM; Table S5: IC50 values of BGB-283 in inhibiting various kinases; Table S6. Anti-tumor efficacy of BGB-283 in CRC xenograft models; Figure S1: BGB-283 is a slow-off B-RAF inhibitor showing potent anti-EGFR activity in multiple cell lines; Figure S2. The effect of BGB-283 on body weight of nude mice subcutaneously implanted with human cancer xenografts.

Excess fluoride in water poses a threat to ecology and human health, which has attracted global attention. In this study, a series of lanthanum-based metal–organic frameworks (La-MOFs) were synthesized by varying the organic ligands (i.e., terephthalic acid (BDC), trimesic acid (BTC), biphenyl-4,4-dicarboxylic acid (BPDC), 2,5-dihydroxyterephthalic acid (BHTA), and 1,2,4,5-benzenetetracarboxylic acid (PMA)) to control the microscopic structure of the MOFs and subsequently apply them for the removal of fluoride in water. The maximum capture capacities of La-BTC, La-BPDC, La-BHTA, La-PMA, and La-BDC at 298 K are 105.2, 125.9, 145.5, 158.9, and 171.7 mg g−1, respectively. The adsorption capacity is greater than most reported adsorbents. The adsorption isotherms of La-MOFs for fluoride are well fit to the Langmuir isotherm model. In addition, the adsorption kinetics of La-BTC, La-BPDC, La-BHTA, La-PMA, and La-BDC follows the pseudo-second-order kinetic model, and the kinetic rate-limiting step of adsorption is chemical adsorption. Thermodynamics revealed that temperature is favorable for the adsorption of fluoride. Meanwhile, La-BTC, La-BPDC, La-BHTA, La-PMA, and La-BDC are suitable for the removal of fluoride in a relatively wide pH range (4.0–9.0). Simultaneously, from X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR) analysis, electrostatic attraction and ligand exchange are identified as the main action mechanisms for the adsorption of fluoride of La-MOFs. The prepared La-MOFs are used as efficient adsorbents for removal of fluoride in actual water, indicating that they have great potential in removing fluoride in real and complex environmental water. This work provides a new strategy for designing adsorbents with adjustable microstructure and expected function to effectively recover fluorosis in water.

This study proposes a new strategy for manufacturing metal-organic frameworks (MOFs) with respective topologies and properties by adjusting the anionic species in the precursor solution. Three MOFs (e.g. Fe/Al (Cl−), Fe/Al (NO3−) and Fe/Al (SO42−)) were successfully synthesized and used for removal of phosphate from water. Surprisingly, when chlorinated salt was used as the precursor, only Al was detected in the Fe/Al (Cl−). However, when nitrate and sulfate were used as the precursors, Fe and Al were simultaneously detected in the Fe/Al (NO3−) and Fe/Al (SO42−). These MOFs exhibit ultrafast adsorption kinetics and high uptake capacity for phosphate. The maximum phosphate uptake capacity (130 mg P/g) of Fe/Al (NO3−) is much higher than that of most phosphate removal materials reported in the literature. More importantly, Fe/Al (NO3−) can still effectively remove phosphate from water bodies after multiple cycles of adsorption/desorption. When there are a large number of common interfering ions (Ca2+, Mg2+, CO32-, HCO3−, Cl−, NO3− and SO42−) in the water, the prepared MOFs can still specifically remove phosphorus from water. In addition, the prepared MOFs can adapt to the removal of phosphorus in a wide pH water body. Furthermore, based on FTIR and XPS spectra, chemical adsorption and ligand exchange were identified as the main phosphorus removal mechanisms by Fe/Al (NO3−). These findings prefigure that MOFs synthesized by regulating the anionic species can efficiently and economically remove phosphate from water.

Solvent extraction based on ionic liquids is generally considered to be an environmentally benign and effective technology for gold(I) recovery. The aim of this work is to study gold(I) extraction from aurocyanide solution using fluorine-free ionic liquids [A336][SCN], [A336][MTBA] and [A336][Mal]. Various factors that affect gold(I) extraction (including concentration of ionic liquids, equilibrium pH, concentration of the modifier tributyl phosphate (TBP), reaction time and initial concentration of gold in an aqueous solution) were studied and optimized. The results indicate that the three Aliquat 336-based ionic liquids all exhibit excellent behaviors for gold(I) extraction. More than 99.8% of gold(I) can be extracted from the aqueous phase into the ionic liquid phase. The gold-loaded ionic liquids were characterized using infrared spectroscopy and mass spectrometry to study the extraction mechanism of gold(I). The results revealed that extraction of gold(I) into the ionic liquid phase was based on an exchange reaction between the anion Au(CN) 2 − in aqueous solution and the anion SCN− in ionic liquid [A336][SCN]. The logarithmic relationship between distribution coefficient and TBP concentration indicates that two TBP molecules are involved in the formation of the extracted complex. The extracted complex was determined to be A336+·Au(CN) 2 − ·2TBP. In addition, the gold(I)-loaded ionic liquids can be efficiently stripped using NH4SCN, 2-methylthiobenzoic acid and methyl maltol. The results establish that Aliquat 336-based ionic liquids have potential application prospects in gold(I) recovery from cyanide solutions.

High-activity and cost-effective transition metal sulfides (TMSs) have attracted tremendous attention as promising catalysts for hydrogen evolution reaction (HER). However, a significant challenge is the simultaneous construction of abundant electrochemical active sites and the fast electronic transmission path to boost a high-efficient HER. Herein, we demonstrate a facile one-step hydrothermal preparation of MoS2 hollow nanospheres decorating Ni3S2 nanowires supported on Ni foam (NF), without any other additional template, surfactant or annealing. In this three-dimensional (3D) heterostructure, the ultrathin-layered MoS2 hollow nanospheres contribute to the promotion of the total surface area and the electrochemical active sites. Meanwhile, the Ni3S2 nanowires are beneficial to the high electrical conductivity. Consequently, the optimized MoS2/Ni3S2/NF-200-24 electrocatalyst presents an extremely superior HER activity to that of individual MoS2/NF and Ni3S2/NF. The HER overpotentials are 85 mV at 10 mA cm−2 and 189 mV at 100 mA cm−2, which are also comparable with the state-of-the-art 20% Pt/C/NF electrode at both low and high current.

In this work, water-stable Al-MIL-101 analogues were successfully synthesized by adjusting the Fe/Al ratio to obtain excellent phosphorus removal efficiencies. The introduction of Fe3+ into the precursor solution allowed the final structure of aluminum metal-organic frameworks (Al-MOFs) to be tuned without introducing Fe into the final structure. The formation of Al-MIL-101 analogues with different morphologies and surface areas was accomplished by adjusting the Fe/Al molar ratio in the precursor solution. Compared with pure Fe-MIL-101 or Al-MIL-101, Al-MIL-101 analogues exhibited ultra-fast phosphorous adsorption kinetics and high phosphorous adsorption capacities. Al-MIL-101, produced with an Fe/Al feed molar ratio of 0.5, achieved a maximum phosphorus uptake capacity of 90 mg P/g, which is much higher than the phosphorus absorption reported in most literatures. More importantly, the Al-MIL-101 analogue obtained using an Fe/Al molar ratio of 0.5 exhibited an excellent phosphorus removal efficiency, even after multiple adsorption/desorption cycles. These results indicate that Al-MOFs produced by adjusting the Fe amount in the precursor solution are promising candidates for the removal of phosphate from water.

Ionic liquid-based polymer inclusion membranes (PIMs) are an environmentally benign separation technology. PIMs are especially suitable for separation of dilute substances, but their application is hindered by their relatively low permeability rate. In this paper, a novel ionic liquid-based PIM system integrated with an electroplating unit was developed to improve the permeability of gold from aurocyanide solutions. Under the optimal conditions, 98.6% of gold(I) was transported, and more than 96.4% of gold was simultaneously deposited on the copper cathode. The gold(I) transport rate was considerably enhanced with in-situ electrodeposition of gold in the stripping phase. With a constant voltage of 1.50 V applied to the stripping solution, the permeability coefficient increased from 9.25 × 10−6 m/s (with no voltage) to 21.5 × 10−6 m/s (with voltage). SEM and EDX analysis show metallic state gold was coated evenly on the surface of the electrode. Results of a stability evaluation experiment show that the PIM can be operated stably for 10 cycles on a continuous run mode. The method of simultaneous transport and in-situ electrodeposition expands the application of the PIM technology for separation, which shows good prospects for the removal and recovery metal ions.

1. The effect of agrimoniin on the activity of cytochrome P450 (CYP450) enzymes would induce drug-drug interaction, which leads to adverse effects or even failure of therapy.2. Agrimoniin was incubated with the specific substrates of eight human liver CYP isoforms in pooled human liver microsomes. The enzyme kinetics and time-dependent study were performed to obtain kinetic parameters and characteristics in vitro.3. Agrimoniin significantly inhibited the activity of CYP1A2, 2D6, and 3A4 in a dose-dependent manner with IC50 values of 6.26, 9.35, and 8.30 μM, respectively. Agrimoniin served as a non-competitive inhibitor of CYP3A4 and a competitive inhibitor of CYP1A2 and 2D6. Moreover, the incubation time also significantly affected the inhibition of CYP3A4.4. In vitro inhibitory effect of agrimoniin on the activity of CYP1A2, 2A6, and 3A4 was reported in this study. The potential drug-drug interactions between agrimoniin and drugs metabolized by CYP1A2, 2D6, and 3A4 should be paid special attention.

Abstract Magnetic nanomaterials were functionalized with dopamine hydrochloride as the functional reagent to afford a core–shell-type Fe3O4 modified with polydopamine (Fe3O4@PDA) composite, which was used for the adsorption of cadmium ions from an aqueous solution. In addition, the effects of environmental factors on the adsorption capacity were investigated. Furthermore, the adsorption kinetics, isotherm, and thermodynamics of the adsorbents were discussed. Results revealed that the adsorption of cadmium by Fe3O4@PDA reaches equilibrium within 120 min, and kinetic fitting data are consistent with the pseudo-second-order kinetics (R2 > 0.999). The adsorption isotherm of Cd2+ on Fe3O4@PDA was in agreement with the Freundlich model, with the maximum adsorption capacity of 21.58 mg/g. The thermodynamic parameters revealed that adsorption is inherently endothermic and spontaneous. Results obtained from the adsorption–desorption cycles revealed that Fe3O4@PDA exhibits ultra-high adsorption stability and reusability. Furthermore, the adsorbents were easily separated from water under an enhanced external magnetic field after adsorption due to the introduction of an iron-based core. Hence, this study demonstrates a promising magnetic nano-adsorbent for the effective removal of cadmium from cadmium-containing wastewater. Graphical Abstract

In this work, ferric chloride was applied to remove phosphorus from natural water bodies of Dianchi Lake. The feasibility and efficiency of phosphorus removal using ferric chloride are reported. The factors that influence the stability of Fe-P coprecipitates formed during the phosphorus removal process (including temperature, pH, coexisting ions, fast mixing speed (FMS), and fast mixing time (FMT)) were studied in detail. Results show that ferric chloride can efficiently remove phosphorus, and Fe-P coprecipitate exhibits high stability. In a water temperature range of 10–35 °C and pH range of 3–11, the phosphorus in the Fe-P coprecipitates is stable and is not released. The maximum phosphorus release efficiency is 9.2% at a pH of 3, and 16.10% at a pH of 11. The presence of Ca2+ and CO32− has little effect on the stability of Fe-P coprecipitates, and the differences in fast mixing speed and time have little effect on the stability of Fe-P coprecipitates. Furthermore, on the basis of Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM) and X-ray diffraction (XRD) analysis, adsorption and ligand exchange were identified as the main phosphorus removal mechanisms by ferric chloride. These findings demonstrate that ferric chloride is a promising candidate for highly efficient and stable phosphorus removal from water of Dianchi Lake.

Binary metal phosphides, a new class of nonprecious catalysts, have drawn tremendous attention in recent years for their synergistic interactions between different components. Herein, a novel in si...

The purpose of this study was to optimize the coagulation–flocculation effect of a wastewater treatment system using the response surface methodology (RSM) and three-step method to minimize phosphorus concentration in the distillate wastewater. In order to minimize the concentration of total phosphorus (TP), experiments were carried out using -factorial designs with three levels and three factors. A Box–Behnken design, which is the standard design of RSM, was used to evaluate the effects and interactions of three major factors (Fe:P (w/w) ratio, coagulation pH and fast mixing speed (FMS)) on the treatment efficiency. A multivariable quadratic model developed for studying the response indicated that the values for optimum conditions for Fe:P (w/w) ratio, coagulation pH and FMS were 2.40, 6.48 and 100 rev min−1, respectively. Under optimal process conditions, the TP concentration in the distillery effluent was reduced from 10 mg L−1 to 0.215 mg L−1, representing a removal efficiency of 97.85%. Based upon the statistical evaluation of results, it is inferred that RSM can be used as an appropriate approach to optimize the coag-flocculation process. Meanwhile, the study has shown that, for the equivalent dose of ferric chloride, the average three-step effect is better than that of the one-time addition.

BackgroundCornin is a commonly used herb in cardiology for its cardioprotective effect. The effect of herbs on the activity of cytochrome P450 enzymes (CYP450s) can induce adverse drug-drug interaction even treatment failure. Therefore, it is necessary to investigate the effect of cornin on the activity of CYP450s, which can provide more guidance for the clinical application of cornin.MethodsCornin (100 μM) was incubated with eight isoforms of CYP450s, including CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1, in pooled human liver microsomes. The inhibition model and corresponding parameters were also investigated.ResultsCornin exerted significant inhibitory effect on the activity of CYP3A4, 2C9, and 2E1 in a dose-dependent manner with the IC50values of 9.20, 22.91, and 14.28 μM, respectively (p Kivalue of 4.69 μM, while the inhibition of CYP2C9 and 2E1 by cornin was competitive with theKivalue of 11.31 and 6.54 μM, respectively. Additionally, the inhibition of CYP3A4 by cornin was found to be time-dependent with theKI/Kinactvalue of 6.40/0.055 min− 1·μM− 1.ConclusionsThe inhibitory effect of cornin on the activity of CYP3A4, 2C9, and 2E1 indicated the potential drug-drug interaction between cornin and drugs metabolized by these CYP450s, which needs further investigation and validation.

In view of the existing distribution line information storage is not unified, the formation of the diagram is not clear, the protection configuration chaos and so on. This paper presents a standard information model based on the electric quantity of distribution lines. Based on this model, an automatic mapping and display method of distribution lines is proposed. On this basis, a set of auxiliary decision-making software for hierarchical protection configuration of distribution lines is developed based on scalable vector graphics (SVG) software mapping technology. The automatic optimization of distribution line protection configuration is realized. The effectiveness and practicability of the technology are verified by the software operation, manual calculation and field application.

Single-phase grounding fault line selection is a long-standing problem in the distribution network. The identification rate of single-phase grounding fault is further reduced due to a large number of grid-connected distributed power supply, as well as short distribution network lines and many branches. In the case of faults, there is a strong similarity between the waveforms of the sound lines, and there is a big difference between the waveforms of the faults and the waveforms of the sound lines. Based on waveform similarity, this paper takes one-fourth power frequency period after fault as an analysis window, uses fractal theory to analyze transient zero-sequence current of multi-points in small current grounding systems of distribution network. By using the difference of fractal dimension between fault lines and sound lines, a new fault identification method is proposed to realize fault line selection. By using the waveform difference between fault line terminals, the fault zone location is realized. The accuracy and validity of the criterion are verified by simulation and field data.

Arsenic pollution of groundwater and surface water has come to the attention of the public. To explore economically affordable and efficient adsorbents for the treatment of arsenic, bimetallic MOFs based on trivalent iron and aluminum were synthesized and used to capture arsenic from wastewater. Characterization methods including SEM, EDX, XRD, and N2 adsorption–desorption were applied to analyze the morphology and element content, crystal structure, porosity and specific surface area of the Fe/Al-BDC-NH2 materials. The microstructures of bimetallic MOFs were tuned through changing the ratio of Al and Fe in the precursor material. Adsorption results show that introducing aluminum into the iron-based material formed bimetallic Fe/Al-BDC-NH2 MOFs that had much better adsorption performance for arsenic than the monometallic Fe-BDC-NH2 or Al-BDC-NH2 MOF. The adsorption isotherm of bimetallic MOF materials for arsenic is in accordance with the Langmuir isotherm model, and the maximum adsorption capability of Fe/Al-BDC-NH2 (1:1) at 298 K was 146.8 mg g−1. The kinetics of arsenic adsorption follow the pseudo-second-order model. Also, the thermodynamics indicate that arsenic adsorption is endothermic. Fe/Al-BDC-NH2 (1:1) is suitable for removal of arsenic from wastewater in a relatively wide pH range (5.0–9.0). Within this pH range, Fe and Al are hardly dissolved in water after arsenic capture, and this indicates that Fe/Al-BDC-NH2 (1:1) is very stable and suitable for arsenic capture from water without generating secondary pollution. Furthermore, through FTIR and XPS analysis, ligand exchange was identified as the main adsorption mechanism of Fe/Al-BDC-NH2 (1:1) for arsenic.

Immobilization of phosphorus in lake sediments and control of internal-loading phosphorus release have become crucial aspects of eutrophication lake management. In this study, the immobilization efficiency of phosphorus by ferric chloride in Dianchi Lake sediments was investigated. In addition, effects of the dosage of ferric chloride and contact time on the release of phosphorus from sediments were investigated. Laboratory experiments revealed that ferric chloride can effectively inhibit the release of phosphorus from sediments. At a ferric chloride dosage of 10 mg/g, the total phosphorus concentration of the overlying water was reduced by ~87%. With the increase in the contact time, the amount of phosphorus immobilized by ferric chloride increased. To further evaluate the feasibility of ferric chloride for immobilising phosphorus in sediments, an amplification experiment with a water volume of 50 L was carried out. By the addition of 6 mg/g of ferric chloride, the total phosphorus concentration of the overlying water was still less than 0.01 mg/L after 100 days. At the same time, the phosphorus species in the sediment after treatment with ferric chloride were analyzed. Results revealed that ferric chloride mainly converts unstable exchangeable phosphorus (Ex-P), ferric phosphate (Fe-P) and organic phosphorus (Or-P) into more stable occluded phosphate (O-P), reducing the possible release of phosphorus from sediments. Practical applications of ferric chloride to control the release of phosphorus from Dianchi Lake sediments were discussed.

In this work, Fe3O4@ZIF-8 core-shell magnetic composite was synthesized by a solvothermal method and used to remove Pb2+ and Cu2+ from wastewater. Various characterization techniques (SEM, TEM, XRD, BET, VSM, and TGA) indicated that the Fe3O4@ZIF-8 microspheres were stable and had a high specific surface area (724.7 m2/g). The factors that affected the performance of Fe3O4@ZIF-8 during the removal of Pb2+ and Cu2+ from wastewater are discussed, including the adsorbent amount, pH, temperature, contact time, concentration, ionic strength, and coexisting ions. Moreover, the adsorption processes were well described by the Langmuir model, and the uptake capacities of Fe3O4@ZIF-8 were calculated to be 719.42 mg/g for Pb2+ and 301.33 mg/g for Cu2+. In addition, Fe3O4@ZIF-8 also had fast adsorption kinetics for the uptake of Pb2+ and Cu2+ from wastewater, and it only took 20 min and 60 min to reach adsorption equilibrium, respectively. More importantly, the material could be reused at least four times. The mechanism study showed that ion-exchange and coordination reactions were the main Pb2+ and Cu2+ removal mechanisms of Fe3O4@ZIF-8. Thus, the synthesized Fe3O4@ZIF-8 composite is a promising candidate material for removing Pb2+ and Cu2+ from wastewater.

Utilization of supported liquid membrane (SLM) for the extraction of Au(I) from alkaline cyanide solution was investigated. The SLM consisted of a synergistic mixture of primary amine N1923 and bis(2-ethylhexyl) sulfoxide (BESO) in kerosene as carrier and a hydrophobic microporous polyvinylidene fluoride (PVDF) membrane as the solid support. The presence of both BESO and N1923 extractants in the liquid membrane induces an evident synergistic effect, allowing the latter to transfer Au(I) from the highly alkaline solution (pH>9.21). The fundamental parameters influencing the gold transport, such as stirring speed, composition of the liquid membrane, feed pH, NaOH concentration in stripping solution, and initial gold concentration in the feed solution were explored. The gold transport is almost quantitative after 7 h under the optimum process conditions: a mixture of (0.50 mol/L N1923 + 0.75 mol/L BESO) in kerosene as membrane phase, stirring rate of 1000 rpm in both phases, 5.0 mg/L gold in 0.20 mol/L NaCl solution with a pH of 9.60, and 0.10 mol/L NaOH as stripping agent. The parameters defining the mass transfer model of Au(I) through the SLM are experimentally determined as: maximum permeability coefficient, P = 31.45 × 10 −6 m/s, the diffusion coefficient for [Au(CN) 2 − ·RNH 3 + ·2BESO] complex across the liquid membrane, D org = 1.42 × 10 –12 m 2 /s, and the thickness of the aqueous diffusion layer, d aq = 2.07 × 10 −5 m. Selectivity of this SLM system was evaluated by performing the permeation test of Au(CN) 2 - with other metal cyanide species in aqueous solution and it was found that the gold ions were preferred over other impurity ones. Finally, stability of this SLM system has also been examined on a continuous run mode and satisfactory stability was observed for five runs.

In this work, water-stable Al-MIL-101 analogues were successfully synthesized by adjusting the Fe/Al ratio to obtain excellent phosphorus removal efficiencies. The introduction of Fe

In this study, five aluminum-based metal-organic frameworks (i.e. Al-BDC, Al-BDC-NH2, Al-BHTA, Al-PMA and Al-BPDC) were synthesized by changing the organic linker. Among the five Al-MOFs, Al-BDC, which used 1,4-benzenedicarboxylate as a linker, showed the highest phosphorus adsorption capacity (97.50 mg P/g), while Al-PMA, which used 1,2,4,5-benzenetetracarboxylic acid as a linker, exhibited the lowest phosphorous adsorption capacity (42.25 mg P/g). The adsorption capacity was higher than most adsorbents reported in the literature. In addition, Al-PMA and Al-BPDC are more cost-effective for removing low concentrations of phosphorous from water. When the aqueous phosphorus concentration was less than 1.0 mg P/L, and the dosage of the five Al-MOFs was only 0.10 g/L, more than 90% of phosphorus was removed. The Al-MOFs are suitable for phosphorus removal from water over a wide pH range (5.0–9.0). In this pH range, almost no Al was detected in water after phosphorus removal, indicating that the Al-MOFs can remove phosphorus from water without causing secondary pollution. Moreover, in a NaCl (0.01 mol/L) background electrolyte solution, the Al-MOFs showed high phosphorus removal stability. The Al-MOFs have the potential to remove phosphorus from natural water. Furthermore, the mechanism study shows that electrostatic interaction and ligand exchange were defined as the main phosphorus removal pathways using the prepared Al-MOFs. These findings demonstrate that the synthesized Al-MOFs are promising candidates for removal of phosphorus from eutrophic water.

(Z) Enol triflates 6, 11b-d, (E) enol triflate 11e, and phenol triflate 11a, derived from β-keto esters or 2-carboalkoxy phenols, respectively, react with N-Boc 2-lithiopyrrolidine (5a), N-Boc N-methylaminomethyllithium (5b), or 2-lithio-1,3-dithiane (14) to afford 3(2H)-furanones in modest to good yields (38-81%). Product and carbanion reagent studies suggest that the 3(2H)-furanone is formed in a cascade of reactions involving nucleophilic acyl substitution, enolate formation, trifluoromethyl transfer, iminium or sulfenium ion formation, and subsequent ring closure to form the 3(2H)-furanone. The use of 2-lithio-1,3-dithiane affords a cyclic α-keto-S,S,O-orthoester in which the functionality can be selectively manipulated for synthetic applications.

A highly effective and neoteric cerium-doped metal-organic framework (MOF Ce-UiO-66-NH2) was triumphantly prepared via a simple and convenient approach of solvothermal reaction; the Ce-UiO-66-NH2 can be used for removing phosphate from water. The physicochemical characteristics of new adsorbent were determined by X-ray diffraction (XRD), Brunauer–Emmett–Teller analysis (BET), transmission electron microscopy (TEM), scanning electron microscopy (SEM), and infrared spectroscopy (FTIR). The results confirmed that the introduction of cerium caused a trivial effect on the UiO-66-NH2 structure; however, a hybrid MOF with polyhedral crystalloid shapes was obtained. When cerium was doped in UiO-66-NH2, the newly developed adsorbent Ce-UiO-66-NH2 exhibited outstanding performance in terms of adsorption of phosphate, and the maximum uptake capacity was up to 211.86 mg g−1. The reaction for capture of phosphate of 0.75Ce-UiO-66-NH2 was quite fast, and could reach equilibrium in 60 min. Furthermore, FTIR and X-ray photoelectron spectroscopy (XPS) characterization indicated that the main mechanism of phosphate capture involved the production of an inner-sphere complex of Zr/Ce–O–P and electrostatic attraction. After adsorption, the phosphate on Ce-UiO-66-NH2 was efficiently desorbed with NaOH (0.10 mol L−1); thus the material could be used repeatedly for at least five cycles, and the adsorption capacity was still more than 100 mg g−1 at the fifth cycle. The repeated utilization potentially provides access to effectively prevent water pollution and further implement cleaner production at the minimum cost. The developed Ce-UiO-66-NH2 is an efficient and regenerative adsorbent that can be used for phosphate uptake to mitigate increasing eutrophication of water.

A novel method for determination of inorganic arsenic in natural water, based on nano ferric hydroxides (FeOOH) preconcentration and electrochemistry detection has been developed. As the nano α-FeOOH could successfully act as the adsorbent and electrode matrix modifier, the method presents great potential in practical routine analysis of inorganic arsenic. With optimization of the experimental conditions, nano α-FeOOH modified carbon paste electrode (α-FeOOH@CPE) was obtained by mixing 0.03 g of nano α-FeOOH and 0.02 g graphite powder in n-eicosane as an adhesive and then embedding them in a Teflon tube. Cyclic voltammetry, chronoamperometry and high resolution transmission electron microscopy were used to check and confirm the presence of nano α-FeOOH on the carbon paste electrodes. According to the results, α-FeOOH@CPE showed a considerably higher response to As(III) in comparison with the bare CPE, indicating the α-FeOOH has well selective enrichment for As(III). The developed modified electrode showed a linear range of 1.0 × 10-8 ~ 2.0 × 10-5 mol·L-1 and detection limit of 5.0 nmol·L-1 (S/N = 3). The newly prepared carbon paste electrode was successfully applied for As(III) determination in Yangzonghai Lake water with RSD of less than 3.6 % (n = 3) and recovery in the range of 100.7 ~ 115.0 %. DOI: http://dx.doi.org/10.5755/j01.ms.24.4.18499

This paper introduces a Distribution Static Synchronous Compensator(DSTATCOM) used in three-phase three-wire system. Reactive harmonic detecting method of directly controlling source current is adopted. The fundamental principles of DSTATCOM of this controlling method are presented and the compensation features of unbalanced load is analyzed. The validity of this kind of DSTATCOM and compensation features of unbalanced load are proved by Matlab/Simulink.

Oncogenic BRAF, which drives cell transformation and proliferation, has been detected in approximately 50% of human malignant melanomas and 5% to 15% of colorectal cancers. Despite the remarkable clinical activities achieved by vemurafenib and dabrafenib in treating BRAFV600E metastatic melanoma, their clinical efficacy in BRAFV600E colorectal cancer is far less impressive. Prior studies suggested that feedback activation of EGFR and MAPK signaling upon BRAF inhibition might contribute to the relative unresponsiveness of colorectal cancer to the first-generation BRAF inhibitors. Here, we report characterization of a dual RAF kinase/EGFR inhibitor, BGB-283, which is currently under clinical investigation. In vitro, BGB-283 potently inhibits BRAFV600E-activated ERK phosphorylation and cell proliferation. It demonstrates selective cytotoxicity and preferentially inhibits proliferation of cancer cells harboring BRAFV600E and EGFR mutation/amplification. In BRAFV600E colorectal cancer cell lines, BGB-283 effectively inhibits the reactivation of EGFR and EGFR-mediated cell proliferation. In vivo, BGB-283 treatment leads to dose-dependent tumor growth inhibition accompanied by partial and complete tumor regressions in both cell line-derived and primary human colorectal tumor xenografts bearing BRAFV600E mutation. These findings support BGB-283 as a potent antitumor drug candidate with clinical potential for treating colorectal cancer harboring BRAFV600E mutation. Mol Cancer Ther; 14(10); 2187–97. ©2015 AACR.

Excess iron induces tissue damage and is implicated in age-related macular degeneration (AMD). Iron toxicity is widely attributed to hydroxyl radical formation through Fenton's reaction. We report that excess iron, but not other Fenton catalytic metals, induces activation of the NLRP3 inflammasome, a pathway also implicated in AMD. Additionally, iron-induced degeneration of the retinal pigmented epithelium (RPE) is suppressed in mice lacking inflammasome components caspase-1/11 or Nlrp3 or by inhibition of caspase-1. Iron overload increases abundance of RNAs transcribed from short interspersed nuclear elements (SINEs): Alu RNAs and the rodent equivalent B1 and B2 RNAs, which are inflammasome agonists. Targeting Alu or B2 RNA prevents iron-induced inflammasome activation and RPE degeneration. Iron-induced SINE RNA accumulation is due to suppression of DICER1 via sequestration of the co-factor poly(C)-binding protein 2 (PCBP2). These findings reveal an unexpected mechanism of iron toxicity, with implications for AMD and neurodegenerative diseases associated with excess iron. journal article research support, n.i.h., extramural research support, non-u.s. gov't 2015 Jun 23 2015 06 11 imported

One Sentence SummaryStructures ofMycobacterium tuberculosisRNA polymerase reveal taxon-specific properties and binding sites of known and new antituberculosis agentsAbstractMycobacterium tuberculosis(Mtb) is the causative agent of tuberculosis, which kills 1.8 million annually.MtbRNA polymerase (RNAP) is the target of the first-line antituberculosis drug rifampin (Rif). We report crystal structures ofMtbRNAP, alone and in complex with Rif. The results identify anMtb-specific structural module ofMtbRNAP and establish that Rif functions by a steric-occlusion mechanism that prevents extension of RNA. We also report novel non-Rif-related compounds–Nα-aroyl-N-aryl-phenylalaninamides (AAPs)–that potently and selectively inhibitMtbRNAP andMtbgrowth, and we report crystal structures ofMtbRNAP in complex with AAPs. AAPs bind to a different site onMtbRNAP than Rif, exhibit no cross-resistance with Rif, function additively when co-administered with Rif, and suppress resistance emergence when co-administered with Rif.

Nucleoside reverse transcriptase inhibitors (NRTIs) are mainstay therapeutics for HIV that block retrovirus replication. Alu (an endogenous retroelement that also requires reverse transcriptase for its life cycle)–derived RNAs activate P2X7 and the NLRP3 inflammasome to cause cell death of the retinal pigment epithelium in geographic atrophy, a type of age-related macular degeneration. We found that NRTIs inhibit P2X7-mediated NLRP3 inflammasome activation independent of reverse transcriptase inhibition. Multiple approved and clinically relevant NRTIs prevented caspase-1 activation, the effector of the NLRP3 inflammasome, induced by Alu RNA. NRTIs were efficacious in mouse models of geographic atrophy, choroidal neovascularization, graft-versus-host disease, and sterile liver inflammation. Our findings suggest that NRTIs are ripe for drug repurposing in P2X7-driven diseases.

When there is a single-phase fault appearing in an indirect grounding electric power system, in order to quickly locate the ground fault section. So here, a new method is proposed which is based on the oringinal localization algorithm. The method of phase section positioning is based on the zero mode of current's phase, when the fault is in this section, there is an opposition before and after the detection point. The simulation model was built by MATLAB, and the simulation conclusion are same as the theoretical proof.

Human intravenous immune globulin (IVIg), a purified IgG fraction composed of ~60% IgG1 and obtained from the pooled plasma of thousands of donors, is clinically used for a wide range of diseases. The biological actions of IVIg are incompletely understood and have been attributed both to the polyclonal antibodies therein and also to their IgG (IgG) Fc regions. Recently, we demonstrated that multiple therapeutic human IgG1 antibodies suppress angiogenesis in a target-independent manner via FcγRI, a high-affinity receptor for IgG1. Here we show that IVIg possesses similar anti-angiogenic activity and inhibited blood vessel growth in five different mouse models of prevalent human diseases, namely, neovascular age-related macular degeneration, corneal neovascularization, colorectal cancer, fibrosarcoma and peripheral arterial ischemic disease. Angioinhibition was mediated by the Fc region of IVIg, required FcγRI and had similar potency in transgenic mice expressing human FcγRs. Finally, IVIg therapy administered to humans for the treatment of inflammatory or autoimmune diseases reduced kidney and muscle blood vessel densities. These data place IVIg, an agent approved by the US Food and Drug Administration, as a novel angioinhibitory drug in doses that are currently administered in the clinical setting. In addition, they raise the possibility of an unintended effect of IVIg on blood vessels.

Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world’s population. The most widely used anti-angiogenic drug is bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits angiogenesis in mice. Here we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI (CD64) and c-Cbl, impairing macrophage migration. Other approved humanized or human IgG1 antibodies without mouse targets (adalimumab, alemtuzumab, ofatumumab, omalizumab, palivizumab and tocilizumab), mouse IgG2a, and overexpression of human IgG1-Fc or mouse IgG2a-Fc, also inhibited angiogenesis in wild-type and FcγR humanized mice. This anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown, Fc cleavage, IgG-Fc inhibition, disruption of Fc-FcγR interaction, or elimination of FcRγ-initated signaling. Furthermore, bevacizumab’s Fc region potentiated its anti-angiogenic activity in humanized VEGFA mice. Finally, mice deficient in FcγRI exhibited increased developmental and pathological angiogenesis. These findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies.

An alpha 1a- and alpha 1d-adrenergic receptor (AR) selective antagonist may be a more efficacious treatment for BPH/LUTS patients and may have fewer side effects than the existing pharmaceuticals. A facile synthesis for a series of (2-cyclopropoxyphenyl)piperidine derivatives has been developed, in which aryl vinyl ether formation and subsequent cyclopropyl formation provide efficient access to key intermediate N-Boc-4-(2-cyclopropoxyphenyl)piperidine. The synthesized (2-cyclopropoxyphenyl)piperidine derivatives display high affinity and selectivity for alpha1a-AR and alpha1d-AR compared to alpha1b-AR and D2 receptor, Ki values for alpha1a-AR are 0.91 nM to 79.0 nM and alpha1d-AR are 2.0 nM to 57 nM; Ki values for alpha1b-AR are 107 nM to 839.8 nM and D2 receptor are 66.2 nM to 187.1 nM. The selectivity ratios of Ki(alpha1b)/Ki(alpha1a) are 11 to 155 fold, Ki(alpha1b)/Ki(alpha1d) are 6 to 171 fold, Ki(D2)/Ki(alpha1a) are 2 to 158 fold, and Ki(D2)/Ki(alpha1d) are 1.2 to 89 fold. Compound 17a shows improved stability in human liver microsome test (t1/2 = 18 minutes).

Background: Although α1 adrenergic receptor blockers can be very effective for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS), their usage is limited by cardiovascular-related side effects that are caused by the subtype nonselective nature of many current drugs. To overcome this problem, it was hypothesized that an α1a/1d subtype selective antagonist would be efficacious yet produce less side effects, and hence would bring greater benefit for the therapy of BPH/LUTS. Unfortunately, such highly selective α1a/1d antagonists were not available, making the validation of the new hypothesis impossible. Objective/method: This review disclosed several series of α1a/1d subtype selective antagonists that have been discovered and developed by Johnson & Johnson recently. These compounds show equal and potent affinity for both α1a and α1d subtypes with good selectivity versus the α1b subtype. Some analogues also possess favorable pharmacokinetic properties. Conclusion: Although d...

Benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) can be effectively treated with alpha(1) adrenergic receptor antagonists. Unfortunately, currently marketed alpha(1) blockers produce CV-related side effects that are caused by the subtype non-selective nature of the drugs. To overcome this problem, it was postulated that an alpha(1a/1d) subtype-selective antagonist would bring more benefit for the treatment of BPH/LUTS. As a continuation of our effort to develop selective alpha(1a/1d) ligands, a series of (phenylpiperazinyl)cyclohexylureas was synthesized and evaluated for the ability to bind to three cloned human alpha(1)-adrenergic receptor subtypes. Several trans isomers were shown to have equal affinity for both alpha(1a), and alpha(1d) subtypes, with 14- to 47-fold selectivity versus the alpha(1b) subtype and15-fold selectivity versus dopamine D(2).

Benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) can be effectively treated by alpha(1) adrenergic receptor antagonists, but these drugs also produce side effects that are related to their subtype non-selective nature. To overcome this limitation, it was hypothesized that an alpha(1a/1d) subtype-selective antagonist would be efficacious while keeping side effects to a minimum. To discover alpha(1a/1d)-selective antagonists and improve metabolic stability of our previously reported compounds, we have designed and synthesized a series of (phenylpiperazinyl)- or (phenylpiperidinyl)-cyclohexylsulfonamides. By incorporating the information obtained from metabolism studies, we were able to discover several compounds that are both alpha(1a/1d) adrenoceptor subtype selective and show increased stability toward human liver microsomal metabolism. The selectivity profile of these compounds provides great improvement over the commercial drug tamsulosin, hence may pave the way to the development of new and efficacious therapeutic agents with reduced side effects.

A series of 3,5-disubstituted pyrazolo[3,4-b]pyridine cyclin-dependent kinase (CDK) inhibitors was synthesized. These compounds showed potent and selective CDK inhibitory activities and inhibited in vitro cellular proliferation in cultured human tumor cells. Selected compounds were evaluated in an in vivo tumor xenograft model. The synthesis and biological evaluation of these pyrazolo[3,4-b]pyridines and related compounds are reported.

Although alpha(1) adrenergic receptor blockers can be very effective for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS), their usage is limited by CV-related side-effects that are caused by the subtype non-selective nature of the current drugs. To overcome this problem, it was hypothesized that a alpha(1a/1d) subtype selective antagonist would bring more benefit for the therapy of BPH/LUTS. In developing such selective alpha(1a/1d) ligands, a series of (phenylpiperidinyl)cyclohexylsulfonamides has been synthesized and evaluated for binding to three cloned human alpha(1)-adrenergic receptor subtypes. Many compounds showed equal affinity for both alpha(1a) and alpha(1d) subtypes with good selectivity versus the alpha(1b) subtype.

RING proteins constitute the largest class of E3 ubiquitin ligases. Unlike most RINGs, AO7 (RNF25) binds the E2 ubiquitin-conjugating enzyme, UbcH5B (UBE2D2), with strikingly high affinity. We have defined, by co-crystallization, the distinctive means by which AO7 binds UbcH5B. AO7 contains a structurally unique UbcH5B binding region (U5BR) that is connected by an 11-amino acid linker to its RING domain, forming a clamp surrounding the E2. The U5BR interacts extensively with a region of UbcH5B that is distinct from both the active site and the RING-interacting region, referred to as the backside of the E2. An apparent paradox is that the high-affinity binding of the AO7 clamp to UbcH5B, which is dependent on the U5BR, decreases the rate of ubiquitination. We establish that this is a consequence of blocking the stimulatory, non-covalent, binding of ubiquitin to the backside of UbcH5B. Interestingly, when non-covalent backside ubiquitin binding cannot occur, the AO7 clamp now enhances the rate of ubiquitination. The high-affinity binding of the AO7 clamp to UbcH5B has also allowed for the co-crystallization of previously described and functionally important RING mutants at the RING-E2 interface. We show that mutations having marked effects on function only minimally affect the intermolecular interactions between the AO7 RING and UbcH5B, establishing a high degree of complexity in activation through the RING-E2 interface.