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Sustained casing pressure (SCP) is a common issue at high temperature, high pressure, and high sour gas fields. It will lead to serious threats to the safety of gas well production. It is very important and imminent to determine the risk level of the well. Based on international standards and the reasons of well losing integrity, 30 parameters affecting gas well integrity are proposed. And the influence of each parameter is evaluated respectively. Based on the combination of field experience and theoretical research, the single well scoring criterion and the model of evaluating well risk level are established. According to the risk evaluation model, the wells can be divided into 3 categories, I, II, and III. Emergency measures need taking immediately for Type III wells. The production characteristics and treating technologies can determine the possibility and severity of integrity losing. The current state is the most important parameter to evaluate the well integrity. The annulus pressure and leaking rate can be viewed as one-vote negation parameters. [ABSTRACT FROM AUTHOR]

Stability is an important pre-analytical variable for quantitative LC-MS/MS analysis of drug molecules and/or their metabolites in biological matrices. Instability of an analyte in any stage of the bioanalytical process, including sample collection, processing, storage, extraction and LC-MS/MS analysis, can result in under-/over-estimation if an adequate preventive procedure is not in place. In the current review on practical strategies in quantitative LC-MS/MS bioanalysis of unstable small molecules, the common causes of analyte instability were examined. The instability of some analytes is readily predictable because of the presence of certain chemically or biologically labile moieties in the molecules or because the compounds are in an inter-convertible form, e.g. lactone vs hydroxyl carboxylic acid. However, the instability of many other analytes is not readily predictable. Necessary evaluation needs to be conducted to identify the possible instability issues. The current review highlighted some general considerations and specific approaches for developing a robust LC-MS/MS method. In particular, incurred samples should be used as part of routine short-term stability assessment of any unstable analyte during the early stages of method development and validation. This can help unveil any 'hidden' instability issues that, if left unaddressed, could lead to the invalidation of a 'validated' method. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A high-throughput LC-MS/MS bioanalytical method was developed and validated for the determination of hydrocortisone in mouse serum via supported liquid extraction (SLE) in a 96-well plate format. Although sample extracts from SLE result in similar matrix effects compared with conventional liquid-liquid extraction (LLE), greater analyte extraction recovery and much higher analysis throughput for the quantitative analysis of hydrocortisone in mouse serum were obtained. The current LC-MS/MS method was validated for a concentration range of 2.00-2000 ng/mL for hydrocortisone using a 0.100 mL volume of mouse serum. The intra- and inter-day precision and accuracy of the quality control samples at low, medium and high concentration levels showed ≤12.9% CV and −3.4-6.2% bias for the analyte in mouse serum. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A liquid chromatographic method with tandem mass spectrometric detection (LC-MS/MS) for the determination of N-methyl-4-isoleucine-cyclosporin (NIM811) was developed and validated over the concentration range 1-2500 ng/mL in human whole blood using a 0.05 mL sample volume. NIM811 and the internal standard, d12-cyclosporin A (d12-CsA), were extracted from blood using MTBE via liquid-liquid extraction. After evaporation of the organic solvent and reconstitution, a 10 µL aliquot of the resulting extract was injected onto the LC-MS/MS system. Chromatographic separation of NIM811 and internal standard was performed using a Waters Symmetry RP-8 (50 × 4.6 mm, 3 µm particle size) column. The mobile phase consists of 10 m m ammonium acetate in water (A) and acetonitrile (B), with 45% B from 0 to 0.2 min, 45 to 85% B from 0.2 to 0.8 min and 85% B from 0.8 to 2.2 min. The total run time was 3.5 min with a flow rate of 0.8 mL/min. The method was validated for sensitivity, linearity, reproducibility, stability, dilution integrity and recovery. The precision and accuracy of quality control samples at low (2.00 ng/mL), medium (20.0 and 400 ng/mL) and high (2000 ng/mL) concentrations were in the range 1.1-4.3% relative standard deviation (RSD) and −2.5-10.0% (bias), respectively, from three validation runs. The method has been used to measure the exposure of NIM811 in human subjects. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

An RP-HPLC method with photodiode array detection and electrospray ionization mass spectrometry was established for the determination of major caffeic acid derivatives (caftaric acid, chlorogenic acid, cynarin, and cichoric acid) in commercial Echinacea purpurea dietary supplements. The samples were extracted with 60% methanol (3 × 15 mL) by means of sonication at room temperature. The components of interest were separated on a RP-18 chromatography column using a 20-min water–methanol–trifluoroacetic acid (TFA) gradient, identified by photodiode array detection, and further confirmed by LC-ESI-MS. The quantification was performed using external standards. The sample preparations and stability of the methanolic extracts were extensively explored. Analyses of 16 commercial E. purpurea products revealed that there is a considerable variability in the content of the caffeic acid derivatives among the products tested. The current method may serve as a valuable tool for the Quality assurance (QA)/Quality control (QC) of echinacea dietary supplements. [ABSTRACT FROM AUTHOR]

This paper presents the results of synthesizing rod-like β-Si3N4 crystals by combustion synthesis (CS) with six rare-earth oxides (Y2O3, La2O3, CeO2, Sm2O3, Gd2O3 and Yb2O3) as additives under high nitrogen pressure. The effect of rare-earth oxide additives on the final morphology of rod-like β-Si3N4 was investigated and the crystal growth mechanism was discussed in detail. The results reveal that the final morphology of combustion synthesized Si3N4 is strongly dependent on the viscosity of liquid formed by the rare-earth oxide and the SiO2 on the Si powder surface. With the increasing of atomic number of the rare-earth elements, the final morphology is from elongated rod-like crystals to short columnar crystals. [Copyright &y& Elsevier]

Ginkgo biloba products are one of the top ten botanical dietary supplements in the USA. The active constituents include flavonoids and terpene lactones (ginkgolides and bilobalide). Ginkgo flavonoids have been associated with reduced lipid peroxidation in vascular walls and nerve cells. Ginkgolides are well known to be antagonists of platelet-activating factor (PAF). Usually, enriched ginkgo extracts used for the preparation of ginkgo products are standardized to contain 24% flavonoids and 6% terpene lactones. In the present work, we examined nine commercial ginkgo products for the content of total flavonoids and terpene lactones by using high performance liquid chromatography (HPLC) with ultraviolet (UV) and evaporative light scattering detection (ELSD), respectively. The methods are reliable and sensitive with detection limits of 2 ng for flavonoids on column with HPLC-UV and 20–35 ng for terpene lactones on column with HPLC-ELSD. The results show that most of the commercial ginkgo products tested contain flavonoids and terpene lactones as claimed on the label. [ABSTRACT FROM AUTHOR]

A high performance liquid chromatography-evaporative light scattering detection (HPLC-ELSD) method was developed to identify Asian ginseng (Panax ginseng C. A. Meyer) and North American ginseng (P. quinquefolius L.), and their products. The method is based on the baseline chromatographic separation of ginsenoside Rf and 24(R)-pseudoginsenoside F11, two potential chemical markers present in the methanolic extracts of ginseng roots and their products, and their on-line detection using an evaporative light scattering detector. As a result, ginsenoside Rf could be detected only in Asian ginseng and 24(R)-pseudoginsenoside F11 could only be detected in North American ginseng in the current study. The method developed is very simple and highly sensitive down to the nanogram level. [ABSTRACT FROM AUTHOR]

Thermal shock behaviors of porous alumina samples with different porosities (4.6–16.0 %) and mean grain sizes (2.72–5.02 μm) were investigated under different quenching temperatures. The slit island method was used to analyze the structures of the pores. The effect of the pore structure on the thermal shock resistance of alumina ceramics was described quantitatively. The results revealed that the thermal shock resistance decreased when the fractal dimension of the pores increased. Alumina ceramic strips with a porosity and mean grain size of 4.6 % and 5.02 μm, respectively, were fabricated using raw powders with a mean particle size of ∼0.3 μm. These samples possessed the highest residual strength ratio (∼46.16 % at 600 °C) and critical temperature difference (∼262 °C). In addition, the fractal characterization of cracks on the surfaces of the alumina ceramics after thermal shock was carried out using the box-counting dimension method. In addition, we investigated the correlation between the mechanical properties and fractal dimensions of the surface cracks. The box-counting dimension increased with crack propagation and negatively correlated with the residual strength. Furthermore, the propagation rate of the surface cracks decreased as the temperature difference increased, resulting in a decrease in the growth rate of the fractal dimension. [ABSTRACT FROM AUTHOR]

When magnetic matching aided navigation is applied to an underwater vehicle, the magnetometer must be installed inside the vehicle, considering the navigation safety and concealment of the underwater vehicle. Then, the interference magnetic field will seriously affect the accuracy of geomagnetic field measurement, which directly affects the accuracy of geomagnetic matching aided navigation. Therefore, improving the accuracy of geomagnetic measurements inside the vehicle through error compensation has become one of the most difficult problems that requires an urgent solution in geomagnetic matching aided navigation. In order to solve this problem, this paper establishes the calculation model of the internal magnetic field of the underwater vehicle and the geomagnetic measurement error model of the ship-borne magnetometer. Then, a compensation method for the geomagnetic measurement error of the ship-borne magnetometer, based on the constrained total least square method, is proposed. To verify the effectiveness of the method proposed in this paper, a simulation experiment of geomagnetic measurement and compensation of a ship-borne three-axis magnetometer was constructed. Among them, to be closer to the real situation, a combination of the geomagnetism model, the elliptic shell model and the magnetic dipole model was used to simulate the internal magnetic field of the underwater vehicle. The experimental results indicated that the root mean square error of geomagnetic measurement in an underwater vehicle was less than 5 nT after compensation, and the accuracy of geomagnetic measurement met the requirements of geomagnetic matching aided navigation. [ABSTRACT FROM AUTHOR]

The existing LOng RAnge Naviating System stations are mostly used by marine users and are situated at offshore, low‐altitude locations. As a result, the impact of height on the system's positioning accuracy is usually ignored. However, the direct transplantation of low‐altitude calculation methods to high‐altitude areas will bring errors in the positioning results due to the lack of elevation consideration. In order to improve the accuracy of the new enhanced Loran system and reduce the error caused by the calculation of the geodetic line length without considering elevation in high altitude areas, this paper proposes two different algorithms to establish new reference ellipsoids to reduce the height‐caused error, namely the direct algorithm and the expansion ellipsoid algorithm. Experiments show that the error of the calculation results by direct algorithm is smaller, except that it is not applicable when the azimuth is 90° or 270°. The new ellipsoid created by expansion ellipsoid algorithm has smaller changes, and the elevation and geographical coordinates can be considered independent, which is more in line with the Loran system's application requirements. [ABSTRACT FROM AUTHOR]

For the electro-hydraulic composite braking system, the regenerative braking is characterized by quick response, while the response of hydraulic braking is hysteretic. As the braking mode is switched, it always has a mutation of the braking torque and causes the driver to produce inconsistent braking sense. This paper mainly discusses the braking sense consistency strategy from two aspects of multi-objective optimization and compensation control. An optimized allocation method of braking force is explored under multi objectives and multi constraint conditions, which is to find the optimal distribution ratios of front and rear axles, as well as regenerative braking and hydraulic braking. Based on this, the braking sense consistency controller is further designed to make up the difference of braking force and keep the braking force change rate unchanged. Simulation results show that the composite braking system with the proposed strategy can not only eliminate the fluctuation in braking mode switching and ensure the driver obtaining consistent braking sense, but also has satisfactory tracking performance and strong anti-interference ability. [ABSTRACT FROM AUTHOR]

A novel class of high-entropy (HE) spinel ferrites (Mg 0.2 Co 0.2 Ni 0.2 Cu 0.2 Zn 0.2)Fe 2 O 4 , have been successfully synthesized by the solution combustion synthesis method followed by heat-treatment at 500–1500 °C. The resultant spinel ferrites were systematically investigated by various methods including XRD, SEM, TEM, EDS, Raman spectra, etc. It was demonstrated that the entropy drives a reversible transformation between a single-phase state and multiphase. And the entropy predominates the thermodynamic landscape. The as-fabricated high-entropy (Mg 0.2 Co 0.2 Ni 0.2 Cu 0.2 Zn 0.2)Fe 2 O 4 solid solution is single-phase with homogeneous transition-metal element distribution. Moreover, a trade-off between grain growth and crystallization during heat-treatment process; the average grain size of product is only 352.96 nm after being annealed at 1000 °C for 3 h probably due to "sluggish diffusion effect". The resultant HE spinel ferrites (Mg 0.2 Co 0.2 Ni 0.2 Cu 0.2 Zn 0.2)Fe 2 O 4 were first used as a heterogeneous catalyst of peroxodisulfate (PDS). Compared with basic solution condition, the HE spinel ferrite/PDS system exhibited a higher degradation rate for the removal of rhodamine B (RhB) and tetracycline (TC) at initial pH range of 3.0–5.1. Both the hydroxyl radicals and sulfate radicals played an important role on RhB and TC degradation. The high catalytic efficiency and good stability of high-entropy (Mg 0.2 Co 0.2 Ni 0.2 Cu 0.2 Zn 0.2)Fe 2 O 4 catalyst demonstrates that it is suitable for application in wastewater disposal. [ABSTRACT FROM AUTHOR]

High harvesting cost and reusing of post-harvest water are the major challenges in commercial production of microalgae. In this work, a flocculants-free electrolytic flotation harvest process was investigated. The electrode design and materials were evaluated in terms of harvesting efficiency. Stainless steel as the cathode and carbon as the anode were selected based on the harvesting efficiency data and non-sacrificial feature for construction of a pilot scale harvesting system. In the pilot scale experiments, 23.72 g/h biomass yield was achieved at the power consumption of 2.73 kWh/kg. With the advantages of no chemical flocculent contamination and relatively low energy requirement, this continuous system is promising for food or feed applications. [ABSTRACT FROM AUTHOR]

Advances in the technologies to enable patient‐centric sampling (PCS) have the potential to improve blood sample collection by enabling clinical trial participants to collect samples via self‐collection or with the help of a caregiver in their home. Typically, blood samples to assess pharmacokinetics and pharmacodynamics of a drug during clinical development are collected at a clinical site via venous blood draw. In this position paper by the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), the potential value PCS can bring to patients, to the clinical datasets generated, and to clinical trial sponsors is discussed, along with considerations for program decision making, bioanalytical feasibility, operations, and regulatory implications. With an understanding of the value of PCS and considerations when implementing during clinical drug development, we can bring the promise of PCS closer to reality and enable decentralized clinical trials. [ABSTRACT FROM AUTHOR]

Yttria-stabilized zirconia (YSZ) ceramic foams are a promising class of materials for lightweight, high specific strength catalyst supports or insulation. Foam morphology is one of the most significant factors that dominate the mechanical properties of the YSZ ceramic foams. However, the foam morphology as a function of gravity and foam film strength for YSZ ceramic foams has been seldom reported up to now. Our work focuses on YSZ ceramic foams fabricated via a novel foam-gelcasting method using Isobam as gelling agent. The relative magnitudes of the foam film strength and the gravitational force can be changed by controlling the foaming yield of slurries. Both the remaining high-temperature strength and the critical difference temperature (△ T c) of YSZ (3.0) ceramic foams were higher than those of YSZ (5.0) ceramic foams, mainly owing to high closed-cells and relatively uniform distributed pore structure. In addition, the YSZ ceramic foams could not break suddenly like dense ceramics. This work demonstrates that tuning the foaming yield of slurries is a viable route to improved thermomechanical property in ceramic foams for use as insulation or catalyst supports in extreme environments. [ABSTRACT FROM AUTHOR]

Intracerebral hemorrhage (ICH) patients frequently encounter cardiovascular complications which may contribute to increased mortality and poor long term outcome. ICH induces systemic oxidative stress and activates peripheral immune responses which are involved in the pathological cascade leading to cardiac dysfunction and heart failure after ICH. We have previously reported that ICH induces progressive cardiac dysfunction in mice without primary cardiac diseases. In this study, we have investigated the role of immune response in mediating cardiac dysfunction post ICH in mice. Adult male C57BL/6 J mice were randomly assigned to the following groups (n = 8/group): 1) sham control; 2) ICH; 3) splenectomy with ICH (ICH + Spx); 4) splenectomy alone (Spx). Echocardiography was performed at 7 and 28 days after ICH. A battery of neurological and cognitive tests were performed. Flow cytometry, western blot and immunostaining were used to test mechanisms of ICH induced cardiac dysfunction. Compared to sham control mice, Spx alone does not induce acute (7 day) or chronic (28 day) cardiac dysfunction. ICH induces significant neurological and cognitive deficits, as well as acute and chronic cardiac dysfunction compared to sham control mice. Mice subjected to ICH + Spx exhibit significantly improved neurological and cognitive function compared to ICH mice. Mice with ICH + Spx also exhibit significantly improved acute and chronic cardiac function compared to ICH mice indicated by increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), decreased cardiac fibrosis, decreased cardiomyocyte hypertrophy, decreased cardiac infiltration of immune cells and decreased expression of inflammatory factor and oxidative stress in the heart. Our study demonstrates that splenectomy attenuates ICH-induced neurological and cognitive impairment as well as ICH-induced cardiac dysfunction in mice. Inflammatory cell infiltration into heart and immune responses mediated by the spleen may contribute to ICH-induce acute and chronic cardiac dysfunction and pathological cardiac remodeling. • ICH increases cardiac deficit, splenectomy attenuates ICH-induced cardiac dysfunction in mice. • Splenectomy decreases inflammatory cell infiltration into heart and reduces oxidative stress in the heart of ICH mice. • Splenectomy attenuates neurological and cognitive impairment induced by ICH in mice. • Spleen associated immune-response mediates brain-heart interaction after ICH in mice. [ABSTRACT FROM AUTHOR]

Recently, significant effort has been made toward the development of graphene-based visible-ligh-responsive photocatalysts and their application to dye wastewater treatment. Herein, a series of octahedral ZnFe 2 O 4 /graphene (ZnFe 2 O 4 -G) nanocomposites were synthesized using a one-pot solvothermal reaction without the need of a surfactant as novel bifunctional materials exhibiting both high adsorption and good visible-light-responsive photocatalyst properties. The crystal structure, morphology and photocatalytic degradation properties, as well as adsorption behavior, of the octahedral ZnFe 2 O 4 /graphene composites were investigated in detail. The adsorption capacity and UV–vis spectrometry results indicate that the dye removal efficiency over the samples followed the order of: methylene blue (MB) > rhodamine B (RhB) > methyl orange (MO). The ZnFe 2 O 4 -G materials exhited enhanced photocatalytic degradation properties for cationic dyes (MB and RhB) compared to those for the anionic dye (MO). In addition, the experimental results indicate that the ZnFe 2 O 4 -G materials can decompose H 2 O 2 in the visible-light photocatalytic process to form hydroxyl radicals (•OH), which are mainly responsible for the photodegradation of the organic contaminants. [ABSTRACT FROM AUTHOR]

Highlights • An edible fungi-assisted harvesting system for efficient microalgae bio-flocculation was developed. • Maximum recovery efficiency of 64.86% was achieved in 150 min. • This system is suitable for flocculent-free harvesting of microalgae as feedstock for feed or food production. Abstract Conventional flocculants, commonly used to improve harvesting efficiency, can contaminate the broth and cause microalgae not suitable for food or feed production. In the present study, Pleurotus ostreatus , an edible fungal strain, was developed to improve the harvesting efficiency of microalgae. The results show that Pleurotus ostreatus pellets cultured under 100 rpm agitation resulted in higher harvesting efficiency than pellets cultured under 0 rpm and 150 rpm agitation. Lower pH of the Chlorella sp. suspension resulted in higher harvesting efficiency. The maximum recovery efficiency reached 64.86% in 150 mins. The above process could be used to achieve low cost, flocculant-free harvesting of microalgae as feedstock for feed or food production. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to assess the pharmacokinetics (PK) and safety/tolerability of siponimod in healthy subjects when coadministered with (1) the moderate cytochrome P450 (CYP) 2C9 and CYP3A inhibitor fluconazole (Study A), and (2) with three different CYP2C9 genotype variants (Study B).Methods: Study A was an open-label, single-dose study comprising periods 1 (14 days; day 1: siponimod 4 mg) and 2 (20 days; day 1: fluconazole 200 mg twice daily; days 2-19: fluconazole 200 mg once daily; day 3: siponimod 4 mg) in healthy subjects (n = 14) with the wild-type CYP2C9 genotype (CYP2C9*1/*1). Study B was a multicentre, open-label study comprising parts 1 (day 1: siponimod 0.25 mg once daily in the CYP2C9*1/*1, CYP2C9*2/*3 and CYP2C9*3/*3 genotypes) and 2 (days 1-2: 0.25 mg once daily; day 3: 0.5 mg once daily in the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes only) in healthy subjects with polymorphic variants of CYP2C9 (n = 24). Pharmacokinetic parameters were calculated using noncompartmental methods.Results: In Study A, coadministration with fluconazole produced an approximately twofold increase in mean area under the curve (AUC) versus siponimod alone (from 1110 to 2160 h*ng/mL), and an increase in maximum plasma concentration (Cmax; from 31.2 to 34.0 ng/mL) and elimination half-life (T½; from 40.6 to 61.6 h). In Study B, the AUCs of siponimod were approximately two to fourfold greater in subjects with the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes, with a minor increase in Cmax versus the CYP2C9*1/*1 genotype. The mean T½ was prolonged in the CYP2C9*2/*3 (51 h) and CYP2C9*3/*3 (126 h) genotypes versus the CYP2C9*1/*1 (28 h) genotype. Siponimod did not result in increased adverse events in healthy subjects in both studies.Conclusions: Changes in siponimod PK, when coadministered with fluconazole at steady-state and in subjects with different CYP2C9 genotypes, indicate that the reduced CYP2C9 enzymatic activity does not affect the absorption phase of siponimod but prolongs the elimination phase. These results confirm the relevance of CYP2C9 activity on siponimod metabolism in humans. [ABSTRACT FROM AUTHOR]

A novel BiO@TiO heterojunction was constructed by a simple two-step method. The charges migration between BiO and TiO via the heterojunction improves the electron/hole separation efficiency. Furthermore, BiO@TiO heterostructures exhibit better adsorption capability for methyl orange molecular due to their higher specific surface area than pure BiO. As a result, BiO@TiO hybrids show an improved visible light photocatalytic activity and photostability for the degradation of methyl orange. [ABSTRACT FROM AUTHOR]

[Display omitted] TiO 2 /Au@rGO(reduced graphene oxide) ternary hybrids were successfully fabricated via a simple two-step method, namely photodepositing of Au nanoparticles (NPs) on large TiO 2 particles first and then coating rGO sheets onto the surface of Au/TiO 2 binary hybrids. The major beneficial structural feature of TiO 2 /Au@rGO hybrids lies in the existence of mutual interfacial area among all of the three components. This outstanding feature enlarges the contact area and improves the separation efficiency of photoexcited charge carriers between components, and thus allowing the efficient realization of fascinating plasmonic effect of Au NPs in photocatalysis. Enabled by this unique structure design, the photocatalytic activity of TiO 2 /Au@rGO hybrids for the degradation of methyl orange was dramatically higher than those of pure TiO 2 , Au/TiO 2 and TiO 2 /@rGO hybrids, under both UV and simulated solar light. The enhancement of photocatalytic activity of TiO 2 /Au@rGO hybrids could be attributed to the synergistic effect between Au NPs, TiO 2 and rGO, and the existence of multi-channel electron transfer paths. This work represents a step toward the rational design of semiconductor-noble metal-graphene hybrids structures for broad-spectrum photocatalysis. [ABSTRACT FROM AUTHOR]

Au/TiO/graphene composite was synthesized by the combination of electrostatic attraction and photo-reduction method. In the composite, graphene sheets act as an adsorption site for dye molecules to provide a high concentration of dye near to the TiO and Au nanoparticles (NPs), and work as an excellent electron transporter to separate photoinduced e / h pairs. Under UV irradiation, photogenerated electrons of TiO are transferred effectively to Au NPs and graphene sheets, respectively, retarding the recombination of electron-hole pairs. Under visible light irradiation, the Au NPs are photo-excited due to the surface plasmon resonance effect, and charge separation is accomplished by the interfacial electron injection from the Au NPs to the conduction band of TiO and then transfer further to graphene sheets. As a result, compared with pure TiO, Au/TiO/graphene composite exhibited much higher photocatalytic activity for degradation of methylene blue under both UV and visible light irradiation, based on the synergistic effect of Au, graphene in contact with TiO, allowing response to the visible light, effective separation of photoinduced charges, and better adsorption of the dye molecules. [ABSTRACT FROM AUTHOR]

NVS123 is a poorly water-soluble protease 56 inhibitor in clinical development. Data from in vitro hepatocyte studies suggested that NVS123 is mainly metabolized by CYP3A4. As a consequence of limited solubility, NVS123 therapeutic plasma exposures could not be achieved even with high doses and optimized formulations. One approach to overcome NVS123 developability issues was to increase plasma exposure by coadministrating it with an inhibitor of CYP3A4 such as ritonavir. A clinical boost effect was predicted by using physiologically based pharmacokinetic (PBPK) modeling. However, initial boost predictions lacked sufficient confidence because a key parameter, fraction of drug metabolized by CYP3A4 ( f m CYP3A4), could not be estimated with accuracy on account of disconnects between in vitro and in vivo preclinical data. To accurately estimate f m CYP3A4 in human, an in vivo boost effect study was conducted using CYP3A4-humanized mouse model which showed a 33- to 56-fold exposure boost effect. Using a top-down approach, human f m CYP3A4 for NVS123 was estimated to be very high and included in the human PBPK modeling to support subsequent clinical study design. The combined use of the in vivo boost study in CYP3A4-humanized mouse model mice along with PBPK modeling accurately predicted the clinical outcome and identified a significant NVS123 exposure boost (∼42-fold increase) with ritonavir. [ABSTRACT FROM AUTHOR]

The somatostatin analog pasireotide and the 11β-hydroxylase inhibitor osilodrostat (LCI699) reduce cortisol levels by distinct mechanisms of action. There exists a scientific rationale to investigate the clinical efficacy of these two agents in combination. This manuscript reports the results of a toxicology study in rats, evaluating different doses of osilodrostat and pasireotide alone and in combination. Sixty male and 60 female rats were randomized into single-sex groups to receive daily doses of pasireotide (0.3 mg/kg/day, subcutaneously), osilodrostat (20 mg/kg/day, orally), osilodrostat/pasireotide in combination (low dose, 1.5/0.03 mg/kg/day; mid-dose, 5/0.1 mg/kg/day; or high dose, 20/0.3 mg/kg/day), or vehicle for 13 weeks. Mean body-weight gains from baseline to Week 13 were significantly lower in the pasireotide-alone and combined-treatment groups compared to controls, and were significantly higher in female rats receiving osilodrostat monotherapy. Osilodrostat and pasireotide monotherapies were associated with significant changes in the histology and mean weights of the pituitary and adrenal glands, liver, and ovary/oviduct. Osilodrostat alone was associated with adrenocortical hypertrophy and hepatocellular hypertrophy. In combination, osilodrostat/pasireotide did not exacerbate any target organ changes and ameliorated the liver and adrenal gland changes observed with monotherapy. C max and AUC 0–24h of osilodrostat and pasireotide increased in an approximately dose-proportional manner. In conclusion, the pasireotide and osilodrostat combination did not exacerbate changes in target organ weight or toxicity compared with either monotherapy, and had an acceptable safety profile; addition of pasireotide to the osilodrostat regimen may attenuate potential adrenal gland hyperactivation and hepatocellular hypertrophy, which are potential side effects of osilodrostat monotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat. Methods: Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5-9, ketoconazole was administered. On day 8, a single panobinostat dose was co-administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward. Results: In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in C and AUC of panobinostat, respectively. No substantial change in T or half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5* 1/* 3 and CYP3A5* 3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting. Conclusions: Co-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary. [ABSTRACT FROM AUTHOR]

Abstract: A simple method is described for the synthesis of carbon nanotube/anatase titania composites by a combination of a sol–gel method with a self-assembly technique at 65°C. This method makes use of polyelectrolyte for wrapping multi-walled carbon nanotube (MWCNT) and providing them with adsorption sites for electrostatically driven TiO2 nanoparticle deposition. The composites were characterized using X-ray diffraction, transmission electron microscopy, Fourier transform infrared and X-ray photoelectron spectroscopy, and photoluminescence for analyzing their crystal phase, microstructure, particle size, and other physicochemical properties. The results showed that MWCNT were covered with an anatase TiO2 thin layer or surrounded by an anatase TiO2 thick coating, which is constructed of TiO2 particles about 6nm in size. The composites were rich in surface hydroxyl groups. The excited e − in conduction band of TiO2 may migrate to MWCNT. Concerning the potential applicability, MWCNT/TiO2 composites showed excellent photocatalytic activity toward the photodegradation of methyl orange. [Copyright &y& Elsevier]

Abstract: Anatase TiO2 coated multiwalled carbon nanotube (MWNT) nanocomposites were prepared by combining the sol–gel method with a self assembly technique at a low temperature. XRD, TEM, FTIR and XPS spectra were applied to characterize the crystal phase, microstructure, and other physicochemical properties of the sample. The results showed that MWNTs were covered with a 12–20nm thickness layer of anatase TiO2 or surrounded by a 30–290nm thickness coating of anatase TiO2. The layer or coating is constructed of TiO2 nanoparticles about 5.8nm. Furthermore, as-prepared composite was rich in surface hydroxyl groups. [Copyright &y& Elsevier]

Abstract: Nanocrystalline anatase TiO2 was prepared by a facile sol–gel route at a temperature of 65°C under mild conditions. Tetrabutyl titanate was used as a titanium precursor, glacial acetic acid was used as an inhibitor, and anhydrous ethanol was used as a solvent. XRD, TEM, FT-IR and XPS spectra were applied to characterize the crystal phase, microstructure, and other physicochemical properties of the nanoanatase TiO2. The results showed that as prepared ellipse-shaped anatase TiO2 with an average diameter of 7nm, which is rich in surface hydroxyl groups, was found to exhibit high dispersibility. [ABSTRACT FROM AUTHOR]

• Regulation of the human ether a-go-go-related gene (HERG) channel by activation of the β-adrenergic receptor. • The role of A-kinase anchoring proteins (AKAPs) in PKA's regulation of the HERG channel. • AKAP5 anchors PKA to upregulate the HERG channel protein. • The underlying mechanism and a potential therapeutic target in the treatment of LQTS. The activation of the β-adrenergic receptor (β-AR) regulates the human ether a-go-go-related gene (HERG) channel via protein kinase A (PKA), which in turn induces lethal arrhythmia in patients with long QT syndromes (LQTS). However, the role of A-kinase anchoring proteins (AKAPs) in PKA's regulation of the HERG channel and its molecular mechanism are not clear. Here, HEK293 cells were transfected with the HERG gene alone or co-transfected with HERG and AKAP5 using Lipofectamine 2000. Western blotting was performed to determine HERG protein expression, and immunofluorescence and immunoprecipitation were used to assess the binding and cellular colocalization of HERG, AKAP5, and PKA. The HEK293-HERG and HEK293-HERG + AKAP5 cells were treated with forskolin at different concentrations and different time. HERG protein expression significantly increased under all treatment conditions (P < 0.001). The level of HERG protein expression in HEK293-HERG + AKAP5 cells was higher than that observed in HEK293-HERG cells (P < 0.001). Immunofluorescence and immunoprecipitation indicated that HERG bound to PKA and AKAP5 and was colocalized at the cell membrane. The HERG channel protein, AKAP5, and PKA interacted with each other and appeared to form intracellular complexes. These results provide evidence for a novel mechanism which AKAP5 anchors PKA to up-regulate the HERG channel protein. [ABSTRACT FROM AUTHOR]

The structures and stabilities of seven face-centered-cubic δ-MoC surfaces have been systematically investigated on the basis of periodic density functional theory computations of surface energies. The effects of carburization conditions in surface stability as well as catalyst morphology have also been researched by ab initio atomistic thermodynamics method. It has been found that with the increase of the carbon chemical potential (μ C), the most stable surface changes from the carbon deficit metallic (311)-Mo termination to mixed Mo/C termination of (100) surface, and eventually to carbon rich (311)-C termination. It has also been found that δ-MoC catalyst has different morphologies at different carburization environments, i.e., only (311) surface is exposed on the nanoparticle at CH 4 /H 2 gas mixture; (100) and (210) surfaces are exposed at μ C comparable with graphite bulk energy; while (100), (210), and (311) surfaces are exposed at CO/CO 2 gas mixture. Our simulations provide the first understanding into the surface stability and morphology of this promising heterogeneous δ-MoC catalyst. In addition, the simulations facilitate a deeper understanding of the relationship between catalyst surface structure and experimental preparation conditions, which eventually provides the insights into the different catalytic properties of Mo carbide catalysts synthesized from different methods and procedures. δ-MoC nanoparticle has different morphologies from Wulff construction at different carburization environments. Unlabelled Image • The structures and stabilities of seven face-centered-cubic δ-MoC surfaces were studied by DFT calculation. • The effects of carburization conditions in surface stability as well catalyst morphology were researched. • The most stable surface of δ-MoC is determined by the carbon chemical potential. • δ-MoC catalyst has different morphologies at different carburization environments. • The first understanding into the surface stability and morphology of δ-MoC catalyst is provided. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of a PD-1 inhibitor combined with a bevacizumab monoclonal antibody on tumor immune cells in patients with first-line treatment failure in MSS/pMMR advanced colorectal cancer., Methods: Control group consisted of 50 patients treated with the FOLFIRI combined with Bevacizumab regimen. The experimental group consisted of 60 patients treated with the Sintilimab combined with Bevacizumab regimen. By comparing the expression levels of CD8+ T lymphocytes, TAMs, and CAFs before and after treatment, short-term efficacy after treatment, and adverse drug reactions between the two groups, we comprehensively evaluated the impact of Sintilimab combined with Bevacizumab on patients with MSS/pMMR advanced colorectal cancer who failed first-line treatment., Results: There was a statistically significant difference in the percentage of CD8+ T lymphocytes, TAMs, and CAFs before and after treatment between the two groups ( P <0.05);Immunohistochemical scoring of CD8+ T lymphocytes, TAMs, and CAFs showed significant differences between the groups post-treatment (P<0.05 ). The experimental group demonstrated statistically significant differences in immunohistochemical scoring of CD8+ T lymphocytes, TAMs, and CAFs before and after treatment ( P<0.05 ). There was a statistically significant difference in the therapeutic effect between the two groups of tumors ( P <0.05). The experimental group had greater PFS, mPFS, ORR, and DCR than did the control group. There was no statistically significant difference in the occurrence rate of drug-related adverse reactions after treatment between the two groups ( P >0.05). The results of the Cox proportional hazards model analysis indicate that age, gender, and group are independent risk factors affecting MSS/pMMR advanced colorectal cancer patients treated with second-line therapy in this study. Patients aged ≤60 years, male patients, and those in the experimental group showed better treatment responses in this study., Conclusion: By administering immune checkpoint inhibitors in combination with bevacizumab to patients with advanced colorectal cancer with MSS/pMMR disease for whom first-line treatment failed, not only did the patients' prognosis improve, but the adverse drug reactions were also safe and controllable., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Li, Lei, Li, Guo, Ma, Luo and Wang.)

The intent of this perspective is to share the recommendations of the International Consortium for Innovation and Quality in Pharmaceutical Development Metabolite Bioanalysis Working Group on the fit-for-purpose metabolite bioanalysis in support of drug development and registration. This report summarizes the considerations for the trigger, timing, and rigor of bioanalysis in the various assessments to address unique challenges due to metabolites, with respect to efficacy and safety, which may arise during drug development from investigational new drug (IND) enabling studies, and phase I, phase II, and phase III clinical trials to regulatory submission. The recommended approaches ensure that important drug metabolites are identified in a timely manner and properly characterized for efficient drug development., (© 2023 Novartis. AbbVie Inc. Incyte Corporation et al. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Background: Sclerotinia stem rot caused by Sclerotinia sclerotiorum seriously endangers oilseed rape production worldwide, and the occurrence of fungicide-resistant mutants of S. sclerotiorum leads to control decline. Thus, it is critical to explore new green substitutes with different action mechanisms and high antifungal activity. Herein, the activity and the action mechanism of natamycin against S. sclerotiorum were evaluated., Results: Natamycin showed potent inhibition on the mycelial growth of S. sclerotiorum, and half-maximal effective concentration (EC 50 ) values against 103 S. sclerotiorum strains ranged from 0.53 to 4.04 μg/mL (mean 1.44 μg/mL). Natamycin also exhibited high efficacy against both carbendazim- and dimethachlone-resistant strains of S. sclerotiorum on detached oilseed rape leaves. No cross-resistance was detected between natamycin and carbendazim. Natamycin markedly disrupted hyphal form, sclerotia formation, integrity of the cell membrane, and reduced the content of oxalic acid and ergosterol, whereas it increased the reactive oxygen species (ROS) and malondialdehyde content. Interestingly, exogenous addition of ergosterol could reduce the inhibition of natamycin against S. sclerotiorum. Importantly, natamycin significantly inhibited expression of the Cyp51 gene, which is contrary to results for the triazole fungicide flusilazole, indicating a different action mechanism from triazole fungicides., Conclusion: Natamycin is a promising effective candidate for the resistance management of S. sclerotiorum. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Structural diversity derivatization from natural products is an important and effective method of discovering novel green pesticides. Cinnamic acids are abundant in plants, and their unparalleled structures endow them with various excellent biological activities. A series of novel cinnamic oxime esters were designed and synthesized to develop high antifungal agrochemicals. The antifungal activity, structure-activity relationship, and action mechanism were systematically studied. Compounds 7i , 7u , 7v , and 7x exhibited satisfactory activity against Gaeumannomyces graminis var. tritici , with inhibition rates of ≥90% at 50 μg/mL. Compounds 7z and 7n demonstrated excellent activities against Valsa mali and Botrytis cinerea , with median effective concentration (EC 50 ) values of 0.71 and 1.41 μg/mL, respectively. Compound 7z exhibited 100% protective and curative activities against apple Valsa canker at 200 μg/mL. The control effects of 7n against gray mold on tomato fruits and leaves were all >96%, exhibiting superior or similar effects to those of the commercial fungicide boscalid. Furthermore, the quantitative structure-activity relationship was established to guide the further design of higher-activity compounds. The preliminary results on the action mechanism revealed that 7n treatment could disrupt the function of the nucleus and mitochondria, leading to reactive oxygen species accumulation and cell membrane damage. Its primary biochemical mechanism may be inhibiting fungal ergosterol biosynthesis. The novel structure, simple synthesis, and excellent activity of cinnamic oxime esters render them promising potential fungicides.

In LC-MS bioanalysis, sample dilution plays various roles, including bringing analyte concentrations within the validated/qualified dynamic range or alleviating matrix effect for accurate determination of the target analyte(s) in the intended study samples. Adherence to health authority requirements, incorporating good dilution practices, and timely demonstration of dilution integrity whenever samples are diluted in an analytical run are essential to ensure the reliability of bioanalytical results.

Background: Current management guidelines for the treatment of carotid stenosis are controversial. We performed this meta-analysis to evaluate the perioperative safety of carotid artery stenting (CAS) and endarterectomy., Methods: We systematically searched EMBASE, PubMed, Web of Science, and the Cochrane Library from inception to November 10, 2022, for randomized controlled trials that compared CAS with carotid endarterectomy (CEA) among patients with carotid stenosis. The analyzed outcomes mainly included stroke, death, myocardial infarction (MI), cranial nerve palsy, the cumulative incidence of mortality, stroke, or MI and the cumulative incidence of death or stroke in the perioperative periods. The risk ratio (RR) and 95% confidence interval (95% CI) were calculated and pooled. Subgroup analyses were based on whether patients were symptomatic or asymptomatic. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework., Results: Seventeen randomized controlled trials with 12,277 participants (6514 and 5763 in the CAS and CEA groups, respectively) were included. Pooled analysis demonstrated that compared with CEA, CAS was associated with decreased risks of perioperative MI (RR = 0.47, 95% CI = 0.29∼0.77) and perioperative cranial nerve palsy (RR = 0.02, 95% CI = 0.01∼0.06) but higher risks of perioperative stroke (RR = 1.48, 95% CI = 1.18∼1.87) and cumulative incidence of death or stroke (RR = 1.52, 95% CI = 1.20∼1.93)., Conclusions: The perioperative safety was equivalent between CAS and CEA. However, CEA may be preferred when considering both procedural safety and long-term efficacy in preventing recurrent stroke., (Copyright © 2023 Elsevier Inc. All rights reserved.)