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Carbon‐based materials have been utilized as effective catalysts for hydrogen peroxide electrosynthesis via two‐electron oxygen reduction reaction (2e ORR), however the insufficient selectivity and productivity still hindered the further industrial applications. In this work, we report the Fe−O4 motif activated graphitic carbon material which enabled highly selective H2O2 electrosynthesis operating at high current density with excellent anti‐poisoning property. In the bulk production test, the concentration of H2O2 cumulated to 8.6 % in 24 h and the corresponding production rate of 33.5 mol gcat−1 h−1 outperformed all previously reported materials. Theoretical model backed by in situ characterization verified α‐C surrounding the Fe−O4 motif as the actual reaction site in terms of thermodynamics and kinetics aspects. The strategy of activating carbon reaction site by metal center via oxo‐bridge provides inspiring insights for the rational design of carbon materials for heterogeneous catalysis. [ABSTRACT FROM AUTHOR]

High‐loading electrode is a prerequisite for achieving high energy density in industrial applications of lithium‐ion batteries. However, an increased loading leads to elevated battery polarization and reduced battery power density, which presents a significant technical bottleneck in the industry. The present study focuses on designing a rapid electrolyte diffusion pathway to diminish lithium concentration polarization for the high‐loading LiNi0.83Mn0.12Co0.05O2 (NMC83) electrode by employing two layers of NMC83 materials with different sizes. This innovative architecture demonstrates exceptional rate performance even under challenging conditions with high‐loading and high‐rate. Additionally, the interrelationships between electrode structure, process route, porosity, and optimal thickness ratio between layers are discussed, providing valuable guidance for industrial promotion and application. The designed L‐Dry‐S electrode structure (coating large particles first and then small particles) effectively mitigates concentration polarization in the thick electrode, which is attributed to the fast electrolyte diffusion channel and the differential reaction speeds of NMC83 particles with varying sizes. The knowledge from this work is broadly applicable to other material systems. [ABSTRACT FROM AUTHOR]

Sustaining the steady state for highly active non‐stoichiometric iridium (Ir)‐based oxide (IrOx) at low Ir loading remains challenging primarily due to the continuous oxidation and sequent dissolution of Ir active sites during the oxygen evolution reaction (OER). In this context, a new iridium–cerium (Ce) substitution solid solution oxide (SSO) has been developed, featuring uniformly dispersed Ir atoms within Ce dioxide (CeO2) matrix as electron buffer, which delivers remarkable acidic OER catalytic activity and enhanced stability. The electron‐buffering capacity of CeO2 facilitates the charge transfer toward Ir atoms, leading to abundant active low‐valence Ir sites and effectively prevent their oxidation and dissolution. As a result, Ir─Ce SSO demonstrates an overpotential of merely 238 mV@10 mA cm−2. Proton exchange membrane water electrolyzer employing Ir─Ce SSO at a low Ir loading of 396 µgIr cm−2 operates consistently for over 100 h@500 mA cm−2. Density functional theory (DFT) calculations corroborate that the electron‐buffering effect of CeO2 enriches the density of IrIII and substantially increases the dissolution energy barrier of Ir atoms. This study presents a viable approach to addressing the issues of instability and low efficiency in Ir‐based OER electrocatalysts for acidic water electrolysis. [ABSTRACT FROM AUTHOR]

Cr3+‐doped phosphors are highly recognized in various fields for their remarkable luminous efficiency and spectral flexibility, including modern agriculture and horticulture. However, the shortage of suitable Cr3+‐doped phosphors for far‐red LED devices has inhibited their popularization in plant lighting. Herein, an innovative Cr3+‐doped phosphor Ca2YAl3Ge2O12:Cr3+ (CYAG:Cr3+), achieving a broad far‐red emission at 770 nm upon 450 nm blue light excitation is designed. The optimal CYAG:Cr3+ phosphor exhibits a high internal quantum yield of 78.2% and low thermal‐quenching behavior of 85%@373 K. Thus, the fabricated phosphor‐converted LEDs (pc‐LEDs) for plant far‐red lighting have a high output power of 33.3 mW and photovoltaic conversion efficiency of 11.5% at 100 mA. The potential of CYAG:Cr3+ in plant lighting is assessed by supplementing the far‐red lighting of Italian lettuce with fabricated pc‐LEDs, and the biomass of Italian lettuce is significantly increased by 33%. The successful development of CYAG:Cr3+ phosphors provides a high‐quality option for plant far‐red light devices and further stimulates the development of new Cr3+‐doped plant‐lighting phosphors. [ABSTRACT FROM AUTHOR]

This article deals with the robust planar rigid formation control problem of three second‐order coleaders with unknown flowfields acting on the velocity and acceleration respectively. To yield the uniform boundedness property of the resulting system, an adaptive projection is introduced to design the novel adaptive neural control law. To avoid the derivatives of Gaussian functions of neural networks, dynamic surface is used. Simulation results are provided to illustrate the effectiveness of the proposed control law. [ABSTRACT FROM AUTHOR]

Beneath Enceladus' ice crust lies an ocean which might host habitable conditions. Here, the scale and productivity of a notional Enceladean methanogenic biosphere are computed as a function of the core‐to‐ocean flux of hydrogen and the ratio between abiotic and biotic methane in Enceladus' space plume. Habitats with an ocean‐top pH range of 8–9 have up to 40%–60% probability of being energy‐limited. Those at pH > 9 are increasingly uninhabitable, and those <8.5 are increasingly likely to host exponential growth, possibly leading to compositional inconsistencies between the ocean and Cassini gas observations. In those cases, energy‐based habitability models cannot infer an inhabited Enceladus consistent with both Earth life and Cassini measurements without including additional microbial growth limiters such as nutrient limitation, toxicity, or spatial constraints. If methanogens are isolated to a 350 K seafloor habitat and consume 10 mol s−1 of H2, the most probable biomass is 103, 103.7 kg C with ocean‐top pH 8,9, respectively. Biomass production consistent with space plume fluxes is 104–106 kgC yr−1—milligrams of cellular carbon per kilogram of H2O ejected—but requires that >50% of the space plume methane is biotic. Alternative scenarios are presented, and biomass is generally lower when habitat temperature is higher. Ocean biomass density cannot yet be reliably estimated owing to uncertainties in the scale and physicochemical properties of Enceladus' putative habitats. Evaluating abiotic to biotic ratios in plume methane and organic material could help identify false negative results from life detection missions and constrain the scale of an underlying biosphere. Plain Language Summary: The Cassini spacecraft observed energy and nutrient sources for life erupting from a water ocean below the icy exterior of Saturn's moon Enceladus. Future spacecraft planned for Enceladus, Europa and Titan will obtain similar measurements in greater detail. In this work, we calculate the probability that different suites of environments inside Enceladus' ocean are habitable for methanogens, an ancient type of organism which may be able to survive there. Three scenarios are possible: uninhabitable, habitable, and energy‐saturated. Next, we extend this calculation to show that the possible biosphere is small but productive. Microbial waste, generated at the seafloor, could be ejected from the ocean and consequently snow down onto Enceladus' surface. Mass spectrometers on future spacecraft could constrain these possibilities further and may be critical to inferring biosignatures when cell densities are too low to detect. Key Points: Spatial habitability on Enceladus is not guaranteed, and additional modeling parameters are needed to evaluate possible vacant habitatsCell turnover is important for life detection missions and can be constrained more tightly than total biomassAbiotic to biotic ratios of space plume carbon are critical as biosignatures and for assessing the scale of Enceladus' notional biosphere [ABSTRACT FROM AUTHOR]

Laser‐driven phosphor‐converted white‐laser diodes are supposed to be next‐generation high‐brightness lighting sources for their unparalleled photoelectric efficiency and light quality, yet a significant obstacle hitherto has resided in the shortage and serious laser‐induced luminescence saturation of red emitters. Here, a hot‐pressing synthesis route to obtain high‐performance red‐emitting cordierite (Mg2Al4Si5O18:Eu2+) ceramic is developed, which enables the in situ formation of bulk specimens with high crystallinity (>90%) from the counterpart glass powders. A preeminent saturation threshold of 21 W mm−2 is realized in a red‐emitting Mg2Al4Si5O18:Eu2+ ceramic film converter. More importantly, the luminous exitance reaches 209 lm mm−2, which is 5 times that of commercial red phosphor‐converted‐LED, indicating breakthrough progress in the comprehensive light‐emitting performance of red converters. This work innovates the solid‐state synthesis of laser bulk converters from glass to meet the demanding requirements of advanced warm white laser lighting. [ABSTRACT FROM AUTHOR]

Near‐infrared (NIR) phosphor‐converted light‐emitting diodes (pc‐LEDs) lighting sources are applied in non‐destructive examination and illumination supplements for night monitoring. As a critical component of NIR pc‐LED, NIR phosphors are required to possess a high external quantum efficiency (EQE), super thermal stability, and broadband emission to meet applications. Here, Na2SrGe6O14:Cr3+ (NSGO:Cr) glass ceramics (GC) bulk via highly crystallization from glass precursor is fabricated and demonstrates an ultrabroad emission band centered at 815 nm with a full width at half‐maximum (FWHM) of 214 nm and a high EQE of 49.2%. Moreover, Yb3+ co‐doping significantly enhances Cr3+ → Yb3+ energy transfer (ET) due to the stronger Yb3+: 2F7/2‐2F5/2 absorption. Benefiting from the ET process, the Cr/Yb co‐doped GC exhibits NIR‐I/II emission with improved thermal stability from 30.1% to 65.0%. Furthermore, an encapsulant‐free NIR GC‐converted LED (GCc‐LED) is prepared and exhibits 52.2 mW NIR output power with a high photoelectric conversion efficiency (PCE) of 19.4%. Under a large current of 600 mA, the NIR device exhibits a watt‐level output power of 922.4 mW with a PCE of 9.1%. Compared to conventional NIR powder phosphors, NSGO:Cr/Yb GC with high performance can open up an avenue for the fabrication of high power NIR lighting sources. [ABSTRACT FROM AUTHOR]

Objective: Systemic lupus erythematosus (SLE) patients are at risk during the COVID‐19 pandemic, yet the underlying molecular mechanisms remain incompletely understood. This study sought to analyze the potential molecular connections between COVID‐19 and SLE, employing a bioinformatics approach to identify effective drugs for both conditions. Methods: The data sets GSE100163 and GSE183071 were utilized to determine share differentially expressed genes (DEGs). These DEGs were later analyzed by various bioinformatic methods, including functional enrichment, protein–protein interaction (PPI) network analysis, regulatory network construction, and gene–drug interaction construction. Results: A total of 50 common DEGs were found between COVID‐19 and SLE. Gene ontology (GO) functional annotation revealed that "immune response," "innate immune response," "plasma membrane," and "protein binding" were most enriched in. Additionally, the pathways that were enriched include "Th1 and Th2 cell differentiation." The study identified 48 genes/nodes enriched with 292 edges in the PPI network, of which the top 10 hub genes were CD4, IL7R, CD3E, CD5, CD247, KLRB1, CD40LG, CD7, CR2, and GZMK. Furthermore, the study found 48 transcription factors and 8 microRNAs regulating these hub genes. Finally, four drugs namely ibalizumab (targeted to CD4), blinatumomab (targeted to CD3E), muromonab‐CD3 (targeted to CD3E), and catumaxomab (targeted to CD3E) were found in gene–drug interaction. Conclusion: Four possible drugs that targeted two specific genes, which may be beneficial for COVID‐19 patients with SLE. [ABSTRACT FROM AUTHOR]

Spreading the formic acid (HCOOH) fuel cells demands a better anode electrocatalyst for the oxidation of formic acid. The catalytic efficiency of platinum (Pt)– the only choice of practicability, is mainly limited by its intrinsic affinity to CO, thus desiring a proper release. Herein, theoretical calculations are first leveraged to find that the introduction of iridium (Ir) can facilitate HCOOH oxidation with robust CO tolerance through a dehydrogenation pathway. Then, this strategy experimentally by designing a new trimetallic catalyst of 2D porous PtIrBi nanoplates (p‐PtIrBi NPs) is implemented. The optimized p‐PtIrBi NPs/C exhibits a very high mass activity of 8.2 A mg−1pt and a high retention rate of 55.9% after the durability test, which is among the best formic acid oxidation catalysts reported to date, much higher than those of PtIrBi NPs/C, PtBi NPs/C, and Pt/C. The CO‐stripping and in situ Fourier transform infrared (FTIR) experiments collectively evidence that two types of due site, i.e., "Pt‐Bi" and "Ir‐Bi", endow the catalyst with suppressed CO‐poisoning property to achieve super‐high activity and stability for formic acid oxidation reaction. [ABSTRACT FROM AUTHOR]

Radioresistance remains a major obstacle to efficacious radiotherapy in non–small‐cell lung cancer (NSCLC). DNA replication proteins are novel targets for radiosensitizers. POLQ is a DNA polymerase involved in DNA damage response and repair. We found that POLQ is overexpressed in NSCLC and is clinically correlated with high tumor stage, poor prognosis, increased tumor mutational burden, and ALK and TP5 mutation status; POLQ inhibition impaired lung tumorigenesis. Notably, POLQ expression was higher in radioresistant lung cancer cells than in wild‐type cancer cells. Moreover, POLQ expression was further increased in radioresistant cells after radiation. Enhanced radioresistance is through a prolonged G2/M phase and faster repair of DNA damage, leading to reduced radiation‐induced apoptosis. Novobiocin (NVB), a POLQ inhibitor, specifically targeted cancer cells. Genetic knockdown of POLQ or pharmacological inhibition by NVB decreased radioresistance in lung adenocarcinoma while causing little toxicity to normal pulmonary epithelial cells. In conclusion, POLQ is a promising and practical cancer‐specific target to impair tumorigenesis and enhance radiosensitivity in NSCLC. [ABSTRACT FROM AUTHOR]

Fully electrical manipulation of magnetism, preferably through spin current, is highly desired to achieve energy-efficient, nonvolatile, and programmable spin logic devices. It is demonstrated in this study that in a single Pt/IrMn/ Co/Ru/CoPt heterojunction, all 16 Boolean logic functions can be realized in a purely electrical way, relying on electrical manipulation of magnetic-field-free spin-orbit torque (SOT) switching. By applying current pulses along with two orthogonal directions, the exchange bias between IrMn and Co, and the SOT switching polarity (clockwise or counterclockwise) of perpendicularly magnetized CoPt, can be reversibly controlled, enabling complete spin logic within a single nonvolatile memory. This study makes a significant step towards practical electrical programmable spin logic devices. [ABSTRACT FROM AUTHOR]

High‐power broadband near‐infrared (NIR) light sources have received extensive attention in long‐distance night vision lighting, non‐invasive detection and imaging, and quantitative analysis of organic components. However, developing targeted NIR‐emitting phosphors with high external quantum efficiency (EQE) and thermal stability remains a challenge to raise the NIR output power and expand the applications. Herein, Ga1.98−xScxO3:0.02Cr3+ luminescent ceramics are prepared with redshifted emission peaks from 710 to 820 nm depending on the weakened crystal field. The optimized Ga1.18Sc0.8O3:0.02Cr3+ ceramic exhibits a high EQE of 79.6% and excellent thermal stability (I423 K/I298 K = 72%) under 468 nm excitation, which brings a saturation threshold up to 893 mW@3 W mm−2 under 450 nm laser pumping. The high‐power laser‐driven broadband NIR light source demonstrates potential in non‐invasive detection and quantitative analysis of alcohol concentration. This study opens up new avenues for the exploration of high‐power broadband NIR light sources. [ABSTRACT FROM AUTHOR]

Young children with liver cirrhosis have a significantly high risk of mortality. However, there are few studies regarding early childhood‐onset cirrhosis. This study aims to explore the causes, clinical findings and prognosis of biopsy‐proven cirrhosis in infants, toddlers and preschoolers. We enroled young children with biopsy‐proven cirrhosis from January 2010. Till January 2020, the study has been going on for 10 years. A total of 139 cirrhotic children were enrolled, including 87 boys and 52 girls. The median age at initially histological diagnosis of cirrhosis was 2 years old (range: 1 month–6 years). Sixty‐two patients reported yellowish discoloration of sclera and/or skin as an initial symptom. Ninety‐three patients had definite aetiologies while 46 had indeterminate causes. Among the confirmed cases, 31 had hepatitis B virus (HBV) infection, accounting for 33.3%. Subsequently, glycogen storage disease was diagnosed in 16 cases and Wilson disease in 14 cases. In these patients with HBV infection, nine finally achieved hepatitis B surface antigen (HBsAg) loss (29.0%) after effective antiviral therapy during the follow‐up. Logistic regression revealed that baseline alanine aminotransferase (odds ratio 1.008, p = 0.028) was the independent predictor of HBsAg loss. Furthermore, one patient who underwent second biopsies showed histological reverse. HBV infection is an important cause of paediatric cirrhosis in our study. The pathogenesis of HBV‐related cirrhosis in early childhood deserves further studies. [ABSTRACT FROM AUTHOR]

Dissolved Ni concentrations inhibiting the growth of juvenile great pond snails (Lymnaea stagnalis) have been documented to vary from about 1 to 200 µg L−1 Ni. This variability makes L. stagnalis either a moderately sensitive or the most sensitive freshwater species to chronic Ni exposure tested to date. Given the role of sensitive species in environmental risk assessment frameworks, it is particularly important to understand this variability, i.e., to characterize the factors that modulate Ni toxicity and that may confound toxicity test outcomes when uncontrolled. In the present study, we tested if this variability was due to analytical (growth calculation: biomass versus growth rate), environmental (water quality), lab‐specific practices, and/or snail population differences among earlier studies. Specifically, we reanalyzed previously published Ni toxicity data and conducted additional measurements of Ni aqueous speciation, short‐term Ni uptake, and chronic Ni toxicity with test waters and snail cultures used in previous studies. Corrections for Ni bioavailability and growth calculations explained a large degree of variability in the published literature. However, a residual 16‐fold difference remained puzzling between 2 studies: Niyogi et al. (2014) (low ECxs) and Crémazy et al. (2018) (high ECxs). Indeed, differences in metal bioavailability due to water chemistry, lab‐specific practices, and snail population sensitivity could not explain the large variation in Ni toxicity in these 2 very similar studies. Other potentially important toxicity‐modifying factors were not directly evaluated in the present work: test duration, diet, snail holding conditions, and snail age at onset of testing. The present analysis highlights the need for further studies to elucidate 1) the mechanisms of growth inhibition in Ni‐exposed L. stagnalis and 2) the important abiotic and biotic factors affecting this biological response. Until these processes are understood, substantial uncertainties will remain about inclusion of this species in Ni environmental risk assessment. Integr Environ Assess Manag 2020;16:983–997. © 2020 SETAC KEY POINTS: Nickel concentrations inhibiting the growth of Lymnaea stagnalis vary by 2 orders of magnitude (1–200 µg L−1) in the literature.The interstudy variability on EC20s was decreased by using specific growth rate instead of biomass as the response variable (by a factor of 5‐fold) and by bioavailability correction with the BLM (by a factor of 3‐fold).A remaining 7‐fold variation in reported EC20s could not be explained by differences in test waters, snail populations, and lab‐specific practices.Other potentially important toxicity‐modifying factors remain to be studied (e.g., test duration and snail age and diet). [ABSTRACT FROM AUTHOR]

In this article author discusses definitions as starting points for exploring English playwright Ben Jonson's ideas about the interrelations of people, things and places. It further discusses various definitions of 'cosmopolitan' in the Oxford English Dictionary; emerging global interaction in the early modern period wrought by a global economic network centring on China; and the English cosmopolitan's fantasy of the baboons near China in "Volpone" play by Jonson.

The prosthetic mesh, which is widely used in tension‐free hernioplasty, often result in avascular stiff fibrotic scar or mesh shrinkage, causing chronic pain and infection. Here, we developed an autologous bionic tissue (ABT), which was composed of autologous bone marrow‐derived mesenchymal stem cells (MSCs), poly (lactic‐co‐glycolic acid) (PLGA) porous scaffolds, and extracellular matrix (ECM) produced by MSCs for inguinal hernioplasty. In ABT, MSCs produced a variety of ECM composites, such as structural proteins (insoluble collagen, elastin) that provided mechanical properties, macromolecules (hyaluronic acid, glycosaminoglycan) as water and cytokines reservoir, and cell‐engaging proteins (fibronectin, laminin). The above ECM composites reached the highest level in 21 days. ECM degradation related cytokines (MMP‐9 and its inhibitor TIMP‐1) reached the highest level on the 14th day. ECM increased the mechanical properties, elasticity, and flexibility of PLGA. Compared with the PLGA, ABT greatly inhibited inflammatory factors and promoted anti‐inflammatory factors (p < 0.05), and gradually reduced the M1/M2 ratio in vivo (p < 0.05). After implantation, the thickness of tissue regeneration (p < 0.05), the number of capillaries or mature vessels (p < 0.05), the mechanical properties of ABT (p < 0.05) were greater than PLGA. MSCs and ECM could reduce the inflammation caused by PLGA, and prevent PLGA from earlier degradation and facilitate host cellular infiltration, thus ABT could greatly promote tissue regeneration in hernia repairs. [ABSTRACT FROM AUTHOR]

RATIONALE: Electrospray ionization mass spectrometry (ESI-MS)-based techniques commonly used in oligonucleotide analyses are known to be sensitive to alkali metal adduct formation. Adducts directly impact the sensitivity of MSbased analyses as the available charge is distributed across the parent peak and adduct(s). The current study systematically evaluated common liquid chromatography (LC) components in LC/ESI-MS configurations used in oligonucleotide analysis to identify metal adduct contributions from LC instrumentation. METHODS: A UPLC liquid chromatography system was configured with a single quadrupole MS detector (ACQUITY QDa, Waters Corp.) to monitor adduct formation in oligonucleotide separations. An ion-pairing mobile phase comprised of 15 mM triethylamine and 400 mM hexafluoro-2-propanol was used in conjunction with an oligonucleotide separation column (Waters OST BEH C18, 2.1 mm ? 50 mm) for all separations. A 10-min method was used to provide statistical figures of merit and evaluate adduct formation over time. RESULTS: Trace alkali metal salts in the mobile phase and reagents were determined to be the main source of metal salt adducts in LC/ESI-MS-based configurations. Non-specific adsorption sites located throughout the fluidic path contribute to adduct formation in oligonucleotide analyses. Ion-pairing mobile phases prepared at neutral or slightly basic pH result in up to a 57% loss of spectral abundance to adduct formation in the current study. CONCLUSIONS: Implementation of a short low pH reconditioning step was observed to effectively displace trace metal salts non-specifically adsorbed to surfaces in the fluidic path and was able to maintain an average MS spectral abundance ≥94% with a high degree of repeatability (relative standard deviation (R.S.D.) 0.8%) over an extended time study. The proposed method offers the ability to rapidly regenerate adsorption sites with minimal impact on productivity while retaining assay sensitivity afforded by MS detection with reduced adduct formation. [ABSTRACT FROM AUTHOR]

RATIONALE Electron transfer dissociation (ETD) within ion trapping mass spectrometers has proven to be a useful tool for the characterisation of post-translational modifications. In this study, we describe the implementation of ETD upon a modified quadrupole time-of-flight (Q-ToF) system and methods for the analysis of glycoproteins. METHODS Liquid chromatography electrospray ionisation mass spectrometry (LC/ESI-MS) was performed using a hybrid quadrupole/ion mobility/oa-ToF mass spectrometer equipped with ETD functionality. 1,4-Dicyanobenzene reagent anions necessary for the ETD reaction were generated from a glow discharge region located within the ESI source block. ETD reactions occurred in the stacked ring travelling wave ion guide (located after the quadrupole mass filter and prior to the oa-ToF mass analyser). LC/ETD was performed upon 'super-charged' tryptic glycopeptide ions produced from the recombinant monoclonal antibody trastuzumab. LC/ETD was also performed on ions from the smaller glycopeptides obtained from erythropoietin. RESULTS ETD performed upon the quadruply 'super-charged' N-linked glycopeptide ions of trastuzumab and the triply charged O-linked glycopeptide ions of erythropoietin provided both glycosylation site assignments and full sequence information, respectively. Tandem mass (MS/MS) spectra employing collision-induced dissociation (CID) were dominated by oxonium product ions hampering full peptide sequence characterisation. CONCLUSIONS LC/ETD on the Q-ToF system proved effective at characterising a number of different N-linked glyco-forms of the tryptic peptide, EEQYNSTYR, from trastuzumab as well as glyco-forms from the O-linked tryptic peptide, EASIPPDAASAAPLR, from erythropoietin. The data demonstrates that the glycopeptide site heterogeneity of trastuzumab and erythropoietin can be accurately characterised. In addition, the post-column mixing of the super-charging reagent, m-NBA, is an effective method to increase the precursor ion charge state and to improve ETD reaction efficiency. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE Inflammation and reactive oxygen species are associated with the promotion of various cancers. The use of non-steroidal anti-inflammatory drugs (NSAIDs) in cancer prevention treatments has been promising in numerous cancers. We report the evaluation of NSAIDs chemically modified by the addition of a redox-active nitroxide group. TEMPO-aspirin (TEMPO-ASA) and TEMPO-indomethacin (TEMPO-IND) were synthesized and evaluated in the lung cancer cell line A549. EXPERIMENTAL APPROACHES We evaluated physico-chemical properties of TEMPO-ASA and TEMPO-IND by electron paramagnetic resonance and cyclic voltammetry. Superoxide dismutase-like properties was assayed by measuring cytochrome c reduction and anti-inflammatory effects were assayed by measuring production of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4). MTT proliferation assay and clonogenic assay were evaluated in the A549 lung carcinoma cell line. Maximum tolerated doses (MTD) and acute ulcerogenic index were also evaluated in in vivo. KEY RESULTS MTD were: TEMPO (140 mg·kg−1), ASA (100 mg·kg−1), indomethacin (5 mg·kg−1), TEMPO-ASA (100 mg·kg−1) and TEMPO-IND (40 mg·kg−1). While TEMPO-ASA was as well tolerated as ASA, TEMPO-IND showed an eightfold improvement over indomethacin. TEMPO-IND showed markedly less gastric toxicity than the parent NSAID. Both TEMPO-ASA and TEMPO-IND inhibited production of PGE2 and LTB4 in A549 cells with maximum effects at 100 µg·mL−1 or 10 µg·mL−1 respectively. CONCLUSIONS AND IMPLICATIONS The nitroxide-NSAIDs retained superoxide scavenging capacity of the parent nitroxide and anti-inflammatory effects, inhibiting cyclooxygenase and 5-lipoxygenase enzymes. These redox-modified NSAIDs might be potential drug candidates, as they exhibit the pharmacological properties of the parent NSAID with antioxidant activity decreasing NSAID-associated toxicity. [ABSTRACT FROM AUTHOR]

Summary In this report we describe the 1500-fold purification and characterization of the haemolytic phospholipase C (PLC) of Pseudomonas aeruginosa , the paradigm member of a novel PLC/phosphatase superfamily. Members include proteins from Mycobacterium tuberculosis, Bordetella spp., Francisella tularensis and Burkholderia pseudomallei . Purification involved overexpression of the plcHR 1,2 operon, ion exchange chromatography and native preparative polyacrylamide gel electrophoresis. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry confirmed the presence of two proteins in the purified sample with sizes of 17 117.2 Da (PlcR2 ) and 78 417 Da (PlcH). Additionally, liquid chromatography electrospray mass spectrometry (LCMS) revealed that PlcH and PlcR2 are at a stoichiometry of 1 : 1. Western blot analysis demonstrated that the enzyme purifies as a heterodimeric complex, PlcHR2 . PlcHR2 is only active on choline-containing phospholipids. It is equally active on phosphatidylcholine (PC) and sphingomyelin (SM) and is able to hydrolyse plasmenylcholine phospholipids (plasmalogens). Neither PlcHR2 nor the M. tuberculosis homologues are inhibited by D609 a widely used, competitive inhibitor of the Bacillus cereus PLC. PlcH, PlcR2 , and the PlcHR2 complex bind calcium. While calcium has no detectable effect on enzymatic activity, it inhibits the haemolytic activity of PlcHR2 . In addition to being required for the secretion of PlcH, the chaperone PlcR2 affects both the enzymatic and haemolytic properties of PlcH. Inclusive in these data is the con-clusion that the members of this PC-PLC and phosphatase family possess a novel mechanism for the recognition and hydrolysis of their respective substrates. [ABSTRACT FROM AUTHOR]

In the crystal structure of the title compound, C21H24ClNO3, there are two independent mol­ecules in the asymmetric unit. The compound is the product of a new procedure for preparing Diels–Alder adducts of thebaine with 7β substit­uents. [ABSTRACT FROM AUTHOR]