bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection of the Short‐Lived Radical Cation Intermediate in the Electrooxidation of N,N‐Dimethylaniline by Mass Spectrometry
Authors: Brown Timothy A. , Chen Hao , Zare Richard N.
Published: August 2015

The N,N‐dimethylaniline (DMA) radical cation DMA.+, a long‐sought transient intermediate, was detected by mass spectrometry (MS) during the electrochemical oxidation of DMA. This was accomplished by coupling desorption electrospray ionization (DESI) MS with a waterwheel working electrode setup to sample the surface of the working electrode during electrochemical analysis. This study clearly shows that DESI‐based electrochemical MS is capable of capturing electrochemically generated intermediates with half‐lives on the order of microseconds, which is 4–5 orders of magnitude faster than previously reported electrochemical mass spectrometry techniques.
Silver‐Mediated Oxidative Trifluoromethylation of Phenols: Direct Synthesis of Aryl Trifluoromethyl Ethers
Authors: Liu Jian‐Bo , Chen Chao , Chu Lingling , Chen Zeng‐Hao , Xu Xiu‐Hua , Qing Feng‐Ling
Published: August 2015

Aryl trifluoromethyl ethers (ArOCF3) are prevalent in pharmaceuticals, agrochemicals, and materials. However, methods for the general and efficient synthesis of these compounds are extremely underdeveloped and limited. Herein, we describe a highly efficient and general procedure for the direct O‐trifluoromethylation of unprotected phenols through a silver‐mediated cross‐coupling reaction using CF3SiMe3 as the CF3 source and exogenous oxidants. This novel oxidative trifluoromethylation provides access to a wide range of aryl trifluoromethyl ethers from simple phenols. The mild process was also applied to the late‐stage trifluoromethylation of a medicinally relevant compound.
Preparation of a Silanone through Oxygen Atom Transfer to a Stable Cyclic Silylene
Authors: Linden Michael M. , Reisenauer Hans Peter , Gerbig Dennis , Karni Miriam , Schäfer Annemarie , Müller Thomas , Apeloig Yitzhak , Schreiner Peter R.
Published: August 2015

We report the evaporation of a stable cyclic silylene and its oxidation (with ozone or N2O) through oxygen atom transfer to form the corresponding silanone under matrix isolation conditions. As uncomplexed silanones are rare owing to their very high reactivity, this method provides an alternative route to these sought‐after molecules. The silanone, as well as a novel bicyclic silane with a bridgehead silicon atom derived from an intramolecular silylene CH bond insertion, were characterized by comparison of high‐resolution infrared spectra with density functional theory (DFT) computations at the M06‐2X/cc‐pVDZ level of theory.
Hollow Zn/Co ZIF Particles Derived from Core–Shell ZIF‐67@ZIF‐8 as Selective Catalyst for the Semi‐Hydrogenation of Acetylene
Authors: Yang Jian , Zhang Fengjun , Lu Haiyuan , Hong Xun , Jiang Hailong , Wu Yuen , Li Yadong
Published: August 2015

The rational design of metal–organic frameworks (MOFs) with hollow features and tunable porosity at the nanoscale can enhance their intrinsic properties and stimulates increasing attentions. In this Communication, we demonstrate that methanol can affect the coordination mode of ZIF‐67 in the presence of Co2+ and induces a mild phase transformation under solvothermal conditions. By applying this transformation process to the ZIF‐67@ZIF‐8 core–shell structures, a well‐defined hollow Zn/Co ZIF rhombic dodecahedron can be obtained. The manufacturing of hollow MOFs enables us to prepare a noble metal@MOF yolk‐shell composite with controlled spatial distribution and morphology. The enhanced gas storage and porous confinement that originate from the hollow interior and coating of ZIF‐8 confers this unique catalyst with superior activity and selectivity toward the semi‐hydrogenation of acetylene.
Biological Chitin–MOF Composites with Hierarchical Pore Systems for Air‐Filtration Applications
Authors: Wisser Dorothea , Wisser Florian M. , Raschke Silvia , Klein Nicole , Leistner Matthias , Grothe Julia , Brunner Eike , Kaskel Stefan
Published: August 2015

Metal–organic frameworks (MOFs) are promising materials for gas‐separation and air‐filtration applications. However, for these applications, MOF crystallites need to be incorporated in robust and manageable support materials. We used chitin‐based networks from a marine sponge as a non‐toxic, biodegradable, and low‐weight support material for MOF deposition. The structural properties of the material favor predominant nucleation of the MOF crystallites at the inside of the hollow fibers. This composite has a hierarchical pore system with surface areas up to 800 m2 g−1 and pore volumes of 3.6 cm3 g−1, allowing good transport kinetics and a very high loading of the active material. Ammonia break‐through experiments highlight the accessibility of the MOF crystallites and the adsorption potential of the composite indicating their high potential for filtration applications for toxic industrial gases.
Regioregular Synthesis of Azaborine Oligomers and a Polymer with a syn Conformation Stabilized by NH⋅⋅⋅π Interactions
Authors: Baggett Andrew W. , Guo Fang , Li Bo , Liu Shih‐Yuan , Jäkle Frieder
Published: August 2015

The regioregular synthesis of the first azaborine oligomers and a corresponding conjugated polymer was accomplished by Suzuki–Miyaura coupling methods. An almost perfectly coplanar syn arrangement of the heterocycles was deduced from an X‐ray crystal structure of the dimer, which also suggested that NH⋅⋅⋅π interactions play an important role. Computational studies further supported these experimental observations and indicated that the electronic structure of the longer azaborine oligomers and polymer resembles that of poly(cyclohexadiene) more than poly(p‐phenylene). A comparison of the absorption and emission properties of the polymer with those of the oligomers revealed dramatic bathochromic shifts upon chain elongation, thus suggesting highly effective extension of conjugation.
Fluorine‐Free Anti‐Smudge Polyurethane Coatings
Authors: Rabnawaz Muhammad , Liu Guojun , Hu Heng
Published: August 2015

Conventionally, low‐surface‐tension fluorinated reagents are incorporated into anti‐smudge (oil‐ and water‐repellent) coatings for oil repellency. However, fluorinated compounds are expensive and an environmental concern because of their high stability and bioaccumulation. These factors limit their widespread application. We report herein the development of fluorine‐free anti‐smudge polyurethane coatings that are clear at thicknesses up to tens of micrometers and are able to sustain extensive surface damage. We demonstrate that these coatings can be applied readily onto a diverse range of substrates.
Activation of α‐Diazocarbonyls by Organic Catalysts: Diazo Group Acting as a Strong N‐Terminal Electrophile
Authors: Li Lei , Chen Jia‐Jia , Li Yi‐Jin , Bu Xiu‐Bin , Liu Qun , Zhao Yu‐Long
Published: August 2015

For the first time α‐diazocarbonyls have been used as highly active N‐terminal electrophiles in the presence of bicyclic amidine catalysts. The CN bond‐forming reactions of active methylene compounds as C nucleophiles with α‐diazocarbonyls as N‐terminal electrophiles proceed quickly under ambient conditions, in the presence of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU), because of the formation of the reactive N‐terminal electrophilic intermediates. DBU activates both the active methylene and α‐diazocarbonyl. Importantly, this reaction is general for both active methylenes and α‐diazocarbonyls, and the activation mode will lead to new synthetic applications of α‐diazocarbonyls.
Selective Ruthenium‐Catalyzed Hydrochlorination of Alkynes: One‐Step Synthesis of Vinylchlorides
Authors: Dérien Sylvie , Klein Hubert , Bruneau Christian
Published: August 2015

An unprecedented ruthenium‐catalyzed direct and selective alkyne hydrochlorination is reported and leads to vinylchlorides in excellent yields with atom economy. The reaction proceeds at room temperature from terminal alkynes and provides a variety of chloroalkenes. Only the regioisomer resulting from the formal Markovnikov addition is selectively formed. Mechanistic studies show the stereoselective syn addition of HCl to alkynes at room temperature and suggest a chloro hydrido RuIV species as a key intermediate of the reaction.
Biomimetic Total Syntheses of (−)‐Leucoridines A and C through the Dimerization of (−)‐Dihydrovalparicine
Authors: Kokkonda Praveen , Brown Keaon R. , Seguin Trevor J. , Wheeler Steven E. , Vaddypally Shivaiah , Zdilla Michael J. , Andrade Rodrigo B.
Published: August 2015

Concise biomimetic syntheses of the Strychnos‐Strychnos‐type bis‐indole alkaloids (−)‐leucoridine A (1) and C (2) were accomplished through the biomimetic dimerization of (−)‐dihydrovalparicine (3). En route to 3, the known alkaloids (+)‐geissoschizoline (8) and (−)‐dehydrogeissoschizoline (10) were also prepared. DFT calculations were employed to elucidate the mechanism, which favors a stepwise aza‐Michael/spirocyclization sequence over the alternate hetero‐Diels–Alder cycloaddition reaction.
Polymeric Micelle Assembly for the Smart Synthesis of Mesoporous Platinum Nanospheres with Tunable Pore Sizes
Authors: Li Yunqi , Bastakoti Bishnu Prasad , Malgras Victor , Li Cuiling , Tang Jing , Kim Jung Ho , Yamauchi Yusuke
Published: August 2015

A facile method for the fabrication of well‐dispersed mesoporous Pt nanospheres involves the use of a polymeric micelle assembly. A core–shell–corona type triblock copolymer [poly(styrene‐b‐2‐vinylpyridine‐b‐ethylene oxide), PS‐b‐P2VP‐b‐PEO] is employed as the pore‐directing agent. Negatively charged PtCl42− ions preferably interact with the protonated P2VP+ blocks while the free PEO chains prevent the aggregation of the Pt nanospheres. The size of the mesopores can be finely tuned by varying the length of the PS chain. Furthermore, it is demonstrated that the metallic mesoporous nanospheres thus obtained are promising candidates for applications in electrochemistry.
Definitive Molecular Level Characterization of Defects in UiO‐66 Crystals
Authors: Trickett Christopher A. , Gagnon Kevin J. , Lee Seungkyu , Gándara Felipe , Bürgi Hans‐Beat , Yaghi Omar M.
Published: August 2015

The identification and characterization of defects, on the molecular level, in metal‐organic frameworks (MOFs) remain a challenge. With the extensive use of single‐crystal X‐ray diffraction (SXRD), the missing linker defects in the zirconium‐based MOF UiO‐66, Zr6O4(OH)4(C8H4O4)6, have been identified as water molecules coordinated directly to the zirconium centers. Charge balancing is achieved by hydroxide anions, which are hydrogen bonded within the pores of the framework. Furthermore, the precise nature of the defects and their concentration can be manipulated by altering the starting materials, synthesis conditions, and post‐synthetic modifications.
Synthesis of ent‐Ketorfanol via a C–H Alkenylation/Torquoselective 6π Electrocyclization Cascade
Authors: Phillips Eric M. , Mesganaw Tehetena , Patel Ashay , Duttwyler Simon , Mercado Brandon Q. , Houk Kendall N. , Ellman Jonathan A.
Published: August 2015

The asymmetric synthesis of ent‐ketorfanol from simple and commercially available precursors is reported. A RhI‐catalyzed intramolecular CH alkenylation/torquoselective 6π electrocyclization cascade provides a fused bicyclic 1,2‐dihydropyridine as a key intermediate. Computational studies were performed to understand the high torquoselectivity of the key 6π electrocyclization. The computational results demonstrate that a conformational effect is responsible for the observed selectivity. The ketone functionality and final ring are introduced in a single step by a redox‐neutral acid‐catalyzed rearrangement of a vicinal diol to give the requisite carbonyl, followed by intramolecular Friedel–Crafts alkylation.
A Strategy to Control the Reactivation of Frustrated Lewis Pairs from Shelf‐Stable Carbene Borane Complexes
Authors: Hoshimoto Yoichi , Kinoshita Takuya , Ohashi Masato , Ogoshi Sensuke
Published: August 2015

N‐Phosphine oxide substituted imidazolylidenes (PoxIms) have been synthesized and fully characterized. These species can undergo significant changes to the spatial environment surrounding their carbene center through rotation of the phosphine oxide moiety. Either classical Lewis adducts (CLAs) or frustrated Lewis pairs (FLPs) are thus formed with B(C6F5)3 depending on the orientation of the phosphine oxide group. A strategy to reactivate FLPs from CLAs by exploiting molecular motions that are responsive to external stimuli has therefore been developed. The reactivation conditions were successfully controlled by tuning the strain in the PoxIm–B(C6F5)3 complexes so that reactivation only occurred above ambient temperature.
Realizing both High Energy and High Power Densities by Twisting Three Carbon‐Nanotube‐Based Hybrid Fibers
Authors: Zhang Ye , Zhao Yang , Cheng Xunliang , Weng Wei , Ren Jing , Fang Xin , Jiang Yishu , Chen Peining , Zhang Zhitao , Wang Yonggang , Peng Huisheng
Published: August 2015

Energy storage devices, such as lithium‐ion batteries and supercapacitors, are required for the modern electronics. However, the intrinsic characteristics of low power densities in batteries and low energy densities in supercapacitors have limited their applications. How to simultaneously realize high energy and power densities in one device remains a challenge. Herein a fiber‐shaped hybrid energy‐storage device (FESD) formed by twisting three carbon nanotube hybrid fibers demonstrates both high energy and power densities. For the FESD, the energy density (50 mWh cm−3 or 90 Wh kg−1) many times higher than for other forms of supercapacitors and approximately 3 times that of thin‐film batteries; the power density (1 W cm−3 or 5970 W kg−1) is approximately 140 times of thin‐film lithium‐ion battery. The FESD is flexible, weaveable and wearable, which offers promising advantages in the modern electronics.
Establishing the Structural Integrity of Core–Shell Nanoparticles against Elemental Migration using Luminescent Lanthanide Probes
Authors: Chen Bing , Peng Dengfeng , Chen Xian , Qiao Xvsheng , Fan Xianping , Wang Feng
Published: August 2015

Core–shell structured nanoparticles are increasingly used to host luminescent lanthanide ions but the structural integrity of these nanoparticles still lacks sufficient understanding. Herein, we present a new approach to detect the diffusion of dopant ions in core–shell nanostructures using luminescent lanthanide probes whose emission profile and luminescence lifetime are sensitive to the chemical environment. We show that dopant ions in solution‐synthesized core–shell nanoparticles are firmly confined in the designed locations. However, annealing at certain temperatures (greater than circa 350 °C) promotes diffusion of the dopant ions and leads to degradation of the integrity of the nanoparticles. These insights into core–shell nanostructures should enhance our ability to understand and use lanthanide‐doped luminescent nanoparticles.
Mitsunobu Reactions Catalytic in Phosphine and a Fully Catalytic System
Authors: Buonomo Joseph A. , Aldrich Courtney C.
Published: August 2015

The Mitsunobu reaction is renowned for its mild reaction conditions and broad substrate tolerance, but has limited utility in process chemistry and industrial applications due to poor atom economy and the generation of stoichiometric phosphine oxide and hydrazine by‐products that complicate purification. A catalytic Mitsunobu reaction using innocuous reagents to recycle these by‐products would overcome both of these shortcomings. Herein we report a protocol that is catalytic in phosphine (1‐phenylphospholane) employing phenylsilane to recycle the catalyst. Integration of this phosphine catalytic cycle with Taniguchi’s azocarboxylate catalytic system provided the first fully catalytic Mitsunobu reaction.
Libraries of modified polyacrylamides using post‐synthetic modification
Authors: da Silveira Kelly Cristine , Sheng Qi , Tian Wendy , Fernandes Lucas Elizabete , Wood Colin D.
Published: August 2015

Polyacrylamide‐based (PAM) polymers are the most widely used synthetic water‐soluble polymer so they are applied in a range of industries. However, they suffer from a number of limitations which requires the development of synthetic routes that can accurately control polymer structure and hence function. This study describes a carbodiimide mediated coupling reaction (CMC) that is used to generate modified polyacrylamide (PAM) including hydrophobically modified water‐soluble polymers (HMWSP). The reaction proceeds efficiently in water and does not require organic solvents or high temperatures. The approach is flexible due to the efficiency of the CMC reaction allowing for accurate control over polymer structure and function. This is confirmed using acid‐base titration, spectroscopy, viscometry, and rheology. The viscosity of the polymers varies over a broad range with those containing larger hydrophobic group (dodecyl) showing the highest viscosity. The hydrophobicity of the pendent group determines how it influences viscosity and using this new synthetic approach polymer with the same molecular weight can be compared. Linear hydrocarbon pendent groups are more hydrophobic than the cyclic versions resulting in higher viscosity. However, the spatial arrangement of the pendent group (linear or cyclic) also affects the viscosity at higher pendent group contents. The number of modified PAMs that can be generated is expansive because the approach works with a number of different functional groups and base polymers. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci.2015,132, 42797.
Study on correlation of filtration performance and charge behavior and crystalline structure for melt‐blown polypropylene electret fabrics
Authors: Xiao Huiming , Gui Jiyang , Chen Gangjin , Xiao Chunping
Published: August 2015

Melt‐blown polypropylene (PP) electret fabrics are widely used as air filter media due to the specific mechanism of electrostatic filtering. In this article, two additives, stearate and modified rosin, are doped to PP fabrics during melt‐blown process. The filtration performance of doped PP gets improved greatly, with filtration efficiency increased by 6% at room temperature but its temperature stability promoted dramatically. As a result, the filtration efficiency of doped PP still remains above 95% of its initial, whereas that of non‐doped PP only remains 58% at 110°C. By XRD characterization the structure modification is observed after doping. The crystallinity increases from 14.17% to 22.64% and 29.62%, respectively. Meanwhile, the crystallite has a smaller size, respectively, 89Å and 86Å as compared to 107Å for non‐doping in the direction vertical to lattice plane (110). This demonstrates that additive doping can give rise to larger crystallinity and more fine‐grained crystallite. Therefore, doped PP improves its charge storage behavior ascribing to expanding interface between crystallite and amorphous region and then enlarging charge trap density. Furthermore, the effect of additive doping on electret charge storage behavior is investigated by short‐circuit TSD, and the filtration performance can be explained relevantly with TSD. A charge storage profile is also adopted to illustrate that the space charge captured by charge traps is in the form of space‐charge dipole with the rigidity of crystallite. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 42807.
Containment of “wayward” females: The buildings of Abbotsford Convent, Victoria
Authors: Kay Edwina
Published: August 2015

The built fabric of institutions plays a fundamental role in both the process and the experience of institutionalisation. This crucial role of the physical fabric makes the buildings and landscape of institutions a rich source of evidence for historical archaeologists, with the potential to provide important insights into the development of institutions and their complex role in society. This paper examines aspects of the built fabric of the largest and longest‐operating Magdalen asylum in Australia, at Abbotsford Convent in Melbourne, to investigate the evolution of this complex site in the second half of the nineteenth century. Magdalen asylums were institutions that attempted to reform “wayward” and vulnerable women and girls. Although they accommodated thousands of women and girls in the nineteenth and twentieth centuries, their role and significance in Australia has not been extensively investigated. In this study, the extant buildings and grounds of Abbotsford Convent, as well as historical maps, photographs and written descriptions, provide evidence of the evolution of this institution over time.
A Randomized Trial Comparing Disease Activity Measures for the Assessment and Prediction of Response in Rheumatoid Arthritis Patients Initiating Certolizumab Pegol
Authors: Curtis Jeffrey R. , Churchill Melvin , Kivitz Alan , Samad Ahmed , Gauer Laura , Gervitz Leon , Koetse Willem , Melin Jeffrey , Yazici Yusuf
Published: August 2015

Objective

The aim of the Patient/Physician Reported Efficacy Determination In Clinical Practice Trial (PREDICT; ClinicalTrials identifier NCT01255761) was to compare the patient‐reported Routine Assessment of Patient Index Data 3 (RAPID‐3) instrument with the investigator‐based Clinical Disease Activity Index (CDAI) for assessing certolizumab pegol (CZP) treatment response in rheumatoid arthritis patients at 12 weeks and to predict the treatment response at week 52 using the data from week 12 (coprimary end points).

Methods

Patients received 400 mg of CZP at weeks 0, 2, and 4 (loading dose), followed by 200 mg every 2 weeks thereafter. Patients were randomized 1:1 to assessment with the RAPID‐3 or the CDAI. Responder classification was performed at week 12; treatment response was defined as a score of ≤6 or a 20% improvement over baseline on the RAPID‐3 or a score of ≤10 or a 20% improvement over baseline on the CDAI. Long‐term treatment success was defined as a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28‐ESR) of ≤3.2 at week 52. Comparisons were made for the coprimary end points using noninferiority methods. Patients with improvement of <1 on the CDAI score or with no improvement on the RAPID‐3 score at week 12 or patients with high levels of disease activity (CDAI score >22 or RAPID‐3 score >12) at 2 consecutive visits were withdrawn from the study.

Results

Patients had longstanding disease (mean 8.9 years) and high levels of disease activity (mean scores of 6.3 on the DAS28‐ESR, 16.1 on the RAPID‐3, and 40.2 on the CDAI). Previous anti–tumor necrosis factor therapy had failed in 55.5% of them. At week 12, a total of 64.7% (by RAPID‐3) and 76.4% (by CDAI) of the patients were classified as responders (difference of −11.9% [95% confidence interval −18.4%, −5.3%]). At week 52, a total of 31.5% (by RAPID‐3) and 32.3% (by CDAI) of the responders achieved a low level of disease activity on the DAS28‐ESR (difference of −1.3% [95% confidence interval −9.3%, 6.6%]).

Conclusion

The CDAI classified more patients as CZP responders at week 12 than did the RAPID‐3. Although these outcome measures were not statistically comparable, the positive predictive value for low disease activity at week 52 was similar. As these tools cover differing domains of therapy response, further evaluation for clinical disease activity assessments and treatment decisions is needed.
Cysteine‐Mediated Redox Regulation of Cell Signaling in Chondrocytes Stimulated With Fibronectin Fragments
Authors: Wood Scott T. , Long David L. , Reisz Julie A. , Yammani Raghunatha R. , Burke Elizabeth A. , Klomsiri Chananat , Poole Leslie B. , Furdui Cristina M. , Loeser Richard F.
Published: August 2015

Objective

Oxidative posttranslational modifications of intracellular proteins can potentially regulate signaling pathways relevant to cartilage destruction in arthritis. In this study, oxidation of cysteine residues to form sulfenic acid (S‐sulfenylation) was examined in osteoarthritic (OA) chondrocytes and investigated in normal chondrocytes as a mechanism by which fragments of fibronectin (FN‐f) stimulate chondrocyte catabolic signaling.

Methods

Chondrocytes isolated from OA and normal human articular cartilage were analyzed using analogs of dimedone that specifically and irreversibly react with protein S‐sulfenylated cysteines. Global S‐sulfenylation was measured in cell lysates with and without FN‐f stimulation by immunoblotting and in fixed cells by confocal microscopy. S‐sulfenylation in specific proteins was identified by mass spectroscopy and confirmed by immunoblotting. Src activity was measured in live cells using a fluorescence resonance energy transfer biosensor.

Results

Proteins in chondrocytes isolated from OA cartilage were found to have elevated basal levels of S‐sulfenylation relative to those of chondrocytes from normal cartilage. Treatment of normal chondrocytes with FN‐f induced increased levels of S‐sulfenylation in multiple proteins, including the tyrosine kinase Src. FN‐f treatment also increased the levels of Src activity. Pretreatment with dimedone to alter S‐sulfenylation function or with Src kinase inhibitors inhibited FN‐f–induced production of matrix metalloproteinase 13.

Conclusion

These results demonstrate for the first time the presence of oxidative posttranslational modification of proteins in human articular chondrocytes by S‐sulfenylation. Due to the ability to regulate the activity of a number of cell signaling pathways, including catabolic mediators induced by fibronectin fragments, S‐sulfenylation may contribute to cartilage destruction in OA and warrants further investigation.
Brief Report: Interleukin‐38 Exerts Antiinflammatory Functions and Is Associated With Disease Activity in Systemic Lupus Erythematosus
Authors: Rudloff Ina , Godsell Jack , Nold‐Petry Claudia A. , Harris James , Hoi Alberta , Morand Eric F. , Nold Marcel F.
Published: August 2015

Objective

Knowledge of interleukin‐38 (IL‐38), formerly IL‐1 family member 10, is sparse, but Il1f10 polymorphisms are associated with inflammatory diseases, and recombinant IL‐38 inhibits inflammatory responses similar to those reported in the context of systemic lupus erythematosus (SLE). We undertook this study to explore the function of endogenous IL‐38 in human peripheral blood mononuclear cells (PBMCs) as well as its abundance in serum in a well‐characterized cohort of SLE patients.

Methods

Serum IL‐38 and IL‐10 levels were quantified by enzyme‐linked immunosorbent assay in 142 SLE patients at ≤3 consecutive visits and in 28 healthy volunteers. To assess IL‐38 function, we silenced IL‐38 in PBMCs from healthy donors using IL‐38 small interfering RNA (siRNA).

Results

IL‐38 (63–5,928 pg/ml) was detectable in 16% of 372 serum samples. IL‐38 abundance was significantly higher in samples from SLE patients than in samples from healthy controls (P = 0.004) and 11‐fold higher in patients with active disease (SLE Disease Activity Index 2000 [SLEDAI‐2K] score of ≥4) than in those with inactive disease (SLEDAI‐2K score of <4) (P = 0.044). Importantly, IL‐38 detection was associated with increased risk of renal lupus (relative risk [RR] 1.6, P = 0.027) and central nervous system lupus (RR 2.3, P = 0.034), and detectable baseline IL‐38 entailed a 1.6‐fold increased risk of subsequently meeting criteria for persistently active disease (P = 0.0097). Longitudinal time‐adjusted mean IL‐38 concentration was also 6‐fold higher in patients with persistently active disease than in those without (P = 0.023). Remarkably, PBMCs treated with IL‐38 siRNA produced up to 28‐fold more of the proinflammatory mediators IL‐6, CCL2, and APRIL than did control siRNA–transfected cells upon stimulation with Toll‐like receptor agonists. Similarly, in SLE patients, the antiinflammatory cytokine IL‐10 was 5‐fold more abundant when IL‐38 was detectable.

Conclusion

This is the first study of the function of endogenous IL‐38, and the data suggest that IL‐38 may be protective in SLE. A strong association between IL‐38 and SLE severity suggests that IL‐38 expression is driven by processes linked to SLE pathogenesis. Exploitation of the regulatory effects of IL‐38 may represent a promising therapeutic strategy in SLE.
2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative
Authors: Ravelli Angelo , Minoia Francesca , Davì Sergio , Horne AnnaCarin , Bovis Francesca , Pistorio Angela , Aricò Maurizio , Avcin Tadej , Behrens Edward M. , De Benedetti Fabrizio , Filipovic Lisa , Grom Alexei A. , Henter Jan‐Inge , Ilowite Norman T. , Jordan Michael B. , Khubchandani Raju , Kitoh Toshiyuki , Lehmberg Kai , Lovell Daniel J. , Miettunen Paivi , Nichols Kim E. , Ozen Seza , Pachlopnik Schmid Jana , Ramanan Athimalaipet V. , Russo Ricardo , Schneider Rayfel , Sterba Gary , Uziel Yosef , Wallace Carol , Wouters Carine , Wulffraat Nico , Demirkaya Erkan , Brunner Hermine I. , Martini Alberto , Ruperto Nicolino , Cron Randy Q. ,   on behalf of the Paediatric Rheumatology International Trials Organisation, the Childhood Arthritis and Rheumatology Research Alliance, the Pediatric Rheumatology Collaborative Study Group, and the Histiocyte Society
Published: August 2015

Objective

To develop criteria for the classification of macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (JIA).

Methods

A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of 28 experts was first asked to classify 428 patient profiles as having or not having MAS, based on clinical and laboratory features at the time of disease onset. The 428 profiles comprised 161 patients with systemic JIA–associated MAS and 267 patients with a condition that could potentially be confused with MAS (active systemic JIA without evidence of MAS, or systemic infection). Next, the ability of candidate criteria to classify individual patients as having MAS or not having MAS was assessed by evaluating the agreement between the classification yielded using the criteria and the consensus classification of the experts. The final criteria were selected in a consensus conference.

Results

Experts achieved consensus on the classification of 391 of the 428 patient profiles (91.4%). A total of 982 candidate criteria were tested statistically. The 37 best‐performing criteria and 8 criteria obtained from the literature were evaluated at the consensus conference. During the conference, 82% consensus among experts was reached on the final MAS classification criteria. In validation analyses, these criteria had a sensitivity of 0.73 and a specificity of 0.99. Agreement between the classification (MAS or not MAS) obtained using the criteria and the original diagnosis made by the treating physician was high (κ = 0.76).

Conclusion

We have developed a set of classification criteria for MAS complicating systemic JIA and provided preliminary evidence of its validity. Use of these criteria will potentially improve understanding of MAS in systemic JIA and enhance efforts to discover effective therapies, by ensuring appropriate patient enrollment in studies.
Muscle Power Is an Independent Determinant of Pain and Quality of Life in Knee Osteoarthritis
Authors: Reid Kieran F. , Price Lori Lyn , Harvey William F. , Driban Jeffrey B. , Hau Cynthia , Fielding Roger A. , Wang Chenchen
Published: August 2015

Objective

This study examined the relationships between leg muscle strength, power, and perceived disease severity in subjects with knee osteoarthritis (OA) in order to determine whether dynamic leg extensor muscle power would be associated with pain and quality of life in knee OA.

Methods

Baseline data on 190 subjects with knee OA (mean ± SD age 60.2 ± 10.4 years, body mass index 32.7 ± 7.2 kg/m2) were obtained from a randomized controlled trial. Knee pain was measured using the Western Ontario and McMaster Universities Osteoarthritis Index, and health‐related quality of life was assessed using the Short Form 36 (SF‐36). One‐repetition maximum (1RM) strength was assessed using the bilateral leg press, and peak muscle power was measured during 5 maximum voluntary velocity repetitions at 40% and 70% of 1RM.

Results

In univariate analysis, greater muscle power was significantly associated with pain (r = −0.17, P < 0.02) and also significantly and positively associated with SF‐36 physical component summary (PCS) scores (r = 0.16, P < 0.05). After adjustment for multiple covariates, muscle power was a significant independent predictor of pain (P ≤ 0.05) and PCS scores (P ≤ 0.04). However, muscle strength was not an independent determinant of pain or quality of life (P ≥ 0.06).

Conclusion

Muscle power is an independent determinant of pain and quality of life in knee OA. Compared to strength, muscle power may be a more clinically important measure of muscle function within this population. New trials to systematically examine the impact of muscle power training interventions on disease severity in knee OA are particularly warranted.
Regulation of Cholesterol Homeostasis by Hedgehog Signaling in Osteoarthritic Cartilage
Authors: Ali Shabana Amanda , Al‐Jazrawe Mushriq , Ma Henry , Whetstone Heather , Poon Raymond , Farr Sarah , Naples Mark , Adeli Khosrow , Alman Benjamin A.
Published: August 2015

Objective

With no effective therapies to attenuate cartilage degeneration in osteoarthritis (OA), the result is pain and disability. Activation of hedgehog (HH) signaling causes changes related to the progression of OA, with higher levels of Gli‐mediated transcriptional activation associated with increased disease severity. To elucidate the mechanism through which this occurs, this study sought to identify genes regulated by HH signaling in human OA chondrocytes.

Methods

Using human OA cartilage samples, microarray analyses were performed to detect changes in gene expression when the HH pathway was modulated. Results were analyzed for differentially expressed genes, grouped into functional networks, and validated in independent samples. To investigate the effects of chondrocyte‐specific sterol accumulation, we generated mice lacking Insig1 and Insig2, which are major negative regulators of cholesterol homeostasis, under Col2a1 regulatory elements.

Results

HH signaling was found to regulate genes that govern cholesterol homeostasis, and this led to alterations in cholesterol accumulation in chondrocytes. A higher level of Gli‐mediated transcription resulted in accumulation of intracellular cholesterol. In genetically modified mice, chondrocyte‐specific cholesterol accumulation was associated with an OA phenotype. Reducing cholesterol accumulation attenuated the severity of OA in mice in vivo and decreased the expression of proteases in human OA cartilage in vitro.

Conclusion

HH signaling regulates cholesterol homeostasis in chondrocytes, and intracellular cholesterol accumulation contributes to the severity of OA. Our findings have therapeutic implications, since reduction of HH signaling reversed cholesterol accumulation and statin treatment attenuated cartilage degeneration.
Identification of a New Susceptibility Locus for Systemic Lupus Erythematosus on Chromosome 12 in Individuals of European Ancestry
Authors: Demirci F. Yesim , Wang Xingbin , Kelly Jennifer A. , Morris David L. , Barmada M. Michael , Feingold Eleanor , Kao Amy H. , Sivils Kathy L. , Bernatsky Sasha , Pineau Christian , Clarke Ann E. , Ramsey‐Goldman Rosalind , Vyse Timothy J. , Gaffney Patrick M. , Manzi Susan , Kamboh M. Ilyas
Published: August 2015

Objective

Genome‐wide association studies (GWAS) in individuals of European ancestry identified a number of systemic lupus erythematosus (SLE) susceptibility loci using earlier versions of high‐density genotyping platforms. Followup studies on suggestive GWAS regions using larger samples and more markers identified additional SLE loci in subjects of European descent. This multistage study was undertaken to identify novel SLE loci.

Methods

In stage 1, we conducted a new GWAS of SLE in a North American case–control sample of subjects of European ancestry (n = 1,166) genotyped on Affymetrix Genome‐Wide Human SNP Array 6.0. In stage 2, we further investigated top new suggestive GWAS hits by in silico evaluation and meta‐analysis using an additional data set of subjects of European descent (>2,500 individuals), followed by replication of top meta‐analysis findings in another data set of subjects of European descent (>10,000 individuals) in stage 3.

Results

As expected, our GWAS revealed the most significant associations at the major histocompatibility complex locus (6p21), which easily surpassed the genome‐wide significance threshold (P < 5 × 10−8). Several other SLE signals/loci previously implicated in Caucasians and/or Asians were also confirmed in the stage 1 discovery sample, and the strongest signals were observed at 2q32/STAT4 (P = 3.6 × 10−7) and at 8p23/BLK (P = 8.1 × 10−6). Stage 2 meta‐analyses identified a new genome‐wide significant SLE locus at 12q12 (meta P = 3.1 × 10−8), which was replicated in stage 3.

Conclusion

Our multistage study identified and replicated a new SLE locus that warrants further followup in additional studies. Publicly available databases suggest that this newly identified SLE signal falls within a functionally relevant genomic region and near biologically important genes.
Brief Report: Pulmonary Function Tests: High Rate of False‐Negative Results in the Early Detection and Screening of Scleroderma‐Related Interstitial Lung Disease
Authors: Suliman Yossra A. , Dobrota Rucsandra , Huscher Dörte , Nguyen‐Kim Thi D. L. , Maurer Britta , Jordan Suzana , Speich Rudolf , Frauenfelder Thomas , Distler Oliver
Published: August 2015

Objective

Validated methods for the screening and early diagnosis of systemic sclerosis (SSc; scleroderma)–related interstitial lung disease (ILD) are needed. The aim of this study was to evaluate the performance of pulmonary function tests (PFTs) compared with that of high‐resolution computed tomography (HRCT) of the chest for the detection of SSc‐related ILD in clinical practice, and to identify predictors of lung involvement that is functionally occult but significant on HRCT.

Methods

Prospectively enrolled patients with SSc were assessed according to the European League Against Rheumatism (EULAR)/EULAR Scleroderma Trial and Research standards. The assessment included PFTs and HRCT. The HRCT images were evaluated in a blinded manner by 2 experienced radiologists. The performance parameters of PFTs for the diagnosis of SSc‐related ILD were calculated. Predictors of significant ILD as determined by HRCT in patients with normal forced vital capacity (FVC) values were identified through logistic regression.

Results

Among the 102 patients, 64 (63.0%) showed significant ILD on HRCT, while only 27 (26.0%) had an FVC <80% of predicted, and 54 (53.0%) had a decrease in the results of at least 1 PFT. Forty (62.5%) of 64 patients with significant ILD on HRCT had a normal FVC value, translating into a high false‐negative rate. Notably, 5 of 40 patients with a normal FVC value had severe, functionally occult lung fibrosis; in 2 of these patients, the results of all of the PFTs were within normal limits. Patients with normal FVC values despite evidence of fibrosis on HRCT more frequently had anti–Scl‐70 antibodies and diffuse SSc and less frequently had anticentromere antibodies (ACAs) compared with patients with both normal FVC values and normal HRCT results.

Conclusion

The derived evidence‐based data reveal a high risk of missing significant SSc‐related ILD when relying solely on PFTs. More comprehensive screening algorithms for early detection are warranted. In particular, additional imaging investigations for the early detection of SSc‐related ILD should be considered in ACA‐negative patients with normal FVC values.
Involvement of Mast Cells in α7 Nicotinic Receptor Agonist Exacerbation of Freund's Complete Adjuvant–Induced Monoarthritis in Mice
Authors: Lopes Fernando , Graepel Rabea , Reyes Jose Luis , Wang Arthur , Petri Björn , McDougall Jason J. , Sharkey Keith A. , McKay Derek M.
Published: August 2015

Objective

Activation of antiinflammatory cholinergic (vagal) pathways can reduce inflammation, and in vitro studies support a pivotal role of α7 nicotinic acetylcholine receptors (α7‐nAChR), macrophages, and T cells in these events. The aim of this study was to assess α7‐nAChR agonists as an antiinflammatory treatment for Freund's complete adjuvant (CFA)–induced monoarthritis.

Methods

Arthritis was induced by intraarticular injection of CFA unilaterally into the knee joints of mice. Animals were treated with α7‐nAChR agonists (AR‐R17779 or A844606), with or without antagonists (COG133 or methyllycaconitine), and joint inflammation and pain were assessed. Experiments were repeated in c‐KitW‐sh mast cell–deficient mice, and the effects of an α7‐nAChR agonist on mast cell proliferation, migration, and activation by lipopolysaccharide (LPS) were tested.

Results

Treatment with α7‐nAChR agonists significantly exacerbated CFA‐induced arthritis and pain, as gauged by all indices of assessment, the specificity of which was confirmed by coadministration of an nAChR antagonist that attenuated the increase in disease severity. Toluidine blue–positive mast cells were increased in the joint capsule of CFA plus AR‐R17779–treated mice, and AR‐R17779 enhanced LPS‐induced TNF proliferation and migration of a human mast cell line. The AR‐R17779–driven increase in severity of CFA‐induced arthritis was significantly reduced in mast cell–deficient mice.

Conclusion

Using CFA to elicit a local inflammatory response, we found that pharmacologic activation of α7‐nAChR exacerbated joint inflammation and pain, in part via mast cells, which illustrates the organ‐ and disease‐specific nature of regulatory neuroimmune mechanisms. Thus, α7‐nAChR activation may not be uniformly antiinflammatory in all types of inflammatory joint disease.
A Novel Allyl Transfer Coupled with a Grob Fragmentation
Authors: Li Shao‐Gang , Chen Hui‐Jun , Yang Yang‐Yang , Wu Wen‐Ju , Wu Yikang
Published: August 2015

A novel acid‐promoted rearrangement is disclosed. In the previously unknown transformation, an allyl group migrated to an in situ formed carbocation stabilized by an electron‐rich aryl or heteroaryl group, resulting in a stereoselective intramolecular Grob fragmentation. The outcome of the rearrangement observed with an array of substrates can be satisfactorily rationalized using a working hypothesis with the aid of a six‐membered transition state similar to those proposed for the anionic oxy‐Cope or oxonia‐Cope rearrangements, but involving only one instead of two double bonds.
Genome‐wide Association Study of Autism Spectrum Disorder in the East Asian Populations
Authors: Liu Xiaoxi , Shimada Takafumi , Otowa Takeshi , Wu Yu‐Yu , Kawamura Yoshiya , Tochigi Mamoru , Iwata Yasuhide , Umekage Tadashi , Toyota Tomoko , Maekawa Motoko , Iwayama Yoshimi , Suzuki Katsuaki , Kakiuchi Chihiro , Kuwabara Hitoshi , Kano Yukiko , Nishida Hisami , Sugiyama Toshiro , Kato Nobumasa , Chen Chia‐Hsiang , Mori Norio , Yamada Kazuo , Yoshikawa Takeo , Kasai Kiyoto , Tokunaga Katsushi , Sasaki Tsukasa , Gau Susan Shur‐Fen
Published: August 2015

Autism spectrum disorder is a heterogeneous neurodevelopmental disorder with strong genetic basis. To identify common genetic variations conferring the risk of ASD, we performed a two‐stage genome‐wide association study using ASD family and healthy control samples obtained from East Asian populations. A total of 166 ASD families (n = 500) and 642 healthy controls from the Japanese population were used as the discovery cohort. Approximately 900,000 single nucleotide polymorphisms (SNPs) were genotyped using Affymetrix Genome‐Wide Human SNP array 6.0 chips. In the replication stage, 205 Japanese ASD cases and 184 healthy controls, as well as 418 Chinese Han trios (n = 1,254), were genotyped by TaqMan platform. Case–control analysis, family based association test, and transmission/disequilibrium test (TDT) were then conducted to test the association. In the discovery stage, significant associations were suggested for 14 loci, including 5 known ASD candidate genes: GPC6, JARID2, YTHDC2, CNTN4, and CSMD1. In addition, significant associations were identified for several novel genes with intriguing functions, such as JPH3, PTPRD, CUX1, and RIT2. After a meta‐analysis combining the Japanese replication samples, the strongest signal was found at rs16976358 (P = 6.04 × 10−7), which is located near the RIT2 gene. In summary, our results provide independent support to known ASD candidate genes and highlight a number of novel genes warranted to be further investigated in a larger sample set in an effort to improve our understanding of the genetic basis of ASD. Autism Res 2016, 9: 340–349. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.
Improved stereoselective bioreduction of t‐butyl 6‐cyano‐(5R)‐hydroxy‐3‐oxohexanoate by Rhodotorula glutinis through heat treatment
Authors: Luo Xi , Wang Ya‐Jun , Zheng Yu‐Guo
Published: August 2015

Optically pure t‐butyl 6‐cyano‐(3R, 5R)‐dihydroxyhexanoate ((R)‐1b) is the key precursor for atorvastatin calcium, the most widely used cholesterol‐lowering drug. In this work, a strain ZJB‐09224 capable of asymmetrically reducing t‐butyl 6‐cyano‐(5R)‐hydroxy‐3‐oxohexanoate (1a) to corresponding optically pure (R)‐1b was successfully isolated from soil sample, identified belonging to Rhodotorula glutinis based on the morphology, physiological tests, and the 18S rDNA sequence analysis. It was found that heat treatment of cell suspension at 45 °C for 25 Min significantly improved R. glutinis ZJB‐09224 stereoselectivity. The asymmetric bioreduction of 1a was most efficient at pH 7.5, 35 °C, 50 mM (15.0 g L−1) substrate concentration, 40.0 g DCW L−1 cell loading size, 0.54 M (60.0 g L−1) sodium lactate acting as co‐substrate. Under these optimal conditions, 0.046 M (R)‐1b was produced with de (diastereomeric excess) value of 99.2% after 40 H conversion. Moreover, R. glutinis ZJB‐09224 has a broad substrate spectrum, making it a potential tool for some valuable chiral alcohol pharmaceutical intermediates synthesis.
Species‐ and gender‐dependent differences in the glucuronidation of a flavonoid glucoside and its aglycone determined using expressed UGT enzymes and microsomes
Authors: Dai Peimin , Luo Feifei , Wang Ying , Jiang Huangyu , Wang Liping , Zhang Guiyu , Zhu Lijun , Hu Ming , Wang Xinchun , Lu Linlin , Liu Zhongqiu
Published: August 2015

Flavonoids occur naturally as glucosides and aglycones. Their common phenolic hydroxyl groups may trigger extensive UDP‐glucuronosyltransferase (UGT)‐ catalysed metabolism. Unlike aglycones, glucosides contain glucose moieties. However, the influence of these glucose moieties on glucuronidation of glucosides and aglycones remains unclear. In this study, the flavonoid glucoside tilianin and its aglycone acacetin were used as model compounds. The glucuronidation characteristics and enzyme kinetics of tilianin and acacetin were compared using human UGT isoforms, liver microsomes and intestinal microsomes obtained from different animal species. Tilianin and acacetin were metabolized into different glucuronides, with UGT1A8 produced as the main isoform. Assessment of enzyme kinetics in UGT1A8, human liver microsomes and human intestinal microsomes revealed that compared with tilianin, acacetin displayed lower Km (0.6‐, 0.7‐ and 0.6‐fold, respectively), higher Vmax (20‐, 60‐ and 230‐fold, respectively) and higher clearance (30‐, 80‐ and 300‐fold, respectively). Furthermore, glucuronidation of acacetin and tilianin showed significant species‐ and gender‐dependent differences. In conclusion, glucuronidation of flavonoid aglycones is faster than that of glucosides in the intestine and the liver. Understanding the metabolism and species‐ and gender‐dependent differences between glucosides and aglycones is crucial for the development of drugs from flavonoids. Copyright © 2015 John Wiley & Sons, Ltd.