bluuebunny/crossref_metadata_2025 huggingface dataset:
Association Between Pain Sensitization and Disease Activity in Patients With Rheumatoid Arthritis: A Cross‐Sectional Study
Authors: Lee Yvonne C. , Bingham Clifton O. , Edwards Robert R. , Marder Wendy , Phillips Kristine , Bolster Marcy B. , Clauw Daniel J. , Moreland Larry W. , Lu Bing , Wohlfahrt Alyssa , Zhang Zhi , Neogi Tuhina
Published: April 2017

Objective

Pain sensitization may contribute to pain severity in rheumatoid arthritis (RA), impacting disease activity assessment. We examined whether pain processing mechanisms were associated with disease activity among RA patients with active disease.

Methods

The study included 139 subjects enrolled in the Central Pain in Rheumatoid Arthritis cohort. Subjects underwent quantitative sensory testing (QST), including assessment of pressure pain thresholds (PPTs) at multiple sites, conditioned pain modulation, and temporal summation. RA disease activity was assessed using the Clinical Disease Activity Index (CDAI) and its components. We examined cross‐sectional associations between QST measures and disease activity using linear regression.

Results

Low PPTs (high pain sensitization) at all sites were associated with high CDAI scores (P ≤ 0.03) and tender joint counts (P ≤ 0.002). Associations between PPTs and patient global assessments were also seen at most sites. High temporal summation at the forearm (also reflecting high pain sensitization) was significantly associated with high CDAI scores (P = 0.02), patient global assessment scores (P = 0.0006), evaluator global assessment scores (P = 0.01), and tender joint counts (P = 0.02). Conversely, conditioned pain modulation (a measure of descending inhibitory pain pathways) was associated only with tender joint count (P = 0.03).

Conclusion

High pain sensitization is associated with elevations in disease activity measures. Longitudinal studies are underway to elucidate the cause–effect relationships between pain sensitization and inflammatory disease activity in RA.
Extracellular Vesicles: Isolation Methods
Authors: Pariset Eloise , Agache Vincent , Millet Arnaud
Published: April 2017

Extracellular vesicles (EVs) have recently been at the center of attention of cellular biologists and physicians as their role in intercellular communications has become progressively revealed. EVs display a huge diversity concerning their biogenesis and functions, leading to a still evolving classification comprising exosomes, microvesicles and apoptotic bodies. One of the main technical challenges to studying EVs is to isolate them without interfering with their structure, in order to be able to reveal their functions and to use them as biomarkers. Moreover, the new area of therapeutically using EVs needs clinical grade methods of isolation. In this review, different methods disposable to researchers and clinicians to isolate EVs are described, focusing on the physical principles that allow understanding the advantages and limitations of each technique. The new growing field of microfluidic systems which offers the opportunity to associate isolation and characterization on a single chip will be presented highlighting its potential in the field of EV studies.
RhMoS2 Nanocomposite Catalysts with Pt‐Like Activity for Hydrogen Evolution Reaction
Authors: Cheng Yafei , Lu Shunkai , Liao Fan , Liu Liangbin , Li Yanqing , Shao Mingwang
Published: April 2017

High overpotentials and low efficiency are two main factors that restrict the practical application for MoS2, the most promising candidate for hydrogen evolution catalysis. Here, RhMoS2 nanocomposites, the addition of a small amount of Rh (5.2 wt%), exhibit the superior electrochemical hydrogen evolution performance with low overpotentials, small Tafel slope (24 mV dec−1), and long term of stability. Experimental results reveal that 5.2 wt% RhMoS2 nanocomposite, even exceeding the commercial 20 wt% Pt/C when the potential is less than −0.18 V, exhibits an excellent mass activity of 13.87 A mgmetal−1 at −0.25 V, four times as large as that of the commercial 20 wt% Pt/C catalyst. The hydrogen yield of 5.2 wt% RhMoS2 nanocomposite is 26.3% larger than that of the commercial 20 wt% Pt/C at the potential of −0.25 V. The dramatically improved electrocatalytic performance of RhMoS2 nanocomposites may be attributed to the hydrogen spillover from Rh to MoS2.
Arginine‐Rich Peptide‐Based mRNA Nanocomplexes Efficiently Instigate Cytotoxic T Cell Immunity Dependent on the Amphipathic Organization of the Peptide
Authors: Udhayakumar Vimal K. , De Beuckelaer Ans , McCaffrey Joanne , McCrudden Cian M. , Kirschman Jonathan L. , Vanover Daryll , Van Hoecke Lien , Roose Kenny , Deswarte Kim , De Geest Bruno G. , Lienenklaus Stefan , Santangelo Philip J. , Grooten Johan , McCarthy Helen O. , De Koker Stefaan
Published: April 2017

To date, the mRNA delivery field has been heavily dominated by lipid‐based systems. Reports on the use of nonlipid carriers for mRNA delivery in contrast are rare in the context of mRNA vaccination. This paper describes the potential of a cell‐penetrating peptide containing the amphipathic RALA motif to deliver antigen‐encoding mRNA to the immune system. RALA condenses mRNA into nanocomplexes that display acidic pH‐dependent membrane disruptive properties. RALA mRNA nanocomplexes enable mRNA escape from endosomes and thereby allow expression of mRNA inside the dendritic cell cytosol. Strikingly, RALA mRNA nanocomplexes containing pseudouridine and 5‐methylcytidine modified mRNA elicit potent cytolytic T cell responses against the antigenic mRNA cargo and show superior efficacy in doing so when compared to RALA mRNA nanocomplexes containing unmodified mRNA. RALA's unique sequence and structural organization are vital to act as mRNA vaccine vehicle, as arginine‐rich peptide variants that lack the RALA motif show reduced mRNA complexation, impaired cellular uptake and lose the ability to transfect dendritic cells in vitro and to evoke T cell immunity in vivo.
High‐Performance Respiration‐Based Biocell Using Artificial Nanochannel Regulation
Authors: Zhang Qianqian , Li Xiulin , Chen Yang , Zhang Qian , Liu Huixue , Zhai Jin , Yang Xiaoda
Published: April 2017

Based on electron and proton transfer events occurring in biological respiration, a mitochondria‐based biocell is constructed by combining with artificial nanochannels. In this biocell, mitochondria transfer electrons to the working electrode and pump protons into the electrolyte through the tricarboxylic acid cycle. The nanochannels provide passages for protons to transport along the transmembrane concentration gradient to consume electrons on the counter electrode, forming a continuous and stable current. Furthermore, the proton transmembrane transport behavior could be modulated by regulating the permeability area and surface charge of nanochannels. A high‐performance biocell is obtained when equipped with the optimized nanochannels, which produces a current of ≈3.1 mA cm−2, a maximum power of ≈0.91 mW cm−2, and a lifetime over 60 h. This respiratory‐based biocell shows great potential for the efficient utilization of bioelectricity.
Facile Formation of a Solid Electrolyte Interface as a Smart Blocking Layer for High‐Stability Sulfur Cathode
Authors: Guo Junling , Du Xinyu , Zhang Xiaolong , Zhang Fengxiang , Liu Jinping
Published: April 2017

The practical application of lithium–sulfur batteries (LSBs) is hindered by their poor cycle life, which stems mainly from the “redox shuttle reactions” of dissolved polysulfides. To develop a high‐performance cathode for LSBs, encapsulation of polysulfides with a blocking layer is potentially straightforward. Herein, a novel strategy is reported encapsulate sulfur and the electrolyte together in porous carbon spheres by using a solid electrolyte interface (SEI) that can selectively sieve Li+ ions while efficiently avoiding polysulfide accumulation and suppressing undesired polysulfide migration. This strategy is simple, straightforward, and effective. The carbon/sulfur cathode only needs to be cycled a few times within a voltage window of 0.3–1.0 V to form such a smart SEI, allowing the resulting cathode to exhibit superior stability extending 600 cycles. This strategy can be combined with other existing advanced sulfur cathode designs to improve the overall performance of LSBs.
Atomic Interface Engineering and Electric‐Field Effect in Ultrathin Bi2MoO6 Nanosheets for Superior Lithium Ion Storage
Authors: Zheng Yang , Zhou Tengfei , Zhao Xudong , Pang Wei Kong , Gao Hong , Li Sean , Zhou Zhen , Liu Huakun , Guo Zaiping
Published: April 2017

Ultrathin 2D materials can offer promising opportunities for exploring advanced energy storage systems, with satisfactory electrochemical performance. Engineering atomic interfaces by stacking 2D crystals holds huge potential for tuning material properties at the atomic level, owing to the strong layer–layer interactions, enabling unprecedented physical properties. In this work, atomically thin Bi2MoO6 sheets are acquired that exhibit remarkable high‐rate cycling performance in Li‐ion batteries, which can be ascribed to the interlayer coupling effect, as well as the 2D configuration and intrinsic structural stability. The unbalanced charge distribution occurs within the crystal and induces built‐in electric fields, significantly boosting lithium ion transfer dynamics, while the extra charge transport channels generated on the open surfaces further promote charge transport. The in situ synchrotron X‐ray powder diffraction results confirm the material's excellent structural stability. This work provides some insights for designing high‐performance electrode materials for energy storage by manipulating the interface interaction and electronic structure.
Polar Side Chains Enhance Processability, Electrical Conductivity, and Thermal Stability of a Molecularly p‐Doped Polythiophene
Authors: Kroon Renee , Kiefer David , Stegerer Dominik , Yu Liyang , Sommer Michael , Müller Christian
Published: April 2017

Molecular doping of organic semiconductors is critical for optimizing a range of optoelectronic devices such as field‐effect transistors, solar cells, and thermoelectric generators. However, many dopant:polymer pairs suffer from poor solubility in common organic solvents, which leads to a suboptimal solid‐state nanostructure and hence low electrical conductivity. A further drawback is the poor thermal stability through sublimation of the dopant. The use of oligo ethylene glycol side chains is demonstrated to significantly improve the processability of the conjugated polymer p(g42T‐T)—a polythiophene—in polar aprotic solvents, which facilitates coprocessing of dopant:polymer pairs from the same solution at room temperature. The use of common molecular dopants such as 2,3,5,6‐tetrafluoro‐7,7,8,8‐tetracyanoquinodimethane (F4TCNQ) and 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone (DDQ) is explored. Doping of p(g42T‐T) with F4TCNQ results in an electrical conductivity of up to 100 S cm−1. Moreover, the increased compatibility of the polar dopant F4TCNQ with the oligo ethylene glycol functionalized polythiophene results in a high degree of thermal stability at up to 150 °C.
A General Surface Swelling‐Induced Electroless Deposition Strategy for Fast Fabrication of Copper Circuits on Various Polymer Substrates
Authors: Sun Xueyan , Zhang Lijing , Tao Shengyang , Yu Yongxian , Li Sijie , Wang Han , Qiu Jieshan
Published: April 2017

A universal, surface swelling‐induced strategy‐based facile electroless deposition method is developed to prepare copper circuits on various polymer substrates. The circuits are grown on silver catalytic centers written in the form of set patterns, rather than via standard reducing material manufacturing, and can be easily erased and repeatedly deposited three times with only a 15% decrease in conductivity. Polymers with different hardness and flexibility are selected as circuit base boards. In addition to hard acrylonitrile butadiene styrene resins, a flexible polyimide‐based copper circuit yields excellent flexural performance, whereas a stretchable silicon rubber‐based circuit exhibits different response to different ranges of finger motions. These results demonstrate the significant advantages of this new strategy—namely, low cost, simple operation, and versatility, showing its great potential in the field of flexible electronics.
Low Temperature Epitaxial Barium Titanate Thin Film Growth in High Vacuum CVD
Authors: Reinke Michael , Kuzminykh Yury , Eltes Felix , Abel Stefan , LaGrange Thomas , Neels Antonia , Fompeyrine Jean , Hoffmann Patrik
Published: April 2017

Barium titanate is a promising perovskite material, exhibiting numerous materials properties advantageous for a range of applications, such as ferroelectricity, piezoelectricity, a high dielectric constant, and large electrooptic coefficients. It represents a potential candidate for the implementation of high bandwidth and low energy consuming modulators for optical communication in future integrated systems. Integration of the optical components with electronic circuits on silicon requires, however, suitable low temperature deposition processes for the growth of high quality epitaxial BaTiO3 films, which are still missing. For integration of novel materials into the complementary metal–oxide–semiconductor platform, a variety of prerequisites must be fulfilled; among them there is a strict limitation of the thermal budget of the growth process. Furthermore, high growth rates are desirable for enhanced throughput. Many chemical vapor deposition (CVD) processes allow growing thin films at high rates, but epitaxial BaTiO3 film formation typically requires high substrate temperatures. It is demonstrated that high vacuum CVD is capable of growing epitaxial barium titanate films on magnesium oxide, strontium titanate, and strontium titanate buffered silicon substrates at process temperatures of 400 °C and growth rates of up to 100 nm h−1 without the need of an additional annealing step; this is the lowest substrate temperature reported for a CVD processes.
Undressing a Water Marble on Oil Film
Authors: Jiang Xiao F. , Zhu Chunying , Ma Youguang , Li Huai Z.
Published: April 2017

Due to a great contact angle with substrate as well as low resistance to motion and stable structure of superhydrophobic powder shell, liquid marbles display attractive potential for easy actuation and manipulation. This work shows the dynamical behavior of a rolling liquid marble on oil film. Static liquid marbles display a much larger contact angle than water drops on an oil film. When liquid marbles move on oil film, three consecutive stages are observed. The first stage exhibits a linear relationship versus the remaining time, implying that liquid marbles are rolling on oil film and the attached particles are multilayer. When the particles become locally monolayer, the transient stage begins and the advancing angle is much larger than receding angle. At this time, liquid marble is sliding rather than rolling. Finally, liquid marble is captured by oil film and spreads to be a cap owing to the liquid–liquid contact. This work introduces an approach to partially undress particle layers and disintegrate liquid marbles, expecting to facilitate the optical probing from the transparent bottom of liquid marbles.
Pancharatnam–Berry Phase Manipulating Metasurface for Visible Color Hologram Based on Low Loss Silver Thin Film
Authors: Choudhury Sajid , Guler Urcan , Shaltout Amr , Shalaev Vladimir M. , Kildishev Alexander V. , Boltasseva Alexandra
Published: April 2017

This study demonstrates visible color hologram using a plasmonic metasurface. The metasurface is fabricated by perforating nanoslits in a 50 nm thick monocrystalline silver film that is ultrasmooth and has ultralow loss compared to conventional polycrystalline silver films commonly used in plasmonics. The designed plasmonic hologram is the thinnest metasurface hologram operating in transmission mode to the best of our knowledge. Holograms of three individual component colors (red, green, and blue) are demonstrated in transmission mode, and a scheme for generating polychromatic hologram is illustrated. By adjusting the slit dimensions and orientation, the phase of a visible spectrum light can be controlled, paving the way to applications of ultracompact polychromatic plasmonic metasurfaces for advanced light manipulation.
Hybrid anion exchange membranes with self‐assembled ionic channels
Authors: Liang Na , Tu Yufei , Xu Jing , Chen Dongzhi , Zhang Hongwei
Published: April 2017

A novel strategy for fabricating nanocomposite anion exchange membranes (AEM), which can construct self‐assembled ionic channels via in situ Menshutkin reaction, is proposed. The TEM image of a nanocomposite AEM based on chloromethylated polysulfone (CMPSF) and functionalized polyhedral oligomeric silsesquioxane (POSS) confirms the existence of core‐shell clusters. The ionic conductivity of these nanocomposite AEMs shows a notable increase when the content of functionalized POSS exceeds the percolation threshold. Furthermore, the optimized nanocomposite AEM has higher ionic conductivity than the control AEM with similar ion‐exchange capacity due to the well‐developed morphology.
Liquid Metal Phagocytosis: Intermetallic Wetting Induced Particle Internalization
Authors: Tang Jianbo , Zhao Xi , Li Jing , Zhou Yuan , Liu Jing
Published: April 2017

A biomimetic cellular‐eating phenomenon in gallium‐based liquid metal to realize particle internalization in full‐pH‐range solutions is reported. The effect, which is called liquid metal phagocytosis, represents a wet‐processing strategy to prepare various metallic liquid metal‐particle mixtures through introducing excitations such as an electrical polarization, a dissolving medium, or a sacrificial metal. A nonwetting‐to‐wetting transition resulting from surface transition and the reactive nature of the intermetallic wetting between the two metallic phases are found to be primarily responsible for such particle‐eating behavior. Theoretical study brings forward a physical picture to the problem, together with a generalized interpretation. The model developed here, which uses the macroscopic contact angle between the two metallic phases as a criterion to predict the particle internalization behavior, shows good consistency with experimental results.
Computational Insights into Materials and Interfaces for Capacitive Energy Storage
Authors: Zhan Cheng , Lian Cheng , Zhang Yu , Thompson Matthew W. , Xie Yu , Wu Jianzhong , Kent Paul R. C. , Cummings Peter T. , Jiang De‐en , Wesolowski David J.
Published: April 2017

Supercapacitors such as electric double‐layer capacitors (EDLCs) and pseudocapacitors are becoming increasingly important in the field of electrical energy storage. Theoretical study of energy storage in EDLCs focuses on solving for the electric double‐layer structure in different electrode geometries and electrolyte components, which can be achieved by molecular simulations such as classical molecular dynamics (MD), classical density functional theory (classical DFT), and Monte‐Carlo (MC) methods. In recent years, combining first‐principles and classical simulations to investigate the carbon‐based EDLCs has shed light on the importance of quantum capacitance in graphene‐like 2D systems. More recently, the development of joint density functional theory (JDFT) enables self‐consistent electronic‐structure calculation for an electrode being solvated by an electrolyte. In contrast with the large amount of theoretical and computational effort on EDLCs, theoretical understanding of pseudocapacitance is very limited. In this review, we first introduce popular modeling methods and then focus on several important aspects of EDLCs including nanoconfinement, quantum capacitance, dielectric screening, and novel 2D electrode design; we also briefly touch upon pseudocapactive mechanism in RuO2. We summarize and conclude with an outlook for the future of materials simulation and design for capacitive energy storage.
Selective removal of 1,2‐propanediol and 1,2‐butanediol from bio‐ethylene glycol by catalytic reaction
Authors: Ai Shuo , Zheng Mingyuan , Jiang Yu , Yang Xiaofeng , Li Xinsheng , Pang Jifeng , Sebastian Joby , Li Weizhen , Wang Aiqin , Wang Xiaodong , Zhang Tao
Published: April 2017

Ethylene glycol (EG), synthesized from biomass, frequently contains refractory 1,2‐propanediol (PDO) and 1,2‐butanediol (BDO). Selective removal of PDO and BDO was realized herein by catalytic dehydration to form volatile aldehydes, ketones, and acetals. Various acidic and basic catalysts were screened under a range of conditions for the conversion of a mixture containing 73 wt % EG, 20 wt % PDO, and 7 wt % BDO. Over H‐Beta 26 zeolite, the most selective catalyst among tested, PDO and BDO conversions reached 99.1 and 99.3%, respectively, after 4 h reaction at 453 K, with separation factors over 2. The activation energies for EG, PDO, and BDO dehydration were ca. 99.3, 69.9, and 54.0 kJ/mol, respectively, accounting for the high reactivity of PDO and BDO. The dehydration largely proceeded in the micropores of H‐Beta and depended on the number of strong Brønsted acid sites, but excessively strong acid sites enhanced the polymerization of EG. © 2017 American Institute of Chemical Engineers AIChE J, 63: 4032–4042, 2017
Aneurysms in neurofibromatosis type 2: Evidence for vasculopathy?
Authors: Afridi Shazia K. , Thomson Suki , Connor Steve E. J. , Walsh Daniel C. , Ferner Rosalie E.
Published: April 2017

There have been anecdotal reports of vasculopathy associated with Neurofibromatosis Type 2 (NF2). Given the increasing use of bevacizumab, a vascular endothelial growth factor inhibitor which results in an increased risk of bleeding, it is important to ascertain if there is a predisposition to vascular abnormalities in NF2. In our unit NF2 patients undergo annual MRI brain and internal auditory meatus imaging. We noted incidental intracranial aneurysms in some patients and sought to determine the prevalence of intracranial aneurysms in our cohort of NF2 patients. We conducted a retrospective audit of the MRI images of 104 NF2 patients from 2014 to 2016. Axial T2 brain MRI images were assessed for vascular abnormalities by two neuroradiologists blinded to patient's clinical details. Intracranial aneurysms were detected in four patients and an aneurysm clip related to previous surgery was noted in one additional patient. Using standard MRI imaging sequences alone we provide evidence of intracranial aneurysms in 4.4% of our cohort. This compares with an estimated overall prevalence of 3% in the general population. We discuss these findings as well as other evidence for a vasculopathy associated with NF2.
The path forward: 2015 International Children's Tumor Foundation conference on neurofibromatosis type 1, type 2, and schwannomatosis
Authors: Blakeley Jaishri O. , Bakker Annette , Barker Anne , Clapp Wade , Ferner Rosalie , Fisher Michael J. , Giovannini Marco , Gutmann David H. , Karajannis Matthias A. , Kissil Joseph L. , Legius Eric , Lloyd Alison C. , Packer Roger J. , Ramesh Vijaya , Riccardi Vincent M. , Stevenson David A. , Ullrich Nicole J. , Upadhyaya Meena , Stemmer‐Rachamimov Anat
Published: April 2017

The Annual Children's Tumor Foundation International Neurofibromatosis Meeting is the premier venue for connecting discovery, translational and clinical scientists who are focused on neurofibromatosis types 1 and 2 (NF1 and NF2) and schwannomatosis (SWN). The meeting also features rare tumors such as glioma, meningioma, sarcoma, and neuroblastoma that occur both within these syndromes and spontaneously; associated with somatic mutations in NF1, NF2, and SWN. The meeting addresses both state of the field for current clinical care as well as emerging preclinical models fueling discovery of new therapeutic targets and discovery science initiatives investigating mechanisms of tumorigenesis. Importantly, this conference is a forum for presenting work in progress and bringing together all stakeholders in the scientific community. A highlight of the conference was the involvement of scientists from the pharmaceutical industry who presented growing efforts for rare disease therapeutic development in general and specifically, in pediatric patients with rare tumor syndromes. Another highlight was the focus on new investigators who presented new data about biomarker discovery, tumor pathogenesis, and diagnostic tools for NF1, NF2, and SWN. This report summarizes the themes of the meeting and a synthesis of the scientific discoveries presented at the conference in order to make the larger research community aware of progress in the neurofibromatoses.
DiGeorge‐like syndrome in a child with a 3p12.3 deletion involving MIR4273 gene born to a mother with gestational diabetes mellitus
Authors: Cirillo Emilia , Giardino Giuliana , Gallo Vera , Galasso Giovanni , Romano Roberta , D'Assante Roberta , Scalia Giulia , Del Vecchio Luigi , Nitsch Lucio , Genesio Rita , Pignata Claudio
Published: April 2017

Chromosome 22q11.2 deletion is the most common chromosomal alteration associated with DiGeorge syndrome (DGS), even though this is not the only underlying cause of DGS. In rare patients, mutations in a single gene, TBX1, have been described resulting in a DGS phenotype. Recently, it has been reported that at least part of the TBX1 mutant phenotype is due to excessive bone morphogenetic proteins (BMP) signaling. Evidence suggests that miRNA may modulate the expression of critical T‐box transcriptional regulators during midface development and Bmp‐signaling. We report on a 7‐year‐old Caucasian male born to a mother affected with gestational diabetes (GDM) who had a 371Kb‐interstitial deletion of 3p12.3 identified by array CGH, involving the ZNF717, MIR1243, and 4273 genes. The child presented with a DiGeorge anomaly (DGA) associated with unilateral renal agenesis and language delay. The immunological evaluation revealed a severe reduction and impairment of T lymphocytes. FISH analysis and TBX1 sequencing were negative. Among the miRNA‐4273 predicted target genes, we found BMP3, which is involved in several steps of embryogenesis including kidney and lung organogenesis and in insulin gene expression. Since, DGA is not commonly found in newborns of diabetic mothers, we hypothesize that the pathogenesis of DGA associated with GDM is multifactorial, involving both genetic and/or epigenetic cofactors.
MTHFR methylation moderates the impact of smoking on DNA methylation at AHRR for African American young adults
Authors: Beach Steven R. H. , Lei Man Kit , Ong Mei Ling , Brody Gene H. , Dogan Meeshanthini V. , Philibert Robert A.
Published: April 2017

Smoking has been shown to have a large, reliable, and rapid effect on demethylation of AHRR, particularly at cg05575921, suggesting that methylation may be used as an index of cigarette consumption. Because the availability of methyl donors may also influence the degree of demethylation in response to smoking, factors that affect the activity of methylene tetrahydrofolate reductase (MTHFR), a key regulator of methyl group availability, may be of interest. In the current investigation, we examined the extent to which individual differences in methylation of MTHFR moderated the association between smoking and demethylation at cg05575921 as well as at other loci on AHRR associated with a main effect of smoking. Using a discovery sample (AIM, N = 293), and a confirmatory sample (SHAPE, N = 368) of young adult African Americans, degree of methylation of loci in the first exon of MTHFR was associated with amplification of the association between smoking and AHRR demethylation at cg05575921. However, genetic variation at a commonly studied MTHFR variant, C677T, did not influence cg05575921 methylation. The significant interaction between MTHFR methylation and the smoking‐induced response at cg05575921 suggests a role for individual differences in methyl cycle regulation in understanding the effects of cigarette consumption on genome wide DNA methylation.
Two cases of life‐threatening arrhythmia induced by risperidone: evaluation of risperidone and 9‐hydroxy‐risperidone concentrations
Authors: Ito Asami , Enokiya Tomoyuki , Kawamoto Eiji , Iwashita Yoshiaki , Takeda Taichi , Ikemura Kenji , Okuda Masahiro , Imai Hiroshi
Published: April 2017

Cases

Case 1: A 20‐year‐old woman suffering a suspected overdose was transported to the hospital. She presented bradycardia with wide QRS waves and QT prolongation, followed by cardiac arrest. Extracorporeal cardiopulmonary resuscitation was implemented, improving circulation. Risperidone and 9OH‐RIS levels were 9.6 ng/mL and 127.6 ng/mL, respectively. Case 2: A 54‐year‐old woman was hospitalized for femoral fracture and underwent surgery. Her electrocardiogram showed bradycardia and complete AV block. Risperidone and 9OH‐RIS levels were 3.2 ng/mL and 61.4 ng/mL, respectively.

Outcome

In both cases, only serum concentration of 90H‐RIS were elevated.

Conclusion

Arrhythmia related to risperidone has proven rare but sometimes fatal. Serum concentrations of risperidone and the metabolite 9‐hydroxy‐risperidone (9OH‐RIS) during these events are seldom documented. As 9OH‐RIS shows pharmacological activity equivalent to risperidone, it may induce life‐threatening arrhythmia (regardless of the intake dosage). It is critical to evaluate the serum concentration of 9OH‐RIS in suspected risperidone toxicity.
Investigation of Japan Disaster Medical Assistance Team response guidelines assuming catastrophic damage from a Nankai Trough earthquake
Authors: Anan Hideaki , Kondo Hisayoshi , Akasaka Osamu , Oshiro Kenichi , Nakamura Mitsunobu , Kiyozumi Tetsuro , Yamada Norihiko , Homma Masato , Morino Kazuma , Nakayama Shinichi , Otomo Yasuhiro , Koido Yuichi
Published: April 2017

Aim

Transporting critically ill patients outside of disaster‐affected areas for treatment is an important activity of Japan Disaster Medical Assistance Teams (DMATs). We investigated whether this activity is possible after possible catastrophic damage from a Nankai Trough earthquake.

Methods

Japan was divided into three areas based on the level of predicted damage (definitely, possibly, and non‐affected areas). A survey of DMATs and the locations of emergency base hospitals and intensive care units (ICUs) in each area was carried out, and the ability to support disaster areas was investigated. Next, a survey of wide‐area medical transport by Self‐Defense Force aircraft and the medical transport abilities of helicopter ambulances was carried out. The numbers of ICU beds in each area were compared, and the capacity to accept patients was investigated. Finally, subjects for further study were examined.

Results

The number of DMATs that could be sent from non‐affected areas was insufficient. The number of patients that can be transported by Self‐Defense Force aircraft and helicopter ambulance during the first 3 days was determined to be 1,443. The number of patients that can be accepted by ICUs in non‐affected areas was insufficient. A system needs to be developed to provide medical treatment for critically ill patients within disaster areas during the acute phase. This will require DMAT operational reforms and the creation of logistics systems such as the supply of resources for earthquake‐reinforced hospitals.

Conclusion

In addition to patient transport, systems to provide medical care inside disaster‐affected areas are needed.
(L)2C2P2: Dicarbondiphosphide Stabilized by N‐Heterocyclic Carbenes or Cyclic Diamido Carbenes
Authors: Li Zhongshu , Chen Xiaodan , Andrada Diego M. , Frenking Gernot , Benkö Zoltán , Li Yaqi , Harmer Jeffrey R. , Su Cheng‐Yong , Grützmacher Hansjörg
Published: April 2017

Carbon phosphides, CnPm, may have highly promising electronic, optical, and mechanical properties, but they are experimentally almost unexplored materials. Phosphaheteroallenes stabilized by N‐heterocyclic carbenes undergo a one‐electron reduction to yield compounds of the type (L)2C2P2with diverse structures. The use of imidazolylidenes as ligands L give complexes with a central four‐membered ring C2P2, while more electrophilic cyclic diamidocarbenes (DAC) give a compound with an acyclic π‐conjugated CP−PC unit. Cyclic C2P2compounds are best described as non‐Kekulé molecules that are stabilized by coordination to the NHC ligands NHC→(C2P2)←NHC. These species can be easily oxidized to give stable radical cations [(NHC)2C2P2]+.. The remarkably stable molecules with an acylic C2P2core are best described with electron‐sharing bonds (DAC)=C=P−P=C=(DAC).
Enantioselektive Synthese von Robinson‐Anellierungsprodukten und Michael‐Addukten als Vorstufen
Authors: Gallier Florian , Martel Arnaud , Dujardin Gilles
Published: April 2017

Die Robinson‐Anellierung hat seit ihrer Entdeckung 1935 in zahlreichen Synthesen Anwendung gefunden, besonders auf dem Gebiet der Steroidsynthese. Die Produkte werden gewöhnlich nach drei aufeinanderfolgenden Stufen erhalten: der Bildung eines Enolats (oder Derivats davon), einer konjugierten Addition und einer Aldolreaktion. Im Laufe der Jahre wurden mehrere methodische Verbesserungen für jede einzelne Stufe vorgenommen oder alternative Synthesewege hin zu Robinson‐Anellierungsprodukten entwickelt. Im ersten Teil dieses Aufsatzes werden die wichtigsten Entwicklungen für die Bildung Monocarbonyl‐abgeleiteter Robinson‐Anellierungsprodukte (MRA‐Produkten, MRAPs) und von einer aktivierten Monocarbonylverbindung abgeleiteter Robinson‐Anellierungsprodukte (AMRA‐Produkten, AMRAPs) erläutert. In den folgenden Abschnitten werden diastereoselektive und enantioselektive Synthesen dieser Produkte beschrieben, und im letzten Abschnitt wird die Racematspaltung von Enantiomerenmischungen dargelegt.
Ammonia Oxide as a Building Block for High‐Performance and Insensitive Energetic Materials
Authors: Tang Yongxing , Mitchell Lauren A. , Imler Gregory H. , Parrish Damon A. , Shreeve Jean'ne M.
Published: April 2017

3,5‐Dinitrimino‐1,2,4‐triazole (2) with three protons has the potential of deprotonation to form energetic salts. Neutralization of 2 with 50 % hydroxylamine in varying molar ratios leads to the formation of the corresponding mono/dihydroxylammonium energetic salts. Additionally compound 5, an ammonia oxide adduct of dihydroxylammonium 3,5‐dinitramino‐1,2,4‐triazolate, was prepared when excess hydroxylamine was used. The structures of 3–5 are supported by single‐crystal X‐ray diffraction. The energetic properties of the new materials are competitive. Utilization of ammonia oxide adducts in hydroxylammonium energetic salts could lead to future practical applications as energetic materials.
(L)2C2P2: Dicarbondiphosphide Stabilized by N‐Heterocyclic Carbenes or Cyclic Diamido Carbenes
Authors: Li Zhongshu , Chen Xiaodan , Andrada Diego M. , Frenking Gernot , Benkö Zoltán , Li Yaqi , Harmer Jeffrey R. , Su Cheng‐Yong , Grützmacher Hansjörg
Published: April 2017

Carbon phosphides, CnPm, may have highly promising electronic, optical, and mechanical properties, but they are experimentally almost unexplored materials. Phosphaheteroallenes stabilized by N‐heterocyclic carbenes undergo a one‐electron reduction to yield compounds of the type (L)2C2P2 with diverse structures. The use of imidazolylidenes as ligands L give complexes with a central four‐membered ring C2P2, while more electrophilic cyclic diamidocarbenes (DAC) give a compound with an acyclic π‐conjugated CP−PC unit. Cyclic C2P2 compounds are best described as non‐Kekulé molecules that are stabilized by coordination to the NHC ligands NHC→(C2P2)←NHC. These species can be easily oxidized to give stable radical cations [(NHC)2C2P2]+.. The remarkably stable molecules with an acylic C2P2 core are best described with electron‐sharing bonds (DAC)=C=P−P=C=(DAC).
Nanodiscs for INPHARMA NMR Characterization of GPCRs: Ligand Binding to the Human A2A Adenosine Receptor
Authors: Fredriksson Kai , Lottmann Philip , Hinz Sonja , Onila Iounut , Shymanets Aliaksei , Harteneck Christian , Müller Christa E. , Griesinger Christian , Exner Thomas E.
Published: April 2017

G‐protein‐coupled‐receptors (GPCRs) are of fundamental importance for signal transduction through cell membranes. This makes them important drug targets, but structure‐based drug design (SBDD) is still hampered by the limitations for structure determination of unmodified GPCRs. We show that the interligand NOEs for pharmacophore mapping (INPHARMA) method can provide valuable information on ligand poses inside the binding site of the unmodified human A2A adenosine receptor reconstituted in nanodiscs. By comparing experimental INPHARMA spectra with back‐calculated spectra based on ligand poses obtained from molecular dynamics simulations, a complex structure for A2AR with the low‐affinity ligand 3‐pyrrolidin‐1‐ylquinoxalin‐2‐amine was determined based on the X‐ray structure of ligand ZM‐241,358 in complex with a modified A2AR.
A Method for the Late‐Stage Formation of Ketones, Acyloins, and Aldols from Alkenylstannanes: Application to the Total Synthesis of Paecilonic Acid A
Authors: Sommer Heiko , Hamilton James Y. , Fürstner Alois
Published: April 2017

Treatment of alkenylstannanes with Cu(OAc)2/Et3N affords the corresponding enol esters or ketones under conditions that proved compatible with many common functionalities; these include groups that would neither survive under the standard Tamao–Fleming conditions for the oxidation of C
−SiR3 bonds nor under the conditions commonly used to oxidize C−B bonds. Chiral centers adjacent to the unveiled carbonyls are not racemized and competing protodestannation is marginal, even if the substrate carries unprotected −OH groups as internal proton sources. Therefore, the procedure is well suited for the preparation of acyloin and aldol derivatives. These enabling virtues are illustrated by a concise approach to the bicyclic lipid paecilonic acid A.
Enantioselective Access to Robinson Annulation Products and Michael Adducts as Precursors
Authors: Gallier Florian , Martel Arnaud , Dujardin Gilles
Published: April 2017

The Robinson annulation is a reaction that has been useful for numerous syntheses since its discovery in 1935, especially in the field of steroid synthesis. The products are usually obtained after three consecutive steps: the formation of an enolate (or derivative), a conjugate addition, and an aldol reaction. Over the years, several methodological improvements have been made for each individual step or alternative routes have been devised to access the Robinson annulation products. The first part of this Review outlines the most relevant developments towards the formation of monocarbonyl‐derived Robinson annulation products (MRA products, MRAPs) and activated monocarbonyl‐derived Robinson annulation products (AMRA products, AMRAPs). The following sections are then devoted to the diastereoselective and enantioselective synthesis of these products, while the last section describes the enantiomeric resolution of racemic mixtures.
Characterizing the Evolution of Wide‐Gauge Features in Stylopodial Limb Elements of Titanosauriform Sauropods via Geometric Morphometrics
Authors: Ullmann Paul V. , Bonnan Matthew F. , Lacovara Kenneth J.
Published: April 2017

Wide‐gauge posture of titanosauriform sauropods remains an enigmatic peculiarity among terrestrial vertebrates. Here, two‐dimensional geometric morphometrics and thin plate splines analyses were used to quantitatively analyze shape differences among sauropodomorph humeri and femora to identify how these elements may differ according to body gauge. Results demonstrate that titanosauriforms generally possess proportionately gracile humeri in comparison to other sauropods, with relatively more medially oriented humeral heads and proximally located deltopectoral crests. Myological repercussions of these features demonstrate a relative sacrificing of muscular torque for forelimb abduction/adduction in exchange for minimization of necessary muscle contraction to generate the same degree of limb excursion. Regarding femora, titanosauriforms possess significantly broader femora mediolaterally than other sauropods, with comparatively proximomedially placed fourth trochanters. Canonical variates results also identify a trend for titanosauriform femora to present distal condyles that are more frequently perpendicular to the long axis of the shaft or beveled medially. All of these femoral shape characteristics are expressed to the greatest degree by titanosaurians. Myologically, mediolateral femoral broadening increases relative mechanical advantages for hind limb abductor and adductor musculature. This supports previous hypotheses that suggested titanosauriforms were capable of a greater degree of hind limb abduction and adduction. This capability may have been necessary to maintain dynamic stability during wide‐gauge locomotion over uneven terrain. Overall, our results corroborate previous qualitative assessments of wide‐gauge attributes, afford new insights into statistically significant but obscure shape patterns, and add new clarity to aspects of the functional morphology of wide‐gauge posture. Anat Rec, 300:1618–1635, 2017. © 2017 Wiley Periodicals, Inc.
An improved uniformly more powerful exact Fisher–Hayter pairwise comparisons procedure
Authors: Wang Bushi , Cui Xinping
Published: April 2017

Pairwise comparison is a very common multiple comparison problem. It is known that Fisher's LSD test does not control the familywise error rate (FWER) when there are more than three groups to be compared. Improved testing strategies include the Tukey–Kramer (TK) test that eliminates the F‐test step and the two‐step Fisher–Hayter (FH) test which requires a significant F‐test. We propose a modified FH‐test that is uniformly more powerful than the original version and relies on exact size α test under the balanced model. We provide simulations to show that the new procedure is preferred to the FH‐test and the TK‐test.
Production and characterization of active recombinant human factor II with consistent sialylation
Authors: Lee Jeong H. , Reier Jason , Heffner Kelley M. , Barton Christopher , Spencer David , Schmelzer Albert E. , Venkat Raghavan
Published: April 2017

Coagulation factor II (prothrombin; FII) is the pre‐proteolyzed precursor to thrombin in the coagulation cascade. It has 10 sites of gamma‐carboxylation, which are required for its bioactivity, and is N‐glycosylated at three of four putative sites. Production of recombinant human FII (rhFII) using a platform fed‐batch process designed for monoclonal antibody production resulted in low levels of gamma‐carboxylation and sialylation. There have not been any prior reports of successful process development and clinical manufacture of rhFII with optimal, consistent gamma‐carboxylation and sialylation. In order to develop such a fed‐batch process, various process parameters were evaluated to determine their impact on product quality. Process temperature and temperature shift timing were important for both sialic acid level and gamma‐carboxyglutamate (Gla) level. In addition, vitamin K concentration and the type of surfactant used for preparation of vitamin K stock solution were also important for gamma carboxylation. A fed‐batch study performed with various medium additives known to be involved in the N‐glycosylation pathway, such as N‐acetyl‐d‐mannosamine (ManNAc), galactose (Gal), dexamethasone, and manganese sulfate, increased the level of sialylation and enabled the elucidation of some potential bottlenecks in the sialylation pathway. The optimized process based on these studies yielded a reduction in the level of missing Gla by 0.4 moles per mole of rhFII in cell culture and a nearly threefold increase in sialic acid level. The process was successfully implemented at the 2000 L scale where a high Gla level and sialylation levels were achieved in all GMP lots. Biotechnol. Bioeng. 2017;114: 1991–2000. © 2017 Wiley Periodicals, Inc.
Bio‐CoDa: A new analysis class to ensure accurate and precise monoclonal antibody CQA estimation and control
Authors: Lonardo Anthony , Saxena Parekh Babita , Srivastava Arvind
Published: April 2017

Monoclonal antibody production processes control critical quality attributes (CQAs), which are the measures that provide proof of a product's identity and quality. Critical decisions rely on the accuracy and precision of these measures, as well as their appropriate statistical treatment. Many measures require special attention. For example, the charge heterogeneity CQA measured by ionic exchange chromatography reports proportions or percentages of the total integrated peak area of known species. Since proportions sum to a constant (1 or 100%), they fall into a special class of data called compositional data that have a unit sum constraint and therefore an inherent correlation. However, these measures are often analyzed assuming independence which is incorrect. Estimating statistics with incorrect assumptions can lead to inferential failures (e.g., shelf life failures), or can lead to missing important structural patterns in the data. Presented here is a new class of analysis methods for CQAs compositional data called Biologic Compositional Data Analysis (Bio‐CoDa). The method is based on the elegant solution to analysis issues by Aitchison (1986). An introduction to the Bio‐CoDa methods with rational is presented as well as examples demonstrating its strengths. Biotechnol. Bioeng. 2017;114: 2001–2010. © 2017 Wiley Periodicals, Inc.
Characterization of the chondrocyte secretome in photoclickable poly(ethylene glycol) hydrogels
Authors: Schneider Margaret C. , Barnes Christopher A. , Bryant Stephanie J.
Published: April 2017

Poly(ethylene glycol) (PEG) hydrogels are highly tunable platforms that are promising cell delivery vehicles for chondrocytes and cartilage tissue engineering. In addition to characterizing the type of extracellular matrix (ECM) that forms, understanding the types of proteins that are secreted by encapsulated cells may be important. Thus, the objectives for this study were to characterize the secretome of chondrocytes encapsulated in PEG hydrogels and determine whether the secretome varies as a function of hydrogel stiffness and culture condition. Bovine chondrocytes were encapsulated in photoclickable PEG hydrogels with a compressive modulus of 8 and 46 kPa and cultured under free swelling or dynamic compressive loading conditions. Cartilage ECM deposition was assessed by biochemical assays and immunohistochemistry. The conditioned medium was analyzed by liquid chromatography‐tandem mass spectrometry. Chondrocytes maintained their phenotype within the hydrogels and deposited cartilage‐specific ECM that increased over time and included aggrecan and collagens II and VI. Analysis of the secretome revealed a total of 64 proteins, which were largely similar among all experimental conditions. The identified proteins have diverse functions such as biological regulation, response to stress, and collagen fibril organization. Notably, many of the proteins important to the assembly of a collagen‐rich cartilage ECM were identified and included collagen types II(α1), VI (α1, α2, and α3), IX (α1), XI (α1 and α2), and biglycan. In addition, many of the other identified proteins have been reported to be present within cell‐secreted exosomes. In summary, chondrocytes encapsulated within photoclickable PEG hydrogels secrete many types of proteins that diffuse out of the hydrogel and which have diverse functions, but which are largely preserved across different hydrogel culture environments. Biotechnol. Bioeng. 2017;114: 2096–2108. © 2017 Wiley Periodicals, Inc.
Galapagos – noch immer Trauminseln im Pazifik
Authors: Petrischak Hannes
Published: April 2017

Das günstige Zusammentreffen mehrerer bedeutsamer Meeresströmungen hat ideale Voraussetzungen geschaffen, dass sich auf Galapagos eine Tier‐ und Pflanzenwelt etablieren konnte, die einem einzigartigen Laboratorium der Evolution gleicht. Im Gegensatz zu manch anderen Regionen der Erde haben fast alle Arten, die sich hier entwickelt haben, den Einfluss des Menschen bis heute überlebt. So können noch immer einzigartige Erlebnisse mit Pinguinen am Äquator, Flugunfähigen Kormoranen, Seelöwen und Seebären, einer Vielzahl von Meeresvögeln, Meeres‐ und Riesenschildkröten, Meerechsen und Landleguanen, Spottdrosseln und Darwinfinken gelingen. Intensive Schutzbemühungen müssen weiterhin den Einfluss invasiver Arten, insbesondere verwilderter Haustiere, minimieren und außerdem dafür sorgen, dass der boomende Tourismus in möglichst sanften Bahnen bleibt.