bluuebunny/crossref_metadata_2025 huggingface dataset:
High Performance Regulator for Fractional Order Systems: A Soft Variable Structure Control Approach
Authors: Kamal Shyam , Bandyopadhyay Bijnan
Published: November 2014

In this paper, soft variable structure control of fractional order systems is proposed for achieving high regulation rates and short settling times. Using the appropriate fractional order Lyapunov approach, a controller based on continuous fractional switch are designed to achieve high control performance. Due to the alleviation of chattering phenomenon soft VSC that is proposed for fractional order systems are quite useful in future for the practical systems.
Fronto‐Temporal Connectivity is Preserved During Sung but Not Spoken Word Listening, Across the Autism Spectrum
Authors: Sharda Megha , Midha Rashi , Malik Supriya , Mukerji Shaneel , Singh Nandini C.
Published: November 2014

Co‐occurrence of preserved musical function with language and socio‐communicative impairments is a common but understudied feature of Autism Spectrum Disorders (ASD). Given the significant overlap in neural organization of these processes, investigating brain mechanisms underlying speech and music may not only help dissociate the nature of these auditory processes in ASD but also provide a neurobiological basis for development of interventions. Using a passive‐listening functional magnetic resonance imaging paradigm with spoken words, sung words and piano tones, we found that 22 children with ASD, with varying levels of functioning, activated bilateral temporal brain networks during sung‐word perception, similarly to an age and gender‐matched control group. In contrast, spoken‐word perception was right‐lateralized in ASD and elicited reduced inferior frontal gyrus (IFG) activity which varied as a function of language ability. Diffusion tensor imaging analysis reflected reduced integrity of the left hemisphere fronto‐temporal tract in the ASD group and further showed that the hypoactivation in IFG was predicted by integrity of this tract. Subsequent psychophysiological interactions revealed that functional fronto‐temporal connectivity, disrupted during spoken‐word perception, was preserved during sung‐word listening in ASD, suggesting alternate mechanisms of speech and music processing in ASD. Our results thus demonstrate the ability of song to overcome the structural deficit for speech across the autism spectrum and provide a mechanistic basis for efficacy of song‐based interventions in ASD. Autism Res 2015, 8: 174–186. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.
Fetal alcohol spectrum disorders among children in a Brazilian orphanage
Authors: Strömland Kerstin , Ventura Liana O. , Mirzaei Layla , Fontes de Oliveira Keyla , Marcelino Bandim José , Parente Ivo Adriana , Brandt Carlos
Published: November 2014

Background: The objective was to investigate the frequency of fetal alcohol spectrum disorders (FASD) and ophthalmologic anomalies in orphanage children in Brazil. Methods: A prospective study was performed on 94 children living in an orphanage in Brazil. The children were examined by a multidisciplinary team consisting of specialists in pediatrics, neurology, psychology, neuropsychiatry, and ophthalmology. Results: The main reasons for living in the orphanage, in 61% of the children, were negligence, child abuse, and abandonment. Of all the children studied, 50% had mothers with known alcohol abuse and 47% had one or more diagnoses of neurodevelopmental/behavioral and/or cognitive deficits. General developmental delay was found in 18%, intellectual disability in 3%, cognitive impairment in 27%, attention‐deficit/hyperactivity disorder in 14%, and autism in 3%. Altogether 17% had FASD, comprising three children with fetal alcohol syndrome (FAS), six with partial FAS, and seven with alcohol‐related neurodevelopmental disorder. 16% had ophthalmological findings such as poor vision, strabismus, and dysmorphology of the optic nerves. Twenty‐eight children (30%) were adopted from the orphanage; of these, six had FASD (two FAS, three partial FAS, one alcohol‐related neurodevelopmental disorder), five had attention‐deficit/hyperactivity disorder, and eight had developmental delay. Conclusion: Nearly half of the children living in the orphanage had neurodevelopmental disorders and a considerable number showed signs of damage from prenatal alcohol exposure. A broader look at the problem of FASD in Brazil and other South American countries is desirable to document the burden of disease and provide data for targeting prevention efforts. Birth Defects Research (Part A) 103:178–185, 2015. © 2014 Wiley Periodicals, Inc.
Membrane potential depolarization causes alterations in neuron arrangement and connectivity in cocultures
Authors: Özkucur Nurdan , Quinn Kyle P. , Pang Jin C. , Du Chuang , Georgakoudi Irene , Miller Eric , Levin Michael , Kaplan David L.
Published: November 2014

Background

The disruption of neuron arrangement is associated with several pathologies. In contrast to action potentials, the role of resting potential (Vmem) in regulating connectivity remains unknown.

Methods

Neuron assemblies were quantified when their Vmem was depolarized using ivermectin (Ivm), a drug that opens chloride channels, for 24 h in cocultures with astrocytes. Cell aggregation was analyzed using automated cluster analysis methods. Neural connectivity was quantified based on the identification of isolated somas in phase‐contrast images using image processing. Vmem was measured using voltage‐sensitive dyes and whole‐cell patch clamping. Immunocytochemistry and Western blotting were used to detect changes in the distribution and production of the proteins.

Results

Data show that Vmem regulates cortical tissue shape and connectivity. Automated cluster analysis methods revealed that the degree of neural aggregation was significantly increased (0.26 clustering factor vs. 0.21 in controls, P ≤ 0.01). The number of beta‐tubulin III positive neural projections was also significantly increased in the neural aggregates in cocultures with Ivm. Hyperpolarized neuron cells formed fewer connections (33% at 24 h, P ≤ 0.05) compared to control cells in 1‐day cultures. Glia cell densities increased (33.3%, P ≤ 0.05) under depolarizing conditions.

Conclusion

Vmem can be a useful tool to probe neuronal cells, disease tissues models, and cortical tissue arrangements.
A Kinetic Study of Sunflower Oil Methanolysis Catalyzed by Barium Hydroxide
Authors: Stamenković Olivera S. , Todorović Zoran B. , Veljković Vlada B.
Published: November 2014

Methanolysis of sunflower oil was investigated in the presence of barium hydroxide as a catalyst. It was observed that the methanolysis reaction was both heterogeneously and homogeneously catalyzed. The heterogeneously catalyzed reaction is faster than the homogeneously catalyzed one and determines the overall reaction rate. Under optimum reaction conditions, a very high fatty acid methyl ester content was obtained within a few minutes. The barium hydroxide‐catalyzed methanolysis is faster than the methanolysis catalyzed by calcium oxide and calcium hydroxide and comparable to the potassium hydroxide‐catalyzed methanolysis.
Cu/Ni‐Loaded CeO2‐ZrO2 Catalyst for the Water‐Gas Shift Reaction: Effects of Loaded Metals and CeO2 Addition
Authors: Chamnankid Busaya , Föttinger Karin , Rupprechter Günther , Kongkachuichay Paisan
Published: November 2014

Two different types of metals (Cu and Ni) and the effect of CeO2 addition to produce a CeO2‐ZrO2 co‐supporter were investigated through the water‐gas shift (WGS) reaction. It was found that the WGS activity could be enhanced with CeO2 addition. At relatively high temperature, Ni‐loaded catalysts exhibited higher CO conversion while Cu‐loaded catalysts demonstrated better performance at low temperatures. The stability and yield of the CO2 and H2 products of the Cu catalysts were higher than those of the Ni catalysts. These results may be caused by an irreversible adsorption of CO on Ni and the reverse WGS reaction occurring on the Ni catalysts. In situ diffuse‐reflection infrared Fourier transform spectroscopy data suggests that the WGS mechanism likely proceeded via formate species.
The syn/anti‐Dichotomy in the Palladium‐Catalyzed Addition of Nucleophiles to Alkenes
Authors: Kočovský Pavel , Bäckvall Jan‐E.
Published: November 2014

In this review the stereochemistry of palladium‐catalyzed addition of nucleophiles to alkenes is discussed, and examples of these reactions in organic synthesis are given. Most of the reactions discussed involve oxygen and nitrogen nucleophiles; the Wacker oxidation of ethylene has been reviewed in detail. An anti‐hydroxypalladation in the Wacker oxidation has strong support from both experimental and computational studies. From the reviewed material it is clear that anti‐addition of oxygen and nitrogen nucleophiles is strongly favored in intermolecular addition to olefin–palladium complexes even if the nucleophile is coordinated to the metal. On the other hand, syn‐addition is common in the case of intramolecular oxy‐ and amidopalladation as a result of the initial coordination of the internal nucleophile to the metal.
Hydrothermal Combination of Trilacunary Dawson Phosphotungstates and Hexanickel Clusters: From an Isolated Cluster to a 3D Framework
Authors: Li Xin‐Xiong , Fang Wei‐Hui , Zhao Jun‐Wei , Yang Guo‐Yu
Published: November 2014

Three novel hexa‐Ni‐substituted Dawson phosphortungstates [Ni6(en)3(H2O)6(μ3‐OH)3(H3P2W15O56)]⋅14 H2O (1), [Ni(enMe)2(H2O)][Ni6(enMe)3(μ3‐OH)3(H2O)6(HP2W15O56)]⋅ 10 H2O (2), and [Ni(enMe)2]3[Ni(enMe)2(H2O)][Ni(enMe)(H2O)2][Ni6(enMe)3(μ3‐OH)3(Ac)2(H2O)(P2W15O56)]2⋅6 H2O (3) (en=ethylenediamine, enMe=1, 2‐diaminopropane, Ac=CH3COO−) have been made under hydrothermal conditions and were characterized by IR spectroscopy, elemental analysis, diffuse reflectance spectroscopy, thermogravimetric analysis, powder X‐ray diffraction, and single‐crystal X‐ray diffraction. The common structural features of compounds 1–3 contain the similar hexa‐Ni‐substituted Dawson polyoxometalate (POM) units that can be viewed as a [Ni6(μ3‐OH)3]9+ cluster capping on a [P2W15O56]12− fragment. Compounds 1 and 2 are two isolated clusters, whereas compound 3 is the first 3D POM framework constructed from hexa‐Ni‐substituted Dawson POM units and Ni(enMe) complex bridges. The preparations of compounds 1–3 not only indicate that triangle coplanar Ni6 clusters are very stable fragments in both trivacant Keggin and trivacant Dawson POM systems, but also offer that the hydrothermal technique can act as an effective strategy for making novel Dawson‐type high‐nuclear transition‐metal cluster substituted POMs by combination of lacunary Dawson precusors with transition‐metal cations in the tunable role of organic ligands. In addition, magnetic measurements illustrate that there exist overall ferromagnetic interactions in compound 3.
Combining [Arene–Ru] with Azocarboxamide to Generate a Complex with Cytotoxic Properties
Authors: Sommer Michael G. , Kureljak Petra , Urankar Damijana , Schweinfurth David , Stojanović Nikolina , Bubrin Martina , Gazvoda Martin , Osmak Maja , Sarkar Biprajit , Košmrlj Janez
Published: November 2014

Azocarboxamide (azcH) has been combined for the first time with [Ru–Cym] to generate metal complexes with N,N‐ and N,O‐coordination mode, [(Cym)Ru(azc)Cl] and [(Cym)Ru(azcH)Cl]+[PF6]−. Geometric and electronic structures of the complexes are reported along with their in vitro activities against different tumour cell lines and preliminary results on solution chemistry. Compound [(Cym)Ru(azc)Cl] exhibited remarkable cytotoxic properties. It was cell‐type specific and had comparable IC50 values towards both cancer cells and their drug‐resistant subline. A tenfold increase in the sensitivity towards [(Cym)Ru(azc)Cl] was noted for the tumour cells with depleted intracellular glutathione (GSH) level, suggesting the essential role of GSH in cell response to this compound.
Multivalency as a Key Factor for High Activity of Selective Supported Organocatalysts for the Baylis–Hillman Reaction
Authors: Goren Kerem , Karabline‐Kuks Jeny , Shiloni Yael , Barak‐Kulbak Einav , Miller Scott J. , Portnoy Moshe
Published: November 2014

The polystyrene‐supported N‐alkylimidazole‐based dendritic catalysts for the Baylis–Hillman reaction exhibit one of the strongest beneficial effects of multivalent architecture ever reported for an organocatalyst. The yields in the model reaction of methyl vinyl ketone with p‐nitrobenzaldehyde are more than tripled when a non‐dendritic catalyst is replaced by a second‐ or third‐generation analogue. Moreover, the reaction of the less active substrates will not occur with the non‐dendritic catalyst and will proceed to a significant extent only with the analogous catalysts of higher generations. A substantial additional enhancement of the reaction yield could be achieved by increasing the content of water in the reaction solvent. The plausible cause of the dendritic effect is the assistance of the second, nearby imidazole moiety in the presumably rate‐determining proton transfer in the intermediate adduct, after the first imidazole unit induced the formation of the new carbon–carbon bond.
Titanium cis‐1,2‐Diaminocyclohexane (cis‐DACH) Salalen Catalysts for the Asymmetric Epoxidation of Terminal Non‐Conjugated Olefins with Hydrogen Peroxide
Authors: Wang Qifang , Neudörfl Jörg‐M. , Berkessel Albrecht
Published: November 2014

Chiral Ti salalen complexes catalyze the asymmetric epoxidation of terminal non‐conjugated olefins with hydrogen peroxide. Modular ligands based on cis‐1,2‐diamino‐cyclohexane (cis‐DACH) were developed, giving high yields and enantiomeric excesses (ee, up to 96 %) at catalyst loadings as low as 0.1–0.5 mol %, and even under solvent‐free conditions.
Synthesis of a Pentasaccharide and Neoglycoconjugates Related to Fungal α‐(1→3)‐Glucan and Their Use in the Generation of Antibodies to Trace Aspergillus fumigatus Cell Wall
Authors: Komarova Bozhena S. , Orekhova Maria V. , Tsvetkov Yury E. , Beau Remi , Aimanianda Vishukumar , Latgé Jean‐Paul , Nifantiev Nikolay E.
Published: November 2014

3‐Aminopropyl α‐(1→3)‐pentaglucoside, a fragment of α‐(1→3)‐glucan of the cell wall of Aspergillus fumigatus, has been synthesized in a blockwise approach. The application of mono‐ and disaccharide N‐phenyltrifluoroacetimidates bearing a stereodirecting 6‐O‐benzoyl group was essential for stereoselective α‐glucosylations. In the products, p‐methoxyphenyl and levulinoyl groups served as orthogonal protecting groups for the anomeric position and 3‐OH group, respectively. Their removal from shared blocks led to donors and acceptors that were used for the synthesis of pentasaccharides. Coupling of free α‐(1→3)‐pentaglucoside with biotin and bovine serum albumin (BSA) gave glycoconjugate tools for mycological studies. Immunization of mice with the BSA conjugate induced the generation of antibodies that recognize α‐(1→3)‐glucan on A. fumigatus cell wall and distinguish its morphotypes. This discovery represents a first step to the development of a diagnostic test system and a vaccine to detect and fight this life‐threatening pathogen.
Controlled Zn‐Mediated Grafting of Thin Layers of Bipodal Diazonium Salt on Gold and Carbon Substrates
Authors: Torréns Mabel , Ortiz Mayreli , Turner Anthony P. F. , Beni Valerio , O'Sullivan Ciara K.
Published: November 2014

A controlled, rapid, and potentiostat‐free method has been developed for grafting the diazonium salt (3,5‐bis(4‐diazophenoxy)benzoic acid tetrafluoroborate (DCOOH)) on gold and carbon substrates, based on a Zn‐mediated chemical dediazonation. The highly stable thin layer organic platforms obtained were characterized by cyclic voltammetry, AFM, impedance, XP, and Raman spectroscopies. A dediazonation mechanism based on radical formation is proposed. Finally, DCOOH was proved as a linker to an aminated electroactive probe.
Platinum(II) Olefin Hydroarylation Catalysts: Tuning Selectivity for the anti‐Markovnikov Product
Authors: Clement Marie L. , Grice Kyle A. , Luedtke Avery T. , Kaminsky Werner , Goldberg Karen I.
Published: November 2014

PtII complexes containing unsymmetrical (pyridyl)pyrrolide ligands are shown to catalyze the hydroarylation of unactivated alkenes with selectivity for the anti‐Markovnikov product. Substitution on the pyrrolide portion of the ligand allows effective tuning of the selectivity to anti‐Markovnikov alkylarene products, whereas substitution on the pyridyl portion can promote competitive alkenylarene production.
CuII/TEMPO‐Promoted One‐Pot Synthesis of Highly Substituted Pyrimidines from Amino Acid Esters
Authors: Zhou Nini , Xie Tao , Li Zhongle , Xie Zhixiang
Published: November 2014

A novel, Cu(OAc)2/TEMPO promoted one‐step approach for the preparation of fully substituted pyrimidines from readily available amino acid esters has been described. In this reaction, the amino acid esters act as the only NC sources for the construction of corresponding pyrimidines. The mechanism of this process includes oxidative dehydrogenation, the generation of an imine radical, and a formal [3+3] cycloaddition. This methodology proves to be a high atom‐economic and straightforward strategy for the synthesis of pyrimidines and diverse substrates which are substituted by various functional groups have been afforded in moderate to good yield.
Biotechnologie und Bioverfahrenstechnik – Vom ersten Ullmanns Artikel bis hin zu aktuellen Forschungsthemen
Authors: Al‐Kaidy Huschyar , Duwe Anna , Huster Manuel , Muffler Kai , Schlegel Christin , Sieker Tim , Stadtmüller Ralf , Tippkötter Nils , Ulber Roland
Published: November 2014

Biotechnologie und die mit ihr verbundenen technischen Prozesse prägen seit Jahrtausenden die Entwicklung der Menschheit. Ausgehend von empirischen Verfahren, insbesondere zur Herstellung von Lebensmitteln und täglichen Gebrauchsgütern, haben sich diese Disziplinen zu einem der innovativsten Zukunftsfelder entwickelt. Durch das immer detailliertere Verständnis zellulärer Vorgänge können mittlerweile Produktionsstämme gezielt optimiert werden. Im Zusammenspiel mit moderner Prozesstechnik können so eine Vielzahl von Bulk‐ und Feinchemikalien sowie Pharmazeutika effizient hergestellt werden. In diesem Artikel werden exemplarisch einige der aktuellen Trends vorgestellt.
Hardware and instrumentation to investigate massive releases of dense phase CO2
Authors: Jamois Didier , Proust Christophe , Hebrard Jérome
Published: November 2014

CCS (carbon capture and storage) is seen as a possibility to mitigate the global warming effect. The practical implementation of this technique faces a few challenges like safety issues. It is wondered if a massive release affecting the pipeline (may be the most vulnerable part of the CCS chain) would not lead to a disaster remembering what happened in Africa about 28 years ago (about Nyos Lake accident see Eos, 2009). Few experimental observations of large‐scale CO2 releases have been made, and the physics and thermochemistry involved are not fully understood, even if considerable progress has been made theoretically.2 In this paper, the experimental techniques used to investigate this specific problem are described and illustrated with some key results extracted from various projects. Innovative techniques were employed to control the mass flowrate, blowdown, nearfield, and farfield dispersion in the atmosphere. A 2 m3 spherical vessel able to store up to 1000 kg of CO2 at a pressure above 8 MPa was used. Dense CO2 was allowed to spill out via a 50 mm pipe. The temperature, CO2 concentration, and density field of the outside cloud were monitored using thermocouples and concentration probes. Among other results, it was in particular shown that when the mass flowrate is large enough, body forces become significant forcing the cloud to stay on the ground.
Alleviating Effect of Calcium on Nickel Toxicity in Rice
Authors: Aziz Humera , Sabir Muhammad , Ahmad Hamaad Raza , Aziz Tariq , Zia‐ur‐Rehman Muhammad , Hakeem Khalid Rehman , Ozturk Munir
Published: November 2014

Urbanization and industrialization have resulted in contamination of soils with heavy metals and other pollutants. Nickel (Ni) is one of the toxic metals, which adversely affect plant growth by altering different physiological and metabolic processes. Mineral nutrients can reduce toxic effects of Ni on physiological and metabolic functions of plants, thus improving plant growth. The role of calcium (Ca) to alleviate Ni toxicity in rice was investigated. Rice plants were grown with Ni (20 and 40 mg kg−1) and Ca (80 and 160 mg kg−1) in different combinations and without Ni and Ca as a control. Nickel (40 mg kg−1) significantly decreased shoot (54%) and root dry weights (54%), chlorophyll content (57%), the photosynthetic rate (two‐fold), transpiration rate (34%) and stomatal conductance (39%) compared to control. Application of Ni (40 mg kg−1) increased the Ni concentration in shoots 22‐fold and in roots 11‐fold compared to control. Application of Ca (160 mg kg−1) reduced the adverse effects of Ni and the studied parameters improved to the maximum values compared to control. Calcium decreased the translocation of Ni towards the shoots that was evident from a lower translocation factor (42%) for the plants supplied with Ca compared to those grown without Ca (62%). The phytotoxicity induced by Ni on different growth and physiological parameters was alleviated by Ca as indicated by the minimum values of the phytotoxicity index for Ca fed plants (0) compared to those without Ca (2.6).
Development of Second‐Generation Small‐Molecule RhoA Inhibitors with Enhanced Water Solubility, Tissue Potency, and Significant in vivo Efficacy
Authors: Ma Sheng , Deng Jing , Li Baoli , Li Xiujiang , Yan Zhaowei , Zhu Jin , Chen Gang , Wang Zhong , Jiang Hualiang , Miao Liyan , Li Jian
Published: November 2014

RhoA, a member of the Rho GTPases, is involved in a variety of cellular functions and could be a suitable therapeutic target for the treatment of cardiovascular diseases. However, few small‐molecule RhoA inhibitors have been reported. Based on our previously reported lead compounds, 32 new 2‐substituted quinoline (or quinoxaline) derivatives were synthesized and tested in biological assays. Six compounds showed high RhoA inhibitory activities, with IC50 values of 1.17–1.84 μM. Among these, (E)‐3‐(3‐(ethyl(quinolin‐2‐yl)amino)phenyl)acrylic acid (26 b) and (E)‐3‐(3‐(butyl(quinolin‐2‐yl)amino)phenyl)acrylic acid (26 d) demonstrated noticeable vasorelaxation effects against phenylephrine‐induced contraction in thoracic aorta artery rings, and compound 26 b had good water solubility and showed significant in vivo efficacy, which was similar to that of 5‐(1,4‐diazepane‐1‐sulfonyl)isoquinoline (fasudil) in a subarachnoid hemorrhage–cardiovascular model. To the best of our knowledge, compound 26 b is the first example of a small‐ molecule RhoA inhibitor with potent in vivo efficacy, which could serve as a good lead for designing cardiovascular agents.
Single‐ and multiple‐dose pharmacokinetic studies of tramadol immediate‐release tablets in children and adolescents
Authors: Vandenbossche J. , Richards H. , Solanki B. , Van Peer A.
Published: November 2014

In these combined analyzes from 3 open‐label, phase‐1 studies, the pharmacokinetic profile of tramadol and its metabolite (M1) following administration of tramadol immediate‐release (IR) tablets in children and adolescents, 7–16 years old (studies 1 and 2: n = 38; study 3: n = 21) with painful conditions following single oral dose of tramadol IR (25–100 mg) (studies 1 and 2) or multiple oral doses of tramadol IR tablets every 6 hours for 3 days (study 3) were compared with that of healthy adults following similar treatment. Area under the curve of tramadol and its metabolite M1 in children and adolescents was lower compared with adults (Dose‐normalized [DN] AUC, h ng/mL: tramadol: 1316.87 [children]; 1418.02 [adolescents];1838.29 [adults]; M1: 342.56 [children]; 475.4 [adolescents]; 636.13 [adults]) while the Cmax remained similar (DN Cmax, ng/mL: tramadol: 203.75 [children]; 165.35 [adolescents]; 226.92 [adults]; M1: 34.93 [children]; 38.42 [adolescents]; 52.14 [adults]). The DN AUC was further lower in children and adolescents with a lower body weight (<50 kg). The weight normalized oral clearance of tramadol was higher in children and adolescents compared with adults (CL/F, mL/min/kg: 12.66 [children]; 11.75 [adolescents]; 9.06 [adults]). No new safety findings emerged. Tramadol was generally safe and well‐tolerated by children and adolescents with painful conditions.
Quantitation of the impact of CYP3A5 A6986G polymorphism on quetiapine pharmacokinetics by simulation of target attainment
Authors: Shilbayeh Sireen A.R. , Sy Sherwin K.B. , Melhem Murad , Zmeili Rawan , Derendorf Hartmut
Published: November 2014

The aim of this study was to evaluate whether genetic polymorphisms in CYP3A5 and ABCB1 are responsible for the interindividual variability observed in quetiapine pharmacokinetics. Pharmacokinetic data from a randomized crossover study evaluating 2 quetiapine 25 mg immediate‐release tablets after single oral dose were used to develop a population pharmacokinetic model. The single nucleotide polymorphisms (SNPs) evaluated for the genotype effects of quetiapine pharmacokinetics were CYP3A5 A6986G and ABCB1 C3435T, along with other demographic variables and formulations. A one‐compartment distribution model with linear elimination plus four transit compartments for the delayed absorption adequately described quetiapine disposition. CYP3A5 *1/*1 individuals (n = 3) had 29% increased clearance compared to *1/*3 and *3/*3 individuals. The impact of an increased clearance was evaluated by simulations. By computing the probability of target attainment (PTA) of steady‐state therapeutic goal at 1‐hour and 12‐hour time points after 50–400 mg twice‐daily regimens, the results indicated that CYP3A5 genotype has minimal impact on the PTA of the 1‐hour concentrations but a significant impact on the 12‐hour concentrations. The interpretation based on the simulations does not call for a genotype‐based dosing scheme and is consistent with consensus guidelines for quetiapine that therapeutic drug monitoring is considered useful. Clinical Pharmacology in Drug Development
Implementation of an in‐field CMOS frequency division multiplexer for 9.4 T magnetic resonance applications
Authors: Jouda Mazin , Gruschke Oliver G. , Korvink Jan G.
Published: November 2014

This paper introduces the implementation of an application‐specific complementary metal oxide semiconductor frequency division multiplexer as a novel solution to interface magnetic resonance (MR) phased arrays of micro‐detectors to an image‐processing unit, thus reducing the complexity and space issues associated with MR detector arrays. The frequency multiplexer, in a compact 3 × 4 mm silicon die, is designed to operate at 400 MHz, which is the Larmor frequency of 1H protons in a 9.4‐T MR imaging system. The system implements eight channels, where each channel consists of a low‐noise amplifier, a frequency mixer, and a band‐pass filter. The maximum gain of an individual channel after the band‐pass filter stage is 38 dB. The suppression of the local oscillator ranges from 40 to −51 dB, and the maximum coupling between channels is −39 dB. The input dynamic range of an individual channel is 8 mV. Each channel consumes 54 mA from a 3.3‐V source. The chip operates without errors within a high 9.4‐T magnetic field. Copyright © 2014 John Wiley & Sons, Ltd.
microRNA‐dependent temporal gene expression in the ureteric bud epithelium during mammalian kidney development
Authors: Nagalakshmi Vidya K. , Lindner Volkhard , Wessels Andy , Yu Jing
Published: November 2014

Background: Our previous study on mouse mutants with the ureteric bud (UB) epithelium‐specific Dicer deletion (Dicer UB mutants) demonstrated the significance of UB epithelium‐derived miRNAs in UB development. Results: Our whole‐genome transcriptional profiling showed that the Dicer mutant UB epithelium abnormally retained transcriptional features of the early UB epithelium and failed to express many genes associated with collecting duct differentiation. Furthermore, we identified a temporal expression pattern of early UB genes during UB epithelium development in which gene expression was detected at early developmental stages and became undetectable by embryonic day 14.5. In contrast, expression of early UB genes persisted at later stages in the Dicer mutant UB epithelium and increased at early stages. Our bioinformatic analysis of the abnormally persistently expressed early genes in the Dicer mutant UB epithelium showed significant enrichment of the let‐7 family miRNA targets. We further identified a temporal expression pattern of let‐7 miRNAs in the UB epithelium that is anti‐parallel to that of some early UB genes during kidney development. Conclusions: We propose a model in which the let‐7 family miRNAs silence the expression of a subset of early genes in the UB epithelium at later developmental stages to promote collecting duct differentiation. Developmental Dynamics 244:444–456, 2015. © 2014 Wiley Periodicals, Inc.
Expression of the heparan sulfate 6‐O‐endosulfatases, Sulf1 and Sulf2, in the avian and mammalian inner ear suggests a role for sulfation during inner ear development
Authors: Freeman Stephen D. , Keino‐Masu Kazuko , Masu Masayuki , Ladher Raj K.
Published: November 2014

Background: Inner ear morphogenesis is tightly regulated by the temporally and spatially coordinated action of signaling ligands and their receptors. Ligand–receptor interactions are influenced by heparan sulfate proteoglycans (HSPGs), cell surface molecules that consist of glycosaminoglycan chains bound to a protein core. Diversity in the sulfation pattern within glycosaminoglycan chains creates binding sites for numerous cell signaling factors, whose activities and distribution are modified by their association with HSPGs. Results: Here we describe the expression patterns of two extracellular 6‐O‐endosulfatases, Sulf1 and Sulf2, whose activity modifies the 6‐O‐sulfation pattern of HSPGs. We use in situ hybridization to determine the temporal and spatial distribution of transcripts during the development of the chick and mouse inner ear. We also use immunocytochemistry to determine the cellular localization of Sulf1 and Sulf2 within the sensory epithelia. Furthermore, we analyze the organ of Corti in Sulf1/Sulf2 double knockout mice and describe an increase in the number of mechanosensory hair cells. Conclusions: Our results suggest that the tuning of intracellular signaling, mediated by Sulf activity, plays an important role in the development of the inner ear. Developmental Dynamics 244:168–180, 2015. © 2014 Wiley Periodicals, Inc.
The prognostic significance of atrial fibrillation in heart failure with a preserved and reduced left ventricular function: insights from a meta‐analysis
Authors: Cheng Min , Lu Xiangfeng , Huang Jianfeng , Zhang Jian , Zhang Shu , Gu Dongfeng
Published: November 2014

Background

The prognostic significance of atrial fibrillation (AF) in patients with heart failure remains inconclusive.

Aims

To perform a meta‐analysis of the published data to study the prognostic significance of AF in heart failure patients and to determine whether this relates to the presence of preserved or reduced left ventricular systolic function.

Methods and results

We searched the MEDLINE (from inception to May 2014) supplemented by manual searches of references of relevant retrieved articles. Randomized clinic trials and observational studies were included with hazard ratios (HRs) of AF for mortality in chronic heart failure patients. The search strategy yielded 20 studies that met our eligibility criteria. A total of 61 240 AF patients in 152 306 heart failure participants were included, with 39 879 deaths occurring during follow‐up. Pooled HRs for AF in mortality in heart failure was 1.17 (95% confidence intervals: 1.11–1.23) using random‐effect model (I2 = 44.5%). There was a significant difference of combined HRs between heart failure patients with preserved and reduced left ventricular ejection fraction (LVEF) in separate analysis. Sensitivity analysis supported the consistence of the results.

Conclusions

Atrial fibrillation is significantly associated with increased mortality in heart failure patients. The prognostic significance of AF may be different between heart failure with preserved and reduced LVEF, and AF is associated with poorer prognosis in heart failure patients with preserved LVEF.
Theoretical Search for an Iron‐Based Magnetic Superhalogen with Halogen or Interhalogen as Ligand
Authors: Ding Li‐Ping , Kuang Xiao‐Yu , Shao Peng
Published: November 2014

By using density functional theory, we have investigated the geometrical structures, electrophilic properties, magnetic properties, and fragmentation channels of FeXn (X = Cl, Br; n = 1–6) clusters as well as the “mixed species” that contain interhalogen compounds. Our main objectives are to design new iron‐based magnetic superhalogens and to explore whether the interhalogen compounds are suitable for the superhalogen ligand. By calculating their adiabatic electron affinities (AEAs) and vertical detachment energies (VDEs), we found that both FeCln and FeBrn can be classified as superhalogens for n ≥ 3. Among mixed species, FeClF3, FeBrF3, FeClF5, and FeBrF5 are superhalogens, but their AEA values are still smaller than those of the correspondingly sized FeFn clusters. Their superhalogen properties are further supported by the natural population analysis (NPA) charge distribution and the HOMO of anions. However, in mixed species, the extra electron and HOMO do not uniformly delocalize over the different halogen atoms. This might be the reason why FeXYn possesses relatively small AEA values. In addition, we also studied the superhalogen salts formed with these superhalogen anions and Na+, which greatly enhance the reliability of our obtained superhalogens.
Rapid Synthesis of Unsymmetrical Sulforhodamines Through Nucleophilic Amination of a Monobrominated Sulfoxanthene Dye
Authors: Chevalier Arnaud , Renault Kevin , Boschetti Frédéric , Renard Pierre‐Yves , Romieu Anthony
Published: November 2014

A transition‐metal‐free method for the synthesis of N‐substituted unsymmetrical sulforhodamine fluorophores from an unusual monobrominated sulfoxanthene dye and primary or secondary amines by direct SNAr‐type reactions is presented. The simplicity and effectiveness of this “postamination” procedure were demonstrated through the rapid preparation of a library of multifunctional red‐emitting rhodamine analogues. Some of these analogues are equipped with a reactive handle and retain the two water‐solubilizing sulfonic acid moieties of the starting halogenated derivative; this makes them ideal candidates for biolabeling applications. The potential utility of this expeditious strategy to finely tune the photophysical (Stokes shift) and physicochemical properties (amphiphilic character and water solubility) of the sulforhodamine scaffold was also demonstrated through the appendage of a fluorescent amine to create a fluorescence resonance energy transfer (FRET) pair, a long‐chain amine, and tetraazamacrocycles derived from cyclen.
The First Bidirectional [4+2] Cycloadditions of Benzo[1,2:4,5]dicyclobutenes: Synthesis of Benzo[1,2‐f:4,5‐f′]diisoindole‐1,3,7,9‐tetraones
Authors: Abdelhamid Ismail Abdelshafy , Butenschön Holger
Published: November 2014

Bidirectional reactions are an efficient tool for the synthesis of larger, often symmetric compounds. Whereas the ring opening of benzocyclobutene derivatives with subsequent cycloaddition of the ortho‐quinodimethanes formed has been used extensively for the syntheses of various classes of compounds such as steroids, acenes, and natural as well as synthetic oligocycles including heterocyclic systems, the respective bidirectional reactions have barely been explored. Here, the first bidirectional cycloadditions starting from benzo[1,2:4,5]dicyclobutene derivatives are presented using N‐methylmaleinimide as the dienophile. The benzo[1,2:4,5]dicyclobutene derivatives used have in common that they are dimethylacetals of the respective diones. As a consequence, the cycloadducts easily undergo elimination of methanol. Subsequent dehydrogenations generate the aromatic anthracene systems, which are part of the benzo[1,2‐f:4,5‐f′]diisoindole‐1,3,7,9‐tetraone derivatives formed as the final products.
Gaze behaviour when monitoring pain faces: An eye‐tracking study
Authors: Priebe J.A. , Messingschlager M. , Lautenbacher S.
Published: November 2014

Background

The vigilance‐(attentional) avoidance hypothesis (VAH) developed for explaining phobic reactions describes an early attentional bias towards a feared stimulus followed by attentional avoidance of this stimulus. Such a pattern of attentional shifts might also be found when processing of pain‐related stimuli is required. The purpose of the present study was to test the VAH for pain‐associated stimuli, i.e., faces displaying pain, using the method of eye‐tracking in a pain‐free sample.

Methods

Forty‐eight healthy participants observed pictures of faces displaying pain and other emotions (anger, joy), presented concurrently with neutral faces, while their gaze behaviours were recorded continuously.

Results

Analysis of the time course of fixation durations revealed a distinct pattern for pain faces. Participants gazed at pain faces longer than at neutral faces at the beginning (up to 1000 ms) but reduced preference for pain faces increasingly thereafter (up to 2000 ms); this decline in vigilance did not occur for anger and joy faces. Strong fear of pain (Fear of Pain Questionnaire) tended to increase attentional preference for negative faces (pain, anger), a finding, which however did not reach significance.

Conclusions

We assume that initial vigilance for pain‐associated stimuli might reflect an adaptive reaction to detect a potentially harmful stimulus. Subsequently, the pain‐associated stimulus might be less attended for the purpose of mood regulation when all clear is given in this situation.
CGRP receptor blockade by MK‐8825 alleviates allodynia in infraorbital nerve‐ligated rats
Authors: Michot B. , Kayser V. , Hamon M. , Bourgoin S.
Published: November 2014

Background

Previous data showed that, in rats, anti‐migraine drugs (triptans, olcegepant) significantly reduced mechanical allodynia induced by infraorbital nerve (ION) ligation but not that evoked by sciatic nerve (SN) ligation. Whether this also occurs with MK‐8825, a novel anti‐migraine drug also acting through CGRP receptor blockade (but chemically unrelated to olcegepant) was tested in the present study, which also investigated possible anti‐neuroinflammatory effects of this drug.

Methods

Adult male Sprague‐Dawley rats underwent unilateral chronic constriction injury (CCI) to either the ION or the SN, and mechanical allodynia was assessed 2 weeks later within the ipsilateral vibrissae territory or hindpaw, respectively. Transcripts of neuroinflammatory markers were quantified by real‐time quantitative RT‐PCR in ipsilateral trigeminal ganglion and spinal trigeminal nucleus in CCI‐ION rats.

Results

Acute as well as repeated (for 4 days) administration of MK‐8825 (30–100 mg/kg, i.p.) significantly reduced CCI‐ION‐induced mechanical allodynia but was ineffective in CCI‐SN rats. CCI‐ION was associated with marked up‐regulation of neuronal and glial inflammatory markers (ATF3, IL6, iNOS, COX2) in ipsilateral trigeminal ganglion but not spinal trigeminal nucleus. MK‐8825‐induced inhibition of iNOS mRNA up‐regulation probably underlay its anti‐allodynic effect because pharmacological blockade of iNOS by AMT (6 mg/kg, s.c.) mimicked this effect.

Conclusions

These data further support the idea that CGRP receptor blockade might be a valuable approach to alleviate trigeminal, but not spinal, neuropathic pain through, at least partly, an inhibitory effect on neuropathic pain‐associated increase in NO production in trigeminal ganglion.
Decontamination of cationic and anionic dyes in single and binary mode from aqueous phase by mesoporous pulp waste
Authors: Ahmaruzzaman M. , Reza Ruhul Amin
Published: November 2014

This work addresses the development of mesoporous pulp waste (MPW) and its application in sequestering of methylene blue (MB) and methyl orange (MO) from single and binary mode. Adsorption interactions of dyes onto MPW were investigated using N2 adsorption/desorption isotherm, fourier transform infrared (FTIR), scanning electron microscopy (SEM), energy dispersive X‐Ray spectroscopy (EDS) P‐XRD, thermo gravimetric analysis (TGA), pHPZC, macro, and micro analyses. The developed MPW showed the presence of surface functional groups (OH, COOH groups), porous surface, higher BET surface area (1022.46 m2/g), pore volume (0.8338 cm3/g), and atomic percentage of carbon (54.93%) and oxygen (10.26%). The adsorptive uptake for both the dyes was computed in single (qMB = 251.0 mg g−1 and qMO = 285.71 mg g−1) and binary mode (qMB = 157.48 mg g−1 and qMO = 142.85 mg g−1). The adsorption mechanisms of MB and MO onto MPW were governed by hydrogen bonding and π‐π interactions. The adsorption kinetics of MB and MO are better reflected by pseudo second‐order for single and binary system with good correlations. Thermodynamic parameters exhibited the adsorption process to be spontaneous and endothermic in nature accompanying the increase of entropy (the driving force for adsorption). The regeneration of the adsorbent was performed with 0.1 M NaOH and CH3COOH (99–100%). The low cost of the developed MPW (USD 42.43 per kg) justify its utilization in the removal of dyes from aqueous phase. © 2014 American Institute of Chemical Engineers Environ Prog, 34: 724–735, 2015
Environmental contaminants and chromosomal damage associated with beak deformities in a resident North American passerine
Authors: Handel Colleen M. , Van Hemert Caroline
Published: November 2014

A large cluster of beak abnormalities among black-capped chickadees (Poecile atricapillus) in Alaska raised concern about underlying environmental factors in this region. Metals and trace elements, organochlorine pesticides, polychlorinated biphenyls (PCBs), and polychlorinated dibenzo-dioxins and polychlorinated dibenzofurans (PCDD-Fs) were analyzed in adults, nestlings, and eggs of the affected population; local bird seed was also tested for organochlorine pesticides. The results offered no support for the hypothesis that selenium or any other inorganic element was responsible for beak deformities among chickadees, but some evidence that organochlorine compounds may be contributing factors. Adults with beak deformities had an elevated level of chromosomal damage, which was correlated with lipid level and concentrations of several organochlorine compounds. Multivariate analyses of pesticides and PCBs did not distinguish abnormal from normal adults, but subsequent univariate analysis demonstrated higher concentrations of heptachlor epoxide and PCB-123 in abnormal adults. Concentrations of all organochlorine compounds were low, and none is known to cause beak or keratin abnormalities. Patterns of PCB congener concentrations differed between nestlings with normal and abnormal parents. Eggs from clutches with low hatchability had higher concentrations of hexachlorobenzene and PCDD-Fs than those with high hatching success, and hexachlorobenzene was found in seeds. Additional testing for PCDD-Fs, polycyclic aromatic hydrocarbons, and other emerging contaminants, including brominated compounds, is needed to rule out environmental contaminants as a cause of beak deformities in chickadees in Alaska. Environ Toxicol Chem 2014;9999:1–14. Published 2014 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.
The clinical course of cirrhosis: The importance of multistate models and competing risks analysis
Authors: Jepsen Peter , Vilstrup Hendrik , Andersen Per Kragh
Published: November 2014

Multistate models are models of disease progression that, for a patient group, define multiple outcome events, each of which may affect the time to develop another outcome event. Multistate models are highly relevant for studies of patients with cirrhosis; both the classical perception of cirrhosis as either compensated or decompensated and the recent, more complex models of cirrhosis progression are multistate models. Therefore, researchers who conduct clinical studies of patients with cirrhosis must realize that most of their research questions assume a multistate disease model. Failure to do so can result in severely biased results and bad clinical decisions. The analyses that can be used to study disease progression in a multistate disease model may be called competing risks analysis, named after the competing risks disease model, which is the simplest multistate disease model. In this review article, we introduce multistate disease models and competing risks analysis and explain why the standard armamentarium of Kaplan‐Meier survival estimates and Cox regression sometimes gives bad answers to good questions. We also use real data to answer typical research questions about the course of cirrhosis and illustrate biases resulting from inadequate methods. Finally, we suggest statistical software packages that are helpful and accessible to the clinician‐researcher. (Hepatology 2015;62:292‐302)
Metformin decreases IL‐22 secretion to suppress tumor growth in an orthotopic mouse model of hepatocellular carcinoma
Authors: Zhao Dong , Long Xi‐Dai , Lu Tian‐Fei , Wang Tao , Zhang Wei‐Wei , Liu Yi‐Xiao , Cui Xiao‐Lan , Dai Hui‐Juan , Xue Feng , Xia Qiang
Published: November 2014

Epidemiological, preclinical and cellular studies in the last 5 years have shown that metformin exerts anti‐tumoral properties, but its mode of action in cancer remains unclear. Here, we investigated the effects of metformin on a mouse hepatocellular carcinoma (HCC) model and tumor‐associated T cell immune responses. Oral metformin administration led to a significant reduction of tumor growth, which was accompanied by decreased interleukin‐22 (IL‐22). Meanwhile, IL‐22‐induced STAT3 phosphorylation and upregulation of downstream genes Bcl‐2 and cyclin D1 were inhibited by metformin. At the cellular level, metformin attenuated Th1‐ and Th17‐derived IL‐22 production. Furthermore, metformin inhibited de novo generation of Th1 and Th17 cells from naive CD4+ cells. These observations were further supported by the fact that metformin treatment inhibited CD3/CD28‐induced IFN‐γ and IL‐17A expression along with the transcription factors that drive their expression (T‐bet [Th1] and ROR‐γt [Th17], respectively). The effects of metformin on T cell differentiation were mediated by downregulated STAT3 and STAT4 phosphorylation via the AMP‐activated kinase‐mammalian target of rapamycin complex 1 pathway. Notably, metformin led to a reduction in glucose transporter Glut1 expression, resulting in less glucose uptake, which is critical to regulate CD4+ T cell fate. Taken together, these findings provide evidence for the growth‐inhibitory and immune‐modulatory effects of metformin in HCC and thus, broaden our understanding about the action of metformin in liver cancer treatment.