bluuebunny/crossref_metadata_2025 huggingface dataset:
Difficulty and Complexity of Language Features and Second Language Instruction
Authors: Housen Alex
Published: December 2014

Since the mid‐1990s applied linguistics and SLA research have given increasing attention to how instruction affects language features, such as forms, items, structures, patterns, and rules, and whether some features are more effectively instructed than others. These issues are of relevance to various stakeholders. For SLA researchers, knowing how the nature of the input stimulus interacts with the human cognitive‐processing and learning mechanisms is important for constructing a comprehensive theory of language acquisition.
Process Research Screen Capture
Authors: Mroz Aurore P.
Published: December 2014

Screen capture, or “screencasting,” refers to a method of data collection in applied linguistics research. The researcher uses a stand‐alone camera or digital software to make video recordings of users' on‐screen activity. Screen capture results in a recording consisting of a series of frames that document moment‐by‐moment on‐screen phenomena used to investigate real‐time computer‐based processes. Screen capture is an important instrument to conduct qualitative research in computer‐assisted or ‐mediated language learning and other online communication investigated by applied linguists.
Gender and Pragmatics
Authors: King Brian W. , Holmes Janet
Published: December 2014

In the field of
language and gender,
there is a widely accepted origin narrative in which Robin Lakoff's seminal article is identified as the inaugural publication that launched investigations of a relationship between men, women, and language. Following its publication, there was a veritable explosion in language and gender research, with pragmatic issues attracting a good deal of attention. In the earliest decades, researchers examined features which could be interpreted as interactional dominance or power strategies, such as the distribution of turns of talk, the number of interruptions, and the amount of feedback contributed by women and men in different contexts, as well as features which expressed politeness, such as linguistic hedges and intensifiers.
Minimal Disease Activity and Anti–Tumor Necrosis Factor Therapy in Psoriatic Arthritis
Authors: Haddad Amir , Thavaneswaran Arane , Ruiz‐Arruza Ioana , Pellett Fawnda , Chandran Vinod , Cook Richard J. , Gladman Dafna D.
Published: December 2014

Objective

A state of minimal disease activity (MDA) was defined and validated as target for treatment in psoriatic arthritis (PsA). We aimed to identify disease characteristics, outcome, and predictors of MDA in patients treated with tumor necrosis factor α (TNFα) blockers.

Methods

Patients fulfilling the Classification of Psoriatic Arthritis criteria treated with TNFα blockers were followed every 3–6 months. Patients were considered in MDA when they meet at least 5 of the 7 criteria. Sustained MDA was defined as an MDA state lasting ≥12 months. Patients achieving MDA were compared to non‐MDA patients. A proportional odds discrete time survival analysis model was applied, adjusting for sex, age, PsA duration, abnormal erythrocyte sedimentation rate (ESR) and clinically damaged joint count at each visit to identify predictors for MDA.

Results

Of the 306 patients treated with TNFα blockers identified from our database, 23 patients were in an MDA state when treatment was commenced; 57 were taking TNFα blockers prior to enrollment. Therefore, 226 subjects were in a non‐MDA state and constituted the study population. One hundred forty‐five patients of 226 patients (64%) achieved MDA within a mean ± SD duration of 1.30 ± 1.68 years. The mean ± SD duration of MDA was 3.46 ± 2.25 years. At total of 17 patients withdrew from therapy and remained in an MDA state. Male sex (odds ratio [OR] 1.65, 95% confidence interval [95% CI] 1.08–2.53; P = 0.02) and normal ESR (OR 2.27, 95% CI 1.22–4.17; P = 0.009) increased the odds for achieving MDA.

Conclusion. MDA is achieved in 64% of patients treated with TNFα blockers in a clinical setting. Male sex and normal ESR are predictors for MDA. On withdrawal or reduction in treatment, 11.6% of patients maintained MDA state.
Synthesis of butyl acrylate in a fixed‐bed adsorptive reactor over Amberlyst 15
Authors: Constantino Dânia S. M. , Pereira Carla S. M. , Faria Rui P. V. , Ferreira Alexandre F. P. , Loureiro José M. , Rodrigues Alírio. E.
Published: December 2014

The butyl acrylate synthesis from the esterification reaction of acrylic acid with 1‐butanol in a fixed‐bed adsorptive reactor packed with Amberlyst 15 ion exchange resin was evaluated. Adsorption experiments were carried out with nonreactive pairs at two temperatures (323 and 363 K). The experimental results were used to obtain multicomponent adsorption equilibrium isotherms of Langmuir type. Reactive adsorption experiments using different feed molar ratios and flow rates were performed, at 363 K, and used to validate a mathematical model developed to describe the dynamic behavior of the fixed‐bed adsorptive reactor for the butyl acrylate synthesis. Due to the simultaneous reaction and separation steps, it was possible to obtain a butyl acrylate maximum concentration 38% higher than the equilibrium concentration (for an equimolar reactants ratio solution as feed at a flow rate of 0.9 mL min−1 and 363 K) showing that sorption‐enhanced reaction technologies are very promising for butyl acrylate synthesis. © 2014 American Institute of Chemical Engineers AIChE J, 61: 1263–1274, 2015
Intensive management of high‐utilizing adults with sickle cell disease lowers admissions
Authors: Koch Kathryn L. , Karafin Matthew S. , Simpson Pippa , Field Joshua J.
Published: December 2014

A minority of super‐utilizing adults with sickle cell disease (SCD) account for a disproportionate number of emergency department (ED) and hospital admissions. We performed a retrospective cohort study comparing the rate of admission before and after the opening of a clinic for adults with SCD. Unique to this clinic was an intensive management strategy, focusing on super‐utilizing adults with 12 or more admissions per year. ED/hospital and 30 days re‐admission rates were compared, 1 year pre‐ and post‐intervention, for those adults who established in the clinic. Prior to the intervention, 17 super‐utilizers, comprising 15% of the pre‐intervention cohort (n = 115), accounted for 58% of the total admissions and had an admission rate of 28 per patient‐year. When pre‐ and post‐intervention years were compared, rate of ED/hospital admission per patient‐year for super‐utilizers decreased from 27.9 to 13.5 (P < 0.001), while there was not a significant reduction for the entire cohort (7.1 vs. 6.1, P = 0.84). Similarly, the decrease in rate of 30 day re‐admission was larger for the super‐utilizers (13.5 per patient‐year to 1.8, P < 0.001), than the whole cohort (2.6 per patient‐year to 0.7, P = 0.006). Among the super‐utilizers, the reduced rate of admission from the pre‐ to post‐clinic intervention year equated to 252 fewer ED/hospital admissions and 227 fewer 30 day re‐admissions. This management strategy focusing on super‐utilizing adults with SCD lowered admission and 30 day re‐admission rate. Am. J. Hematol. 90:215–219, 2015. © 2014 Wiley Periodicals, Inc.
New model for estimating the relationship between surface area and volume in the human body using skeletal remains
Authors: Kasabova Boryana E. , Holliday Trenton W.
Published: December 2014

A new model for estimating human body surface area and body volume/mass from standard skeletal metrics is presented. This model is then tested against both 1) “independently estimated” body surface areas and “independently estimated” body volume/mass (both derived from anthropometric data) and 2) the cylindrical model of Ruff. The model is found to be more accurate in estimating both body surface area and body volume/mass than the cylindrical model, but it is more accurate in estimating body surface area than it is for estimating body volume/mass (as reflected by the standard error of the estimate when “independently estimated” surface area or volume/mass is regressed on estimates derived from the present model). Two practical applications of the model are tested. In the first test, the relative contribution of the limbs versus the trunk to the body's volume and surface area is compared between “heat‐adapted” and “cold‐adapted” populations. As expected, the “cold‐adapted” group has significantly more of its body surface area and volume in its trunk than does the “heat‐adapted” group. In the second test, we evaluate the effect of variation in bi‐iliac breadth, elongated or foreshortened limbs, and differences in crural index on the body's surface area to volume ratio (SA:V). Results indicate that the effects of bi‐iliac breadth on SA:V are substantial, while those of limb lengths and (especially) the crural index are minor, which suggests that factors other than surface area relative to volume are driving morphological variation and ecogeographical patterning in limb prorportions. Am J Phys Anthropol 156:614–624, 2015. © 2014 Wiley Periodicals, Inc.
A Three‐Minute Synthesis and Purification of Ibuprofen: Pushing the Limits of Continuous‐Flow Processing
Authors: Snead David R. , Jamison Timothy F.
Published: December 2014

In a total residence time of three minutes, ibuprofen was assembled from its elementary building blocks with an average yield of above 90 % for each step. A scale‐up of this five‐stage process (3 bond‐forming steps, one work‐up, and one in‐line liquid–liquid separation) provided ibuprofen at a rate of 8.09 g h−1 (equivalent to 70.8 kg y−1) using a system with an overall footprint of half the size of a standard laboratory fume hood. Aside from the high throughput, several other aspects of this synthesis expand the capabilities of continuous‐flow processing, including a Friedel–Crafts acylation run under neat conditions and promoted by AlCl3, an exothermic in‐line quench of high concentrations of precipitation‐prone AlCl3, liquid–liquid separations run at or above 200 psi to provide solvent‐free product, and the use of highly aggressive oxidants, such as iodine monochloride. The use of simple, inexpensive, and readily available reagents thus affords a practical synthesis of this important generic pharmaceutical.
LED‐beleuchtete NMR‐Spektroskopie Flavin‐katalysierter Photooxidationen zeigt Lösungsmittelkontrolle des Elektronentransfermechanismus
Authors: Feldmeier Christian , Bartling Hanna , Magerl Kathrin , Gschwind Ruth M.
Published: December 2014

Mechanistische Einblicke in die Photokatalyse erhält man vor allem durch UV/Vis‐Spektroskopie, da die Möglichkeiten der NMR‐Spektroskopie bislang durch die Art der Beleuchtung limitiert waren. Mit einer LED‐Beleuchtungseinheit können nun sowohl Reaktionsprofile von Photoreaktionen unter Synthesebedingungen detektiert als auch Photo‐CIDNP‐spektroskopische und Intermediatstudien durchgeführt werden. Das Potenzial dieses Aufbaus wird anhand Flavin‐katalysierter Photooxidationen von Alkoholen gezeigt. Nach identischer Photoinitialisierung ist die Stabilisierung eines nachgelagerten Intermediats der Schlüssel zum weiteren Reaktionsmechanismus und zur Reaktivität. Flavin als chemischer Photokatalysator kann als Ein‐ wie auch als Zwei‐Elektronen‐Mediator fungieren, indem die Stabilität der zwitterionischen Radikalpaare durch verschiedene Lösungsmittel gesteuert wird. Dies demonstriert die Bedeutung nachgelagerter Intermediate und der NMR‐Spektroskopie zugänglicher, ergänzender Informationen in der Photokatalyse und demonstriert das Potenzial, photoorganische Reaktionen durch Lösungsmitteleffekte zu steuern.
Copper‐Catalyzed 1,2‐Addition of α‐Carbonyl Iodides to Alkynes
Authors: Xu Tao , Hu Xile
Published: December 2014

β,γ‐Unsaturated ketones are an important class of organic molecules. Herein, copper catalysis has been developed for the synthesis of β‐γ‐unsaturated ketones through 1,2‐addition of α‐carbonyl iodides to alkynes. The reactions exhibit wide substrate scope and high functional group tolerance. The reaction products are versatile synthetic intermediates to complex small molecules. The method was applied for the formal synthesis of (±)‐trichostatin A, a histone deacetylase inhibitor.
Transition metal‐catalyzed oxidative transformations of methylarenes
Authors: Feng Jian‐Bo , Wu Xiao‐Feng
Published: December 2014

Oxidation is one of the fundamental transformations in organic synthesis. The selective oxidation of inert substrates is interesting and important. In this review, the transition metal‐catalyzed oxidation of methylarenes is discussed. Benzaldehyde, benzoic acid, benzyl alcohol, etc., were produced as the target products. Copyright © 2014 John Wiley & Sons, Ltd.
Effect of Certolizumab Pegol Over Ninety‐Six Weeks in Patients With Axial Spondyloarthritis: Results from a Phase III Randomized Trial
Authors: Sieper J. , Landewé R. , Rudwaleit M. , van der Heijde D. , Dougados M. , Mease P. J. , Braun J. , Deodhar A. , Kivitz A. , Walsh J. , Hoepken B. , Nurminen T. , Maksymowych W. P.
Published: December 2014

Objective

Previous reports of the RAPID‐axSpA trial (NCT01087762) described the efficacy and safety of certolizumab pegol (CZP) over 24 weeks in patients with axial spondyloarthritis (SpA), including ankylosing spondylitis (AS) and nonradiographic axial SpA. We report efficacy and safety data up to week 96 of the study.

Methods

The RAPID‐axSpA trial is double‐blind and placebo‐controlled to week 24, dose‐blind to week 48, and open‐label to week 204. Outcome variables included Assessment of SpondyloArthritis international Society criteria for 20% and 40% improvement in disease activity (ASAS20/40), ASAS partial remission responses (analyzed by nonresponder imputation), AS Disease Activity Score (ASDAS), ASDAS inactive disease, ASDAS major improvement, Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), and Bath AS Metrology Index (BASMI) linear score (analyzed by the last observation carried forward method). Safety data were collected for patients treated with ≥1 dose of CZP.

Results

Of the 325 patients who were randomized, 218 received CZP from week 0. Of these, 93% completed week 24, 88% completed week 48, and 80% completed week 96. Improvements in ASAS responses were maintained to week 96 (for ASAS20, 67.4%, 72.0%, and 62.8% at weeks 24, 48, and 96, respectively), as well as improvements in ASDAS, BASDAI (mean score 3.3, 3.1, and 3.0 at weeks 24, 48, and 96, respectively), BASFI, and BASMI linear score. Comparable improvements were observed with both dosing regimens (200 mg every 2 weeks or 400 mg every 4 weeks) and in patients with AS and those with nonradiographic axial SpA. In the safety set, adverse events occurred in 279 patients (88.6%) and serious adverse events in 41 (13.0%). No deaths or malignancies were reported.

Conclusion

Clinical improvements to week 24 in both CZP dosing regimens were sustained to week 96. Similar sustained improvements were observed in AS and nonradiographic axial SpA subpopulations. The safety profile was consistent with previous reports from RAPID‐axSpA, with no new safety signals observed with longer exposure.
Frühgeschichte des modernen Konstruktionsbetons
Authors: Holzer Stefan M.
Published: December 2014

Lange bevor der Beton mit Eiseneinlagen die Architektur und den Ingenieurbau der Moderne prägen konnte, hatten Ingenieure schon ausführliche Erfahrungen mit dem Werkstoff gewonnen. Die Wurzeln des modernen Betons reichen bis in die italienische Renaissance zurück. Der Beton entwickelte sich zunächst im Verborgenen, in Fundamenten, Unterwasserbauten oder versteckt im Inneren mehrschaliger Mauern. Eine dreiteilige Serie von Beiträgen wird die Entwicklungsgeschichte des modernen Betons von seinen Ursprüngen im 16. Jahrhundert bis in die Zeit des Aufkommens der Bewehrung beleuchten. Der vorliegende erste Teil zeigt am Beispiel von Molen und Wellenbrechern, wie die Betonbauweise sich zunächst dort etablieren konnte, wo an das Herstellen einer trockenen Baugrube nicht im Entferntesten gedacht werden konnte. Der zweite Teil des Aufsatzes wird sich dann dem Schleusenbau zuwenden, bei dem der Einsatz von Beton vielleicht nicht zwingend war, aber doch ebenfalls erhebliche Erleichterungen mit sich brachte. Im dritten Teil schließlich wird die frühe neuzeitliche Geschichte des Betons bei Bogen‐ und Gewölbetragwerken nachgezeichnet.

On the early history of modern concrete – Part I: Jetties and breakwaters

The history of modern concrete can be traced back to the Italian Renaissance period. Some of the earliest recorded early modern uses of concrete are in hydraulic engineering, particularly the construction of jetties and breakwaters. These applications and the technologies developed around them are analyzed in the present contribution, the first of a three‐part series of articles on the early modern history of concrete prior to the introduction of reinforcement. The parts to follow will deal with the construction of canal locks and early concrete vaults, respectively.
Freie Form – experimentelle Tragstruktur
Authors: Schling Eike , Barthel Rainer , Tutsch Joram
Published: December 2014

In dem Studentenprojekt “Experimental Structures” wurden im Sommersemester 2014 am Lehrstuhl für Tragwerksplanung der Technischen Universität München sieben Tragstrukturen auf experimentelle Weise entwickelt. Die Masterstudenten nutzten Techniken wie Flechten, Falten oder Biegen, um parametrisch kontrollierte Strukturen auf modularer Basis zu erstellen. Dabei wurden unterschiedliche Lösungsansätze für die Unterteilung und Konstruktion von gekrümmten Flächen aufgezeigt. Die Ergebnisse bewegen sich zwischen effizientem Tragwerk und spielerischer Skulptur. Die Strukturen von ca. 2 × 2 m Spannweite wurden am Technischen Zentrum der TU mithilfe computergesteuerter Werkzeuge gefertigt und im Rahmen der Jahresschau der Architekturfakultät ausgestellt.

Free form – experimental structure – design and realisation of modular surface structures

During the summer project 2014 “Experimental Structures” seven structures were developed through experimental trials at the Department for Structural Design at the Technical University in Munich. The master students utilized various techniques like braiding, folding or bending to generate parametrically controlled modular structures. This produced different approaches of tessellating and constructing double curved surfaces. The resulting works cover a range between efficient structures and playful sculptures. The structures of approximately 2 × 2 m span were produced at the Technical Center of the TU using computer aided tools. They were exhibited at the Annual Show of the Architecture Faculty.
seele Glasbrücke: Eine gläserne Brückenkonstruktion aus kaltverformtem Glas
Authors: Peters Stefan , Engelsmann Stephan , Dengler Christoph
Published: December 2014

Eine begehbare gläserne Brückenkonstruktion ist der weltweit erste Prototyp für Brückenbauwerke aus kaltgebogenem Glas. Der kaltverformte transparente Werkstoff, ein komplexes räumliches und steifigkeitsabhängiges Tragverhalten sowie ein umfassender Einsatz von Klebeverbindungen sind die besonderen Kennzeichen der seele Glasbrücke. Das spektakuläre transparente Experiment ist das Ergebnis einer Kooperation zwischen seele GmbH, dem IBK Forschung und Entwicklung der Universität Stuttgart und Engelsmann Peters Beratende Ingenieure GmbH. Der Beitrag beschreibt das Entwurfskonzept und die Tragwerksplanung sowie Fertigung und Montage der gläsernen Brücke.

seele glassbridge: a glass bridge structure made from cold bentglass

An accessible glass bridge is the world‐wide first prototype for bridge structures made from cold bent glass. The cold bent material, an ambitious structural concept and the comprehensive use of bonded joints are the particular characteristics of this glass bridge. The spectacular transparent experiment is the result of a cooperation between seele GmbH, IBK Forschung und Entwicklung of Stuttgart University and Engelsmann Peters Beratende Ingenieure GmbH. This article describes the structural design concept and the structural design process as well as the fabrication of the glass bridge.
Setting up a wide panel of patient‐derived tumor xenografts of non–small cell lung cancer by improving the preanalytical steps
Authors: Ilie Marius , Nunes Manoel , Blot Lydia , Hofman Véronique , Long‐Mira Elodie , Butori Catherine , Selva Eric , Merino‐Trigo Ana , Vénissac Nicolas , Mouroux Jérôme , Vrignaud Patricia , Hofman Paul
Published: December 2014

With the ongoing need to improve therapy for non–small cell lung cancer (NSCLC) there has been increasing interest in developing reliable preclinical models to test novel therapeutics. Patient‐derived tumor xenografts (PDX) are considered to be interesting candidates. However, the establishment of such model systems requires highly specialized research facilities and introduces logistic challenges. We aimed to establish an extensive well‐characterized panel of NSCLC xenograft models in the context of a long‐distance research network after careful control of the preanalytical steps. One hundred fresh surgically resected NSCLC specimens were shipped in survival medium at room temperature from a hospital‐integrated biobank to animal facilities. Within 24 h post‐surgery, tumor fragments were subcutaneously xenografted into immunodeficient mice. PDX characterization was performed by histopathological, immunohistochemical, aCGH and next‐generation sequencing approaches. For this model system, the tumor take rate was 35%, with higher rates for squamous carcinoma (60%) than for adenocarcinoma (13%). Patients for whom PDX tumors were obtained had a significantly shorter disease‐free survival (DFS) compared to patients for whom no PDX tumors (P = 0.039) were obtained. We established a large panel of PDX NSCLC models with a high frequency of mutations (29%) in EGFR, KRAS, NRAS, MEK1, BRAF, PTEN, and PI3KCA genes and with gene amplification (20%) of c‐MET and FGFR1. This new patient‐derived NSCLC xenograft collection, established regardless of the considerable time required and the distance between the clinic and the animal facilities, recapitulated the histopathology and molecular diversity of NSCLC and provides stable and reliable preclinical models for human lung cancer research.
Controlling the Fluorescence of Benzofuran‐Modified Uracil Residues in Oligonucleotides by Triple‐Helix Formation
Authors: Kanamori Takashi , Ohzeki Hiroki , Masaki Yoshiaki , Ohkubo Akihiro , Takahashi Mari , Tsuda Kengo , Ito Takuhiro , Shirouzu Mikako , Kuwasako Kanako , Muto Yutaka , Sekine Mitsuo , Seio Kohji
Published: December 2014

We developed fluorescent turn‐on probes containing a fluorescent nucleoside, 5‐(benzofuran‐2‐yl)deoxyuridine (dUBF) or 5‐(3‐methylbenzofuran‐2‐yl)deoxyuridine (dUMBF), for the detection of single‐stranded DNA or RNA by utilizing DNA triplex formation. Fluorescence measurements revealed that the probe containing dUMBF achieved superior fluorescence enhancement than that containing dUBF. NMR and fluorescence analyses indicated that the fluorescence intensity increased upon triplex formation partly as a consequence of a conformational change at the bond between the 3‐methylbenzofuran and uracil rings. In addition, it is suggested that the microenvironment around the 3‐methylbenzofuran ring contributed to the fluorescence enhancement. Further, we developed a method for detecting RNA by rolling circular amplification in combination with triplex‐induced fluorescence enhancement of the oligonucleotide probe containing dUMBF.
Cyclability of a Lithium–Oxygen Battery Containing N‐Methyl‐2‐Pyrrolidone and a Vertically Aligned Carbon Nanotube Cathode
Authors: Chen Yu‐Ming , Xie Aozhen , Zhu Yu
Published: December 2014

The lithium–air battery has a high specific capacity but suffers from a poor cyclability. The reason for its poor cycle life is still unclear and many explanations, such as the degradation of the solvent, the lithium salt, and the carbon cathode, have been suggested. Although N‐methyl‐2‐pyrrolidone (NMP) was shown to be stable under superoxide anion radical conditions in stand‐alone tests, lithium–air cells containing NMP still showed a very low reversibility in previous work. Here, a freestanding vertically aligned carbon nanotube is used as a binder‐free electrode in a lithium–air battery cathode, and the results indicate that the cyclability of the cell is significantly improved. This research proves that the content of the carbon electrode is of pivotal importance for the stability of lithium–air batteries.
Synthesis of [3]Rotaxanes that Utilize the Catalytic Activity of a Macrocyclic Phenanthroline–Cu Complex: Remarkable Effect of the Length of the Axle Precursor
Authors: Yamashita Yoshiaki , Mutoh Yuichiro , Yamasaki Ryu , Kasama Takeshi , Saito Shinichi
Published: December 2014

[3]Rotaxanes, which consist of one macrocyclic phenanthroline compound and two axle components, were prepared by the oxidative dimerization of an alkyne compound with bulky tris[4′‐cyclohexyl‐(1,1′‐biphenyl)‐4‐yl]methyl blocking group. The catalytic activity of a macrocyclic phenanthroline–Cu complex was utilized to thread the two axle components inside the ring. The alkyne compound with chain of 15 or 20 methylene groups gave [3]rotaxanes in high yields, whereas the axle with a chain of six methylene groups afforded a [3]rotaxane in very poor yield. We also examined the effect of the ring size on the synthesis of [3]rotaxanes. [3]Rotaxanes were not isolated when a macrocyclic phenanthroline compound with a smaller ring size was used.
Straightforward Synthetic Protocol for the Introduction of Stabilized C Nucleophiles in the BODIPY Core for Advanced Sensing and Photonic Applications
Authors: Gutiérrez‐Ramos Brenda D. , Bañuelos Jorge , Arbeloa Teresa , Arbeloa Iñigo López , González‐Navarro Paulina E. , Wrobel Kazimierz , Cerdán Luis , García‐Moreno Inmaculada , Costela Angel , Peña‐Cabrera Eduardo
Published: December 2014

A straightforward synthetic protocol to directly incorporate stabilized 1,3‐dicarbonyl C nucleophiles to the meso position of BODIPY (4,4‐difluoro‐4‐bora‐3a,4a‐diaza‐s‐indacene) is reported. Soft nucleophiles generated by deprotonation of 1,3‐dicarbonyl derivatives smoothly displace the 8‐methylthio group from 8‐(methylthio)BODIPY analogues in the presence of CuI thiophenecarboxylate in stoichiometric amounts at room temperature. Seven highly fluorescent new derivatives are prepared with varying yields (20–92 %) in short reaction times (5–30 min). The excellent photophysical properties of the new dyes allow focusing on applications never analyzed before for BODIPYs substituted with stabilized C nucleophiles such as pH sensors and lasers in liquid and solid state, highlighting the relevance of the synthetic protocol described in the present work. The attainment of these dyes, with strong UV absorption and highly efficient and stable laser emission in the green spectral region, concerns to one of the greatest challenges in the ongoing development of advanced photonic materials with relevant applications. In fact, organic dyes with emission in the green are the only ones that allow, by frequency‐doubling processes, the generation of tunable ultraviolet (250‐350 nm) radiation, with ultra‐short pulses.
BN Heterosuperbenzenes: Synthesis and Properties
Authors: Wang Xiao‐Ye , Wang Jie‐Yu , Pei Jian
Published: December 2014

Replacement of CC unit with its isoelectronic BN unit in aromatics provides a new class of molecules with appealing properties, which have attracted great attention recently. In this Concept, we focus on BN‐substituted polycyclic aromatics with fused structures, and review their synthesis, photophysical, and redox properties, as well as their applications in organic electronics. We also present challenging synthetic targets, large BN‐ substituted polycyclic aromatics, such as regioregular BN heterosuperbenzenes, which can be viewed as BN‐doped nanographenes. Finally, we propose an atomically precise bottom‐up synthesis of structurally well‐defined BN‐doped graphenes.
Development of an AND Logic‐Gate‐Type Fluorescent Probe for Ratiometric Imaging of Autolysosome in Cell Autophagy
Authors: Takashima Ippei , Kawagoe Ryosuke , Hamachi Itaru , Ojida Akio
Published: December 2014

The concomitant detection of two biological events facilitates the highly selective and sensitive analysis of specific biological functions. In this article, we report an AND logic‐gate‐type fluorescent probe that can concurrently sense two biological events in living cells: H2O2 accumulation and acidification. The probe exhibits a unique fluorescence sensing mechanism, in which a xanthene fluorophore is oxidatively transformed to a xanthone derivative by H2O2, thereby resulting in a clear dual‐emission change. This transformation is significantly accelerated under weak acidic conditions, which enables the selective and sensitive detection of H2O2 production in an acidic cellular compartment. This unique sensing property was successfully applied to the ratiometric fluorescence imaging of autolysosome formation in selective mitochondrial autophagy (mitophagy), which highlights the utility of this novel probe in autophagy research.
Asymmetric Synthesis of Fully Substituted Cyclopentane‐Oxindoles through an Organocatalytic Triple Michael Domino Reaction
Authors: Zou Liang‐Hua , Philipps Arne R. , Raabe Gerhard , Enders Dieter
Published: December 2014

An efficient, highly stereoselective asymmetric synthesis of fully functionalized cyclopentanes bearing an oxindole moiety and several other functional groups in one pot has been developed. Key step is an organocatalytic triple Michael domino reaction forming three CC bonds and six stereocenters, including a quaternary one. Starting from equimolar amounts of simple substrates, a high molecular complexity can be reached after a Wittig olefination in one pot. The new protocol can easily be scaled up to gram amounts.
Discovery of MK‐8970: An Acetal Carbonate Prodrug of Raltegravir with Enhanced Colonic Absorption
Authors: Walji Abbas M. , Sanchez Rosa I. , Clas Sophie‐Dorothee , Nofsinger Rebecca , de Lera Ruiz Manuel , Li Jing , Bennet Amrithraj , John Christopher , Bennett David Jonathan , Sanders John M. , Di Marco Christina N. , Kim Somang Hope , Balsells Jaume , Ceglia Scott S. , Dang Qun , Manser Kimberly , Nissley Becky , Wai John S. , Hafey Michael , Wang Junying , Chessen Gene , Templeton Allen , Higgins John , Smith Ronald , Wu Yunhui , Grobler Jay , Coleman Paul J.
Published: December 2014

Developing new antiretroviral therapies for HIV‐1 infection with potential for less frequent dosing represents an important goal within drug discovery. Herein, we present the discovery of ethyl (1‐((4‐((4‐fluorobenzyl)carbamoyl)‐1‐methyl‐2‐(2‐(5‐methyl‐ 1,3,4‐oxadiazole‐2‐carboxamido)propan‐2‐yl)‐6‐oxo‐1,6‐dihydropyrimidin‐5‐yl)oxy)ethyl) carbonate (MK‐8970), a highly optimized prodrug of raltegravir (Isentress). Raltegravir is a small molecule HIV integrase strand‐transfer inhibitor approved for the treatment of HIV infection with twice‐daily administration. Two classes of prodrugs were designed to have enhanced colonic absorption, and derivatives were evaluated in pharmacokinetic studies, both in vitro and in vivo in different species, ultimately leading to the identification of MK‐8970 as a suitable candidate for development as an HIV therapeutic with the potential to require less frequent administration while maintaining the favorable efficacy, tolerability, and minimal drug–drug interaction profile of raltegravir.
Racial/ethnic disparities in inflammatory gene single‐nucleotide polymorphisms as predictors of a high risk for symptom burden in patients with multiple myeloma 1 year after diagnosis
Authors: Shi Qiuling , Wang Xin Shelley , Li Guojun , Shah Nina D. , Orlowski Robert Z. , Williams Loretta A. , Mendoza Tito R. , Cleeland Charles S.
Published: December 2014

BACKGROUND

This study was conducted to determine whether any regulatory single‐nucleotide polymorphism (SNP) in an inflammatory gene was associated with a high symptom burden in patients 1 year after the diagnosis of multiple myeloma (MM).

METHODS

MM patients rated symptoms with the MD Anderson Symptom Inventory multiple myeloma module (MDASI‐MM) and provided buccal‐swab DNA samples. SNPs for 4 cytokine genes (interleukin 6 [IL6] −174G>C, IL1β −511C>T, tumor necrosis factor α [TNFα] −308G>A, and IL10 −1082G>A) were tested. Logistic regression models were used to identify SNPs that might predict moderate/severe symptoms (rated ≥4 on the MDASI‐MM 0‐10 scale). For the evaluation of the relationship between SNPs and overall symptom burden, a 2‐step cluster analysis was used to divide patients into subgroups with high or low symptom levels.

RESULTS

Forty‐one percent of the 344 patients enrolled had a high overall symptom burden. The most prevalent moderate/severe symptoms were fatigue (47%), pain (42%), numbness (38%), and bone aches (32%). For non‐Hispanic whites, the IL1β −511 CC genotype was associated with a high overall symptom burden (odds ratio [OR], 2.35; 95% confidence interval [CI], 1.25‐4.72; P = .004), whereas the IL6 −174 GG genotype predicted less moderate/severe fatigue (OR, 0.53; 95% CI, 0.29‐0.88; P = .013). For other patients, the IL6 −174 GG genotype predicted moderate/severe pain (OR, 3.36; 95% CI, 1.23‐13.64; P = .010).

CONCLUSIONS

These results support growing evidence showing that inflammation is associated with cancer‐related symptoms, and they suggest that racial/ethnic factors contribute to this association. Cancer 2015;121:1138–1146. © 2014 American Cancer Society.
Lithium–Air Oxygen Shuttle Battery with a ZrO2‐Based Ion‐Conducting Oxide Electrolyte
Authors: Inoishi Atsushi , Matsuka Maki , Sakai Takaaki , Ju Young‐Wan , Ida Shintaro , Ishihara Tatsumi
Published: December 2014

Invited for this month’s cover is the group of Prof. Tatsumi Ishihara from Kyushu University, Fukuoka (Japan). The cover picture shows the newly proposed concept of an “oxygen shuttle” for a Li–air battery, in which a stabilized ZrO2 ion conductor is the electrolyte, and the red balls represent oxygen molecules that permeate through the electrolyte. Read the full text of the article at 10.1002/cplu.201402041.
Guaiacol Hydrodeoxygenation Mechanism on Pt(111): Insights from Density Functional Theory and Linear Free Energy Relations
Authors: Lee Kyungtae , Gu Geun Ho , Mullen Charles A. , Boateng Akwasi A. , Vlachos Dionisios G.
Published: December 2014

Density functional theory is used to study the adsorption of guaiacol and its initial hydrodeoxygenation (HDO) reactions on Pt(111). Previous Brønsted–Evans–Polanyi (BEP) correlations for small open‐chain molecules are inadequate in estimating the reaction barriers of phenolic compounds except for the side group (methoxy) carbon‐dehydrogenation. New BEP relations are established using a select group of phenolic compounds. These relations are applied to construct a potential‐energy surface of guaiacol‐HDO to catechol. Analysis shows that catechol is mainly produced via dehydrogenation of the methoxy functional group followed by the CHx (x<3) removal of the functional group and hydrogenation of the ring carbon, in contrast to a hypothesis of a direct demethylation path. Dehydroxylation and demethoxylation are slow, implying that phenol is likely produced from catechol but not through its direct dehydroxylation followed by aromatic carbon‐ring hydrogenation.
Genetic basis of dyslipidemia in disease precipitation of coronary artery disease (CAD) associated type 2 diabetes mellitus (T2DM)
Authors: Raj Resal , Bhatti Jasvinder Singh , Badada Sanjay Kumar , Ramteke Pramod W.
Published: December 2014

Type 2 diabetes mellitus (T2DM) and its complications are linked to environmental, clinical, and genetic factors. This review analyses the disorders of lipids and their genetics with respect to coronary artery disease (CAD) associated with T2DM. Cell organelles, hepatitis C‐virus infection, reactive oxygen species produced in mitochondria, and defective insulin signaling due to the arrest of G1 phase to S phase transition of β‐cells have significant roles in the precipitation of the diseases. Adiponectin is anti‐inflammatory and anti‐atherosclerotic and improves insulin resistance. Low‐density lipoprotein (LDL) is atherosclerotic, and LDL‐cholesterol in T2DM is associated with high‐cardiovascular risk. Further, LDL cholesterol reduction significantly reduces cardiovascular morbidity and mortality. High‐density lipoprotein (HDL) is also anti‐atherosclerotic due to HDL associated paraoxonase‐1 serum enzyme, which prevents LDL oxidative modifications and the development of CAD. Moreover, elevated apolipoprotein B and apolipoprotein A‐I (ApoB/ApoA‐I) ratio in plasma is also a risk factor for CAD. LDL receptor, adiponectin, and endocannabinoid receptor‐1 genes are independently associated with CAD and T2DM. Polymorphism of Apo E2 (epsilon2) is a positive factor to increase the T2DM risk and Apo E4 (epsilon4) is a negative factor to reduce the disease risk. Taq 1B polymorphism of cholesterol ester transfer protein (CETP) gene contributes to the development of atherosclerosis, whereas haplotypes of APOA5, APOC3, APOC4, and APOC5 genes are in the same cluster and are independently associated with high plasma triglyceride level, CAD and T2DM. In conclusion, because various genes, LDLR, CETP, APOA5, Apo E, Apo B, and Apo A‐I, are associated with the precipitation of CAD associated with T2DM, a personalized diet–gene intervention therapy may be advocated to reduce the disease precipitation. Copyright © 2014 John Wiley & Sons, Ltd.
Wnt and FGF mediated epithelial‐mesenchymal crosstalk during lung development
Authors: Volckaert Thomas , De Langhe Stijn P.
Published: December 2014

Background: The adaptation to terrestrial life required the development of an organ capable of efficient air‐blood gas exchange. To meet the metabolic load of cellular respiration, the mammalian respiratory system has evolved from a relatively simple structure, similar to the two‐tube amphibian lung, to a highly complex tree‐like system of branched epithelial airways connected to a vast network of gas exchanging units called alveoli. The development of such an elaborate organ in a relatively short time window is therefore an extraordinary feat and involves an intimate crosstalk between mesodermal and endodermal cell lineages. Results: This review describes the molecular processes governing lung development with an emphasis on the current knowledge on the role of Wnt and FGF signaling in lung epithelial differentiation. Conclusions: The Wnt and FGF signaling pathways are crucial for the dynamic and reciprocal communication between epithelium and mesenchyme during lung development. In addition, some of this developmental crosstalk is reemployed in the adult lung after injury to drive regeneration, and may, when aberrantly or chronically activated, result in chronic lung diseases. Novel insights into how the Wnt and FGF pathways interact and are integrated into a complex gene regulatory network will not only provide us with essential information about how the lung regenerates itself, but also enhance our understanding of the pathogenesis of chronic lung diseases, as well as improve the controlled differentiation of lung epithelium from pluripotent stem cells. Developmental Dynamics 244:342–366, 2015. © 2014 Wiley Periodicals, Inc.
A tool for simulating and communicating uncertainty when modelling species distributions under future climates
Authors: Gould Susan F. , Beeton Nicholas J. , Harris Rebecca M. B. , Hutchinson Michael F. , Lechner Alex M. , Porfirio Luciana L. , Mackey Brendan G.
Published: December 2014

Tools for exploring and communicating the impact of uncertainty on spatial prediction are urgently needed, particularly when projecting species distributions to future conditions.

We provide a tool for simulating uncertainty, focusing on uncertainty due to data quality. We illustrate the use of the tool using a Tasmanian endemic species as a case study. Our simulations provide probabilistic, spatially explicit illustrations of the impact of uncertainty on model projections. We also illustrate differences in model projections using six different global climate models and two contrasting emissions scenarios.

Our case study results illustrate how different sources of uncertainty have different impacts on model output and how the geographic distribution of uncertainty can vary.

Synthesis and applications: We provide a conceptual framework for understanding sources of uncertainty based on a review of potential sources of uncertainty in species distribution modelling; a tool for simulating uncertainty in species distribution models; and protocols for dealing with uncertainty due to climate models and emissions scenarios. Our tool provides a step forward in understanding and communicating the impacts of uncertainty on species distribution models under future climates which will be particularly helpful for informing discussions between researchers, policy makers, and conservation practitioners.
Longer consumption of flaxseed oil enhances n‐3 fatty acid content of chicken meat and expression of FADS2 gene
Authors: Mirshekar Reza , Boldaji Fathollah , Dastar Behrouz , Yamchi Ahad , Pashaei Somayeh
Published: December 2014

The aim of this study was to evaluate the effect of different durations of flaxseed oil consumption on broiler performance, fatty acid content of meat and expression of FADS2 gene in the liver of chicken. A total of 336 unsexed day old chicks were randomly assigned to 7 dietary treatments with 4 replicates of 12 chickens in each. Body weight, weight gain, feed intake and feed conversion ratio were not affected by dietary treatments. Longer consumption of flaxseed oil resulted in higher deposition of long chain n‐3 fatty acids in broiler breast and thigh (P < 0.05). Regression analysis showed that feeding broilers with diet enriched with flaxseed oil 17 and 7 days prior to slaughter for breast and thigh respectively, is enough for producing n‐3 labeled meat. Weekly replacement of oil source of diet (soybean oil) with flaxseed oil increased expression of FADS2 gene. To incorporate enough n‐3 fatty acids into chicken meat through addition of flaxseed oil to broiler diet and to maximize de novo long chain n‐3 fatty acid synthesis in broiler body, we recommend adding flaxseed oil to broiler diets 17 days prior to slaughter.

Practical applications: Omega‐3 enrichment of broiler chickens depends on both nutrition and gene expression. Flaxseed oil is an omega‐3 oil source that can be supplemented to broiler diet to enrich chicken meat with the beneficial n‐3 fatty acids. However, adding such oil sources to broiler rations is restricted because of their negative effects on broiler performance and meat quality. Therefore, shorter period of such oil sources consumption is preferred. Flaxseed oil consumption can affect gene expression too. Thus, it is necessary to determine the optimum duration of flaxseed oil supplementation to broiler diets to produce omega‐3 labeled chicken using both nutrition and gene expression.

Flaxseed oil consumption can affect fatty acid profile of chicken meat through manipulation of fatty acid deposition, de novo fatty acid synthesis, fatty acid oxidation and expression of genes involved in fatty acid metabolism. To incorporate enough n‐3 fatty acids into chicken, providing at least 3 g n‐3 fatty acid per kilogram of meat, by adding flaxseed oil to broiler diet, we recommend adding flaxseed oil to broiler diets 17 days prior to slaughter.
Seed oils recovered from industrial fruit by‐products are a rich source of tocopherols and tocotrienols: Rapid separation of α/β/γ/δ homologues by RP‐HPLC/FLD
Authors: Górnaś Paweł , Soliven Arianne , Segliņa Dalija
Published: December 2014

The profiles of tocopherols and tocotrienols (vitamin E) in the seed oils recovered from apple (Malus domestica Borkh.), canary melon (Cucumis melo L.), gooseberry (Ribes uva‐crispa L.), grape (Vitis vinifera L.), Japanese quince (Chaenomeles japonica), pomegranate (Punica granatum L.), red currant (Ribes rubrum L.), sea buckthorn (Hippophae rhamnoides L.), and watermelon (Citrullus lanatus) by‐products of the fruit industry were studied. The highest concentration of tocochromanols was found in pomegranate seed oil (398.73 mg/100 g) and the lowest in gooseberry seed oil (69.13 mg/100 g). The γ and α homologues were the predominant forms of tocopherol and tocotrienol in all fruit seed oils studied. The pomegranate, canary melon, watermelon, gooseberry and red currants seed oils contained mainly γ‐tocopherol (382.69, 63.08, 111.01, 60.35, and 156.39 mg/100 g, respectively). In the apple, sea buckthorn and Japanese quince seed oils, α‐tocopherol was the predominant tocochromanol (58.77, 121.79, and 198.94 mg/100 g, respectively). High concentrations of tocotrienol homologes (γ and α) (49.49 and 34.53 mg/100 g, respectively) were found only in grape seed oil. A significant correlation (r = 0.994, p < 0.00001) between the total content of tocochromanols in the seed oils and scavenging of the free radical DPPH was found.

Practical applications

This study demonstrated that seed oils recovered from industrial fruit by‐products generated by the food industry are valuable source of tocochromanols. Therefore, fruit seed oils may be successfully applied to obtain new products rich in vitamin E for the food, pharmaceutical and cosmetic industries, with environmental sustainability benefits and a more effective use of harvested plant material.

The profiles of tocopherols and tocotrienols in the seed oils recovered from apple (Malus domestica Borkh.), canary melon (Cucumis melo L.), gooseberry (Ribes uva‐crispa L.), grape (Vitis vinifera L.), Japanese quince (Chaenomeles japonica (Thunb.) Lindl. ex Spach), pomegranate (Punica granatum L.), red currant (Ribes rubrum L.), sea buckthorn (Hippophae rhamnoides L.) and watermelon (Citrullus lanatus (Thunb.) Matsum. & Nakai) by‐products of the fruit industry were studied. The homologues γ and α were predominant for both, tocopherols and tocotrienols. However, the concentration and composition of tocochromanols varied considerably in seed oils recovered from industrial fruit by‐products.
Effects of centrally acting analgesics on spinal segmental reflexes and wind‐up
Authors: Mazo I. , Roza C. , Zamanillo D. , Merlos M. , Vela J.M. , Lopez‐Garcia J.A.
Published: December 2014

Background

The spinal cord is a prime site of action for analgesia. Here we characterize the effects of established analgesics on segmental spinal reflexes. The aim of the study was to look for the pattern of action or signature of analgesic effects on these reflexes.

Methods

We used a spinal cord in vitro preparation of neonate mice to record ventral root responses to dorsal root stimulation. Pregabalin, clonidine, morphine and duloxetine and an experimental sigma‐1 receptor antagonist (S1RA) were applied to the preparation in a cumulative concentration protocol. Drug effects on the wind‐up produced by repetitive stimulation of C‐fibres and on responses to single A‐ and C‐fibre intensity stimuli were analysed.

Results

All compounds produced a concentration‐dependent inhibition of total spikes elicited by repetitive stimulation. Concentrations producing ∼50% reduction in this parameter were (in μM) clonidine (0.01), morphine (0.1), pregabalin (1), duloxetine (10) and S1RA (30). At these concentrations clonidine, pregabalin and S1RA had significant effects on the wind‐up index and little depressant effects on responses to single stimuli. Morphine and duloxetine did not depress wind‐up index and showed large effects on responses to single stimuli. None of the compounds had strong effects on the amplitude of the non‐nociceptive monosynaptic reflex.

Conclusions

morphine and duloxetine had general depressant effects on spinal reflexes, whereas the effects of clonidine, pregabalin and S1RA appeared to be restricted to signals originated by strong repetitive activation of C‐fibres. Results are discussed in the context of reported behavioural effects of the compounds studied.