bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a novel and efficient cell culture flocculation process using a stimulus responsive polymer to streamline antibody purification processes
Authors: Kang Yun (Kenneth) , Hamzik James , Felo Michael , Qi Bo , Lee Julia , Ng Stanley , Liebisch Gregory , Shanehsaz Behnam , Singh Nripen , Persaud Kris , Ludwig Dale L. , Balderes Paul
Published: June 2013

Recent advances in mammalian cell culture processes have significantly increased product titers, but have also resulted in substantial increases in cell density and cellular debris as well as process and product related impurities. As such, with improvements in titer, corresponding improvements in downstream processing are essential. In this study we have developed an alternative antibody harvest process that incorporates flocculation using a novel stimulus responsive polymer, benzylated poly(allylamine), followed by depth filtration. As tested on multiple antibodies, this process demonstrates high process yield, improved clearance of cells and cell debris, and efficient reduction of aggregates, host cell proteins (HCP) and DNA. A wide operating window was established for this novel flocculation process through design of experiments condition screening and optimization. Residual levels of impurities in the Protein A eluate were achieved that potentially meet requirements of drug substance and thus alleviate the burden for further impurities removal in subsequent chromatography steps. In addition, efficient clearance of residual polymer was demonstrated using a fluorescence tagged polymer in the presence of a stimulus reagent. The mechanism of HCP and aggregates removal during flocculation was also explored. This novel and efficient process can be easily integrated into current mAb purification platforms, and may overcome downstream processing challenges. Biotechnol. Bioeng. 2013;110: 2928–2937. © 2013 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc.
Moderate physical exercise attenuates the alterations of feeding behaviour induced by social stress in female rats
Authors: Benite‐Ribeiro Sandra Aparecida , Santos Júlia Matzenbacher dos , Duarte José Alberto Ramos
Published: June 2013

Epidemiological studies have demonstrated that stress‐related disorders, such as the increase on the caloric intake, are twice as common in women as in men, but surprisingly, very few studies have been tested this subject on female experimental animals. Additionally, it has been proposed that regular physical exercise can improve the deleterious effects of stress. Therefore, the present longitudinal study, performed in female rats, aimed to test the influence of chronic stress (ST) imposed by social isolation on the animals’ caloric intake and to assess the effect of regular physical exercise of low intensity on this behaviour. In 4 groups of Wistars rats (control sedentary, n = 6; control exercised, n = 6; ST sedentary, n = 6; ST exercised, n = 6), body weight, food intake, abdominal fat weight, adrenal weight, corticosterone metabolites in faeces and plasma insulin levels were measured during the experimental protocol and/or at its end. The results showed that social isolation was not able to modify the amount of abdominal fat and the body weight; however, it promoted significant increases in the corticosterone metabolites and in the amount of caloric intake, which were attenuated in exercised rats. Additionally, exercised groups presented lower levels of fasting insulin than sedentary groups. Therefore, the present study demonstrated that regular physical exercise of low intensity attenuates the corticosterone metabolites and overeating behaviour triggered by social stress. Copyright © 2013 John Wiley & Sons, Ltd.
α‐L‐Fucosidase Inhibition by Pyrrolidine–Ferrocene Hybrids: Rationalization of Ligand‐Binding Properties by Structural Studies
Authors: Hottin Audrey , Wright Daniel W. , Steenackers Agata , Delannoy Philippe , Dubar Faustine , Biot Christophe , Davies Gideon J. , Behr Jean‐Bernard
Published: June 2013

Enhanced metabolism of fucose through fucosidase overexpression is a signature of some cancer types, thus suggesting that fucosidase‐targetted ligands could play the role of drug‐delivery vectors. Herein, we describe the synthesis of a new series of pyrrolidine–ferrocene conjugates, consisting of a L‐fuco‐configured dihydroxypyrrolidine as the fucosidase ligand armed with a cytotoxic ferrocenylamine moeity. Three‐dimensional structures of several of these fucosidase inhibitors reveal transition‐state‐mimicking 3E conformations. Elaboration with the ferrocenyl moiety results in sub‐micromolar inhibitors of both bovine and bacterial fucosidases, with the 3D structure of the latter revealing electron density indicative of highly mobile alkylferrocene compounds. The best compounds show a strong antiproliferative effect, with up to 100 % inhibition of the proliferation of MDA‐MB‐231 cancer cells at 50 μM.
Derivatization and Solidification of Floating Dispersive Liquid‐phase Microextraction for the Analysis of Kanamycin in Wastewater and Soil by HPLC with Fluorescence Detection
Authors: Hu Shuang , Song Yan‐hong , Bai Xiao‐hong , Jiang Xue , Yang Xiao‐li
Published: June 2013

The abuse and uncontrolled discharge of kanamycin may result in potential risks to human health through food chain or environmental residues. Hence, the determination of kanamycin in various matrices is necessary. A sensitive and simple dispersive liquid–liquid microextraction based on solidification of floating organic droplet (DLLME‐SFO) method has been developed for monitoring kanamycin in environmental samples. The method of DLLME‐SFO after derivatization is coupled with high performance LC with fluorescence detection. The comparison was carried out between the staged and one‐step procedure. The results indicated that the fluorescence derivatization reaction with 9‐fluorenylmethyl chloroformate should be performed prior to extraction. The derivatization and DLLME‐SFO conditions were optimized, respectively. Under the optimal conditions, the proposed method presented good linearity with square correlation coefficient of 0.9934, good reproducibility with relative standard deviations less than 9.6%, and the recoveries of kanamycin ranged from 91.3 to 102.7% for wastewater, and from 90.3 to 107.7% for soil. Furthermore, the detection limit was observed as 0.012 ng/mL. The proposed method was successfully applied to determine low levels of kanamycin in wastewater and soil samples.
An ecological genetic delineation of local seed‐source provenance for ecological restoration
Authors: Krauss Siegfried L. , Sinclair Elizabeth A. , Bussell John D. , Hobbs Richard J.
Published: June 2013

An increasingly important practical application of the analysis of spatial genetic structure within plant species is to help define the extent of local provenance seed collection zones that minimize negative impacts in ecological restoration programs. Here, we derive seed sourcing guidelines from a novel range‐wide assessment of spatial genetic structure of 24 populations ofBanksia menziesii(Proteaceae), a widely distributedWesternAustralian tree of significance in local ecological restoration programs. An analysis of molecular variance (AMOVA) of 100 amplified fragment length polymorphism (AFLP) markers revealed significant genetic differentiation among populations (ΦPT = 0.18). Pairwise population genetic dissimilarity was correlated with geographic distance, but not environmental distance derived from 15 climate variables, suggesting overall neutrality of these markers with regard to these climate variables. Nevertheless,Bayesian outlier analysis identified four markers potentially under selection, although these were not correlated with the climate variables. We calculated a globalR‐statistic using analysis of similarities (ANOSIM) to test the statistical significance of population differentiation and to infer a threshold seed collection zone distance of ~60 km (all markers) and 100 km (outlier markers) when genetic distance was regressed against geographic distance. Population pairs separated by >60 km were, on average, twice as likely to be significantly genetically differentiated than population pairs separated by <60 km, suggesting that habitat‐matched sites within a 30‐km radius around a restoration site genetically defines a local provenance seed collection zone forB. menziesii. Our approach is a novel probability‐based practical solution for the delineation of a local seed collection zone to minimize negative genetic impacts in ecological restoration.
Heterologous vaccination against human tuberculosis modulates antigen‐specific CD4+T‐cell function
Authors: Dintwe One B. , Day Cheryl L. , Smit Erica , Nemes Elisa , Gray Clive , Tameris Michele , McShane Helen , Mahomed Hassan , Hanekom Willem A. , Scriba Thomas J.
Published: June 2013

Heterologous prime‐boost strategies hold promise for vaccination against tuberculosis. However, the T‐cell characteristics required for protection are not known. We proposed that boost vaccines should induce long‐lived functional and phenotypic changes to T cells primed by Bacille Calmette Guerin (BCG) and/or natural exposure to mycobacteria. We characterized changes among specific CD4+ T cells after vaccination with the MVA85A vaccine in adults, adolescents, and children. CD4+ T cells identified with Ag85A peptide‐bearing HLA class II tetramers were characterized by flow cytometry. We also measured proliferative potential and cytokine expression of Ag85A‐specific CD4+ T cells. During the effector phase, MVA85A‐induced specific CD4+ T cells coexpressed IFN‐γ and IL‐2, skin homing integrins, and the activation marker CD38. This was followed by contraction and a transition to predominantly IL‐2‐expressing, CD45RA−CCR7+CD27+ or CD45RA+CCR7+CD27+ specific CD4+ T cells. These surface phenotypes were similar to Ag85A‐specific T cells prior to MVA85A. However, functional differences were observed postvaccination: specific proliferative capacity was markedly higher after 6–12 months than before vaccination. Our data suggest that MVA85A vaccination may modulate Ag85A‐specific CD4+ T‐cell function, resulting in greater recall potential. Importantly, surface phenotypes commonly used as proxies for memory T‐cell function did not associate with functional effects of vaccination.
Controlled Synthesis of Well‐Ordered Mesoporous Titania Films with Large Mesopores Templated by Spherical PS‐b‐PEO Micelles
Authors: Jiang Xiangfen , Suzuki Norihiro , Bastakoti Bishnu Prasad , Chen Wei‐Jung , Huang Yu‐Tzu , Yamauchi Yusuke
Published: June 2013

We focus on the effects of solvent and the hydrolysis rate of inorganic precursors in the synthesis of ordered mesoporous titania thin film with uniform and large‐sized pores. The amphiphilic diblock copolymer poly(styrene‐b‐ethylene oxide) was used as the structure‐directing agent. The formation of orderly arranged polymeric micelles is primarily necessary to obtain well‐ordered mesoporous titania. Here, we achieve both large‐sized mesopores and long‐range ordering by precisely controlling the properties of the precursor solution. The mesostructural domains successfully extend up to the micrometer scale, which has never seen in previous reports.
Tröger's Base Derived Phosphanes for ­Suzuki–Miyaura and Buchwald–Hartwig Cross‐Coupling Reactions
Authors: Pereira Raul , Cvengroš Ján
Published: June 2013

A library of bis(phosphane) ligands based on the 2,8‐substituted Tröger's base scaffold was synthesized through an efficient two‐step protocol by starting from a commercially available aniline. The new ligands proved their efficiency in palladium‐catalyzed Suzuki–Miyaura cross‐coupling reactions and Buchwald–Hartwig aminations of aryl chlorides and bromides.
Effect of organic carbon, C:N ratio and light on the growth and lipid productivity of microalgae/cyanobacteria coculture
Authors: Silaban Athens , Bai Rong , Gutierrez‐Wing M. Teresa , Negulescu Ioan I. , Rusch Kelly A.
Published: June 2013

Current culture methods based on monocultures under phototrophic regimes are prone to contamination, predation, and collapse. Native cultures of multiple species are adapted to the local conditions and are more robust against contamination and predation. Growth, lipid and biomass productivity of a Louisiana native coculture of microalgae (Chlorella vulgaris) and cyanobacteria (Leptolyngbya sp.) in heterotrophic and mixotrophic regimes were investigated. Dextrose and sodium acetate at C:N ratios of 15:1 and 30:1 under heterotrophic (dark) and mixotrophic (400 μmol m−2 s−1) regimes were compared with autotrophic controls. The carbon source and C:N ratio impacted growth and biomass productivity. Mixotrophic cultures with sodium acetate (C:N 15:1) resulted in the highest mean biomass productivity (156 g m−3 d−1) and neutral lipid productivity (24.07 g m−3 d−1). The maximum net specific growth rate (U) was higher (0.97 d−1) in mixotrophic cultures with dextrose (C:N 15:1) but could not be sustained resulting in lower total biomass than in mixotrophic cultures with acetate (C:N 15:1), with a U of 0.67 d−1. The ability of the Louisiana coculture to use organic carbon for biomass and lipid production makes it a viable feedstock for biofuels and bioproducts.
Design of β‐galactosidase/silica biocatalysts: Impact of the enzyme properties and immobilization pathways on their catalytic performance
Authors: Bernal Claudia , Sierra Ligia , Mesa Monica
Published: June 2013

The use of heterogeneous biocatalysis in industrial applications is advantageous and the enzyme stability improvement is a continuous challenge. Therefore, we designed β‐galactosidase heterogeneous biocatalysts by immobilization, involving the support synthesis and enzyme selection (from Bacillus circulans, Kluyveromyces lactis, and Aspergillus oryzae). The underivatized, tailored, macro‐mesoporous silica exhibited high surface area, offered high enzyme immobilization yields and activity. Its chemical activation with glyoxyl groups bound the enzyme covalently, which suppressed lixiviation and conferred higher pH and thermal stability (120‐fold than for the soluble enzyme), without observable reduction of activity/stability due to the presence of silica. The best balance between the immobilization yield (68%), activity (48%), and stability was achieved for Bacillus circulans β‐galactosidase immobilized on glyoxyl‐activated silica, without using stabilizing agents or modifying the enzyme. The enzyme stabilization after immobilization in glyoxyl‐activated silica was similar to that observed in macroporous agarose‐glyoxyl support, with the reported microbiological and mechanical advantages of inorganic supports. The whey lactolysis at pH 6.0 and 25°C by using this catalyst (1 mg ml−1, 290 UI g−1) was still 90%, even after 10 cycles of 10 min, in batch process but it could be also implemented on continuous processes at industrial level with similar results.
Denudation and retreat of the Serra do Mar escarpment in southern Brazil derived from in situ‐produced 10Be concentration in river sediment
Authors: Salgado André A. R. , Marent Breno R. , Cherem Luís F. S. , Bourlès Didier , Santos Leonardo J. C. , Braucher Régis , Barreto Helen N.
Published: June 2013

The Serra do Mar escarpment, located along the southeastern coast of Brazil, is a high‐elevation passive margin escarpment. This escarpment evolved from the denudation of granites, migmatites and gneisses. The granites outcrop in the form of a ridge along the escarpment crest, due to its differential erosion (‘sugarloaf’ hills) from the surrounding lithologies. Several studies suggest that the passive margin escarpments are actively retreating toward the interior of the continent. However, no prior study has calculated the long‐term denudation rates of Serra do Mar to test this hypothesis. In this study, we measured the in situ‐produced 10Be concentration in fluvial sediments to quantify the catchment‐wide long‐term denudation rates of the Serra do Mar escarpment in southern Brazil. We sampled the fluvial sediments from ten watersheds that drain both sides of the escarpment. The average long‐term denudation rate of the oceanic side is between 2.1‐ and 2.6‐fold higher than the rate of the continental side: 26.04 ± 1.88 mm ka‐1 (integrating over between 15.8 ka‐1 and 46.6 ka‐1) and 11.10 ± 0.37 mm ka‐1 (integrating over between 52.9 ka‐1 and 85.4 ka‐1), respectively. These rates indicate that the coastal base level is controlling the escarpment retreat toward the continental high lands, which is consistent with observations made at other high‐elevation passive margins around the globe. The results also demonstrate the differential erosion along the Serra do Mar escarpment in southern Brazil during the Quaternary, where drainages over granites had lower average denudation rates in comparison with those over migmatites and gneisses. Moreover, the results demonstrate that the ocean‐facing catchments have been eroded more intensely than those facing the continent. The results also reveal that drainage over the granites decreases the average denudation rates of the ocean‐facing catchments and the ‘sugarloaf’ hills therefore are natural barriers that slowly retreat once they are exhumed. Copyright © 2013 John Wiley & Sons, Ltd.
Encore: Genetic Association Interaction Network Centrality Pipeline and Application to SLE Exome Data
Authors: Davis Nicholas A. , Lareau Caleb A. , White Bill C. , Pandey Ahwan , Wiley Graham , Montgomery Courtney G. , Gaffney Patrick M. , McKinney B. A.
Published: June 2013

Open source tools are needed to facilitate the construction, analysis, and visualization of gene‐gene interaction networks for sequencing data. To address this need, we present Encore, an open source network analysis pipeline for genome‐wide association studies and rare variant data. Encore constructs Genetic Association Interaction Networks or epistasis networks using two optional approaches: our previous information‐theory method or a generalized linear model approach. Additionally, Encore includes multiple data filtering options, including Random Forest/Random Jungle for main effect enrichment and Evaporative Cooling and Relief‐F filters for enrichment of interaction effects. Encore implements SNPrank network centrality for identifying susceptibility hubs (nodes containing a large amount of disease susceptibility information through the combination of multivariate main effects and multiple gene‐gene interactions in the network), and it provides appropriate files for interactive visualization of a network using tools from our online Galaxy instance. We implemented these algorithms in C++ using OpenMP for shared‐memory parallel analysis on a server or desktop. To demonstrate Encore's utility in analysis of genetic sequencing data, we present an analysis of exome resequencing data from healthy individuals and those with Systemic Lupus Erythematous (SLE). Our results verify the importance of the previously associated SLE genesHLA‐DRBandNCF2, and these two genes had the highest gene‐gene interaction degrees among the susceptibility hubs. An additional 14 genes previously associated with SLE emerged in our epistasis network model of the exome data, and three novel candidate genes,ST8SIA4,CMTM4, andC2CD4B, were implicated in the model. In summary, we present a comprehensive tool for epistasis network analysis and the first such analysis of exome data from a genetic study of SLE.
Haplotype Kernel Association Test as a Powerful Method to Identify Chromosomal Regions Harboring Uncommon Causal Variants
Authors: Lin Wan‐Yu , Yi Nengjun , Lou Xiang‐Yang , Zhi Degui , Zhang Kui , Gao Guimin , Tiwari Hemant K. , Liu Nianjun
Published: June 2013

For most complex diseases, the fraction of heritability that can be explained by the variants discovered from genome‐wide association studies is minor. Although the so‐called “rare variants” (minor allele frequency [MAF] < 1%) have attracted increasing attention, they are unlikely to account for much of the “missing heritability” because very few people may carry these rare variants. The genetic variants that are likely to fill in the “missing heritability” include uncommon causal variants (MAF < 5%), which are generally untyped in association studies using tagging single‐nucleotide polymorphisms (SNPs) or commercial SNP arrays. Developing powerful statistical methods can help to identify chromosomal regions harboring uncommon causal variants, while bypassing the genome‐wide or exome‐wide next‐generation sequencing. In this work, we propose a haplotype kernel association test (HKAT) that is equivalent to testing the variance component of random effects for distinct haplotypes. With an appropriate weighting scheme given to haplotypes, we can further enhance the ability ofHKATto detect uncommon causal variants. With scenarios simulated according to the population genetics theory,HKATis shown to be a powerful method for detecting chromosomal regions harboring uncommon causal variants.
Sea‐state‐dependent wind work on the oceanic general circulation
Authors: Liu Guoqiang , Perrie William
Published: June 2013

We examine sea‐state‐dependent wind work on the oceanic general circulation, using a wave hindcast dataset, QuikSCAT winds, and geostrophic and total ocean surface currents from (1) AVISO and (2) ECCO2 model products. For wind work on surface geostrophic currents estimated from AVISO or ECCO2, sea‐state‐dependent wind stress increases an average of 24% (0.17TW) or 23% (0.15TW), compared with estimates that exclude sea state effects. For wind work on the total surface currents, the sea‐state‐dependent wind stress increases the wind work by about 24% (0.4TW). In terms of spatial distribution, the increase in wind power input occurs mainly in high‐wind tropical regions and the mid‐latitude storm track regions, like the Antarctic Circumpolar Current region, where the relatively rough ocean surface is characterized by young waves and high winds. By comparison, in some regions with relatively low winds and mature ocean waves, there is a slight reduction in estimated wind power input.
Evolution and slow decay of an unusual narrow ring of relativistic electrons near L ~ 3.2 following the September 2012 magnetic storm
Authors: Thorne R. M. , Li W. , Ni B. , Ma Q. , Bortnik J. , Baker D. N. , Spence H. E. , Reeves G. D. , Henderson M. G. , Kletzing C. A. , Kurth W. S. , Hospodarsky G. B. , Turner D. , Angelopoulos V.
Published: June 2013

A quantitative analysis is performed on the decay of an unusual ring of relativistic electrons between 3 and 3.5 RE, which was observed by the Relativistic Electron Proton Telescope instrument on the Van Allen probes. The ring formed on 3 September 2012 during the main phase of a magnetic storm due to the partial depletion of the outer radiation belt for L > 3.5, and this remnant belt of relativistic electrons persisted at energies above 2 MeV, exhibiting only slow decay, until it was finally destroyed during another magnetic storm on 1 October. This long‐term stability of the relativistic electron ring was associated with the rapid outward migration and maintenance of the plasmapause to distances greater than L = 4. The remnant ring was thus immune from the dynamic process, which caused rapid rebuilding of the outer radiation belt at L > 4, and was only subject to slow decay due to pitch angle scattering by plasmaspheric hiss on timescales exceeding 10–20 days for electron energies above 3 MeV. At lower energies, the decay is much more rapid, consistent with the absence of a long‐duration electron ring at energies below 2 MeV.
Atmospheric annular modes in simulations over the past millennium: No long‐term response to external forcing
Authors: Gómez‐Navarro J. J. , Zorita E.
Published: June 2013

This study analyzes whether the imprint of external forcings can be detected in the long‐term evolution of the main atmospheric circulation patterns in climate simulations over the last millennium. The external forcing is not found to significantly add variability in any frequency band compared to control simulations where the external drivers are kept constant. Additionally, a method designed to detect a common signal in the time evolution of these circulation patterns among all simulations is proposed, and employed to demonstrate that the null hypothesis of an evolution dominated by internal variability cannot be rejected regardless of the time smoothing applied to the series. Given that the fingerprint of external forcings on atmospheric circulation has been successfully detected in simulations of the 20th century climate and in future climate change projections, we argue that either the effect of past natural forcing is too small, state‐of‐the‐art climate models underestimate their climate sensitivity, or the anthropogenic forcing qualitatively differs from the natural forcing in its effect on main circulation patterns.
Exploring the impacts of personal factors on self‐leadership in a hospital setting
Authors: Ugurluoglu Ozgur , Saygılı Meltem , Ozer Ozlem , Santas Fatih
Published: June 2013

Self‐leadership may be defined as a self‐effecting process that individuals experience by maintaining the motivation they require for fulfilling their roles and duties. The self‐leadership process comprises three key strategies: behaviour‐oriented strategies, natural reward strategies and constructive thought pattern strategies. What is intended herein is to inquire about the implementation of self‐leadership within organisations and to examine the effects of such variables as age, gender, total terms of employment, marital status and education on self‐leadership strategies. The primary data collection instrument was a survey distributed to 450 personnel working at a state hospital in Kırıkkale, Turkey, and feedback thereto was received from 308 (68.4%) of those surveyed. As a result of the findings taken from the analyses, age, total terms of employment and receipt of education in leadership affect the use of self‐leadership strategies. Although age and total terms of employment display a negative‐directional correlation with the self‐leadership strategies, female employees and those who receive education in leadership are more inclined towards self‐leadership strategies. Copyright © 2013 John Wiley & Sons, Ltd.
Coupled groundwater flow and heat transport simulation for estimating transient aquifer–stream exchange at the lowland River Spree (Germany)
Authors: Nützmann Gunnar , Levers Christian , Lewandowski Jörg
Published: June 2013

Subsurface flow and heat transport near Freienbrink, NE Germany, was simulated in order to study groundwater–surface water exchange between a floodplains aquifer and a section of the lowland River Spree and an adjacent oxbow. Groundwater exfiltration was the dominant process, and only fast surface water level rises resulted in temporary infiltration into the aquifer. The main groundwater flow paths are identified based on a 3D groundwater flow model. To estimate mass fluxes across the aquifer–surface water interfaces, a 2D flow and heat transport modelling approach along a transect of 12 piezometers was performed. Results of steady‐state and transient water level simulations show an overall high accuracy with a Spearman coefficient ρ = 0.9996 and root mean square error (RMSE) = 0.008 m. Based on small groundwater flow velocities of about 10−7 to 10−6 ms−1, mean groundwater exfiltration rates of 233 l m−2 d−1 are calculated. Short periods of surface water infiltration into the aquifer do not exceed 10 days, and the infiltration rates are in the same range. The heat transport was modelled with slightly less accuracy (ρ = 0.8359 and RMSE = 0.34 °C). In contrast to the predominant groundwater exfiltration, surface water temperatures determine the calculated temperatures in the upper aquifer below both surface water bodies down to 10 m during the whole simulation period. These findings emphasize prevailing of heat conduction over advection in the upper aquifer zones, which seems to be typical for lowland streams with sandy aquifer materials and low hydraulic gradients. Moreover, this study shows the potential of coupled numerical flow and heat transport modelling to understand groundwater–surface water exchange processes in detail. Copyright © 2013 John Wiley & Sons, Ltd.
Nanopore‐Based Analysis of Chemically Modified DNA and Nucleic Acid Drug Targets
Authors: Larkin Joseph , Carson Spencer , Stoloff Daniel H. , Wanunu Meni
Published: June 2013

Nucleic acids are central figures in many of life’s key molecular processes, e.g., enzymatic activity, epigenetics/gene regulation, viral replication, aging, cancer, and other diseases. Over the past two decades, nanopores have emerged as a new tool for studying the properties of nucleic acids at the single‐molecule level. In this review, we summarize the use of nanopores as sensors of nucleic acid structure, particularly for studying chemically modified and damaged DNA, and for probing the interactions of small‐molecule drugs with nucleic acid targets.
Ketoprofen: The European Experience
Authors: Avouac B. , Teule M.
Published: June 2013

An overview of European experience with ketoprofen, a nonsteroidal anti‐inflammatory drug (NSAID) with analgesic properties, from the time of its marketing in 1973 until the present is presented. Orally administered ketoprofen (200 mg/day) has been proven effective in treating rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. Furthermore, several alternate dosage forms, including intramuscular injection for relief of acutely painful conditions, suppositories, two slow‐release forms (a sustained‐release tablet [IBP 200®] and a controlled‐release capsule [Oruvaii®]), and a topical gel for local treatment of certain superficial conditions and minor rheumatologic disease are available. The safety of ketoprofen has also been proven in several European postmarketing surveillance studies and more importantly, by French and British drug monitoring data. Ketoprofen was rated as one of the safest NSAIDs available in the United Kingdom (UK) by the Committee on the Safety of Medicine in 1986. For incidence of gastrointestinal complaints per million prescriptions, ketoprofen ranked seventh among 19 NSAIDs in its first five years of marketing in the UK. Ketoprofen has been associated with a very low incidence of serious renal, hepatic, or cutaneous reactions. Thus ketoprofen, in 15 years of marketed use in Europe, has proven to be an effective anti‐inflammatory and analgesic agent with an excellent safety profile and several convenient dosage forms.
Double‐Blind Parallel Comparison of Ketoprofen (Orudis®), Acetaminophen Plus Codeine, and Placebo in Postoperative Pain
Authors: Turek M. D. , Baird W. M.
Published: June 2013

One hundred sixty‐one patients with postoperative pain were treated at a single center in a double‐blind, randomized, parallei study designed to compare the efficacy and safety of single oral doses of ketoprofen (50 and 150 mg), an acetaminophen (650 mg) plus codeine (60 mg) combination, and placebo. From 1 through 4 hours after administration of the study drugs, the mean summed pain intensity difference (SPID) and time‐weighted total pain relief (TOPAR) scores for the three active treatments generally were significantly (P < 0.05) higher than those for placebo but not significantly different from each other. At the 6‐hour evaluation, the ketoprofen groups, but not the acetaminophen‐codeine group, had higher (P < 0.05) mean SPID and TOPAR scores than the placebo group, as a result of a shorter duration of pain relief in the acetaminophen‐codeine group. The 6‐hour TOPAR scores were significantly (P < 0.05) higher for both ketoprofen groups than for the acetaminophen‐codeine group; the ketoprofen 150 mg group also had significantly (P < 0.05) higher mean 6‐hour SPID and global subjective assessment scores. As a result of a higher frequency of somnolence, there was a significantly (P < 0.05) greater incidence of central nervous system adverse drug reactions among patients treated with acetaminophen pius codeine than among those treated with 150 mg of ketoprofen. These results indicate that the analgesic efficacy of both 50 and 150 mg doses of ketoprofen equals that of acetaminophen 650 mg plus codeine 60 mg and the duration of the analgesic effect of ketoprofen is significantly longer.
Ketoprofen, Ibuprofen, and Placebo in the Treatment of Primary Dysmenorrhea: A Double‐Blind Crossover Comparison
Authors: Mehlisch Donald R.
Published: June 2013

Under double‐blind, crossover conditions, 43 women with primary dysmenorrhea received ketoprofen, ibuprofen, and placebo during three consecutive menstrual cycles. Pain intensity and pain relief were determined before and for 6 hours after the loading dose (ketoprofen 150 mg, ibuprofen 800 mg) and before and 2 hours after the maintenance dose (ketoprofen 75 mg, ibuprofen 400 mg). Mean pain intensity difference and pain relief scores consistently indicated greater pain relief after the loading doses of ketoprofen and ibuprofen than after placebo. Significant (P < 0.05) mean changes that were measured by 13 indices of analgesia after the loading doses of both ketoprofen and ibuprofen indicated greater efficacy for the active treatments than for placebo. The patients' giobai evaluations after the loading doses were significantly (P < 0.05) better for the active treatments than for piacebo. The efficacy results were similar after the maintenance doses. The rates of a “good” to “excellent” response were 77% for ketoprofen, 73% for ibuprofen, and 35% for placebo. Ketoprofen and ibuprofen were equally well tolerated, the most frequent adverse experiences being gastrointestinal symptoms for ketoprofen and central nervous system side effects for ibuprofen.
Analgesic Efficacy of Ketoprofen in Postpartum, General Surgery, and Chronic Cancer Pain
Authors: Sunshine Abraham , Olson Nancy Z.
Published: June 2013

This article summarizes the results of five single‐dose clinical studies of three pain models: postpartum, postoperative, and chronic cancer pain. The efficacy of ketoprofen (in varying doses from 25 to 225 mg) was compared with one of the following standards: aspirin (650 mg), codeine (90 mg), acetaminophen (650 mg) plus codeine (60 mg), and parenteral morphine (5 mg and 10 mg). The results indicate that ketoprofen in doses as low as 25 mg has analgesic properties significantly superior to those of placebo. For the treatment of postpartum pain, ketoprofen was significantly more effective than aspirin 650 mg but not significantly different from codeine 90 mg. Ketoprofen doses of 50 mg and 150 mg also provided analgesia superior to that with acetaminophen 650 mg plus codeine 60 mg for the management of moderate to severe postoperative pain. Moreover, oral doses of ketoprofen (75 and 225 mgj provided analgesia similar to that obtained with 5 and 10 mg parenteral doses of morphine. Adverse effects related to ketoprofen were relatively minor and infrequent. Ketoprofen was recently approved for use as an analgesic for treatment of mild to moderate pain in total daily doses up to 300 mg; the recommended initial dose is 25 to 50 mg every 6 to 8 hours as necessary.
Comparison of the Safety of Several Nonsteroidal Anti‐inflammatory Drugs Currently or Formerly Marketed in the United Kingdom
Authors: Speirs C. J.
Published: June 2013

Reports of suspected adverse reactions to nonsteroidal anti‐inflammatory drugs (NSAIDs) were related to estimated numbers of prescriptions for these drugs during the years 1968 to 1981. The 16 drugs first marketed during this period had similarly high initial rates of adverse effects reported, followed by a rapid decline. There was a marked variation between drugs in initial reporting rates. A number of factors may confound comparisons between drugs and appeared to apply to two drugs: fenbufen, for which the numbers of reports was increased by reports from a postmarketing surveillance study, and zomepirac, which was labeled and tested as a general analgesic (i.e., differently from the other NSAIDs). Otherwise, the drugs with higher initial rates of reported adverse experiences later were withdrawn from the market. Naproxen and ketoprofen, which were marketed the same year (1973) and used continuously for over 14 years in the United Kingdom, were associated with similar reporting patterns that were different from those for many other NSAIDS. It is concluded that anomalies in the frequency and pattern of suspected drug‐related adverse reactions in the absence of any confounding factor are an important signal of the need for further investigation.
Influence of chlorhexidine on dentin adhesive interface micromorphology and nanoleakage expression of resin cements
Authors: Scarabello Stape Thiago Henrique , Menezes Murilo De Sousa , Barreto Bruno De Castro Ferreira , Naves Lucas Zago , Baggio Aguiar Flávio Henrique , Quagliatto Paulo Sérgio , Marcondes Martins Luís Roberto
Published: June 2013

This study focused on adhesive interface morphologic characterization and nanoleakage expression of resin cements bonded to human dentin pretreated with 1% chlorhexidine (CHX). Thirty‐two non‐carious human third molars were ground flat to expose superficial dentin. Resin composite blocks were luted to the exposed dentin using one conventional (RelyX ARC) and one self‐adhesive resin cement (RelyX U100), with/without CHX pretreatment. Four groups (n = 8) were obtained: control groups (ARC and U100); experimental groups (ARC/CHX and U100/CHX) were pretreated with 1% CHX prior to the luting process. After storage in water for 24 h, the bonded teeth were sectioned into 0.9 × 0.9 mm2 sticks producing a minimum of 12 sticks per tooth. Four sticks from each tooth were prepared for hybrid layer evaluation by scanning electron microscope analysis. The remaining sticks were immersed in silver nitrate for 24 h for either nanoleakage evaluation along the bonded interfaces or after rupture. Nanoleakage samples were carbon coated and examined using backscattered electron mode. Well‐established hybrid layers were observed in the groups luted with RelyX ARC. Nanoleakage evaluation revealed increase nanoleakage in groups treated with CHX for both resin cements. Group U100/CHX exhibited the most pronouncing nanoleakage expression along with porous zones adjacent to the CHX pretreated dentin. The results suggest a possible incompatibility between CHX and RelyX U100 that raises the concern that the use of CHX with self‐adhesive cements may adversely affect resin‐dentin bond. Microsc. Res. Tech. 76:788–794, 2013. © 2013 Wiley Periodicals, Inc.
Precipitation extremes over the continental United States in a transient, high‐resolution, ensemble climate model experiment
Authors: Singh Deepti , Tsiang Michael , Rajaratnam Bala , Diffenbaugh Noah S.
Published: June 2013

Understanding future changes in the frequency, intensity, and duration of extreme events in response to increased greenhouse gas forcing is important for formulating adaptation and mitigation strategies that minimize damages to natural and human systems. We quantify transient changes in daily‐scale seasonal extreme precipitation events over the U.S. using a five‐member ensemble of nested, high‐resolution climate model simulations covering the 21st century in the Intergovernmental Panel on Climate Change (IPCC) Special Report on Emission Scenarios (SRES) A1B scenario. We find a strong drying trend in annual and seasonal precipitation over the Southwest in autumn, winter, and spring and over the central U.S. in summer. These changes are accompanied by statistically significant increases in dry‐day frequency and dry‐spell lengths. Our results also show substantial increases in the frequency of extreme wet events over the northwestern U.S. in autumn, winter, and spring and the eastern U.S. in spring and summer. In addition, the average precipitation intensity increases relative to the extreme precipitation intensity in all seasons and most regions, with the exception of the Southeast. Further, most regions receive a greater fraction of total seasonal precipitation from extreme events. These results imply fewer but heavier precipitation events in the future, leading to more frequent wet and dry extremes in most regions of the U.S. Our simulations suggest that many of these changes are likely to become statistically significant by the mid‐21st century. Given current vulnerabilities, such changes in extreme precipitation could be expected to increase stress on water resources in many areas of the U.S., including during the near‐term decades.
The free boundary problem of American butterfly option
Authors: Guan Chonghu , Yi Fahuai
Published: June 2013

This article aims to characterize behaviors of the free boundary arising from American butterfly option pricing. We prove the existence and uniqueness of the solution and free boundary. And then, we classify the shape of the free boundary under different conditions. The main contribution of this paper is to prove that the free boundary of evolutionary problem converges to the free boundary of stationary problem. Copyright © 2013 John Wiley & Sons, Ltd.
Derivation of Korteweg‐de Vries flow equations from fourth order nonlinear Schrödinger equation
Authors: Koparan Murat
Published: June 2013

We perform a multiple scale analysis on the fourth order nonlinear Schrödinger equation in the Hamiltonian form together with the Hamiltonian function. We derive, as amplitude equations, Korteweg‐de Vries flow equations in the bi‐Hamiltonian form with the corresponding Hamiltonian functions. Copyright © 2013 John Wiley & Sons, Ltd.
1H NMR metabolite fingerprinting as a new tool for body fluid identification in forensic science
Authors: Scano Paola , Locci Emanuela , Noto Antonio , Navarra Gabriele , Murgia Federica , Lussu Milena , Barberini Luigi , Atzori Luigi , De Giorgio Fabio , Rosa Maria Francesca , d'Aloja Ernesto
Published: June 2013

In this feasibility study, we propose, for the first time, 1H NMR spectroscopy coupled with mathematical strategies as a valid tool for body fluid (BF) trace identification in forensic science. In order to assess the ability of this approach to identify traces composed either by a single or by two different BFs, samples of blood, urine, saliva, and semen were collected from different donors, and binary mixtures were prepared. 1H NMR analyses were carried out for all samples. Spectral data of the whole set were firstly submitted to unsupervised principal component analysis (PCA); it showed that samples of the same BF cluster well on the basis of their characterizing molecular components and that mixtures exhibit intermediate characteristics among BF typologies. Furthermore, samples were divided into a training set and a test set. An average NMR spectral profile for each typology of BF was obtained from the training set and validated as representative of each BF class. Finally, a fitting procedure, based on a system of linear equations with the four obtained average spectral profiles, was applied to the test set and the mixture samples; it showed that BFs can be unambiguously identified, even as components of a mixture. The successful use of this mathematical procedure has the advantage, in forensics, of overcoming bias due to the analyst's personal judgment. We therefore propose this combined approach as a valid, fast, and non‐destructive tool for addressing the challenges in the identification of composite traces in forensics. Copyright © 2013 John Wiley & Sons, Ltd.
States of water, surface and rheological characterisation of a new biohydrogel as articular cartilage substitute
Authors: Leone Gemma , Bidini Alessandra , Lamponi Stefania , Magnani Agnese
Published: June 2013

PVA based hydrogel was synthesised using, as crosslinking agent, trisodium trimetaphosphate (STMP) and its morphology was modified inducing a microporous structure to obtain potential substitutes for cartilage tissue. The hydrogel was characterised by Infrared Spectroscopy combined with Time of flight mass spectrometry (ToF‐SIMS) that confirmed the successful occurrence of crosslinking reaction, the hyphotised crosslinking arm and its homogeneous distribution.

The mechanical spectra of the fully hydrated samples confirmed covalently crosslinked systems with a rheological behaviour similar to that of tibial cartilage. Further analysis in terms of water content measurements, thermal stability and cytotoxicity confirmed the applicability of such a hydrogel as cartilage substitute. Copyright © 2013 John Wiley & Sons, Ltd.
Effective childhood cancer treatment: The impact of large scale clinical trials in Germany and Austria
Authors: Rossig C. , Juergens H. , Schrappe M. , Moericke A. , Henze G. , von Stackelberg A. , Reinhardt D. , Burkhardt B. , Woessmann W. , Zimmermann M. , Gadner H. , Mann G. , Schellong G. , Mauz‐Koerholz C. , Dirksen U. , Bielack S. , Berthold F. , Graf N. , Rutkowski S. , Calaminus G. , Kaatsch P. , Creutzig U.
Published: June 2013

In Germany and Austria, more than 90% of pediatric cancer patients are enrolled into nationwide disease‐specific first‐line clinical trials or interim registries. Essential components are a pediatric cancer registry and centralized reference laboratories, imaging review, and tumor board assistance. The five‐year overall survival rate in countries where such infrastructures are established has improved from <20% before 1950 to >80% since 1995. Today, treatment intensity is tailored to the individual patient's risk to provide the highest chances of survival while minimizing deleterious late effects. Multicenter clinical trials are internationalized and serve as platforms for further improvements by novel drugs and biologicals. Pediatr Blood Cancer 2013;60:1574–1581. © 2013 Wiley Periodicals, Inc.
Validation of a Generic Quantitative 1H NMR Method for Natural Products Analysis
Authors: Gödecke Tanja , Napolitano José G. , Rodríguez‐Brasco María F. , Chen Shao‐Nong , Jaki Birgit U. , Lankin David C. , Pauli Guido F.
Published: June 2013

Introduction

Nuclear magnetic resonance (NMR) spectroscopy is increasingly employed in the quantitative analysis and quality control (QC) of natural products (NP) including botanical dietary supplements (BDS). The establishment of QC protocols based on quantitative 1H NMR (qHNMR) requires method validation.

Objective

Develop and validate a generic qHNMR method. Optimize acquisition and processing parameters, with specific attention to the requirements for the analysis of complex NP samples, including botanicals and purity assessment of NP isolates.

Methods

In order to establish the validated qHNMR method, samples containing two highly pure reference materials were used. The influence of acquisition and processing parameters on the method validation was examined, and general aspects of method validation of qHNMR methods discussed. Subsequently, the method established was applied to the analysis of two NP samples: a purified reference compound and a crude mixture.

Results

The accuracy and precision of qHNMR using internal or external calibration were compared, using a validated method suitable for complex samples. The impact of post‐acquisition processing on method validation was examined using three software packages: TopSpin, Mnova and NUTS. The dynamic range of the qHNMR method developed was 5000:1 with a limit of detection (LOD) of better than 10 µm. The limit of quantification (LOQ) depends on the desired level of accuracy and experiment time spent.

Conclusion

This study revealed that acquisition parameters, processing parameters and processing software all contribute to qHNMR method validation. A validated method with a high dynamic range and general workflow for qHNMR analysis of NP is proposed. Copyright © 2013 John Wiley & Sons, Ltd.