bluuebunny/crossref_metadata_2025 huggingface dataset:
Simulation of Electrical Properties of Grain Boundaries in Titanate Ceramics
Authors: Hagenbeck R. , Waser R.
Published: March 2014

Using a numerical simulation method, the electrostatic properties of grain boundaries in titanate ceramics (SrTiO3 and BaTiO3) are calculated by the combination of a defect chemistry model and the general potential equation. Based on these results and a simple three‐dimensional “brick‐wall‐model” of the ceramic microstructure, an equivalent network is developed for the ceramic body which consists of a great number of R C‐branches. Using this network it is possible to calculate the frequency dependence of the complex impedance of the ceramic. The results of the impedance simulation can be compared to experimental results. This comparison yields information about the charge transport across and along the grain boundaries and about the influence of the temperature, the bulk dopant concentrations, and the donor‐ or acceptor‐like grain boundary interface states on the electrical properties of the grain boundaries. By using the simulation technique one gets additional information to interpret and understand the experimental results and to model the physical and electrical behaviour of the grain boundaries which mainly determine the electrical characteristics of the ceramic.
First Principles Calculations of Solute‐Hole Interactions in the High Tc Oxyfluoride Superconductor Sr2CuO2F2
Authors: Mackrodt W.C. , Gotsis H.J. , Allan N.L.
Published: March 2014

First principles periodic Hartree‐Fock calculations are reported of the electronic and magnetic structures and hole states in the T (La2CuO4) phases of Sr2CuO2F2, Sr2CuO2F2.5 and NaSrCuO2F2. Sr2CuO2F2 is predicted to be a highly ionic antiferromagnetic charge transfer insulator with Cu in a d9 ((dx2–y2)1) configuration. Holes are predicted to be highly localised spin polarons which destroy the AF ordering at concentrations of 0.5 per formula unit.
Nonlinear Charge Transport in Acceptor‐Doped Titanates
Authors: Vollmann M. , Weber U. , Waser R.
Published: March 2014

The field‐enhanced conductivity of grain boundary space charge depletion layers in acceptor‐doped SrTiO3ceramics was investigated by impedance analysis in the time domain. The dependence of the GB conductivity on the external applied electrical field are discussed and interpreted in terms of a Schottky diffusion model.
Studying the Environments of Ion‐Implanted Arsenic Defects in Amorphous and Recrystallised Silicon with Impurity EXAFS
Authors: Greaves G.N. , Dent A.J. , Derst G. , Kalbitzer S. , Müller G.
Published: March 2014

With recent developments in solid state detectors combined with X‐rays at glancing angles of incidence, Extended X‐ray Absorption Fine Structure (EXAFS) experiments on arsenic ion‐implanted into amorphous silicon surfaces have been obtained at dilutions down to 0.01 at%. Structural relaxation processes in both hydrogen‐containing and hydrogen‐free material have been examined, including the effects of single doping and of counterdoping. In addition the different careers of solid phase epitaxy and amorphisation have been followed from the standpoint of the arsenic environment. EXAFS has been used to establish the degree of crystallinity in the vicinity of arsenic impurities at each stage so that this can be compared with the overall extent of crystalline order in the ion‐implanted silicon.
Defects in Cubic Zirconia Studied by Mechanical Loss Spectroscopy
Authors: Weller M. , Lakki A.
Published: March 2014

In cubic Y2O3 (10–25 mol%) or CaO (14 and 17 mol%) stabilized ZrO2, oxygen vacancies are created as charge‐compensating defects. Mechanical loss (internal friction) measurements are performed on single crystals of cubic zirconia with various orientation at frequencies of f ≈︁ 1 Hz and 1 kHz, to study the local crystallographic structure of the defects. The mechanical spectra show a composite loss maximum at 400–600 K consisting of two overlapping submaxima: I and IA in ZrO2‐Y2O3; I' and I'A in ZrO2‐CaO. Submaxima I (I') are assigned to defect pairs of oxygen vacancies and impurity atoms forming elastic (and electric) dipoles. These are oriented parallel to <111>, with the vacancy on nearest neighbour sites (trigonal symmetry). Submaxima IA(I'A) are attributed to relaxation of vacancies within Y‐ (or Ca‐) clusters with various sizes and configurations corresponding to lower defect symmetry. The electrical conductivity (4 probe d.c. technique) decreases for concentrations ≥10mol% Y2O3, whereas the activation enthalpy increases with Y2O3 content. A high temperature peak C in ZrO2‐CaO around 1400 K (0.1 Hz) is probably due to local atomic jumps of cations.
Quantum Wells within Quantum Dots, a CdS/HgS Nanoheterostructure with Global and Local Confinement
Authors: Mews Alf , Eychmüller Alexander
Published: March 2014

Semiconductor nanocrystals prepared by methods of wet chemistry are similar to MBE grown quantum dots where the mobility of the charge carriers is reduced to zero dimensionality. In this paper we summarize the physics of a unique system in which the charge carriers are locally confined within a heterogeneous quantum dot. With high resolution electron microscopy we will show that epitaxial growth ot atomic layer precision is possible by methods of solution chemistry leading to CdS quantum dots with embedded HgS quantum wells (QDQWs). The photophysics of this system is investigated by time‐correlated single photon counting, transient differential absorption and fluorescence line narrowing spectroscopies. The results reflect the very complex electronic structure of this new kind of matter which can be explained by an extended effective mass approach.
Investigation of the Pyrolysis and Crystallization of Lead Zirconate Titanate Ceramics Prepared via the Sol Gel Process
Authors: Brieger Jens , Merkle Rotraut , Bertagnolli Helmut , Müller Klaus
Published: March 2014

The sol gel process for the preparation of lead zirconate, lead titanate and lead zirconate titanate is studied by various experimental techniques, comprising solid state NMR methods, FT IR spectroscopy, DTA/TG and XRD. Two temperature ranges are examined that cover (i) the pyrolysis step from the solid gel to the amorphous oxide mixture and (ii) the calcination step from the amorphous state to the crystalline ceramics. 13C NMR and FT IR spectroscopy studies primarily are used to monitor the structural changes during the pyrolysis step. 207Pb NMR spectroscopy is employed to examine the development of the short range order at the lead nuclei over the whole temperature range. The latter studies clearly show that the observed changes in the short range order are accompanied by alterations in the long range order, as derived from the XRD data. In addition, 207Pb NMR experiments are performed on ceramic samples that were obtained via the sol gel or the mixed oxide route. It is demonstrated that these samples exhibit significant differences in the short range order, although the long range order was found to be the same, being independent of the actual preparation route.
Hydrogen Carbonate Inhibited and Induced Substitution Reactions of Labile Square‐Planar Diethylenetriaminepalladium(II) Complexes
Authors: Breet Ernst , van Eldik Rudi
Published: March 2014

The reaction of labile square‐planar diethylenetriaminepalladium(II) complexes with hydrogen carbonate ion was studied by stopped flow spectrophotometry as a function of [HCO−3] and [Cl−] and constant [Pd], ionic strength and temperature to investigate the substitution behaviour with a nucleophile capable of affecting the solution pH. The kinetic results significantly deviate from those for normal square‐planar substitution behaviour. The reaction comprises two consecutive equilibrations, which have complex kinetics compared to the simple two‐term rate law normally encountered, and which represent hydrogen carbonate inhibited and induced substitution reactions, respectively. The suggested mechanism and data treatment account for the observed deviating kinetics and provide alternative ways of obtaining formerly determined aquation and anation rate constants with comparable accuracy, even for complexes too labile to be monitored directly.
Shock Tube Study of the Reaction of Si Atoms with SiCl4
Authors: Kunz A. , Roth P.
Published: March 2014

The reaction of Si atoms with SiCl4 was studied behind reflected shock waves at temperatures between 1530 and 1800 K and pressures around 1.7 bar by applying atomic resonance absorption spectroscopy (ARAS) for time‐resolved measurement of Si atoms. The thermal decomposition of a few ppm Si2H6 was used as source for Si‐atoms. The presence of an excess of SiCl4 causes a fast consumption of Si atoms, which follows a pseudo‐first‐order rate law. The rate coefficient for the reaction of Si atoms with SiCl4

magnified image

was determined to be:

k1 = 4.0±0.2×1013cm3 mol−1s−1

with no observable temperature dependence in the temperature range of the present study.
Characterization of preclinical in vitro and in vivo ADME properties and prediction of human PK using a physiologically based pharmacokinetic model for YQA‐14, a new dopamine D3 receptor antagonist candidate for treatment of drug addiction
Authors: Liu Fei , Zhuang Xiaomei , Yang Cuiping , Li Zheng , Xiong Shan , Zhang Zhiwei , Li Jin , Lu Chuang , Zhang Zhenqing
Published: March 2014

YQA‐14 is a novel and selective dopamine D3 receptor antagonist, with potential for the treatment of drug addiction. However, earlier compounds in its structural class tend to have poor oral bioavailability. The objectives of this study were to characterize the preclinical absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK) of YQA‐14, then to simulate the clinical PK of YQA‐14 using a physiologically based pharmacokinetics (PBPK) model to assess the likelihood of developing YQA‐14 as a clinical candidate. For human PK prediction, PBPK models were first built in preclinical species, rats and dogs, for validation purposes. The model was then modified by input of human in vitro ADME data obtained from in vitro studies. The study data showed that YQA‐14 is a basic lipophilic compound, with rapid absorption (Tmax ~ 1 h) in both rats and dogs. Liver microsomal clearances and in vivo clearances were moderate in rats and dogs consistent with the moderate bioavailability observed in both species. The PBPK models built for rats and dogs simulated the observed PK data well in both species. The PBPK model refined with human data predicted that YQA‐14 would have a clearance of 8.0 ml/min/kg, a volume distribution of 1.7 l/kg and a bioavailability of 16.9%. These acceptable PK properties make YQA‐14 an improved candidate for further research and development as a potential dopamine D3R antagonism for the treatment of drug addiction in the clinic. Copyright © 2014 John Wiley & Sons, Ltd.
Chromosome replication origins: Do we really need them?
Authors: Michel Bénédicte , Bernander Rolf
Published: March 2014

Replication of the main chromosome in the halophilic archaeon Haloferax volcanii was recently reported to continue despite deletion of all active replication origins. Equally surprising, the deletion strain grew faster than the parent strain. It was proposed that origin‐less H. volcanii duplicate their chromosomes via recombination‐dependent replication. Here, we recall our present knowledge of this mode of chromosome replication in different organisms. We consider the likelihood that it accounts for the viability of H. volcanii deleted for its main specific replication origins, as well as possible alternative interpretations of the results. The selective advantages of having defined chromosome replication origins are discussed from a functional and evolutionary perspective.
Semiparametric empirical likelihood confidence intervals for the difference of areas under two correlated ROC curves under density ratio model
Authors: Zhang Dong , Zhang Biao
Published: March 2014

The area under the receiver operating characteristic (ROC) curve, AUC, is commonly used to assess the ability of a diagnostic test to correctly classify individuals into diseased and nondiseased populations. When there are two diagnostic tests available, it is of interest to evaluate and compare their performances. Based on the difference of two placement values, we propose a two‐sample empirical likelihood method for comparing AUCs of two ROC curves. The proposed empirical likelihood ratio statistic converges in distribution to a scaled chi‐squared random variable. Simulation results show that the proposed empirical likelihood method has better finite‐sample performance than other competitors.
Fragmented proteins as food emulsion stabilizers: A theoretical study
Authors: Ettelaie Rammile , Zengin Adem , Lee Hazel
Published: March 2014

Using a model based on the primary structure of αs1‐casein, the colloid stabilizing ability of fragmented protein and that of the intact chains are compared. We perform self consistent field (SCF) calculations to obtain the induced interaction potentials between the oil droplets, resulting from the overlap of adsorbed protein layers in each case. For the intact αs1‐casein, we confirm the known result, that the mediated interparticle interaction potential develops a deep attractive energy minimum at high salt concentrations and pH values close to the isoelectric point of the protein. The same does not occur for the appropriately fragmented systems, with improved emulsion stability predicted as a result, even at pH values close to pI. It is shown that this superior performance, for the case considered, is due to the diblock‐type behavior of one of the fragments. However, it is well known that αs1‐casein more closely resembles the less favorable triblock structure. However, it is also demonstrated that the presence of a “diblock” like fragment by itself may not always be enough to produce a better emulsion stabilizer. It is seen that the hydrolysis of some peptide bonds may indeed lead to a suitable polypeptide, but that this is displaced from the interface by the structurally less desirable ones, also generated by the fragmentation process. The displacement occurs due to the competitive adsorption between different fragments. The removal of the undesirable fragments from the solution is found to greatly enhance the predicted colloid stabilizing ability of the remaining polypeptide. © 2014 Wiley Periodicals, Inc. Biopolymers 101: 945–958, 2014.
Modern treatment in chronic lymphocytic leukemia: impact on survival and efficacy in high‐risk subgroups
Authors: Cuneo Antonio , Cavazzini Francesco , Ciccone Maria , Daghia Giulia , Sofritti Olga , Saccenti Elena , Negrini Massimo , Rigolin Gian Matteo
Published: March 2014

Treatment of chronic lymphocytic leukemia (CLL) has dramatically changed over the last years, with significant improvement in overall survival (OS) and increased efficacy in genetically defined “high‐risk” disease. Besides prospective clinical trials usually enrolling young and fit patients, retrospective studies were performed comparing the outcome of patients belonging to different age groups and showing longer survival in patients diagnosed in the most recent periods. In patients younger than 70 years the 10‐year relative survival was 43–53% in the 1980s as compared with 59–63% in the 2000s. Likewise, the 10‐year relative survival in patients >70 years was 22–42% in the 1980s and 46–55% in the 2000s. Improved outcome derived in part by the introduction of effective regimens in genetically defined “high‐risk” disease (i.e., 17p−, 11q−, TP53, NOTCH1, SF3B1 mutations), especially in the younger and/or fit patients. The unfavorable prognostic significance of 11q− was overcome by chemoimmunotherapy. High‐dose steroids with anti‐CD52 appeared to improve the response rate in 17p‐/TP53 mutated cases and allogeneic transplantation achieved prolonged disease control irrespective of high‐risk disease. Further improvement is being generated by the new anti‐CD20 obinutuzumab in the elderly and by mechanism‐based treatment using kinase‐targeting agents or anti‐BCL2 molecules yielding high‐response rate and impressive progression‐free survival in the chemorefractory setting as well as in previously untreated patients.
Tumor cell‐expressed SerpinB2 is present on microparticles and inhibits metastasis
Authors: Schroder Wayne A. , Major Lee D. , Le Thuy T. , Gardner Joy , Sweet Matthew J. , Janciauskiene Sabina , Suhrbier Andreas
Published: March 2014

Expression of SerpinB2 (plasminogen activator inhibitor type 2/PAI‐2) by certain cancers is associated with a favorable prognosis. Although tumor‐associated host tissues can express SerpinB2, no significant differences in the growth of a panel of different tumors in SerpinB2−/− and SerpinB2+/+ mice were observed. SerpinB2 expression by cancer cells (via lentiviral transduction) also had no significant effect on the growth of panel of mouse and human tumor lines in vivo or in vitro. SerpinB2 expression by cancer cells did, however, significantly reduce the number of metastases in a B16 metastasis model. SerpinB2‐expressing B16 cells also showed reduced migration and increased length of invadopodia‐like structures, supporting the classical view that that tumor‐derived SerpinB2 is inhibiting extracellular urokinase. Importantly, although SerpinB2 is usually poorly secreted, we found that SerpinB2 effectively reaches the extracellular milieu on the surface of 0.5–1 μm microparticles (MPs), where it was able to inhibit urokinase. We also provide evidence that annexins mediate the binding of SerpinB2 to phosphatidylserine, a lipid characteristically exposed on the surface of MPs. The presence of SerpinB2 on the surface of MPs provides a physiological mechanism whereby cancer cell SerpinB2 can reach the extracellular milieu and access urokinase plasminogen activator (uPA). This may then lead to inhibition of metastasis and a favorable prognosis.
Acute renal failure in a Caucasian traveler with severe malaria: a case report
Authors: Meremo Alfred J. , Kilonzo Semvua B. , Munisi David , Kapinga Janet , Juma Mwinyikondo , Mwanakulya Simfukwe , Mpondo Bonaventura
Published: March 2014

Key Clinical Message

Acute renal failure (ARF) secondary to severe malaria is uncommon. We report a case of a patient visiting Africa for the first time presenting with malaria and ARF. There was complete recovery after hemodialysis. Early initiation of hemodialysis proves to be useful in restoration of renal function.
Simulation of Multi‐Stage Particle Classification in a Zigzag Apparatus
Authors: Hagemeier Thomas , Glöckner Hannes , Roloff Christoph , Thévenin Dominique , Tomas Jürgen
Published: March 2014

The separation efficiency of a pilot‐scale zigzag apparatus is investigated numerically using computational fluid dynamics simulations and discrete particle modeling in a coupled manner. The effects of various process variables, like particle size and air flow velocity, and of turbulence models were analyzed. The resulting changes concerning the process performance expressed by separation function and sharpness are discussed. Moreover, the residence time distribution was found to differ for fine and coarse particle discharges. Small particles are easily carried away by the fluid and respond immediately to almost every change in flow velocity. Therefore, they are affected by vortices, which increase their residence times compared to bigger particles.
Comparison of a Molecular and an Immobilized Gadolinium(III)‐tris[(1R,4S)‐3‐heptafluorobutanoyl‐camphor] as Catalyst in the Asymmetric Danishefsky‐Hetero‐Diels‐Alder‐Reaction
Authors: Stockinger Skrollan , Trapp Oliver
Published: March 2014

On‐column reaction gas chromatography combines the power of separation and rapid analysis of reactants and reaction products with screening of reactions in a single step. Not only conversions but the reaction rates at various temperatures can be obtained from single measurements, making this approach superior to the time‐consuming measurements typically performed in reaction progress analysis. However, this approach has only been used in the investigation of interconversion processes, rearrangement reactions, and only a few examples of higher‐order reactions are known. Here we present the screening of immobilized gadolinium(III)‐tris[(1R,4S)‐3‐heptafluorobutanoyl‐camphor] in the Danishefsky‐hetero‐Diels‐Alder‐reaction by enantioselective on‐column reaction gas chromatography utilizing cryogenic focusing to achieve catalytic conversions in this higher‐order reaction and subsequent separation of the enantiomeric product mixture to determine the enantiomeric ratio. The results obtained by this approach could be transferred to the conventional batch reaction at a larger scale, demonstrating that on‐column reaction chromatography provides reliable results in the screening of enantioselective reactions. Chirality 26:243–248, 2014. © 2014 Wiley Periodicals, Inc.
Conformational Stable Alleno‐Acetylenic Cyclophanes Bearing Chiral Axes
Authors: Lahoz Inmaculada R. , Castro‐Fernández Silvia , Navarro‐Vázquez Armando , Alonso‐Gómez José Lorenzo , Magdalena Cid M.
Published: March 2014

The design and synthesis of chiral cyclophanes containing signaling functional groups as an integral part of the macrocyclic framework offer promising possibilities for chiral sensing, molecular recognition, and chiral supramolecular architectures. Our research group has been involved in the construction and study of chiroptical properties of several allenic meta‐ and para‐cyclophanes bearing anthracene and pyridine rings as spacers. A revision of our results is presented. Chirality 26:563–573, 2014. © 2014 Wiley Periodicals, Inc.
Asymmetric Addition of Triethylaluminium to Aromatic Aldehydes Catalyzed by Titanium‐(5,5’‐Biquinoline‐6,6’‐Diol) Complexes
Authors: Chen Qian , Ou Jun , Chen Guo‐Shu , Liu Tian‐Hui , Xie Bin , Liang Hai‐Bo , Xie Li‐Qiong , Chen Yi‐Xin
Published: March 2014

A novel convenient procedure for the resolution of 5,5’‐biquinoline‐6,6’‐diol (BIQOL) was achieved by separating the corresponding diastereomeric mixture of (S)‐(+)‐camphorsulfonates on a semiprepared XDB‐C8 column followed by hydrolysis. The efficient asymmetric addition of triethylaluminium to aromatic aldehydes catalyzed by Ti‐(+)/(–)BIQOL complexes under mild conditions is described. The reactions led to the formation of 1‐arylpropan‐1‐ol in up to 87.5% ee. Chirality 26:268‐271, 2014. © 2014 Wiley Periodicals, Inc.
Comparison of Experimental and Calculated Chiroptical Spectra for Chiral Molecular Structure Determination
Authors: Polavarapu Prasad L. , Covington Cody L.
Published: March 2014

For three different chiroptical spectroscopic methods, namely, vibrational circular dichroism (VCD), electronic circular dichroism (ECD), and Raman optical activity (ROA), the measures of similarity of the experimental spectra to the corresponding spectra predicted using quantum chemical theories are summarized. In determining the absolute configuration and/or predominant conformations of chiral molecules, these similarity measures provide numerical estimates of agreement between experimental observations and theoretical predictions. Selected applications illustrating the similarity measures for absorption, circular dichroism, and corresponding dissymmetry factor (DF) spectra, in the case of VCD and ECD, and for Raman, ROA, and circular intensity differential (CID) spectra in the case of ROA, are presented. The analysis of similarity in DF or CID spectra is considered to be much more discerning and accurate than that in absorption (or Raman) and circular dichroism (or ROA) spectra, undertaken individually. Chirality 26:539–552, 2014. © 2014 Wiley Periodicals, Inc.
Early Maladaptive Schemas: A Comparison Between Bipolar Disorder and Major Depressive Disorder
Authors: Nilsson Kristine Kahr , Nielsen Straarup Krista , Halvorsen Marianne
Published: March 2014

Background

It is still unclear how bipolar disorder (BD) differentiates from major depressive disorder (MDD) outside major mood episodes. To further elucidate this area, the present study compared the two mood disorders in terms of early maladaptive schemas (EMSs) during remission.

Method

The sample consisted of 49 participants with BD and 30 participants with MDD who were currently in remission. The participants completed the Young Schema Questionnaire.

Results

The BD group scored significantly higher than the MDD group on seven EMSs: abandonment, failure to achieve, insufficient self‐control, subjugation, unrelenting standards, enmeshment and entitlement.

Conclusion

By suggesting that EMSs are more severe in BD compared with MDD, the findings highlight potential vulnerabilities in BD, which merit further examination in terms of their underlying causes and potential treatment implications. Copyright © 2014 John Wiley & Sons, Ltd.

Key Practitioner Message

Early maladaptive schemas are relevant psychological dimensions to consider in remitted phases of major mood disorders.

Findings from the current study suggest that early maladaptive schemas are more prevalent in adults with bipolar disorder compared to adults with major depressive disorder when measured during remission.

Interventions targeting early maladaptive schemas may be valuable in treatment of bipolar disorder.
Primary effusion lymphoma with aberrant T‐cell phenotype in an iatrogenically immunosuppressed renal transplant male: Cytologic diagnosis in peritoneal fluid
Authors: Kalogeraki A. , Haniotis V. , Karvelas‐Kalogerakis M. , Karvela‐Kalogeraki I. , Psyllaki M. , Tamiolakis D.
Published: March 2014

Primary effusion lymphoma (PEL) is an unusual class of non‐Hodgkin's lymphoma that develops in body cavities, without associated mass lesions. It has been linked to human herpes virus 8 (HHV‐8), an etiological factor of Kaposi's sarcoma. Although PEL is a B‐cell lymphoma, the neoplastic cells are usually of the “null” phenotype by immunocytochemistry. The relative infrequency of this entity, the absence of wide casuistic allowing a better characterization, and its unfavorable outcome, strongly support the need of a deeper knowledge. We report the clinico‐biological findings of a 49‐year‐old male who was iatrogenically suppressed patient for 29 years because of renal transplantation. This case was diagnosed cytologically as peritoneal PEL and confirmed histologically on peritoneal biopsies. The immune status for both HHV‐8 and Epstein–Barr virus (EBV) was evaluated and showed positive immunostaining only for the former. The combination of the immunocytochemistry results with the existence of a clonal rearrangement in the immunoglobulin heavy chain gene (identified by PCR) was compatible with the diagnosis of PEL. The presence of T‐cell markers was consistent with the diagnosis of PEL with an aberrant T‐cell phenotype. Diagn. Cytopathol. 2015;43:144–148. © 2014 Wiley Periodicals, Inc.
A Perceptual Learning Deficit in Chinese Developmental Dyslexia as Revealed by Visual Texture Discrimination Training
Authors: Wang Zhengke , Cheng‐Lai Alice , Song Yan , Cutting Laurie , Jiang Yuzheng , Lin Ou , Meng Xiangzhi , Zhou Xiaolin
Published: March 2014

Learning to read involves discriminating between different written forms and establishing connections with phonology and semantics. This process may be partially built upon visual perceptual learning, during which the ability to process the attributes of visual stimuli progressively improves with practice. The present study investigated to what extent Chinese children with developmental dyslexia have deficits in perceptual learning by using a texture discrimination task, in which participants were asked to discriminate the orientation of target bars. Experiment l demonstrated that, when all of the participants started with the same initial stimulus‐to‐mask onset asynchrony (SOA) at 300 ms, the threshold SOA, adjusted according to response accuracy for reaching 80% accuracy, did not show a decrement over 5 days of training for children with dyslexia, whereas this threshold SOA steadily decreased over the training for the control group. Experiment 2 used an adaptive procedure to determine the threshold SOA for each participant during training. Results showed that both the group of dyslexia and the control group attained perceptual learning over the sessions in 5 days, although the threshold SOAs were significantly higher for the group of dyslexia than for the control group; moreover, over individual participants, the threshold SOA negatively correlated with their performance in Chinese character recognition. These findings suggest that deficits in visual perceptual processing and learning might, in part, underpin difficulty in reading Chinese. Copyright © 2014 John Wiley & Sons, Ltd.
The type 1 diabetes resistance locus B10 Idd9.3 mediates impaired B‐cell lymphopoiesis and implicates microRNA‐34a in diabetes protection
Authors: Berry Gregory J. , Budgeon Lynn R. , Cooper Timothy K. , Christensen Neil D. , Waldner Hanspeter
Published: March 2014

NOD.B10 Idd9.3 mice are congenic for the insulin‐dependent diabetes (Idd) Idd9.3 locus, which confers significant type 1 diabetes (T1D) protection and encodes 19 genes, including microRNA (miR)‐34a, from T1D‐resistant C57BL/10 mice. B cells have been shown to play a critical role in the priming of autoantigen‐specific CD4+ T cells in T1D pathogenesis in non‐obese diabetic (NOD) mice. We show that early B‐cell development is impaired in NOD.B10 Idd9.3 mice, resulting in the profound reduction of transitional and mature splenic B cells as compared with NOD mice. Molecular analysis revealed that miR‐34a expression was significantly higher in B‐cell progenitors and marginal zone B cells from NOD.B10 Idd9.3 mice than in NOD mice. Furthermore, miR‐34a expression in these cell populations inversely correlated with levels of Foxp1, an essential regulator of B‐cell lymphopoiesis, which is directly repressed by miR‐34a. In addition, we show that islet‐specific CD4+ T cells proliferated inefficiently when primed by NOD.B10 Idd9.3 B cells in vitro or in response to endogenous autoantigen in NOD.B10 Idd9.3 mice. Thus, Idd9.3‐encoded miR‐34a is a likely candidate in negatively regulating B‐cell lymphopoiesis, which may contribute to inefficient expansion of islet‐specific CD4+ T cells and to T1D protection in NOD.B10 Idd9.3 mice.
Analytical QbD: Development of a native gel electrophoresis method for measurement of monoclonal antibody aggregates
Authors: Pathak Mili , Dutta Debayon , Rathore Anurag
Published: March 2014

This paper presents a quality by design (QbD) based development of a novel native PAGE (N‐PAGE) method as a low‐cost analytical tool for analysis of aggregates of monoclonal antibodies. Comparability to the present gold standard of SEC has been established. The motivation is the fact that SEC requires relatively expensive equipment and consumables, thus making N‐PAGE relevant to those academicians and other small companies involved in early‐stage development of biotherapeutics that do not have access to SEC, especially in developing countries. Furthermore, SEC suffers from certain disadvantages including the possibility of secondary interactions between the stationary phase and analyte resulting in higher elution time and therefore underestimation of the analyte size. The proposed N‐PAGE method can also serve as an orthogonal analytical method for aggregate analysis. A QbD‐based approach has been used for development and optimization of the protocol. First, initial screening studies were carried out with parameters including the running buffer pH, running buffer molarity, gel buffer pH, loading dye, sample concentration, and running voltage. Next, optimization of operating parameters was performed using principles of design of experiments. The final optimized protocol was compared to the traditional SEC method and the results were found to be comparable. While N‐PAGE has been in use for protein analysis for several decades, use of N‐PAGE for analysis of mAb aggregates with data comparable to SEC such as the case presented here is novel.
A magic bullet to specifically eliminate mutated mitochondrial genomes from patients' cells
Authors: Moraes Carlos T
Published: March 2014

When mitochondrial diseases result from mutations found in the mitochondrial DNA, engineered mitochondrial‐targeted nucleases such as mitochondrial‐targeted zinc finger nucleases are shown to specifically eliminate the mutated molecules, leaving the wild‐type mitochondrial DNA intact to replicate and restore normal copy number. In this issue, Gammage and colleagues successfully apply this improved technology on patients' cells with two types of genetic alterations responsible for neuropathy ataxia and retinitis pigmentosa (NARP) syndrome and Kearns Sayre syndrome and progressive external ophthalmoplegia (PEO).
The heart‐liver metabolic axis: defective communication exacerbates disease
Authors: Baskin Kedryn K , Bookout Angie L , Olson Eric N
Published: March 2014

The heart has been recognized as an endocrine organ for over 30 years (de Bold, ); however, little is known about how the heart communicates with other organs in the body, and even less is known about this process in the diseased heart. In this issue of EMBO Molecular Medicine, Magida and Leinwand () introduce the concept that a primary genetic defect in the heart results in aberrant hepatic lipid metabolism, which consequently exacerbates hypertrophic cardiomyopathy (HCM). This study provides evidence in support of the hypothesis that crosstalk occurs between the heart and liver, and that this becomes disrupted in the diseased state.
The importance of experimental time when assessing the effect of temperature on toxicity in poikilotherms
Authors: Nørhave Nils J. , Spurgeon David , Svendsen Claus , Cedergreen Nina
Published: March 2014

Temperature is an important factor affecting toxicity, determining chemical toxicokinetics and toxicodynamics in poikilothermic organisms. Because metabolic rates are also affected by temperature, interactions between the emergence of toxic effects and time are very likely. The aim of the present study was to investigate how temperature affects the toxicity of copper toward the nematode Caenorhabditis elegans when measured during short, fixed time frames compared with full life cycles. Copper toxicity was tested in 2 experiments at 4 or 6 temperatures in the range of 11 °C to 24 °C, with Cu concentrations spanning from 1 mg Cu/L agar to 40 mg Cu/L agar, respectively. Reproduction and mortality were determined across the entire life cycle, and the time to production of first egg and the population growth rate were calculated. The results showed that the 50% effect concentrations (EC50s) of Cu increased 1.5-fold to 2.5-fold with increasing temperature within the tested range, depending on endpoint. When calculating EC50 on reproduction after 24 h or 96 h, the typical setup for temperature-chemical interaction studies, results ranged from no temperature effect to effects much larger than those for the full life cycle. Studies of temperature effects on toxicity must therefore be carefully designed in relation to the research question being investigated. Environ Toxicol Chem 2014;33:1363–1371. © 2014 SETAC
What Do the Next 25 Years Hold for HRD Research in Areas of Our Interest?
Authors: Russ‐Eft Darlene , Watkins Karen E. , Marsick Victoria J. , Jacobs Ronald L. , McLean Gary N.
Published: March 2014

This invited feature article presents the perspectives of five highly recognized and influential HRD Scholars who are also past and present leaders within the Academy of Human Resource Development. These scholars were asked to reflect on the past and present of research in an area of their interest and expertise and they have each offered projections for the next 25 years of HRD Research in their respective areas.
Eicosapentaenoic acid free fatty acid prevents and suppresses colonic neoplasia in colitis‐associated colorectal cancer acting on Notch signaling and gut microbiota
Authors: Piazzi Giulia , D'Argenio Giuseppe , Prossomariti Anna , Lembo Vincenzo , Mazzone Giovanna , Candela Marco , Biagi Elena , Brigidi Patrizia , Vitaglione Paola , Fogliano Vincenzo , D'Angelo Leonarda , Fazio Chiara , Munarini Alessandra , Belluzzi Andrea , Ceccarelli Claudio , Chieco Pasquale , Balbi Tiziana , Loadman Paul M. , Hull Mark A. , Romano Marco , Bazzoli Franco , Ricciardiello Luigi
Published: March 2014

Inflammatory bowel diseases are associated with increased risk of developing colitis‐associated colorectal cancer (CAC). Epidemiological data show that the consumption of ω‐3 polyunsaturated fatty acids (ω‐3 PUFAs) decreases the risk of sporadic colorectal cancer (CRC). Importantly, recent data have shown that eicosapentaenoic acid‐free fatty acid (EPA‐FFA) reduces polyp formation and growth in models of familial adenomatous polyposis. However, the effects of dietary EPA‐FFA are unknown in CAC. We tested the effectiveness of substituting EPA‐FFA, for other dietary fats, in preventing inflammation and cancer in the AOM‐DSS model of CAC. The AOM‐DSS protocols were designed to evaluate the effect of EPA‐FFA on both initiation and promotion of carcinogenesis. We found that EPA‐FFA diet strongly decreased tumor multiplicity, incidence and maximum tumor size in the promotion and initiation arms. Moreover EPA–FFA, in particular in the initiation arm, led to reduced cell proliferation and nuclear β‐catenin expression, whilst it increased apoptosis. In both arms, EPA‐FFA treatment led to increased membrane switch from ω‐6 to ω‐3 PUFAs and a concomitant reduction in PGE2 production. We observed no significant changes in intestinal inflammation between EPA‐FFA treated arms and AOM‐DSS controls. Importantly, we found that EPA‐FFA treatment restored the loss of Notch signaling found in the AOM‐DSS control and resulted in the enrichment of Lactobacillus species in the gut microbiota. Taken together, our data suggest that EPA‐FFA is an excellent candidate for CRC chemoprevention in CAC.
Calcium‐sensing receptor silencing in colorectal cancer is associated with promoter hypermethylation and loss of acetylation on histone 3
Authors: Fetahu Irfete S. , Höbaus Julia , Aggarwal Abhishek , Hummel Doris M. , Tennakoon Samawansha , Mesteri Ildiko , Baumgartner‐Parzer Sabina , Kállay Enikő
Published: March 2014

The calcium‐sensing receptor (CaSR) is suggested to mediate the antiproliferative effects of calcium in colon. However, in colorectal cancer (CRC) the expression of the CaSR is silenced and the underlying mechanisms leading to its loss are poorly understood. We investigated whether loss of the CaSR expression in colorectal tumors is caused by DNA hypermethylation and imbalance of transcriptionally permissive/repressive histone alterations. We observed significantly lower CaSR mRNA expression (n = 65, p < 0.001) in colorectal tumors compared with the adjacent mucosa from the same patient. Immunofluorescence staining confirmed downregulation of the CaSR protein also. The CaSR promoter was methylated to a greater extent in tumors compared with adjacent mucosa as determined by bisulfite sequencing (n = 20, p < 0.01) and by pyrosequencing (n = 45, p < 0.001), and methylation correlated inversely with mRNA expression (n = 20, ρ = −0.310, p < 0.05 and n = 45, ρ = −0.588, p < 0.001). Treatments with 5‐aza‐2′‐deoxycytidine (DAC), a DNA methyltransferase inhibitor and/or with two different histone deacetylase inhibitors, trichostatin A (TSA) or suberoylanilide hydroxamic acid (SAHA) restored the expression of CaSR in colon cancer cells. Restored CaSR expression in Coga1A and HT29 cells was functional. Inhibition of lysine‐specific demethylase 1 (LSD1) to prevent demethylation of mono‐ and dimethylated H3K4, increased CaSR expression only marginally. Our data show that hypermethylation of the CaSR promoter and H3K9 deacetylation, but not H3K4me2 demethylation are important factors that cause silencing of the CaSR in colorectal cancer.
Aberrantly activated claudin 6 and 18.2 as potential therapy targets in non‐small‐cell lung cancer
Authors: Micke Patrick , Mattsson Johanna Sofia Margareta , Edlund Karolina , Lohr Miriam , Jirström Karin , Berglund Anders , Botling Johan , Rahnenfuehrer Jörg , Marincevic Millaray , Pontén Fredrik , Ekman Simon , Hengstler Jan , Wöll Stefan , Sahin Ugur , Türeci Özlem
Published: March 2014

Claudins (CLDNs) are central components of tight junctions that regulate epithelial‐cell barrier function and polarity. Altered CLDN expression patterns have been demonstrated in numerous cancer types and lineage‐specific CLDNs have been proposed as therapy targets. The objective of this study was to assess which fraction of patients with non‐small‐cell lung cancer (NSCLC) express CLDN6 and CLDN18 isoform 2 (CLDN18.2). Protein expression of CLDN6 and CLDN18.2 was examined by immunohistochemistry on a tissue microarray (n = 355) and transcript levels were supportively determined based on gene expression microarray data from fresh‐frozen NSCLC tissues (n = 196). Both were analyzed with regard to frequency, distribution and association with clinical parameters. Immunohistochemical analysis of tissue sections revealed distinct membranous positivity of CLDN6 (6.5%) and CLDN18.2 (3.7%) proteins in virtually non‐overlapping subgroups of adenocarcinomas and large‐cell carcinomas. Pneumocytes and bronchial epithelial cells were consistently negative. Corresponding to the protein expression, in subsets of non‐squamous lung carcinoma high mRNA levels of CLDN6 (7–16%) and total CLDN18 (5–12%) were observed. Protein expression correlated well with total mRNA expression of the corresponding gene (rho = 0.4–0.8). CLDN18.2 positive tumors were enriched among slowly proliferating, thyroid transcription factor 1 (TTF‐1)‐negative adenocarcinomas, suggesting that isoform‐specific CLDN expression may delineate a specific subtype. Noteworthy, high CLDN6 protein expression was associated with worse prognosis in lung adenocarcinoma in the univariate [hazard ratio (HR): 1.8; p = 0.03] and multivariate COX regression model (HR: 1.9; p = 0.02). These findings encourage further clinical exploration of targeting ectopically activated CLDN expression as a valuable treatment concept in NSCLC.
Effective immunotherapy of rat glioblastoma with prolonged intratumoral delivery of exogenous heat shock protein Hsp70
Authors: Shevtsov Maxim A. , Pozdnyakov Alexander V. , Mikhrina Anastasia L. , Yakovleva Ludmila Y. , Nikolaev Boris P. , Dobrodumov Anatolii V. , Komarova Elena Y. , Meshalkina Darya A. , Ischenko Alexander M. , Pitkin Emil , Guzhova Irina V. , Margulis Boris A.
Published: March 2014

Chaperone Hsp70 can activate adaptive immunity suggesting its possible application as an antitumor vaccine. To assess the therapeutic capacity of Hsp70 we administered purified chaperone into a C6 glioblastoma brain tumor and explored the viability and tumor size as well as interferon gamma (IFNγ) production and cytotoxicity of lymphocytes in the treated animals. Targeted intratumoral injection of Hsp70 resulted in its distribution within the area of glioblastoma, and caused significant inhibition of tumor progression as confirmed by magnetic resonance imaging. The delay in tumor growth corresponded to the prolonged survival of tumor‐bearing animals of up to 31 days versus 20 days in control. Continuous administration of Hsp70 with an osmotic pump increased survival even further (39 days). Therapeutic efficacy was associated with infiltration to glioblastoma of NK cells (Ly‐6c+) and T lymphocytes (CD3+, CD4+ and CD8+) as well as with an increase in the activity of NK cells (granzyme B production) and CD8+ T lymphocytes as shown by IFNγ ELISPOT assay. Furthermore, we found that Hsp70 treatment caused concomitantly, with a tenfold elevated IFNγ production, an increase in anti‐C6 tumor cytotoxicity of lymphocytes. In conclusion, continuous intratumoral delivery of Hsp70 demonstrates high therapeutic potential and therefore could be applied in the treatment of glioblastoma.
Investigation of age and gender effects on positive orientation in Italian twins
Authors: Fagnani Corrado , Medda Emanuela , Stazi Maria A. , Caprara Gian V. , Alessandri Guido
Published: March 2014

We investigated age and gender effects on “Positive Orientation” (POS)—an individual's tendency to view life with a positive outlook—using a genetically informed design. Study subjects were 1016 twins aged 22–75 from the Italian twin registry. We assessed POS by the recently developed P‐scale. First, we used confirmatory factor analysis to investigate scale's measurement invariance by age and gender. Then, we applied biometric modelling to estimate genetic and environmental components of POS score. Overall, we found a satisfactory degree of measurement invariance by both age and gender. Results from these analyses further indicated an increasing mean level of POS across the lifespan. Additive genetic and unshared environmental factors explained respectively 58% and 42% of variance in POS score, with no significant gender differences; furthermore, the pattern of change of gene‐environment architecture of POS over time was consistent with a greater plasticity of personality at older ages.
Vibrational spectroscopy of biofluids for disease screening or diagnosis: translation from the laboratory to a clinical setting
Authors: Mitchell Alana L. , Gajjar Ketan B. , Theophilou Georgios , Martin Francis L. , Martin‐Hirsch Pierre L.
Published: March 2014

There remains a need for objective and cost‐effective approaches capable of diagnosing early‐stage disease in point‐of‐care clinical settings. Given an increasingly ageing population resulting in a rising prevalence of chronic diseases, the need for screening to facilitate the personalising of therapies to prevent or slow down pathology development will increase. Such a tool needs to be robust but simple enough to be implemented into clinical practice. There is interest in extracting biomarkers from biofluids (e.g., plasma or serum); techniques based on vibrational spectroscopy provide an option. Sample preparation is minimal, techniques involved are relatively low‐cost, and data frameworks are available. This review explores the evidence supporting the applicability of vibrational spectroscopy to generate spectral biomarkers of disease in biofluids. We extend the inter‐disciplinary nature of this approach to hypothesise a microfluidic platform that could allow such measurements. With an appropriate lightsource, such engineering could revolutionize screening in the 21st century. (© 2014 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Identifying essential pairwise interactions in elastic network model using the alpha shape theory
Authors: Xia Fei , Tong Dudu , Yang Lifeng , Wang Dayong , Hoi Steven C. H. , Koehl Patrice , Lu Lanyuan
Published: March 2014

Elastic network models (ENM) are based on the idea that the geometry of a protein structure provides enough information for computing its fluctuations around its equilibrium conformation. This geometry is represented as an elastic network (EN) that is, a network of links between residues. A spring is associated with each of these links. The normal modes of the protein are then identified with the normal modes of the corresponding network of springs. Standard approaches for generating ENs rely on a cutoff distance. There is no consensus on how to choose this cutoff. In this work, we propose instead to filter the set of all residue pairs in a protein using the concept of alpha shapes. The main alpha shape we considered is based on the Delaunay triangulation of the Cα positions; we referred to the corresponding EN as EN(∞). We have shown that heterogeneous anisotropic network models, called αHANMs, that are based on EN(∞) reproduce experimental B‐factors very well, with correlation coefficients above 0.99 and root‐mean‐square deviations below 0.1 Å2 for a large set of high resolution protein structures. The construction of EN(∞) is simple to implement and may be used automatically for generating ENs for all types of ENMs. © 2014 Wiley Periodicals, Inc.