bluuebunny/crossref_metadata_2025 huggingface dataset:
Significant nonlinear‐optical switching capacity in atomic clusters built from silicon and lithium: A combined ab initio and density functional study
Authors: Karamanis Panaghiotis , Otero Nicolás , Pouchan Claude , Torres Juan José , Tiznado William , Avramopoulos Aggelos , Papadopoulos Manthos G.
Published: February 2014

Starting from a hypothetical but fundamental charge/discharge sequence, the topic of nonlinear optical switching in atomic clusters built from silicon and alkali metals is opened up. The outcomes presented in this work, obtained with ab initio methods of exceptional predictive capabilities, offer strong evidences that sizable hyperpolarizability contrasts between neutral and charged alkali metal doped cluster forms might be simultaneously accomplished. The observed switching procedure involves redox polyatomic clusters formed by Si atoms. These centers function as electron acceptors at the ground state and as electron donors at the excited states facilitating low energy charge transfer transitions upon electronic excitation. © 2014 Wiley Periodicals, Inc.
Reelin/DAB‐1 Signaling in the Embryonic Limb Regulates the Chondrogenic Differentiation of Digit Mesodermal Progenitors
Authors: Diaz‐Mendoza Manuel J. , Lorda‐Diez Carlos I. , Montero Juan A. , Garcia‐Porrero Juan A. , Hurle Juan M.
Published: February 2014

Reelin is a bioactive component of some extracellular matrices. Most studies on this signaling glycoprotein have been performed in the developing nervous system, where Reelin binds to the very‐low‐density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) of target cells. This induces phosphorylation of the intracellular adaptor protein Disabled‐1 (Dab‐1), which subsequently activates downstream effectors to regulate important aspects of neuroblast biology. Here, we show that the components of the Reelin signaling pathway exhibit a dynamic expression pattern during the development of the digits in chick and mouse embryonic limbs. Reelin and Dab‐1 are highly expressed in the differentiating digit cartilages and tendinous blastemas. Immunolabeling of phospho‐Dab‐1 indicates that the pattern of gene expression correlates with zones of active signaling. Intense signaling is also present in the early stages of cartilage differentiation in micromass cultures of digit mesodermal progenitors. In this in vitro assay, disruption of the Reelin signaling pathway by gene silencing causes cystoskeletal and cell shape modifications accompanied by reduced chondrogenesis and down‐regulation of specific cartilage molecular markers. Of note, Scleraxis and Six2, which are master genes of tendinous blastemas, become up‐regulated in these experiments. We further show that the receptors ApoER2 and VLDLR are differentially expressed in cartilage and tendons and that these receptors show temporal expression differences in the micromass cultures. Sox9 and other chondrogenic markers were downregulated in micromass cultures after ApoER2 gene silencing, while gene silencing of VLDLR up‐regulates Scleraxis. In summary, our findings provide evidence of a role for Reelin signaling in skeletogenesis that promotes chondrogenesis through ApoER2 and inhibits tenogenic differentiation through VLDLR. J. Cell. Physiol. 229: 1397–1404, 2014. © 2014 Wiley Periodicals, Inc.
Altered Histone Mark Deposition and DNA Methylation at Homeobox Genes in Human Oral Squamous Cell Carcinoma
Authors: Marcinkiewicz Katarzyna M. , Gudas Lorraine J.
Published: February 2014

We recently reported a role of polycomb repressive complex 2 (PRC2) and PRC2 trimethylation of histone 3 lysine 27 (H3K27me3) in the regulation of homeobox (HOX) (Marcinkiewicz and Gudas, 2013, Exp Cell Res) gene transcript levels in human oral keratinocytes (OKF6‐TERT1R) and tongue squamous cell carcinoma (SCC) cells. Here, we assessed both the levels of various histone modifications at a subset of homeobox genes and genome wide DNA methylation patterns in OKF6‐TERT1R and SCC‐9 cells by using ERRBS (enhanced reduced representation bisulfite sequencing). We detected the H3K9me3 mark at HOXB7, HOXC10, HOXC13, and HOXD8 at levels higher in OKF6‐TERT1R than in SCC‐9 cells; at IRX1 and SIX2 the H3K9me3 levels were conversely higher in SCC‐9 than in OKF6‐TERT1R. The H3K79me3 mark was detectable only at IRX1 in OKF6‐TERT1R and at IRX4 in SCC‐9 cells. The levels of H3K4me3 and H3K36me3 marks correlate with the transcript levels of the assessed homeobox genes in both OKF6‐TERT1R and SCC‐9. We detected generally lower CpG methylation levels on DNA in SCC‐9 cells at annotated genomic regions which were differentially methylated between OKF6‐TERT1R and SCC‐9 cells; however, some genomic regions, including the HOX gene clusters, showed DNA methylation at higher levels in SCC‐9 than OKF6‐TERT1R. Thus, both altered histone modification patterns and changes in DNA methylation are associated with dysregulation of homeobox gene expression in human oral cavity SCC cells, and this dysregulation potentially plays a role in the neoplastic phenotype of oral keratinocytes. J. Cell. Physiol. 229: 1405–1416, 2014. © 2014 Wiley Periodicals, Inc.
Cancer biomarker discovery for cholangiocarcinoma: the high‐throughput approaches
Authors: Silsirivanit Atit , Sawanyawisuth Kanlayanee , Riggins Gregory J. , Wongkham Chaisiri
Published: February 2014

Cholangiocarcinoma (CCA) is difficult to diagnose at an early stage and most tumors are detected at late stage where surgery or other therapy is ineffective. Many advanced techniques are applied to diagnose CCA; however, most are expensive and have varying degrees of accuracy. A less invasive and simpler procedure such as serum markers would be of substantial clinical benefit for diagnosis, monitoring, and predicting outcome for CCA patients. Recent advances in “Omics” technologies offer remarkable opportunities for establishment of biomarker‐related to diseases. In this review, the potential biomarkers obtained from proteomics and glycomic studies are evaluated. Several protein markers were discovered from patient specimen, using two dimensional‐differential gel electrophoresis couple with liquid chromatography tandem mass spectrometry (2D‐DIGE/LC‐MS‐MS), matrix‐assisted laser desorption/ionization‐time of flight mass spectrometry (MALDI‐TOF‐MS), surface enhanced laser desorption/ionization (SELDI)‐TOF‐MS and capillary electrophoresis (CE)‐MS, etc. Newly reported CCA‐associated glyco‐biomarkers were identified using lectin‐assisted, monoclonal antibody‐assisted or specific‐target strategies. The combination between carbohydrate binding‐lectin and core protein‐binding mAb significantly increased the values for detection of the glyco‐biomarkers for CCA. Searching for specific and sensitive molecular markers to be used for population screening is worth being evaluated. This could lead to earlier diagnosis and improve outcome. Further investigation of those biomarker functions is also of value in order to better understand the tumor biology and use them as targets for future therapeutic agents.
Regioselective syntheses of [13C]4‐labelled sodium 1‐carboxy‐2‐(2‐ethylhexyloxycarbonyl)ethanesulfonate and sodium 2‐carboxy‐1‐(2‐ethylhexyloxycarbonyl)ethanesulfonate from [13C]4‐maleic anhydride
Authors: Barsamian Adam L. , Perkins Matt J. , Field Jennifer A. , Blakemore Paul R.
Published: February 2014

The entitled monohydrolysis products, also known as α‐ethylhexyl and β‐ethylhexyl sulfosuccinate (EHSS), of the surfactant diisooctyl sulfosuccinate (DOSS) were synthesized in stable isotope‐labelled form from [13C]4‐maleic anhydride. Sodium [13C]4‐1‐carboxy‐2‐(2‐ethylhexyloxycarbonyl)ethanesulfonate (α‐EHSS) was prepared by the method of Larpent by reaction of 2‐ethylhexan‐1‐ol with [13C]4‐maleic anhydride followed by regioselective conjugate addition of sodium bisulfite to the resulting monoester (38% overall yield). The regiochemical outcome of bisulfite addition was confirmed by a combination of 13C/13C (incredible natural abundance double quantum transfer) and 1H/13C (heteronuclear multiple‐bond correlation (HMBC)) NMR spectral correlation experiments. Sodium [13C]4‐2‐carboxy‐1‐(2‐ethylhexyloxycarbonyl)ethanesulfonate (β‐EHSS) was prepared in four steps by reaction of 4‐methoxybenzyl alcohol with [13C]4‐maleic anhydride, regioselective sodium bisulfite addition, N,N′‐dicyclohexylcarbodiimide‐mediated esterification with 2‐ethylhexan‐1‐ol, and p‐methoxybenzyl ester deprotection with trifluoroacetic acid (13% overall yield). The regiochemical outcome of the second synthesis was confirmed by a combination of 1JCC scalar coupling constant analysis and 1H/13C (HMBC) NMR spectral correlation. The materials prepared are required as internal standards for the liquid chromatography–mass spectrometry (LC‐MS)/MS trace analysis of the degradation products of DOSS, the anionic surfactant found in Corexit, the oil dispersant used during emergency response efforts connected to the Deepwater Horizon oil spill of April 2010. Copyright © 2014 John Wiley & Sons, Ltd.
Formation of adherens and communicating junctions coordinate the differentiation of the shedding‐layer and beta‐epidermal generation in regenerating lizard epidermis
Authors: Alibardi Lorenzo
Published: February 2014

In the lizard epidermis, the formation of a stratified alpha‐ and beta‐layer, separated by a shedding complex for molting, suggests that keratinocytes communicate in a coordinated manner after they leave the basal layers during the shedding cycle. I have therefore studied the localization of cell junctional proteins such as beta‐catenin and connexins 43 and 26 during scale regeneration in lizard using immunocytochemistry. Beta‐catenin is also detected in nuclei of basal cells destined to give rise to the Oberhäutchen and beta‐cells suggesting activation of the Wnt‐pathway during beta‐cell differentiation. The observations show that cells of the entire shedding layer (clear and Oberhäutchen) and beta‐layer are connected by beta‐catenin (adherens junctions) and connexins (communicating junctions) during their differentiation. This likely cell coupling determines the formation of a distinct shedding and beta‐layer within the regenerating epidermis. The observed pattern of cell junctional stratification suggests that after departing from the basal layer Oberhäutchen and beta‐cells form a continuous communicating compartment that coordinates the contemporaneous differentiation along the entire scale. While the beta‐layer matures the junctions are lost while other cell junctions are formed in the following mesos‐ and alpha‐cell layers. This process determines the formation of layers with different texture (harder or softer) and the precise localization of the shedding layer within lizard epidermis. J. Morphol. 275:693–702, 2014. © 2014 Wiley Periodicals, Inc.
Enhanced tolerance and accumulation of heavy metal ions by engineered Escherichia coli expressing Pyrus calleryana phytochelatin synthase
Authors: Li Hui , Cong Yu , Lin Jing , Chang Youhong
Published: February 2014

Contamination by heavy metals is a major environmental problem worldwide and microbial bioremediation is an efficient method for removing this type of pollution. The plant enzyme phytochelatin synthase (PCS, also known as glutathione γ‐glutamylcysteinyltransferase, EC 2.3.2.15) involved in the synthesis of phytochelatins (PCs), which are metal‐binding cysteine‐rich peptides, has a major role in the detoxification of heavy metals in plants. Expression of the PcPCS1 gene from the bean pear (Pyrus calleryana Dcne.) was induced after cadmium and copper treatments. However, functional analysis of this gene in vivo has not been reported. And it is or not suitable for bioremediation also needs to be assessed. In this study, we found Escherichia coli with over‐expressed PcPCS1 had enhanced tolerance to cadmium, copper, sodium, and mercury. E. coli cells transformed with pPcPCS1 was found to survive in solid M9 medium containing 2.0 mM Cd2+, 4.0 mM Cu2+, 4.5% (w/v) Na+, or 200 µM Hg2+. Moreover, the growth curve showed 1.5 mM Cd2+, 2.5 mM Cu2+, 3.5% (w/v) Na+, and 100 µM Hg2+ had no effect on the growth of the E. coli cells transformed with pPcPCS1. Also, we found the contents of PCs and the accumulation of cadmium, copper, sodium, and mercury ions were enhanced in the recombinant E. coli strain Rosetta™ (DE3). These results suggested the PcPCS1 gene might be a candidate for heavy metal bioremediation via recombinant bacteria.
A novel ribonuclease with HIV‐1 reverse transcriptase inhibitory activity purified from the fungus Ramaria formosa
Authors: Zhang Rui , Tian Guoting , Zhao Yongchang , Zhao Liyan , Wang Hexiang , Gong Zhiyuan , Ng Tzi Bun
Published: February 2014

A purification protocol that encompassed anion exchange chromatography (EC) on DEAE‐cellulose, cation EC on CM‐cellulose, anion EC on Q‐Sepharose, and fast protein liquid chromatography‐gel filtration of Superdex 75 was used to isolate a ribonuclease from dried fruiting bodies of Ramaria formosa. The ribonuclease was unadsorbed on CM‐cellulose but adsorbed on both DEAE‐cellulose and Q‐Sepharose. It displayed a molecular mass of 29‐kDa in both gel filtration and sodium dodecyl sulfate–polyacrylamide gel electrophoresis. The ranking of its ribonucleolytic activity toward polyhomoribonucleotides was poly(U) > poly(C) > poly(G) > poly(A). It exhibited a pH optimum of pH 5 and a temperature optimum at 60 °C. The ribonuclease inhibited HIV‐1 reverse transcriptase with an IC50 of 3 µM.
Autumn Eurasian snow depth, autumn Arctic sea ice cover and East Asian winter monsoon
Authors: Li Fei , Wang Huijun
Published: February 2014

We present observational evidence and model simulation demonstrating a significant change in the early 1990s in the relationships of the autumn Eurasian snow depth (AESD) and the autumn Arctic sea ice cover (ASIC) with the East Asian winter monsoon (EAWM). A weakening of the AESD–EAWM relationship occurs over a period when the ASIC–EAWM relationship strengthens. The possible physical process can be described as follows: before the early 1990s, the positive AESD anomaly tends to persist into winter. In contrast, after the early 1990s, the negative ASIC anomaly tends to excite a stationary Rossby wave across the North America–Atlantic sector in autumn. This wave train propagates eastward in winter and favours the winter Eurasian snow depth (WESD) increase. The WESD anomaly is associated with the strengthening and expansions of the Siberian high west and north across the pole and the zonally elongated cold anomalies from Europe to the Far East. It has a stable connection with the EAWM throughout the period observed (1979–2006) and may serve as a bridge linking AESD or ASIC with the EAWM.
Multimodel ensemble forecasting of rainfall over East Asia: regularized regression approach
Authors: Lim Yaeji , Jo Seongil , Lee Jaeyong , Oh Hee‐Seok , Lee Sang‐Goo , Park Yongtae , Kang Hyun‐Suk
Published: February 2014

This paper considers the problem of predicting the rainfall over East Asia from multimode outputs. For this purpose, we propose a new multimode ensemble method based on regularized regression approach, which consists of two steps, the pre‐processing step and the ensemble step. In the pre‐processing step, we improve prediction from each model output using regularized regression, and in the ensemble step, we apply regularization‐based regression method to combine the result from the pre‐processing step. The main benefits of the proposed method are that it improves prediction accuracy, and it is capable of solving the singularity problem so that it can integrate many climate variables from multimode outputs for a better prediction. The proposed method is applied to monthly outputs from nine general circulation models (GCMs) on boreal summer (June, July, and August) over 20 years (1983–2002). The prediction ability of the proposed ensemble forecast is compared with the observations and the outputs (prediction) from eachGCM. The results show that the proposed method is capable of improving forecast accuracy by adjusting each model before combining.
In‐situ and laboratory Raman analysis in the field of cultural heritage: the case of a mural painting
Authors: Veneranda Marco , Irazola Mireia , Pitarch Africa , Olivares Maitane , Iturregui Ane , Castro Kepa , Madariaga Juan Manuel
Published: February 2014

The present work exemplifies, over a mural painting from the 14th century, the advantages of an initial exhaustive research using latest generation hand‐held spectrometers (Raman mainly) in order to perform the characterization of valuable objects of cultural heritage. These in‐situ techniques (meaning on‐site and non‐destructive) are very useful to study the pigments and materials, to identify the nature and causes of some of the main sources of deterioration and to examine past repaints. In addition, the in‐situ measurements are of great importance in the selection of micro‐samples for the laboratory analyses. In this particular case, the combination of these results with the chemical imaging analyses in the laboratory (such as Raman and energy dispersive X‐ray spectrometry imaging) allowed the characterization of the mural painting, including, the identification of all restoration works applied in the past. Copyright © 2014 John Wiley & Sons, Ltd.
Distortion conspicuity on stereoscopically viewed 3D images may correlate to scene content and distortion type
Authors: Chen Ming‐Jun , Cormack Lawrence K. , Bovik Alan C.
Published: February 2014

We describe two studies that were aimed towards increasing our understanding of how the visibility of distortions on stereoscopically viewed 3D images is affected by scene content and distortion types. By assuming that subjects' performance would be highly correlated with the visibility of local distorted patches, we analyzed subjects' performance in locating distortion patches when viewing stereoscopic 3D images. Subjects' performances are measured by whether they successfully locate a local distorted patch, the times they spent to finish the task, and subjective quality ratings given by subjects. The visual data used in this work are co‐registered stereo images with co‐registered “ground truth” range (depth) data. Varied statistical analysis methods were used to discuss the significance of our observations. Three observations are drawn from our analyses. First, blur, JPEG, and JP2K distortions in stereo 3D images may be suppressed if one of the left or right views is undistorted. Second, contrast masking does not occur, or is reduced, while viewing white noise distorted stereo 3D images. Third, there is no depth/disparity masking effect when viewing stereo 3D images, but there may be (conversely) depth‐related facilitation effects for blur, JPEG, and JP2K distorted stereo 3D images.
Pixel structures using the negative feedback method for high‐resolution active matrix organic light‐emitting diode displays
Authors: Keum Nack‐Hyeon , Kwon Oh‐Kyong
Published: February 2014

Novel two pixel structures are proposed for high‐resolution active matrix organic light‐emitting diode displays. The proposed two pixels (pixel structures A and B) use the negative feedback method for high‐resolution displays that requires to have small‐sized storage capacitance. The proposed pixel structures A and B improve the luminance uniformity by reducing the voltage distortion in the storage capacitor. However, the proposed pixel structure A is vulnerable to the organic light‐emitting diode (OLED) degradation because the anode voltage of the OLED affects the emission current. In order to compensate the OLED degradation, the proposed pixel structure B stores the turn‐on voltage of OLEDs in the storage capacitor. The simulation results show that the emission current error of the proposed pixel structure B is improved by four times in comparison with the proposed pixel structure A when the OLED turn‐on voltage increases by 0.1 V. Also, the emission current error of the proposed pixel structure B when the threshold voltage of driving thin‐film transistors varies from −2.2 to −1.8 V is from −0.69 least significant bit (LSB) to 0.13 LSB, which shows the excellent luminance uniformity. The proposed pixels are designed for 5.5‐in. full high‐definition displays.
Rapid analysis of Origanum majorana L. fragrance using a nanofiber sheet, gas chromatography with mass spectrometry, and chemometrics
Authors: Asadollahi‐Baboli Mohammad , Aghakhani Ali
Published: February 2014

Headspace nanofiber sheet microextraction together with GC–MS and chemometrics resolution techniques were implemented to separate and identify the volatiles emitted by intact marjoram (Origanum majorana L.) and their relative concentrations. A novel polyaniline‐nylon‐6 nanofiber composite was applied for headspace microextraction. Characteristics such as high surface‐to‐volume ratio and π–π functional groups in polyaniline together with the NH and C=O functional groups in nylon‐6 make the polyaniline‐nylon‐6 nanofiber composite a suitable candidate for the extraction of volatiles and semivolatiles. The extracted constituents were desorbed and injected into the GC–MS system under the optimum conditions. Chemometric resolution techniques were utilized to solve the baseline offset, asymmetric peaks, and overlapped peaks problems that arise from GC–MS analysis. By means of these techniques and resolving the overlapped peak clusters, the number of identified constituents was increased to 67 compounds. The major released constituents from the intact marjoram leaves are 4‐terpineol, β‐linalool, cis‐sabinol, and trans‐geraniol.
Consecutive Chemical Activation Steps in the OH‐Initiated Atmospheric Degradation of Isoprene: An Analysis with Coupled Master Equations
Authors: Pfeifle Mark , Olzmann Matthias
Published: February 2014

The influence of a two‐step chemical activation on 1,5‐H and 1,6‐H shift reactions of hydroxyl‐peroxy radicals formed in the atmospheric photooxidation of isoprene was investigated by means of a master equation analysis. To account for multiple chemical activation processes, three master equations were coupled. The general approach of this coupling is described, and consequences for steady‐state regimes are examined. The specific calculations show that chemical activation has no substantial influence on the rate coefficients of the above‐mentioned reactions under tropospheric conditions. However, it is demonstrated that high‐pressure limits of the thermal rate coefficients instead of the falloff‐corrected values have to be used for kinetic modeling. This is a consequence of the continuous population of the high‐energy part of the isoprene‐OH‐O2 adduct distribution by the forming reactions under steady‐state conditions. The rate coefficients of the isomerization reactions at T = 298 K were calculated to be k3a∞ = 1.5 × 10−3 s−1 (1,5‐H‐shift of the 1,2‐isomer) and k4a∞ = 6.5 s−1 (1,6‐H‐shift of the (Z)‐1,4‐isomer). The calculated value of k4a∞ is three orders of magnitude larger than a recently reported experimentally observed rate coefficient for the hydrogen shift reactions of the hydroxyl‐peroxy intermediates. It is shown that this discrepancy is in part due to the fact that the experiment does not distinguish between different structural isomers. A comparison of the experimentally determined isotope effect with the calculated value shows a reasonable agreement.
Latent and Delayed Action Polymerization Systems
Authors: Naumann Stefan , Buchmeiser Michael R.
Published: February 2014

Various approaches to latent polymerization processes are described. In order to highlight recent advances in this field, the discussion is subdivided into chapters dedicated to diverse classes of polymers, namely polyurethanes, polyamides, polyesters, polyacrylates, epoxy resins, and metathesis‐derived polymers. The described latent initiating systems encompass metal‐containing as well as purely organic compounds that are activated by external triggers such as light, heat, or mechanical force. Special emphasis is put on the different chemical venues that can be taken to achieve true latency, which include masked N‐heterocyclic carbenes, latent metathesis catalysts, and photolatent radical initiators, among others. Scientific challenges and the advantageous application of latent polymerization processes are discussed.

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ABT‐089 and ABT‐894 reduce levodopa‐induced dyskinesias in a monkey model of Parkinson's disease
Authors: Zhang Danhui , Bordia Tanuja , McGregor Matthew , McIntosh J. Michael , Decker Michael W. , Quik Maryka
Published: February 2014

Levodopa‐induced dyskinesias (LIDs) are a serious complication of levodopa therapy for Parkinson's disease for which there is little treatment. Accumulating evidence shows that nicotinic acetylcholine receptor (nAChR) drugs decrease LIDs in parkinsonian animals. Here, we examined the effect of two β2 nAChR agonists, ABT‐089 and ABT‐894, that previously were approved for phase 2 clinical trials for other indications. Two sets of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned monkeys were administered levodopa/carbidopa (10 mg/kg and 2.5 mg/kg, respectively) twice daily 5 days a week until they were stably dyskinetic. Each set had a vehicle‐treated group, an nAChR agonist‐treated group, and a nicotine‐treated group as a positive control. Set A monkeys had previously received other nAChR drugs (nAChR drug‐primed), whereas Set B monkeys were initially nAChR drug‐naive. Both sets were administered the partial agonist ABT‐089 (range, 0.01‐1.0 mg/kg) orally 5 days a week twice daily 30 minutes before levodopa with each dose given for 1 to 5 weeks. ABT‐089 decreased LIDs by 30% to 50% compared with vehicle‐treated monkeys. Nicotine reduced LIDs by 70% in a parallel group. After 4 weeks of washout, the effect of the full agonist ABT‐894 (range, 0.0001‐0.10 mg/kg) was assessed on LIDs in Set A and Set B. ABT‐894 reduced LIDs by 70%, similar to nicotine. Both drugs acted equally well at α4β2* and α6β2* nAChRs; however, ABT‐089 was 30 to 60 times less potent than ABT‐894. Tolerance did not develop for the time periods tested (range, 3‐4 months). The nAChR drugs did not worsen parkinsonism or cognitive ability. Emesis, a common problem with nAChR drugs, was not observed. ABT‐894 and ABT‐089 appear to be good candidate nAChR drugs for the management of LIDs in Parkinson's disease. © 2014 International Parkinson and Movement Disorder Society
Safety and tolerability of carbamylated erythropoietin in Friedreich's ataxia
Authors: Boesch Sylvia , Nachbauer Wolfgang , Mariotti Caterina , Sacca Francesco , Filla Alessandro , Klockgether Thomas , Klopstock Thomas , Schöls Ludger , Jacobi Heike , Büchner Boriana , vom Hagen Jennifer Müller , Nanetti Lorenzo , Manicom Karen
Published: February 2014

Background

Erythropoietin (EPO) derivatives have been found to increase frataxin levels in Friedreich's ataxia (FRDA) in vitro. This multicenter, double‐blind, placebo‐controlled, phase II clinical trial aimed to evaluate the safety and tolerability of Lu AA24493 (carbamylated EPO; CEPO).

Methods

Thirty‐six ambulatory FRDA patients harboring >400 GAA repeats were 2:1 randomly assigned to either CEPO in a fixed dose (325 µg thrice‐weekly) or placebo. Safety and tolerability were assessed up to 103 days after baseline. Secondary outcome measures of efficacy (exploration of biomarkers and ataxia ratings) were performed up to 43 days after baseline.

Results

All patients received six doses of study medication. Adverse events were equally distributed between CEPO and placebo. There was no evidence for immunogenicity of CEPO after multiple dosing. Biomarkers, such as frataxin, or measures for oxidative stress and ataxia ratings did not differ between CEPO and placebo.

Conclusion

CEPO was safe and well tolerated in a 2‐week treatment phase. Secondary outcome measures remained without apparent difference between CEPO and placebo. © 2014 International Parkinson and Movement Disorder Society
The Complexation of the Anticancer Drug ThioTEPA with Methylated DNA Base Guanine: Combined Ab Initio and QTAIM Investigation
Authors: Nikolaienko Tymofii Yu. , Bulavin Leonid A. , Sukhodub Leonid F.
Published: February 2014

Non‐covalent complexes of methylated nitrogenous DNA base guanine (m9Gua) with 1 to 6 molecules of anticancer drug ThioTEPA (1,1′,1′′‐phosphorothioyltriaziridine) have been investigated by molecular modeling techniques (molecular docking and DFT geometry optimization), ab initio wavefunction calculations and the quantum theory of atoms in molecules (QTAIM). The accuracy of complex structures predicted by standard molecular docking techniques have been assessed by comparing them with ab initio calculations, and the most important differences have been discussed. Obtained stabilization enthalpies (kcal/mol) for the m9Gua⋅⋅⋅(ThioTEPA)n complexes with n=1…6 have been found to be −15.6, −26.5, −38.4, −49.6, −60.5 and −69.3 respectively. The non‐covalent interactions revealed by the QTAIM method have been shown to be a dominating factor responsible for the complex stability, with hydrogen bonds of NH⋅⋅⋅N type being the most important interactions in small (n=1 to 4) and CH⋅⋅⋅N bonds – in large (n=5, 6) complexes. The obtained results may help to understand ThioTEPA‐DNA interactions and clarify the mechanism of the drug action.
eFindSite: Enhanced Fingerprint‐Based Virtual Screening Against Predicted Ligand Binding Sites in Protein Models
Authors: Feinstein Wei P. , Brylinski Michal
Published: February 2014

A standard practice for lead identification in drug discovery is ligand virtual screening, which utilizes computing technologies to detect small compounds that likely bind to target proteins prior to experimental screens. A high accuracy is often achieved when the target protein has a resolved crystal structure; however, using protein models still renders significant challenges. Towards this goal, we recently developed eFindSite that predicts ligand binding sites using a collection of effective algorithms, including meta‐threading, machine learning and reliable confidence estimation systems. Here, we incorporate fingerprint‐based virtual screening capabilities in eFindSite in addition to its flagship role as a ligand binding pocket predictor. Virtual screening benchmarks using the enhanced Directory of Useful Decoys demonstrate that eFindSite significantly outperforms AutoDock Vina as assessed by several evaluation metrics. Importantly, this holds true regardless of the quality of target protein structures. As a first genome‐wide application of eFindSite, we conduct large‐scale virtual screening of the entire proteome of Escherichia coli with encouraging results. In the new approach to fingerprint‐based virtual screening using remote protein homology, eFindSite demonstrates its compelling proficiency offering a high ranking accuracy and low susceptibility to target structure deformations. The enhanced version of eFindSite is freely available to the academic community at http://www.brylinski.org/efindsite.
Influence of fluorine substituents on the NMR properties of phenylboronic acids
Authors: Gierczyk Błażej , Kaźmierczak Marcin , Popenda Łukasz , Sporzyński Andrzej , Schroeder Grzegorz , Jurga Stefan
Published: February 2014

The paper presents results of a systematic NMR studies on fluorinated phenylboronic acids. All possible derivatives were studied. The experimental 1H, 13C, 19F, 11B, and 17O spectral data were compared with the results of theoretical calculations. The relation between the calculated natural bond orbital parameters and spectral data (chemical shifts and coupling constants) is discussed. The first examples of 10B/11B isotopic effect on the 19F spectra and 4JFO scalar coupling in organic compounds are reported. Copyright © 2014 John Wiley & Sons, Ltd.
Porcine natriuretic peptide type B (pNPPB) maintains mouse oocyte meiotic arrest via natriuretic peptide receptor 2 (NPR2) in cumulus cells
Authors: Zhang Yu , Hao Xiaoqiong , Xiang Xi , Wei Kaiwen , Xia Guoliang , Zhang Meijia
Published: February 2014

In mouse ovarian follicles, the oocyte is maintained in meiotic prophase arrest by natriuretic peptide type C (NPPC) acting via its cognate receptor, natriuretic peptide receptor 2 (NPR2). As there is a marked species difference in the receptor selectivity of the natriuretic peptide family, this study examined the functional effect of other natriuretic peptides, type A (NPPA) and type B (NPPB), acting via NPR2 on mouse‐oocyte meiotic arrest. The results by quantitative, reverse‐transcriptase PCR showed that Npr2 was the predominant natriuretic peptide receptor transcript, and that Npr1 and Npr3 mRNA levels were negligible in cumulus cells isolated from equine chorionic gonadotropin (eCG)‐primed, immature female mice. While NPPA and NPPB from human and rat had no effect on oocyte maturation, porcine NPPB (pNPPB) maintained oocyte meiotic arrest in a dose‐dependent manner. Furthermore, pNPPB‐mediated meiotic arrest and cGMP production could be completely blocked by the NPR2 inhibitor sphingosine‐1‐phosphate (S1P). Neither the NPR1 antagonist anantin or Npr1 knockout had an effect on pNPPB‐mediated meiotic arrest. Thus, pNPPB can functionally maintain mouse‐oocyte meiotic arrest by the receptor NPR2 of cumulus cells. These findings demonstrate that pNPPB may be used as a probe to identify the essential amino acid sequences for activation of NPR2. Mol. Reprod. Dev. 81: ???–???, 2014. © 2014 Wiley Periodicals, Inc.
Accelerated and navigator‐gated look‐locker imaging for cardiac t1 estimation (ANGIE): Development and application to T1 mapping of the right ventricle
Authors: Mehta Bhairav B. , Chen Xiao , Bilchick Kenneth C. , Salerno Michael , Epstein Frederick H.
Published: February 2014

Purpose

To develop a method for high‐resolution cardiac T1 mapping.

Methods

A new method, accelerated and navigator‐gated look‐locker imaging for cardiac T1 estimation (ANGIE), was developed. An adaptive acquisition algorithm that accounts for the interplay between navigator gating and undersampling patterns well‐suited for compressed sensing was used to minimize scan time. Computer simulations, phantom experiments, and imaging of the left ventricle (LV) were used to optimize and evaluate ANGIE. ANGIE's high spatial resolution was demonstrated by T1 mapping of the right ventricle (RV). Comparisons were made to modified Look‐Locker imaging (MOLLI).

Results

Retrospective reconstruction of fully sampled datasets demonstrated the advantages of the adaptive algorithm. For the LV, ANGIE measurements of T1 were in good agreement with MOLLI. For the RV, ANGIE achieved a spatial resolution of 1.2 × 1.2 mm2 with a scan time of 157 ± 53 s per slice, and measured RV T1 values of 980 ± 96 ms versus 1076 ± 157 ms for lower‐resolution MOLLI. ANGIE provided lower intrascan variation in the RV T1 estimate compared with MOLLI (P < 0.05).

Conclusion

ANGIE enables high‐resolution cardiac T1 mapping in clinically reasonable scan times. ANGIE opens the prospect of quantitative T1 mapping of thin cardiovascular structures such as the RV wall. Magn Reson Med 73:150–160, 2015. © 2014 Wiley Periodicals, Inc.
Comparison of myelin water fraction from multiecho T2 decay curve and steady‐state methods
Authors: Zhang Jing , Kolind Shannon H. , Laule Cornelia , MacKay Alex L.
Published: February 2014

Purpose

Myelin water fraction is conventionally measured from the T2 decay curve. Recently, a steady‐state approach entitled multicomponent‐driven equilibrium single pulse observation of T1/T2 (mcDESPOT) was employed for myelin water fraction mapping. However, no direct comparison between the established multiecho T2 relaxation method and mcDESPOT has been performed.

Methods

Gradient and spin echo (GRASE) acquired T2 decay curve and mcDESPOT measurements were acquired from 10 healthy volunteers using a 3T MRI. We compared myelin water fraction, transmit radio frequency field (B1), and T2's of intra‐ and extracellular water obtained from both methods.

Results

For all brain regions examined, myelin water fractions from mcDESPOT were significantly higher than those from multiecho GRASE. B1 maps were qualitatively similar between GRASE and mcDESPOT, but multicomponent T2 times were significantly different. To investigate the effect of exchange, mcDESPOT data were analyzed with and without exchange. When exchange was turned off, intra‐ and extracellular T2 times from mcDESPOT were roughly consistent with GRASE results; however, myelin water fractions derived from mcDESPOT were still significantly higher than those derived from GRASE.

Conclusion

Myelin water fraction values derived from mcDESPOT cannot be considered to be equivalent to those derived from T2 decay curve approaches. Magn Reson Med 73:223–232, 2015. © 2014 Wiley Periodicals, Inc.
Brain high‐energy phosphates and creatine kinase synthesis rate under graded isoflurane anesthesia: An in vivo 31P magnetization transfer study at 11.7 tesla
Authors: Bresnen Andrew , Duong Timothy Q.
Published: February 2014

Purpose

The creatine kinase rate of metabolic adenosine triphosphate (ATP) synthesis is an important metabolic parameter but is challenging to measure in vivo due to limited signal‐to‐noise ratio and long measurement time.

Theory and Methods

This study reports the implementation of an accelerated 31P Four Angle Saturation Transfer (FAST) method to measure the forward creatine kinase (CK) rate of ATP synthesis. Along with a high‐field scanner (11.7 Tesla) and a small sensitive surface coil, the forward CK rate in the rat brain was measured in ∼5 min.

Results

Under 1.2% isoflurane, the forward CK rate constant and metabolic flux were, respectively, kf,CK = 0.26 ± 0.02 s−1 and Ff,CK = 70.8 ± 4.6 μmol/g/min. As a demonstration of utility and sensitivity, measurements were made under graded isoflurane. Under 2.0% isoflurane, kf,CK = 0.16 ± 0.02 s−1 and Ff,CK = 41.0 ± 4.2 μmol/g/min, corresponding to a 38% and 42% reduction, respectively, relative to 1.2% isoflurane. By contrast, the ATP and phosphocreatine concentrations were unaltered.

Conclusion

This study demonstrated the 31P FAST measurement of creatine kinase rate of ATP synthesis in rat brain with reasonable temporal resolution. Different isoflurane levels commonly used in animal models significantly alter the CK reaction rate but not ATP and phosphocreatine concentrations. Magn Reson Med 73:726–730, 2015. © 2014 Wiley Periodicals, Inc.
Evaluation of short‐TE 1H MRSI for quantification of metabolites in the prostate
Authors: Basharat Meer , Jafar Maysam , deSouza Nandita M. , Payne Geoffrey S.
Published: February 2014

Back‐to‐back 1H MRSI scans, using an endorectal and phased‐array coil combination, were performed on 18 low‐risk patients with prostate cancer at 3 T, employing TEs of 32 and 100 ms in order to compare metabolite visualization at each TE. Outer‐volume suppression of lipid signals was performed using regional saturation (REST) slabs and the quantification of spectra at both TEs was achieved with the quantitation using quantum estimation (QUEST) routine. Metabolite nulling experiments in an additional five patients found that there were negligible macromolecule background signals in prostate spectra at TE = 32 ms. Metabolite visibility was judged using the criterion Cramér–Rao lower bound (CRLB)/amplitude < 20%, and metabolite concentrations were corrected for relaxation effects and referenced to the data acquired in corresponding water‐unsuppressed MRSI scans. For the first time, the prostate metabolites spermine and myo‐inositol were quantified individually in vivo, together with citrate, choline and creatine. All five metabolite visibilities were higher in TE = 32 ms MRSI than in TE = 100 ms MRSI. At TE = 32 ms, citrate was visible in 99.0% of lipid‐free spectra, whereas, at TE = 100 ms, no metabolite simulation of citrate matched the in vivo peaks. Spermine, choline and creatine were visualised separately in 30.4% more spectra at TE = 32 ms than at TE = 100 ms, and myo‐inositol in 72.5% more spectra. T2 values were calculated for spermine (53 ± 16 ms), choline (62 ± 17 ms) and myo‐inositol (90 ± 48 ms). Data from the TE = 32 ms spectra showed that the concentrations of citrate and spermine secretions were positively correlated in both the peripheral zone and central gland (R2 = 0.73 and R2 = 0.43, respectively), and that the citrate content was significantly higher in the former at 64 ± 22 mm than in the latter at 32 ± 16 mm (p = 0.01). However, lipid contamination at TE = 32 ms was substantial; therefore, to make clinical use of the greater visualisation of prostate metabolites at TE = 32 ms rather than at TE = 100 ms, three‐dimensional MRSI at TE = 32 ms with effective lipid suppression must be implemented. ©2014 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd.
A scalable multigrid method for solving indefinite Helmholtz equations with constant wave numbers
Authors: Livshits Ira
Published: February 2014

Multigrid techniques are applied to two‐dimensional indefinite Helmholtz equations, with a standard geometric approach aided by a special treatment of oscillatory near‐kernel components of the Helmholtz operator. The algorithm is a modification of the wave‐ray method by Brandt and Livshits, 1997. Its biggest difference from the original is a more traditional problem formulation: the Helmholtz equations with standard, in applications, Sommerfeld boundary conditions. The new slimmed wave‐ray solver is less technical, and it is easier to implement. The algorithm is tested for a combination of problems and discretization parameters, and in all experiments with constant wave numbers, it shows stable convergence and scalability, all at computational costs comparable to the ones of the V (1,1) multigrid cycle. While not the main focus of the paper, Helmholtz equations with variable coefficients are considered, and some preliminaries are presented, followed by a discussion of the limited applicability of the method for such problems and the ways to expand it. Also briefly outlined is the potential and plans for a parallel implementation. Copyright © 2014 John Wiley & Sons, Ltd.
Theoretical bounds for algebraic multigrid performance: review and analysis
Authors: MacLachlan Scott P. , Olson Luke N.
Published: February 2014

Algebraic multigrid methods continue to grow in robustness as effective solvers for the large and sparse linear systems of equations that arise in many applications. Unlike geometric multigrid approaches, however, the theoretical analysis of algebraic multigrid is less predictive of true performance. Multigrid convergence factors naturally depend on the properties of the relaxation, interpolation, and coarse‐grid correction routines used, yet without the tools of Fourier analysis, optimal and practical bounds for algebraic multigrid are not easily quantified. In this paper, we survey bounds from existing literature, with particular focus on the predictive capabilities of the theory, and provide new results relating existing bounds. We highlight the impact of these theoretical observations through several model problems and discuss the role of theoretical bounds on practical performance. Copyright © 2014 John Wiley & Sons, Ltd.
Reducing the stigma of bariatric surgery: Benefits of providing information about necessary lifestyle changes
Authors: Vartanian Lenny R. , Fardouly Jasmine
Published: February 2014

Objective

The aim of this study was to determine whether providing information about the lifestyle changes required for an individual to lose weight following bariatric surgery would mitigate the negative judgments of that individual.

Methods

In an experimental design, participants provided their initial impressions of a woman with obesity before learning that she had lost a significant amount of weight through: (1) diet/exercise, (2) surgery, or (3) surgery + diet/exercise. Participants then provided their impressions of the woman after she had lost weight.

Results

For ratings of laziness, competence, and responsibility for weight loss, the individual who lost weight through surgery was rated most negatively, followed by the individual who lost weight through surgery + diet/exercise, with the individual who lost weight through diet/exercise alone rated as least lazy, most competent, and most responsible for her weight loss. Mediation analyses further showed that group differences in target ratings of laziness/competence were due to perceptions of responsibility for weight loss.

Conclusions

Providing information about the lifestyle changes required for losing weight following bariatric surgery can somewhat dampen the negative evaluations of surgery patients. These findings also highlight the importance of perceived effort in judgments of individuals with obesity.
Risk and resilience factors for grade retention in youth with sickle cell disease
Authors: Ladd Rebecca J. , Valrie Cecelia R. , Walcott Christy M.
Published: February 2014

Background

Youth with sickle cell disease (SCD) are at higher risk for grade retention than healthy peers. This is salient because research suggests grade retention is ineffective and places youth at additional risk for negative outcomes. The aims of the present study were to identify possible risk factors for grade retention in youth with SCD and to examine positive family functioning as a possible resilience factor.

Procedure

Data were extracted from phase 3 of the Cooperative Study of Sickle Cell Disease, a multisite, longitudinal study of individuals with SCD. Participants were 370 youth, aged 6–16 years, with complete data on history of grade retention. Collected data included demographics, history of grade retention, disease severity factors, evidence of stroke, family functioning, and academic achievement. A logistic regression model predicting grade retention was calculated.

Results

Increasing age, lower reading achievement, and lower family cohesion were predictive of higher likelihood of grade retention. Also, high family achievement‐orientation moderated the negative effects of increasing age on likelihood of grade retention, such that at increasing levels of family achievement‐orientation, the relationship between age and grade retention decreased.

Conclusions

These findings suggest the need for interventions that promote connectedness and achievement‐orientation in families of youth with SCD. Research is also needed to further explore other possible risk or resilience factors for grade retention in this population, such as school absenteeism. Pediatr Blood Cancer 2014;61:1252–1256. © 2014 Wiley Periodicals, Inc.
PLK1 expression and BI 2536 effects in childhood acute lymphoblastic leukemia
Authors: Oliveira J.C. , Pezuk J.A. , Brassesco M.S. , Morales A.G. , Queiroz R.G.P. , Scrideli C.A. , Tone L.G.
Published: February 2014

Background

Polo‐like kinase 1 (PLK1) is a conserved kinase that mediates various mitotic events. Compelling data have repeatedly demonstrated its upregulation in different neoplasia, being frequently associated with poor prognosis. However, in childhood acute lymphoblastic leukemia (ALL), no studies have yet been conducted.

Procedure

PLK1 expression and association with biological features were evaluated in 65 consecutively diagnosed childhood ALL samples by quantitative real‐time PCR. Moreover, the effects of a specific PLK1 inhibitor, BI 2536, was tested against a panel of nine ALL cell lines at nanomolar concentrations (10, 50, 100 nM).

Results

The mRNA expression of PLK1 showed great variability in pediatric ALL, but no difference was evidenced compared to normal bone marrow. Additionally, no association was found between PLK1 mRNA expression with any clinical or biological features. Alternatively, high mRNA expression of PLK1 was present in ALL cell lines. In vitro treatment with BI 2536 strongly diminished growth, while presenting significant reduction in colony formation capacity and increased apoptosis rates. Moreover, strong G2/M arrest was detected suggesting important impaired proliferation after treatment.

Conclusions

PLK1 mRNA expression level is not associated with prognosis in childhood ALL; however, considering the great variability observed in the sample and the in vitro experiments presented herein, BI 2536 treatment might serve as a promising therapeutic to enhance the efficacy of conventional treatment modalities in some childhood ALL cases. Pediatr Blood Cancer 2014;61:1227–1231. © 2014 Wiley Periodicals, Inc.