bluuebunny/crossref_metadata_2025 huggingface dataset:
Solid‐state NMR for the analysis of high‐affinity ligand/receptor interactions
Authors: Williamson P.T.F.
Published: May 2009

The rational development of drugs which target integral membrane proteins relies intimately on our understanding of their interactions with their binding sites. Advances in solid‐state NMR methodology coupled to improved expression and purification strategies for membrane proteins now enable us to probe the structure, dynamics, and binding modes of these drugs with ever‐increasing resolution. This article seeks to highlight these advances demonstrating how improvements in protein expression and purification can be coupled with recent developments in instrumentation and pulse sequences in magic‐angle spinning, static, and oriented sample solid‐state NMR to reveal structural and dynamic information of high‐affinity drugs/ligands within their binding sites on membrane proteins. Furthermore, we will highlight some of the major experimental considerations associated with performing these studies. © 2009 Wiley Periodicals, Inc. Concepts Magn Reson Part A 34A: 144–172, 2009.
Carcinoma of the upper urinary tract
Authors: Inman Brant A. , Tran Viet‐Tan , Fradet Yves , Lacombe Louis
Published: May 2009

BACKGROUND:

Carcinomas of the upper urinary tract are uncommon tumors that usually occurred in elderly patients. Competing causes of mortality should be considered when treating these patients.

METHODS:

All patients with upper urinary tract tumors who were treated surgically at Centre Hospitalier Universitaire de Québec and affiliated hospitals from 1978 to 2001 were retrospectively reviewed. Clinical and pathologic variables were assessed from both the preoperative and postoperative periods of management, and clinical outcomes were tracked. Competing risks regression, Cox proportional hazards modeling, and multiple imputation were used to assess predictors of cancer‐related and competing risks‒related mortality in both preoperative and postoperative settings.

RESULTS:

Competing risks were responsible for 46% of deaths in this cohort of 168 patients. Preoperatively, the most important predictor of cancer‐related mortality was a clinically invasive tumor (hazards ratio [HR], 3.97; P < .001), whereas increasing age (HR, 1.07; P < .001) was found to be the most important predictor of competing mortality. Postoperatively, tumor grade was the most important predictor of cancer‐related mortality (HR, 3.92; P < .001) whereas constitutional symptoms (HR, 1.91; P = .015) and increasing age (HR, 1.06; P < .001) were found to be predictive of competing mortality.

CONCLUSIONS:

In the current study, stage and grade were found to be the 2 most important independent predictors of survival in patients with tumors of the upper urinary tract and were highly correlated. Pain or weight loss was found to be a novel predictor of survival in this cancer. Although a survival disadvantage was not noted for women, nephron‐sparing surgery, ureteral tumors, or older patients with respect to cancer, competing causes of mortality were found to be responsible for greater than one‐third of observed deaths and age was the best predictor of this occurrence. Cancer 2009. © 2009 American Cancer Society.
The 59th Annual Meeting of the International Society of Electrochemistry in Seville
Authors: Baltruschat Helmut
Published: May 2009

Electrochemistry down to the molecular level was the main theme of the 59th annual meeting of the International Society of Electrochemistry (ISE, see logo). Around 1400 scientists from all over the world met in Seville to discuss modern aspects, progress in methods and new mechanistic insights.

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Complex dynamic behavior during transition in a solid combustion model
Authors: Yu Jun , Gross Laura K. , Danforth Christopher M.
Published: May 2009

Through examples in a free‐boundary model of solid combustion, this study concerns nonlinear transition behavior of small disturbances of front propagation and temperature as they evolve in time. This includes complex dynamics of period doubling, and quadrupling, and it eventually leads to chaotic oscillations. Within this complex dynamic domain we also observe a period six‐folding. Both asymptotic and numerical solutions are studied.We show that for special parameters our asymptotic method with some dominant modes captures the formation of coherent structures. Finally,we discuss possible methods to improve our prediction of the solutions in the chaotic case. © 2009 Wiley Periodicals, Inc. Complexity, 2009
Are complex systems hard to evolve?
Authors: Adamatzky Andy , Bull Larry
Published: May 2009

Evolutionary complexity is measured here by the number of trials/evaluations needed for evolving a logical gate in a nonlinear medium. Behavioral complexity of the gates evolved is characterized in terms of cellular automata behavior. We speculate that hierarchies of behavioral and evolutionary complexities are isomorphic up to some degree, subject to substrate specificity of evolution, and the spectrum of evolution parameters. © 2009 Wiley Periodicals, Inc. Complexity, 2009
In first presentation adolescent anorexia nervosa, do cognitive markers of underweight status change with weight gain following a refeeding intervention?
Authors: Hatch Ainslie , Madden Sloane , Kohn Michael R. , Clarke Simon , Touyz Stephen , Gordon Evian , Williams Leanne M.
Published: May 2009

Objective:

To determine the nature and severity of cognitive functioning impairment in adolescent anorexia nervosa (AN) when underweight and following weight gain.

Method:

In 37 first admission adolescent (12–18 years) AN patients and 45 matched controls, general cognitive functions were assessed at baseline and follow‐up using the IntegNeuro‐computerized battery. AN participants were tested between days 3 and 10 of their admission when underweight, with retesting conducted after weight restoration.

Results:

When underweight, AN participants performed more poorly than controls on sensori‐motor speed tasks and exhibited a susceptibility to interference, but had superior working memory. Once the weight is restored, individuals significantly improved relative to their own performance. Relative to controls, they were significantly faster on attention and executive function tasks, exhibited superior verbal fluency, working memory, and a significantly superior ability to inhibit well‐learnt responses.

Discussion:

Cognitive impairments in adolescent AN appear to normalize with refeeding and weight gain. © 2009 by Wiley Periodicals, Inc. Int J Eat Disord 2010
Polynuclear Complexes Containing the Redox Noninnocent Schiff Base Ligand 2‐[(E)‐2‐Mercaptophenylimino]methyl‐4,6‐di‐tert‐butylphenolate(2–)
Authors: Roy Nabarun , Sproules Stephen , Bothe Eberhard , Weyhermüller Thomas , Wieghardt Karl
Published: May 2009

The N,O,S‐donor Schiff base ligand 2‐[(E)‐(2‐mercaptophenylimino)methyl]‐4,6‐di‐tert‐butylphenolate(2–) (H2L) was deprotonated with triethylamine (2 equiv.) and treated with equimolar amounts of Cu(OAc)2·H2O, PtCl2, Pd(OAc)2, and CoCl2, respectively. The versatility of L2– is realized in the self‐assembly of four polynuclear complexes: dimeric [CuII2(L)2] (1), trimeric [PtII3(L)3] (2), and the two tetrameric complexes [PdII4(L)4] (3) and [CoIII4(L)6] (4), all characterized by X‐ray crystallography. Electronic structure calculations (DFT) on dimeric 1 show that the two singly occupied Cud orbitals are antiferromagnetically coupled, and the calculated J = –724 cm–1 agrees well with the experimental data. Complexes 3 and 4 possess several reversible one‐electron, ligand‐centered oxidations with electronic absorption and EPR spectroscopy displaying all the hallmarks of coordinated phenoxyl radicals. This feature further endorses our assignment of the generation of phenoxyl radicals upon oxidation and underscores the redox noninnocence of this Schiff base ligand.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
An Electron‐Poor Host Receptor for Electron‐Rich Guests Involving Anion–π and Lone‐Pair–π Interactions
Authors: de Hoog Paul , Robertazzi Arturo , Mutikainen Ilpo , Turpeinen Urho , Gamez Patrick , Reedijk Jan
Published: May 2009

The binding of the ligand N,N′,N″,N″′‐tetrakis{2,4‐bis[(dipyridin‐2‐yl)amino]‐1,3,5‐triazin‐2‐yl}‐1,4,8,11‐tetraazacyclotetradecane (azadendtriz) to four copper(II) ions generates two electron‐deficient cavities formed by four coordinated pyridine rings that are capable of hosting electron‐rich guests. The molecular structures of [Cu4(azadendtriz)Cl4](Cl)4(H2O)13 (1) and [Cu4(azadendtriz)Br4](Br)4(H2O)28 (2), determined from single‐crystal X‐ray data, reveal that the π‐acidic receptor binds a chloride anion through anion–π interactions in 1, whereas it hosts a water molecule through lone‐pair–π interactions in 2. This differentiation between Br– and Cl– may be explained by the different size of the (hydrated) anions.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Egg yolk conjugated linoleic acid alters phospholipid molecular species in chick tissues
Authors: Cherian Gita
Published: May 2009

The effects of egg conjugated linoleic acid (CLA) on chick yolk sac and liver phospholipid composition and molecular species were determined. Fertile eggs with no (control), low (CLA1) or high (CLA2) levels of CLA were incubated. Upon hatching, total lipid in the remnant yolk sac constituted 11.5, 18.9 and 15.3% in control, CLA1 and CLA2, respectively (p <0.05). Maternal CLA led to a decrease in phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn) and an increase in lysophosphatidylcholine (LPtdCho) in the yolk sac and liver tissues of CLA1 and CLA2 when compared to control (p <0.05). The effect of maternal dietary CLA was very prominent in yolk sac PtdCho (34:1) where 13 and 38% reductions were observed in CLA1 and CLA2, respectively, when compared to control. Among different liver PtdCho species, the highest difference was found in 36:2, where a 41% increase was observed in CLA2 when compared with control chicks. The liver LPtdCho of CLA1 and CLA2 chicks had a 92% increase in 16:0 and 18:0 when compared to control. Over 80% increase was observed for 18:2 and 20:4 in the liver LPtdCho of CLA2 chicks compared to control. These results suggest that the yolk CLA content alters the proportions of phospholipids in the progeny during avian embryogenesis.
Influence of silica gel in production of diacylglycerol via enzymatic glycerolysis of palm olein
Authors: Yeoh Chiou Moi , Choong Thomas Shean Yaw , Abdullah Luqman Chuah , Yunus Robiah , Siew Wai Lin
Published: May 2009

Enzymatic glycerolysis was explored in this paper for the production of diacylglycerol (DAG) oils from palm olein. Three commercial enzymes, Lipozyme TL IM, Lipozyme RM IM and Novozym 435 were used for their ability to synthesize DAG in a solvent‐free system. Novozym 435 was found to be the more effective enzyme, resulting in a high DAG production even in the absence of an adsorbent such as silica gel. The yields of DAG were between 43 and 50 wt‐%. Lipozyme TL IM and RM IM, being supported on hydrophilic materials, require an adsorbent to allow slow release of glycerol for reaction with the enzyme and oil. In the absence of silica, no reaction was observed. The success of the reaction is therefore very dependent on the amount of silica used. The yields of DAG using Lipozyme TL IM and RM IM were 52 and 45 wt‐%, respectively. In addition, the degree of reduction in tocopherols and tocotrienols appeared correlated with the efficacy of the glycerolysis reaction. Changes in the slip melting points and solid fat contents of the products are indicative of the reaction occurring.
Catalytic behavior of ruthenium in soybean oil hydrogenation
Authors: Cizmeci Melih , Musavi Anar , Tekin Aziz , Kayahan Muammer
Published: May 2009

Soybean oil was hydrogenated with a carbon‐supported ruthenium catalyst (Ru/C) at 165 °C, 2 bar H2 and 500 rpm stirring speed. Reaction rates, trans isomer formation, selectivity ratios and melting behaviors of the samples were monitored. No catalytic activity was found for the application of 10 ppm of the catalyst, and significant catalytic activity appeared at >50 ppm of active catalyst. The catalyst concentration had an effect on the reaction rate of hydrogenation, but the weight‐normalized reaction rate constant (kc) was almost independent of the catalyst concentration at lower iodine values. Ru/C generated considerable amounts of trans fatty acids (TFA), including high amounts of trans 18:2, and also stearic acid, due to its very non‐selective nature. The selectivity ratios were found to be low and varied between 1.12 and 4.32 during the reactions. On the other hand, because of the low selectivity, higher slip melting points and solid fat contents at high temperatures were obtained than those for nickel and palladium catalysts. Another different characteristic of this catalyst was the formation (max 1.67%) of conjugated linoleic acid (CLA) during hydrogenation. Besides, CLA formation in the early stages of the reactions did not change very much with the lower iodine values.
On the Electrophilicity of Cyclic Acylphosphoramidates (CAPAs) Postulated as Intermediates
Authors: Ni Feng , Gao Xiang , Zhao Zeng‐Xiang , Huang Chao , Zhao Yu‐Fen
Published: May 2009

Cyclic acylphosphoramidates (2‐hydroxy‐2‐oxy‐1,3,2‐oxazaphospholidine‐5‐ones, CAPAs) are phosphate‐activated amino acids possessing both a carboxyl–phosphoryl anhydride and a phosphoramidate bond in a ring. They structurally resemble NCAs (amino acidN‐carboxyanhydrides,Leuchs' anhydrides), which have been extensively investigated. By contrast, the chemistry of CAPAs has remained almost unexplored since it was proposed in a prebiotic reaction of inorganic polyphosphates (PolyPs) with amino acids. In the present work, the bielectrophilicity of α‐CAPAs (Gly‐CAPA, Ala‐CAPA) was identified by isotopic analysis (18O,15N) and further proved by trapping α‐CAPA with nucleophiles such as water, amino acids, phosphate and methanol in alkaline media, which yieldedN‐phosphoamino acids and peptide phosphoanhydride and phosphate ester derivatives. By comparison with the reactivity of NCAs, the bielectrophilicity of CAPAs indicates that CAPAs can provide rich chemistry.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)
Synthesis and Biological Evaluation of Non‐Hydrolyzable 1,2,3‐Triazole‐Linked Sialic Acid Derivatives as Neuraminidase Inhibitors (Eur. J. Org. Chem. 16/2009)
Authors: Weïwer Michel , Chen Chi‐Chang , Kemp Melissa M. , Linhardt Robert J.
Published: May 2009

The cover picture shows the binding of an influenza virus to the surface of a host cell. The hemaglutinin (blue spikes) binds to the sialic acid (green hexagons) residues present on the non‐reducing end of the surface glycoprotein to gain entry into the cell. Once the cell is infected, the viral neuraminidases (pink pinwheels) cleave the sialic acids to escape. The 1,2,3‐triazole‐linked sialic acid derivatives (green spheres) were designed to act as non‐hydrolyzable inhibitors to block the virus. Details are discussed in the article by R. J. Linhardt et al. on p. 2611 ff.
Bismuth Modified Gold Microelectrode for Pb(II) Determination in Wine Using Alkaline Medium
Authors: Oliveira Salles Maiara , Ruas de Souza Ana Paula , Naozuka Juliana , de Oliveira Pedro Vitoriano , Bertotti Mauro
Published: May 2009

Electrodeposition of bismuth on gold microelectrodes for determination of Pb(II) by square wave anodic stripping voltammetry (SWASV) was accomplished by an in situ procedure in alkaline solution. A linear calibration plot for Pb(II) in the concentration range 40 to 6700 nmol L−1 (r=0.998) was obtained, the detection limit was found to be 12.5 nmol L−1 (S/N=3) and the relative standard deviation in solutions containing 1 μmol L−1 Pb(II) was 4% (n=12). The analytical performance of the proposed sensor was tested by measuring the Pb(II) concentration in a wine sample. The result was in good agreement with the one obtained by GFAAS.
Electrodeposited Silver Nanoparticles on Carbon Ionic Liquid Electrode for Electrocatalytic Sensing of Hydrogen Peroxide
Authors: Safavi Afsaneh , Maleki Norouz , Farjami Elaheh
Published: May 2009

Silver nanoparticles (narrowly dispersed in diameter) were electrodeposited on carbon ionic liquid electrode (CILE) surface using a two‐step potentiostatic method. Potentiostatic double pulse technique was used as a suitable and simple method for controlling the size and morphologies of silver nanoparticles electrodeposited on CILE. The obtained silver nanoparticles deposited on CILE surface showed excellent electrocatalytic activity (low overpotential of −0.35 V vs. Ag/AgCl) towards reduction of hydrogen peroxide. A linear dynamic range of 2–200 μM with an experimental detection limit of 0.7 μM (S/N=3) and reproducibility of 4.1% (n=5) make the constructed sensor suitable for peroxide determination in aqueous solutions.
Electrochemical Aptasensors – Recent Achievements and Perspectives
Authors: Hianik Tibor , Wang Joseph
Published: May 2009

This article reviews recent achievements in developing aptamer‐based electrochemical biosensors (electrochemical aptasensors). Aptamers are single stranded DNA or RNA molecules with high specificity to various ligands. Their specificity is comparable and in certain cases even higher than those of antibodies. In contrast to antibodies, aptamers are prepared by an in vitro selection procedure developed simultaneously in the early 1990s by L. Gold and A. Ellington. Due to their stability and the possibility of chemical modification aptamers can be immobilized on various supports and serve as artificial receptors in biosensors. The first aptasensors developed in the second half of 1990s were based on optical detection. However, in early 2000 substantial interest arose to the development of electrochemical aptasensors. It has been shown that due to their simplicity and fast response they represent an excellent tool in practical applications. The main focus of this review is to discuss the configuration of aptamers and electrochemical methods for detecting aptamers–analyte interactions. We will also provide a brief history of aptamer development, along with molecular structure and methods of aptamer engineering. Methods for immobilizing aptamers onto a solid support are also discussed.
Electroanalysis of Norepinephrine at Bare Gold Electrode Pure and Modified with Gold Nanoparticles and S‐Functionalized Self‐Assembled Layers in Aqueous Solution
Authors: Łuczak Teresa
Published: May 2009

Gold nanoparticles (Au‐NPs), cystamine (CA) and 3,3′‐dithiodipropionic acid (DTDPA) modified gold bare electrodes were applied in voltammetric sensors for simultaneous detection of norepinephrine (NEP), ascorbic (AA) and uric (UA) acids. A linear relationship between norepinephrine concentration and current response was obtained in the range of 0.1 μM to 600 μM M with the detection limit ≤0.091 μM for the electrodes modified at 2D template and in the range of 0.1 μM to 700 μM M with the detection limit ≤0.087 μM for the electrodes modified at 3D template The results have shown that using modified electrodes it is possible to perform electrochemical analysis of norepinephrine without interference of ascorbic and uric acids, whose presence is the major limitation in norepinephrine determination at a bare gold electrode. The modified SAMs electrodes show good selectivity, sensitivity, reproducibility and high stability.
Performance analysis of random uniform power allocation for wireless networks in Rayleigh fading channels
Authors: Elmusrati Mohammed , Tarhuni Naser , Jäntti Riku
Published: May 2009

When there is no feedback channels in wireless sensor networks or when the sensors are deaf (cannot listen to the feedback channels), the conventional and practical method for power allocation is to use fixed power transmission. This method has many limitations such as near–far problems where the relatively far away sensors are blocked by near sensors and also the unnecessarily high power consumption for good channel sensors. One recent proposal to overcome such limitations is to use uniform random power allocation for terminals. In that work the system performance is analysed for static channels (i.e. snapshot assumption), where it shows that there is a considerable obtained gain when using uniform random power allocation over fixed power. An important question is about the performance of such transmission power strategy in case of a more realistic channel scenario such as Rayleigh fading channels. This paper answers this question. Detailed mathematical analysis as well as Monte‐Carlo simulations for the system performance in Rayleigh fading channels are given in this paper. We show that the performance of uniform power allocation is much worse in case of fading channels than in static channels. Almost there is no gain of using uniform random power over fixed power in terms of average probability of outage. However, uniform random power may considerably reduce the total power consumption at small degradation of the average performance. This can be critical feature in energy constrained networks. Copyright © 2009 John Wiley & Sons, Ltd.
Modeling multi‐stage decomposition of cotton fabrics considering char oxidation in the presence of oxygen
Authors: Zhu F. L. , Wang X. J. , Cheng X. P. , Ma S. Q.
Published: May 2009

A theoretical model, describing thermal degradation behavior of cotton fabrics that exposed to a constant radiant heat flux, is proposed in the paper. The model describes thermal and oxidative degradation of cotton fabric under the oxygen‐containing atmosphere and considers pseudo‐bi‐component separate‐stage kinetic process. Both exothermic and endothermic reactions are included in the decomposition process. At present, gas phase oxidation reactions are not included. Comparison with experimental results demonstrates that the predictions of the mass loss rate and temperature profile with these cotton fabrics are in agreement with the experiment. Effects of thermal radiation and ambient oxygen concentration on decomposition have also been investigated. The gas phase temperature is also predicted by the present numerical model. Results from numerical model will help contribute to a better understanding of the ignition mechanism of flame‐resistant cotton fabrics used for fire safety garments. Copyright © 2009 John Wiley & Sons, Ltd.
Aerodynamic shape optimization on overset grids using the adjoint method
Authors: Liao Wei , Tsai Her Mann
Published: May 2009

This paper deals with the use of the continuous adjoint equation for aerodynamic shape optimization of complex configurations with overset grids methods. While the use of overset grid eases the grid generation process, the non‐trivial task of ensuring communication between overlapping grids needs careful attention. This need is effectively addressed by using a practically useful technique known as the implicit hole cutting (IHC) method. The method depends on a simple cell selection process based on the criterion of cell size, and all grid points including interior points and fringe points are treated indiscriminately in the computation of the flow field. This paper demonstrates the simplicity of the IHC method for the adjoint equation. Similar to the flow solver, the adjoint equations are solved on conventional point‐matched and overlapped grids within a multi‐block framework. Parallel computing with message passing interface is also used to improve the overall efficiency of the optimization process. The method is successfully demonstrated in several two‐ and a three‐dimensional shape optimization cases for both external and internal flow problems. Copyright © 2009 John Wiley & Sons, Ltd.
Nanostructured Electrodes and Gel‐Polymer Electrolyte for an Improved Li‐ion Battery
Authors: Penazzi N. , Bodoardo S. , Bongiovanni R. , Gerbaldi C. , Meligrana G. , Mulas G. , Nair J.
Published: May 2009

The present communication deals with the results obtained by the electrochemistry research group at the Politecnico di Torino in Italy in the field of materials for Li‐ion cells. Cathode (LiFePO4/C powder), anode (Ni3Sn4–C alloy) and electrolyte (gel‐polymer membrane) cell components have been prepared with the aim of obtaining, beyond high performance, cheap materials from easily disposable reagents via simple and reliable preparations.
Case‐only genome‐wide interaction study of disease risk, prognosis and treatment
Authors: Pierce Brandon L. , Ahsan Habibul
Published: May 2009

Case‐control genome‐wide association (GWA) studies have facilitated the identification of susceptibility loci for many complex diseases; however, these studies are often not adequately powered to detect gene‐environment (G×E) and gene‐gene (G×G) interactions. Case‐only studies are more efficient than case‐control studies for detecting interactions and require no data on control subjects. In this article, we discuss the concept and utility of the case‐only genome‐wide interaction (COGWI) study, in which common genetic variants, measured genome‐wide, are screened for association with environmental exposures or genetic variants of interest. An observed G‐E (or G‐G) association, as measured by the case‐only odds ratio (OR), suggests interaction, but only if the interacting factors are unassociated in the population from which the cases were drawn. The case‐only OR is equivalent to the interaction risk ratio. In addition to risk‐related interactions, we discuss how the COGWI design can be used to efficiently detect G×G, G×E and pharmacogenetic interactions related to disease outcomes in the context of observational clinical studies or randomized clinical trials. Such studies can be conducted using only data on individuals experiencing an outcome of interest or individuals not experiencing the outcome of interest. Sharing data among GWA and COGWI studies of disease risk and outcome can further enhance efficiency. Sample size requirements for COGWI studies, as compared to case‐control GWA studies, are provided. In the current era of genome‐wide analyses, the COGWI design is an efficient and straightforward method for detecting G×G, G×E and pharmacogenetic interactions related to disease risk, prognosis and treatment response. Genet. Epidemiol. 34:7–15, 2010. © 2009 Wiley‐Liss, Inc.
Shrinkage estimation for robust and efficient screening of single‐SNP association from case‐control genome‐wide association studies
Authors: Luo Sheng , Mukherjee Bhramar , Chen Jinbo , Chatterjee Nilanjan
Published: May 2009

Population‐based case‐control design has become one of the most popular approaches for conducting genome‐wide association scans for rare diseases like cancer. In this article, we propose a novel method for improving the power of the widely used single‐single‐nucleotide polymorphism (SNP) two‐degrees‐of‐freedom (2 d.f.) association test for case‐control studies by exploiting the common assumption of Hardy‐Weinberg Equilibrium (HWE) for the underlying population. A key feature of the method is that it can relax the assumed model constraints via a completely data‐adaptive shrinkage estimation approach so that the number of false‐positive results due to the departure of HWE is controlled. The method is computationally simple and is easily scalable to association tests involving hundreds of thousands or millions of genetic markers. Simulation studies as well as an application involving data from a real genome‐wide association study illustrate that the proposed method is very robust for large‐scale association studies and can improve the power for detecting susceptibility SNPs with recessive effects, when compared to existing methods. Implications of the general estimation strategy beyond the simple 2 d.f. association test are discussed. Genet. Epidemiol. 33:740–750, 2009. Published 2009 Wiley‐Liss, Inc.
Avoiding the high Bonferroni penalty in genome‐wide association studies
Authors: Gao Xiaoyi , Becker Lewis C. , Becker Diane M. , Starmer Joshua D. , Province Michael A.
Published: May 2009

A major challenge in genome‐wide association studies (GWASs) is to derive the multiple testing threshold when hypothesis tests are conducted using a large number of single nucleotide polymorphisms. Permutation tests are considered the gold standard in multiple testing adjustment in genetic association studies. However, it is computationally intensive, especially for GWASs, and can be impractical if a large number of random shuffles are used to ensure accuracy. Many researchers have developed approximation algorithms to relieve the computing burden imposed by permutation. One particularly attractive alternative to permutation is to calculate the effective number of independent tests, Meff, which has been shown to be promising in genetic association studies. In this study, we compare recently developed Meff methods and validate them by the permutation test with 10,000 random shuffles using two real GWAS data sets: an Illumina 1M BeadChip and an Affymetrix GeneChip® Human Mapping 500K Array Set. Our results show that the simpleM method produces the best approximation of the permutation threshold, and it does so in the shortest amount of time. We also show that Meff is indeed valid on a genome‐wide scale in these data sets based on statistical theory and significance tests. The significance thresholds derived can provide practical guidelines for other studies using similar population samples and genotyping platforms. Genet. Epidemiol. 34:100–105, 2010. © 2009 Wiley‐Liss, Inc.
Neural correlates of exemplar novelty processing under different spatial attention conditions
Authors: Stoppel Christian Michael , Boehler Carsten Nicolas , Strumpf Hendrik , Heinze Hans‐Jochen , Hopf Jens Max , Düzel Emrah , Schoenfeld Mircea Ariel
Published: May 2009

The detection of novel events and their identification is a basic prerequisite in a rapidly changing environment. Recently, the processing of novelty has been shown to rely on the hippocampus and to be associated with activity in reward‐related areas. The present study investigated the influence of spatial attention on neural processing of novel relative to frequently presented standard and target stimuli. Never‐before‐seen Mandelbrot‐fractals absent of semantic content were employed as stimulus material. Consistent with current theories, novelty activated a widespread network of brain areas including the hippocampus. No activity, however, could be observed in reward‐related areas with the novel stimuli absent of a semantic meaning employed here. In the perceptual part of the novelty‐processing network a region in the lingual gyrus was found to specifically process novel events when they occurred outside the focus of spatial attention. These findings indicate that the initial detection of unexpected novel events generally occurs in specialized perceptual areas within the ventral visual stream, whereas activation of reward‐related areas appears to be restricted to events that do possess a semantic content indicative of the biological relevance of the stimulus. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.
Dysregulation of working memory and default‐mode networks in schizophrenia using independent component analysis, an fBIRN and MCIC study
Authors: Kim Dae Il , Manoach Dara S. , Mathalon Daniel H. , Turner Jessica A. , Mannell Maggie , Brown Greg G. , Ford Judith M. , Gollub Randy L. , White Tonya , Wible Cynthia , Belger Aysenil , Bockholt H.Jeremy , Clark Vince P. , Lauriello John , O'Leary Daniel , Mueller Bryon A. , Lim Kelvin O. , Andreasen Nancy , Potkin Steve G. , Calhoun Vince D.
Published: May 2009

Deficits in working memory (WM) are a consistent neurocognitive marker for schizophrenia. Previous studies have suggested that WM is the product of coordinated activity in distributed functionally connected brain regions. Independent component analysis (ICA) is a data‐driven approach that can identify temporally coherent networks that underlie fMRI activity. We applied ICA to an fMRI dataset for 115 patients with chronic schizophrenia and 130 healthy controls by performing the Sternberg Item Recognition Paradigm. Here, we describe the first results using ICA to identify differences in the function of WM networks in schizophrenia compared to controls. ICA revealed six networks that showed significant differences between patients with schizophrenia and healthy controls. Four of these networks were negatively task‐correlated and showed deactivation across the posterior cingulate, precuneus, medial prefrontal cortex, anterior cingulate, inferior parietal lobules, and parahippocampus. These networks comprise brain regions known as the default‐mode network (DMN), a well‐characterized set of regions shown to be active during internal modes of cognition and implicated in schizophrenia. Two networks were positively task‐correlated, with one network engaging WM regions such as bilateral DLPFC and inferior parietal lobules while the other network engaged primarily the cerebellum. Our results suggest that DLPFC dysfunction in schizophrenia might be lateralized to the left and intrinsically tied to other regions such as the inferior parietal lobule and cingulate gyrus. Furthermore, we found that DMN dysfunction in schizophrenia exists across multiple subnetworks of the DMN and that these subnetworks are individually relevant to the pathophysiology of schizophrenia. In summary, this large multsite study identified multiple temporally coherent networks, which are aberrant in schizophrenia versus healthy controls and suggests that both task‐correlated and task‐anticorrelated networks may serve as potential biomarkers. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.
Apolipoprotein B100 acts as a molecular link between lipid-induced endoplasmic reticulum stress and hepatic insulin resistance #
Authors: Su Qiaozhu , Tsai Julie , Xu Elaine , Qiu Wei , Bereczki Erika , Santha Miklos , Adeli Khosrow
Published: May 2009

Accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER) results in ER stress and lipid overload-induced ER stress has been implicated in the development of insulin resistance. Here, evidence is provided for a molecular link between hepatic apolipoprotein B100 (apoB100), induction of ER stress, and attenuated insulin signaling. First, in vivo upregulation of hepatic apoB100 by a lipogenic diet was found to be closely associated with ER stress and attenuated insulin signaling in the liver. Direct in vivo overexpression of human apoB100 in a mouse transgenic model further supported the link between excessive apoB100 expression and hepatic ER stress. Human apoB100 transgenic mice exhibited hypertriglyceridemia and hyperglycemia. In vitro, accumulation of cellular apoB100 by free fatty acid (oleate) stimulation or constant expression of wild-type or N-glycosylation mutant apoB50 in hepatic cells induced ER stress. This led to perturbed activation of glycogen synthase kinase 3 and glycogen synthase by way of the activation of c-Jun N-terminal kinase and suppression of insulin signaling cascade, suggesting that dysregulation of apoB was sufficient to disturb ER homeostasis and induce hepatic insulin resistance. Small interfering (si)RNA-mediated attenuation of elevated apoB level in the apoB50-expressing cells rescued cells from lipid-induced ER stress and reversed insulin insensitivity. Conclusion: These findings implicate apoB100 as a molecular link between lipid-induced ER stress and hepatic insulin resistance. (Hepatology 2009.)
The role of the hepatocyte cytokeratin network in bile formation and resistance to bile acid challenge and cholestasis in mice #
Authors: Fickert Peter , Fuchsbichler Andrea , Wagner Martin , Silbert Dagmar , Zatloukal Kurt , Denk Helmut , Trauner Michael
Published: May 2009

The intermediate filament cytoskeleton of hepatocytes is composed of keratin (K) 8 and K18 and has important mechanical and nonmechanical functions. However, the potential role of the K8/K18 network for proper membrane targeting of hepatocellular adenosine triphosphate–binding cassette transporters and bile formation is unknown. We therefore designed a comparative study in K8 and K18 knockout mice and respective wild-type controls to test the hypothesis that intermediate filaments of hepatocytes play a role in normal bile formation. In addition, we challenged mice either with a 1% cholic acid–supplemented diet or a diet containing the porphyrinogenic xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine to determine the effect of K8/K18 loss on bile flow/composition and liver injury under different physiological and toxic stress stimuli. Protein expression levels and membrane localization of various transporters and anion exchangers were compared using western blotting and immunofluorescence microscopy, respectively, and bile flow and composition were determined under various experimental conditions. Our results demonstrate that loss of the intermediate filament network had no significant effect on bile formation and composition, as well as expression levels and membrane targeting of key hepatobiliary transporters under baseline and stress conditions. However, loss of K8 significantly increased liver injury in response to toxic stress. Conclusion: The intermediate filament network of hepatocytes is not specifically required for proper bile formation in mice. (Hepatology 2009.)
E2F4 and ribonucleotide reductase mediate S‐phase arrest in colon cancer cells treated with chlorophyllin
Authors: Chimploy Korakod , Díaz G. Dario , Li Qingjie , Carter Orianna , Dashwood Wan‐Mohaiza , Mathews Christopher K. , Williams David E. , Bailey George S. , Dashwood Roderick H.
Published: May 2009

Chlorophyllin (CHL) is a water‐soluble derivative of chlorophyll that exhibits cancer chemopreventive properties, but which also has been studied for its possible cancer therapeutic effects. We report here that human colon cancer cells treated with CHL accumulate in S‐phase of the cell cycle, and this is associated with reduced expression levels of p53, p21, and other G1/S checkpoint controls. At the same time, E2F1 and E2F4 transcription factors become elevated and exhibit increased DNA binding activity. In CHL‐treated colon cancer cells, bromodeoxyuridine pulse‐chase experiments provided evidence for the inhibition of DNA synthesis. Ribonucleotide reductase (RR), a pivotal enzyme for DNA synthesis and repair, was reduced at the mRNA and protein level after CHL treatment, and the enzymatic activity was inhibited in a concentration‐dependent manner both in vitro and in vivo. Immunoblotting revealed that expression levels of RR subunits R1, R2, and p53R2 were reduced by CHL treatment in HCT116 (p53+/+) and HCT116 (p53−/−) cells, supporting a p53‐independent mechanism. Prior studies have shown that reduced levels of RR small subunits can increase the sensitivity of colon cancer cells to clinically used DNA‐damaging agents and RR inhibitors. We conclude that by inhibiting R1, R2, and p53R2, CHL has the potential to be effective in the clinical setting, when used alone or in combination with currently available cancer therapeutic agents. © 2009 UICC
Characteristics of menstruation and pregnancy and the risk of lung cancer in women
Authors: Koushik Anita , Parent Marie‐Élise , Siemiatycki Jack
Published: May 2009

Lung tissue, both normal and cancerous, has been found to express estrogen receptors and patterns of expression have differed between men and women, suggesting a possible role for hormone‐related factors in lung carcinogenesis in women. Few epidemiological studies have examined hormone‐related variables and lung cancer risk and the findings have not been consistent. We investigated the association between characteristics of menstruation and pregnancy in relation to lung cancer risk in a population‐based case–control study carried out in Montreal, Canada, including 422 women with lung cancer and 577 controls. For each variable, odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regression modeling. Associations were also examined according to level of smoking and by lung cancer histology. All statistical tests were two‐sided. Most characteristics of menstruation and pregnancy were not associated with lung cancer risk. However, an increased risk was observed for women who had had a non‐natural menopause, which predominantly included women who had had a bilateral oophorectomy, compared with women who had had a natural menopause (OR = 1.92, 95% CI: 1.22–3.01). An inverse association with age at menopause was suggested. These results did not vary by level of smoking and they were similar for adenocarcinomas compared with other histological types. Our results suggest that hormonal factors, related to early menopause and/or ovary removal, may play a role in the risk of lung cancer. Further studies are needed to confirm these findings, and to assess the possible contribution of hormone replacement therapy. © 2009 UICC
Modified heparins inhibit integrin αIIbβ3 mediated adhesion of melanoma cells to platelets in vitro and in vivo
Authors: Zhang ChunMei , Liu Yan , Gao YanGuang , Shen Jian , Zheng Sheng , Wei Min , Zeng XianLu
Published: May 2009

The adhesion of tumor cells with platelets is important in the process of tumor metastasis. A huge work has indicated that anti‐adhesion is an effective strategy for metastasis inhibition. In this article, we assess the role of platelet integrin αIIbβ3 in adhesion of melanoma cells to platelets and the effects of heparin and modified heparins on the adhesion in vitro and in vivo. We show that platelet integrin αIIbβ3 is involved in the interaction of human melanoma A375 cells with platelets, and the high affinity epitope resides on the αIIb subunit rather than β3 subunit. Heparin sulfate‐like proteoglycans on tumor cell surface are implicated in the adhesion of A375 cells to integrin αIIbβ3. We also show that RO‐heparin, CR‐heparin, N‐2,3‐DS‐heparin and 2,3‐O‐DS‐heparin can significantly inhibit A375 cells binding to the CHO cells expressing integrin αIIbβ3 under static and flow conditions, and remarkably inhibit the adhesion of A375 cells to the immobilized platelet layers under flow conditions. We find that A375 cells and B16F10 cells are arrested in the pulmonary vessels and adhered to platelets, and the initial interaction of tumor cells with platelets in lung vessel and long‐term establishment of metastatic foci can be inhibited by heparin as well as CR‐heparin and N‐2,3‐DS‐heparin. These data suggest that modified heparins can inhibit tumor cell‐platelet interaction mediated by platelet integrin αIIbβ3 and modified heparins may be a potential substitute for heparin in inhibiting tumor metastasis. © 2009 UICC
Overexpression of Sp1 leads to p53‐dependent apoptosis in cancer cells
Authors: Chuang Jian‐Ying , Wu Chien‐Hsing , Lai Ming‐Derg , Chang Wen‐Chang , Hung Jan‐Jong
Published: May 2009

Numerous studies have documented that Sp1 expression level were elevated in various human cancers. However, the promoters of many pro‐apoptotic genes have been found to contain the Sp1 binding elements and are activated by Sp1 overexpression. To better understand the role and the mechanism of increased Sp1 levels on apoptosis, we used adenovirus to ectopically express GFP‐Sp1 protein in various cancer cell lines. First, in HeLa and A549 cells, we found that Sp1 overexpression suppressed the cell growth and increased the detection of sub‐G1 fraction, caspase‐3 cleavage, and annexin‐V signal revealed that apoptosis occurred. Furthermore, when cells entered the mitotic stage, the cell apoptosis was induced by Sp1 overexpression through affecting mitotic chromatin packaging. We also verified that p53 protein was accumulated and activated the p53‐dependent apoptotic pathways in the wild‐type p53 cells but not in the p53‐mutated or p53‐deleted cell lines when these cells were infected with adeno‐GFP‐Sp1 virus. In addition, A549 (p53+/+) cells could be protected from apoptosis under Sp1 overexpression when p53 was knockdown by p53 shRNA. Finally, H1299 (p53−/−) cell viability was significantly inhibited by adeno‐GFP‐Sp1 virus infection in the expression of p53. In conclusion, p53 was an essential factor for Sp1 overexpression‐induced apoptotic cell death in transforming cells. © 2009 UICC
Learning to sleep through the night: Solution or strain for mothers and young children?
Authors: Germo Gary R. , Goldberg Wendy A. , Keller Meret A.
Published: May 2009

Is the process of helping infants and young children learn to sleep through the night a solution to family sleep problems or does it exacerbate matters for mother and child? Retrospective and current accounts from a nonclinical, convenience sample of 102 mothers of preschool‐aged children provided information on sleep issues from early infancy through preschool age. Child, mother, and parenting characteristics, along with family sleep arrangements, were differentially related to the age at which children learned to sleep through the night and to the extent of difficulty that characterized this experience. Mothers who indicated more difficulty as their children learned to sleep through the night also reported more depressive symptoms and more strain in the mother–child relationship. Later age at sleeping through the night was more common among early bedsharers, but timing of sleeping through the night was not associated with preschool children's reported independence in several nonsleep domains. Sleep arrangements and the importance placed on sleeping through the night were the strongest contributors to variance explained in whether children learned to sleep through the night during infancy or toddlerhood. When advising parents about sleep interventions, practitioners should seek to understand whether families' parenting values fit their nighttime sleep practices.
Video interaction guidance inviting transcendence of postpartum depressed mothers' self‐centered state and holding behavior
Authors: Vik Kari , Braten Stein
Published: May 2009

By sometimes evoking self‐absorbed and avoidance behaviors in new mothers, postnatal depression affects the quality of mother–infant interaction, which in turn may invoke distress and avoidance in the infant and cause even more lasting impairment in the child's development. Three depressed mothers, A, B, and C, are reported upon after having been offered counseling in accordance with the Marte Meo approach through jointly watching with the therapist video replays of themselves interacting with their newborns. Clinical vignettes are offered which indicate how empathic and positive support of a sensitive therapist can be helpful in inviting the mother's recognition of her importance to her infant and facilitating mutually gratifying interaction between mother and child. Protocol analyses of select sessions of video‐related therapy reveal that two of the mothers sometimes complete the therapist's unfinished statements in an other‐centered manner, thereby transcending their initial self‐centered state. This is most dramatic in the case of Mother A, who starts out in the first session almost incapable of speech, merely nodding or shaking her head. In addition to other indications of improved mother–infant interaction, comparison of pre‐ and postguidance windows regarding the three mothers' holding behaviors reveals a shift from an avoidance or anxious stance to closer and more secure holding.
Ab Initio quantum mechanical charge field study of hydrated bicarbonate ion: Structural and dynamical properties
Authors: Vchirawongkwin Viwat , Pribil Andreas B. , Rode Bernd M.
Published: May 2009

The ab initio quantum mechanical charge field molecular dynamics (QMCF MD) formalism was applied to simulate the bicarbonate ion, HCO3−, in aqueous solution. The difference in coordination numbers obtained by summation over atoms (6.6) and for the solvent‐accessible surface (5.4) indicates the sharing of some water molecules between the individual atomic hydration shells. It also proved the importance to consider the hydration of the chemically different atoms individually for the evaluation of structural and dynamical properties of the ion. The orientation of water molecules in the hydration shell was visualized by the θ–tilt surface plot. The mean residence time in the surroundings of the HCO3− ion classify it generally as a structure‐breaking ion, but the analysis of the individual ion‐water hydrogen bonds revealed a more complex behavior of the different coordination sites. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010