bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel combination markers for predicting progression of nonmuscle invasive bladder cancer
Authors: Ha Yun‐Sok , Kim Ji Sang , Yoon Hyung‐Yoon , Jeong Pildu , Kim Tae‐Hwan , Yun Seok‐Joong , Lee Sang‐Cheol , Kim Gi‐Young , Choi Yung‐Hyun , Moon Sung‐Kwon , Yi Kim Isaac , Kim Wun‐Jae
Published: October 2011

To identify prognostic markers in nonmuscle invasive bladder cancer (NMIBC), the combined effect of RUNX3 and MGC17624 for predicting NMIBC progression was assessed. RUNX3 promoter methylation was examined using methylation specific‐polymerase chain reaction (MS‐PCR). MGC17624 mRNA expression was evaluated by real‐time PCR. Patients were divided into three groups according to the status of the two genes and the prognostic effects of these markers were evaluated. The median follow‐up period was 57.8 months (range, 9.1–189.7). The mRNA expression level of MGC17624 was significantly lower in patients with positive RUNX3 methylation than in those with negative methylation (p = 0.047). Kaplan–Meier estimates showed significant differences in time‐to‐progression between the genetic combination predictors (log‐rank test; p < 0.001). Patients with a poor predictive combination were at a significantly higher risk for progression [Hazard ratio (HR), 22.579] than patients with a good predictive combination in multivariate Cox regression analysis. In the subgroup analysis, a poor predictive combination accurately estimated progression in patients with intravesical therapy (HR, 20.081) and in those who experienced recurrence (HR, 54.233). Assessment of the status of RUNX3 and MGC17624 in combination was identified as a reliable method for predicting NMIBC progression.
Clinical significance of pleural effusion in the new influenza A (H1N1) viral pneumonia in children and adolescent
Authors: Kim Young Nam , Cho Hwa Jin , Cho Young Kuk , Ma Jae Sook
Published: October 2011

Background

Parapneumonic effusion has been reported to develop either in typical bacterial infection or in viral pneumonia with bacterial co‐infection and to cause death. Swine‐origin influenza A (H1N1) virus infection can be accompanied with pleural effusion; however, there are no reports about the significance of pleural effusion in H1N1 pneumonia. We retrospectively analyzed both the clinical characteristics and the significance of pleural effusion associated with H1N1 pneumonia in children and adolescent.

Method

Eighty‐nine patients who were admitted with H1N1 pneumonia were divided into two groups: 17 patients with pleural effusion (i.e., the effusion group), and 72 patients without pleural effusion (the non‐effusion group).

Results

Lymphopenia (P = 0.030), elevation of the C‐reactive protein (P = 0.026), and positive rate of anti‐sptreptolysin O titer (P = 0.040) were significantly increased in the effusion group than in the non‐effusion group. In addition, the need for treatment with both oxygen (P < 0.001) and oseltamivir (P = 0.013) was significantly increased in the effusion group. However, there was no significant difference between the two investigated groups in the duration of the treatment with intravenous antibiotics, the time of fever remission calculated from admission, and the days of hospital stay. Also, there was no documented bacterial co‐infection in any of the studied groups.

Conclusion

This result suggested that pleural effusion in H1N1 pneumonia could develop without bacterial co‐infection and had mild clinical course. Pediatr Pulmonol. 2012; 47:505–509. © 2011 Wiley Periodicals, Inc.
Comprehension Strategies for Reading Historical Fiction Picturebooks
Authors: Youngs Suzette , Serafini Frank
Published: October 2011

As the texts readers encounter in and out of school grow in complexity, the strategies that teachers demonstrate and encourage students to employ need to expand to accommodate the changing nature of these texts. In this article, the authors present a three‐part framework for utilizing historical fiction picturebooks as instructional resources. First they share various strategies for previewing a text, and calling students’ attention to the visual, textual and design elements of historical fiction picturebooks. Second, various strategies are presented for moving beyond noticing to strategies for interpreting what has been presented in the visual and verbal text. Third, they suggest several strategies for moving beyond interpretation to develop readers’ ability to critically analyze the historical perspectives and contexts of these texts. In this article, the authors guide readers through the reading of two historical fiction picturebooks while modeling how to employ strategies for reading multimodal texts.
Confessions of a baseball mom: The impact of youth sports on parents' feelings and behaviors
Authors: Peter Nancy E.
Published: October 2011

To explore parents' emotional investment in and behaviors in response to youth sports, the author conducted a mixed‐methods investigation to answer four research questions: (1)How do parents feel about their children's participation in organized youth team sports? (2) Which situations trigger which feelings? (3) How do parents' feelings influence their behaviors? (4) What parental characteristics (such as personal histories or demographics) are linked to different feelings and behaviors? The research indicated that many parents' feelings are triggered by their children's sports experiences and that adults must learn how to translate these feelings into productive behaviors.
Prediction of ketoacyl synthase family using reduced amino acid alphabets
Authors: Chen Wei , Feng Pengmian , Lin Hao
Published: October 2011

Ketoacyl synthases are enzymes involved in fatty acid synthesis and can be classified into five families based on primary sequence similarity. Different families have different catalytic mechanisms. Developing cost-effective computational models to identify the family of ketoacyl synthases will be helpful for enzyme engineering and in knowing individual enzymes’ catalytic mechanisms. In this work, a support vector machine-based method was developed to predict ketoacyl synthase family using the n-peptide composition of reduced amino acid alphabets. In jackknife cross-validation, the model based on the 2-peptide composition of a reduced amino acid alphabet of size 13 yielded the best overall accuracy of 96.44% with average accuracy of 93.36%, which is superior to other state-of-the-art methods. This result suggests that the information provided by n-peptide compositions of reduced amino acid alphabets provides efficient means for enzyme family classification and that the proposed model can be efficiently used for ketoacyl synthase family annotation.
Genomic imbalances in endometrial adenocarcinomas — Comparison of DNA ploidy, karyotyping and comparative genomic hybridization
Authors: Kildal Wanja , Micci Francesca , Risberg Bjørn , Abeler Vera M. , Kristensen Gunnar B. , Heim Sverre , Danielsen Håvard E.
Published: October 2011

DNA ploidy analysis is useful for prognostication in cancer patients, but the genomic details underlying ploidy changes are not fully understood. To improve this understanding, we compared DNA ploidy status with karyotypic and comparative genomic hybridization data on 51 endometrial adenocarcinomas. Out of 34 DNA diploid tumors evaluated by CGH, 16 (47%) showed imbalances, though only two had more than four copy number changes. Ten (29%) had aberrations involving chromosome 1, seven (21%) involving chromosome 10, while one tumor had a chromosome 8 aberration. Four of the seven DNA tetraploid tumors (57%) had imbalances detected by CGH with two (29%) having more than four. Six out of eight DNA aneuploid tumors showed imbalances by CGH, with five (63%) having more than four. The aberrations were observed on chromosomes 1 and 8 in five/eight (63%) cases while four imbalances (50%) involved chromosomes 5, 7 and X. Not surprisingly, we observed a significant correlation between increasing DNA ploidy complexity and increasing number of copy alterations. Gains of material from chromosomes 8 and 7 might be specifically correlated to DNA aneuploidy in endometrial adenocarcinomas since 63% and 50% of the aneuploid compared to 3% of the diploid tumors showed imbalances involving these chromosomes.
Subjektives Wirksamkeitserleben in psychoedukativen Gruppen bei Schizophrenie
Authors: Pitschel-Walz Gabriele , Froböse Teresa , Krämer Sibylle , Gsottschneider Anna , Bäuml Josef , Jahn Thomas
Published: October 2011

Zusammenfassung. Theoretischer Hintergrund: Psychoedukation gilt als psychotherapeutische Basisintervention bei Schizophrenie. Die Frage, was die therapeutisch wirksamen Elemente der Psychoedukation sind, ist noch nicht hinreichend geklärt. Fragestellung: Welches sind die bedeutenden therapeutischen Wirkfaktoren der Psychoedukation aus Sicht der Patienten und mit welchen Faktoren hängt das Wirksamkeitserleben zusammen? Methode: 97 stationär behandelte Patienten mit Schizophrenie besuchten psychoedukative Gruppen (8 Sitzungen in vier Wochen) und beurteilten anhand ausgewählter Items des Stundenbogens STEPP ( Krampen, 2002 ) die einzelnen Gruppensitzungen. Zusammenhänge mit soziodemografischen Variablen, Neurokognition und den Psychoedukationserfolgsmaßen Wissen und Compliance wurden untersucht. Ergebnisse: Die therapeutische Beziehung und die Kompetenzerweiterung erwiesen sich als wichtige therapeutische Dimensionen der Psychoedukation. Alter und Symptomatik beeinflussten das Wirksamkeitserleben. Patienten mit kognitiven Defiziten profitierten subjektiv von der Psychoedukation, auch wenn der Wissenserwerb eingeschränkt war. Schlussfolgerungen: Neben der Vermittlung von Kompetenzen spielt die therapeutische Beziehung bei psychoedukativen Gruppen eine entscheidende Rolle. Daher sollte auf Therapeutenkonstanz geachtet werden.
Nanoimprinted lithography high performance in-plane organic diodes
Authors: Thornton Martin J. , Ketelaars Bas , van den Heuve Eric , Roosen Harold , Smout Steve , Iosad Nikolay
Published: October 2011

We have used nanoimprint lithography to fabricate organic in-plane diodes whose design and process are suitable for mass produced by roll to roll production for simple radio frequency circuitry. The diode characteristics are a result of a channel constriction with rectifying ratios up to 3.25 × 104. Above the threshold voltage their behavior is quadratic, and there is a non-quadratic relationship between the threshold voltage and channel width and channel length. The phenomenon is the resultant interaction of the distribution of the localized states and the additional in-plane transverse electric field through the device channel.
Hole transport improvement in InGaN/GaN light-emitting diodes by graded-composition multiple quantum barriers
Authors: Wang C. H. , Chang S. P. , Ku P. H. , Li J. C. , Lan Y. P. , Lin C. C. , Yang H. C. , Kuo H. C. , Lu T. C. , Wang S. C. , Chang C. Y.
Published: October 2011

Graded-composition multiple quantum barriers (GQB) were designed and incorporated in c-plane InGaN/GaN light-emitting diodes (LEDs) grown on c-plane sapphire substrate to improve hole transport and efficiency droop. The simulation of GQB LED design predicts enhancement of the hole transport in the active region at both low and high current densities. The fabricated LED with GQB structure exhibits lower series resistance and substantially reduced droop behavior of only 6% in comparison with 34% for conventional LED, supporting the improvement of hole transport in our design.
Nonequilibrium candidate Monte Carlo is an efficient tool for equilibrium simulation
Authors: Nilmeier Jerome P. , Crooks Gavin E. , Minh David D. L. , Chodera John D.
Published: October 2011

Metropolis Monte Carlo simulation is a powerful tool for studying the equilibrium properties of matter. In complex condensed-phase systems, however, it is difficult to design Monte Carlo moves with high acceptance probabilities that also rapidly sample uncorrelated configurations. Here, we introduce a new class of moves based on nonequilibrium dynamics: Candidate configurations are generated through a finite-time process in which a system is actively driven out of equilibrium, and accepted with criteria that preserve the equilibrium distribution. The acceptance rule is similar to the Metropolis acceptance probability, but related to the nonequilibrium work rather than the instantaneous energy difference. Our method is applicable to sampling from both a single thermodynamic state or a mixture of thermodynamic states, and allows both coordinates and thermodynamic parameters to be driven in nonequilibrium proposals. Whereas generating finite-time switching trajectories incurs an additional cost, driving some degrees of freedom while allowing others to evolve naturally can lead to large enhancements in acceptance probabilities, greatly reducing structural correlation times. Using nonequilibrium driven processes vastly expands the repertoire of useful Monte Carlo proposals in simulations of dense solvated systems.
Homogenization patterns of the world’s freshwater fish faunas
Authors: Villéger Sébastien , Blanchet Simon , Beauchard Olivier , Oberdorff Thierry , Brosse Sébastien
Published: October 2011

The world is currently undergoing an unprecedented decline in biodiversity, which is mainly attributable to human activities. For instance, nonnative species introduction, combined with the extirpation of native species, affects biodiversity patterns, notably by increasing the similarity among species assemblages. This biodiversity change, called taxonomic homogenization, has rarely been assessed at the world scale. Here, we fill this gap by assessing the current homogenization status of one of the most diverse vertebrate groups (i.e., freshwater fishes) at global and regional scales. We demonstrate that current homogenization of the freshwater fish faunas is still low at the world scale (0.5%) but reaches substantial levels (up to 10%) in some highly invaded river basins from the Nearctic and Palearctic realms. In these realms experiencing high changes, nonnative species introductions rather than native species extirpations drive taxonomic homogenization. Our results suggest that the “Homogocene era” is not yet the case for freshwater fish fauna at the worldwide scale. However, the distressingly high level of homogenization noted for some biogeographical realms stresses the need for further understanding of the ecological consequences of homogenization processes.
Mania-like behavior induced by genetic dysfunction of the neuron-specific Na
+
,K
+
-ATPase α3 sodium pump
Authors: Kirshenbaum Greer S. , Clapcote Steven J. , Duffy Steven , Burgess Christian R. , Petersen Janne , Jarowek Karolina J. , Yücel Yeni H. , Cortez Miguel A. , Snead O. Carter , Vilsen Bente , Peever John H. , Ralph Martin R. , Roder John C.
Published: October 2011

Bipolar disorder is a debilitating psychopathology with unknown etiology. Accumulating evidence suggests the possible involvement of Na
+
,K
+
-ATPase dysfunction in the pathophysiology of bipolar disorder. Here we show that
Myshkin
mice carrying an inactivating mutation in the neuron-specific Na
+
,K
+
-ATPase α3 subunit display a behavioral profile remarkably similar to bipolar patients in the manic state.
Myshkin
mice show increased Ca
2+
signaling in cultured cortical neurons and phospho-activation of extracellular signal regulated kinase (ERK) and Akt in the hippocampus. The mood-stabilizing drugs lithium and valproic acid, specific ERK inhibitor SL327, rostafuroxin, and transgenic expression of a functional Na
+
,K
+
-ATPase α3 protein rescue the mania-like phenotype of
Myshkin
mice. These findings establish
Myshkin
mice as a unique model of mania, reveal an important role for Na
+
,K
+
-ATPase α3 in the control of mania-like behavior, and identify Na
+
,K
+
-ATPase α3, its physiological regulators and downstream signal transduction pathways as putative targets for the design of new antimanic therapies.
Conversion of tryptophan to indole-3-acetic acid by TRYPTOPHAN AMINOTRANSFERASES OF
ARABIDOPSIS
and YUCCAs in
Arabidopsis
Authors: Won Christina , Shen Xiangling , Mashiguchi Kiyoshi , Zheng Zuyu , Dai Xinhua , Cheng Youfa , Kasahara Hiroyuki , Kamiya Yuji , Chory Joanne , Zhao Yunde
Published: October 2011

Auxin is an essential hormone, but its biosynthetic routes in plants have not been fully defined. In this paper, we show that the TRYPTOPHAN AMINOTRANSFERASE OF
ARABIDOPSIS
(TAA) family of amino transferases converts tryptophan to indole-3-pyruvate (IPA) and that the YUCCA (YUC) family of flavin monooxygenases participates in converting IPA to indole-3-acetic acid, the main auxin in plants. Both the YUCs and the TAAs have been shown to play essential roles in auxin biosynthesis, but it has been suggested that they participate in two independent pathways. Here, we show that all of the
taa
mutant phenotypes, including defects in shade avoidance, root resistance to ethylene and
N
-1-naphthylphthalamic acid (NPA), are phenocopied by inactivating
YUC
genes. On the other hand, we show that the
taa
mutants in several known auxin mutant backgrounds, including
pid
and
npy1
, mimic all of the well-characterized developmental defects caused by combining
yuc
mutants with the auxin mutants. Furthermore, we show that overexpression of
YUC1
partially suppresses the shade avoidance defects of
taa1
and the sterile phenotypes of the weak but not the strong
taa
mutants. In addition, we discovered that the auxin overproduction phenotypes of
YUC
overexpression lines are dependent on active
TAA
genes. Our genetic data show that
YUC
and
TAA
work in the same pathway and that
YUC
is downstream of
TAA
. The
yuc
mutants accumulate IPA, and the
taa
mutants are partially IPA-deficient, indicating that
TAA
s are responsible for converting tryptophan to IPA, whereas
YUCs
play an important role in converting IPA to indole-3-acetic acid.
A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial–mesenchymal transition
Authors: Kim Nam Hee , Kim Hyun Sil , Li Xiao-Yan , Lee Inhan , Choi Hyung-Seok , Kang Shi Eun , Cha So Young , Ryu Joo Kyung , Yoon Dojun , Fearon Eric R. , Rowe R. Grant , Lee Sanghyuk , Maher Christopher A. , Weiss Stephen J. , Yook Jong In
Published: October 2011

Snail1 is a zinc finger transcriptional repressor whose pathological expression has been linked to cancer cell epithelial–mesenchymal transition (EMT) programs and the induction of tissue-invasive activity, but pro-oncogenic events capable of regulating Snail1 activity remain largely uncharacterized. Herein, we demonstrate that p53 loss-of-function or mutation promotes cancer cell EMT by de-repressing Snail1 protein expression and activity. In the absence of wild-type p53 function, Snail1-dependent EMT is activated in colon, breast, and lung carcinoma cells as a consequence of a decrease in miRNA-34 levels, which suppress Snail1 activity by binding to highly conserved 3′ untranslated regions in Snail1 itself as well as those of key Snail1 regulatory molecules, including β-catenin, LEF1, and Axin2. Although p53 activity can impact cell cycle regulation, apoptosis, and DNA repair pathways, the EMT and invasion programs initiated by p53 loss of function or mutation are completely dependent on Snail1 expression. These results identify a new link between p53, miR-34, and Snail1 in the regulation of cancer cell EMT programs.
Dissociation of VE-PTP from VE-cadherin is required for leukocyte extravasation and for VEGF-induced vascular permeability in vivo
Authors: Broermann Andre , Winderlich Mark , Block Helena , Frye Maike , Rossaint Jan , Zarbock Alexander , Cagna Giuseppe , Linnepe Ruth , Schulte Dörte , Nottebaum Astrid Fee , Vestweber Dietmar
Published: October 2011

We have recently shown that vascular endothelial protein tyrosine phosphatase (VE-PTP), an endothelial membrane protein, associates with VE-cadherin and is required for optimal VE-cadherin function and endothelial cell contact integrity. The dissociation of VE-PTP from VE-cadherin is triggered by vascular endothelial growth factor (VEGF) and by the binding of leukocytes to endothelial cells in vitro, suggesting that this dissociation is a prerequisite for the destabilization of endothelial cell contacts. Here, we show that VE-cadherin/VE-PTP dissociation also occurs in vivo in response to LPS stimulation of the lung or systemic VEGF stimulation. To show that this dissociation is indeed necessary in vivo for leukocyte extravasation and VEGF-induced vascular permeability, we generated knock-in mice expressing the fusion proteins VE-cadherin-FK 506 binding protein and VE-PTP-FRB* under the control of the endogenous VE-cadherin promoter, thus replacing endogenous VE-cadherin. The additional domains in both fusion proteins allow the heterodimeric complex to be stabilized by a chemical compound (rapalog). We found that intravenous application of the rapalog strongly inhibited VEGF-induced (skin) and LPS-induced (lung) vascular permeability and inhibited neutrophil extravasation in the IL-1β inflamed cremaster and the LPS-inflamed lung. We conclude that the dissociation of VE-PTP from VE-cadherin is indeed required in vivo for the opening of endothelial cell contacts during induction of vascular permeability and leukocyte extravasation.
PoPoolation2: identifying differentiation between populations using sequencing of pooled DNA samples (Pool-Seq)
Authors: Kofler Robert , Pandey Ram Vinay , Schlötterer Christian
Published: October 2011

Summary: Sequencing pooled DNA samples (Pool-Seq) is the most cost-effective approach for the genome-wide comparison of population samples. Here, we introduce PoPoolation2, the first software tool specifically designed for the comparison of populations with Pool-Seq data. PoPoolation2 implements a range of commonly used measures of differentiation (FST, Fisher's exact test and Cochran-Mantel-Haenszel test) that can be applied on different scales (windows, genes, exons, SNPs). The result may be visualized with the widely used Integrated Genomics Viewer.

Availability and Implementation: PoPoolation2 is implemented in Perl and R. It is freely available on http://code.google.com/p/popoolation2/

Contact:  christian.schloetterer@vetmeduni.ac.at

Supplementary Information: Manual: http://code.google.com/p/popoolation2/wiki/Manual Test data and tutorial: http://code.google.com/p/popoolation2/wiki/Tutorial Validation: http://code.google.com/p/popoolation2/wiki/Validation
Elections and the Regression Discontinuity Design: Lessons from Close U.S. House Races, 1942–2008
Authors: Caughey Devin , Sekhon Jasjeet S.
Published: October 2011

Following David Lee's pioneering work, numerous scholars have applied the regression discontinuity (RD) design to popular elections. Contrary to the assumptions of RD, however, we show that bare winners and bare losers in U.S. House elections (1942–2008) differ markedly on pretreatment covariates. Bare winners possess largeex antefinancial, experience, and incumbency advantages over their opponents and are usually the candidates predicted to win byCongressional Quarterly's pre-election ratings. Covariate imbalance actually worsens in the closest House elections. National partisan tides help explain these patterns. Previous works have missed this imbalance because they rely excessively on model-based extrapolation. We present evidence suggesting that sorting in close House elections is due mainly to activities on or before Election Day rather than postelection recounts or other manipulation. The sorting is so strong that it is impossible to achieve covariate balance between matched treated and control observations, making covariate adjustment a dubious enterprise. Although RD is problematic for postwar House elections, this example does highlight the design's advantages over alternatives: RD's assumptions are clear and weaker than model-based alternatives, and their implications are empirically testable.
Brain‐Gut Axis
Authors: Camilleri Michael , Di Lorenzo Carlo
Published: October 2011

The present review describes advances in understanding the mechanisms and provide an update of present and promising therapy directed at the gut or the brain in the treatment of irritable bowel syndrome (IBS). The diagnosis of IBS typically is based on identification of symptoms, such as the Rome III criteria for IBS in adults and children. The criteria are similar in children and adults. The focus of the present review is the bowel dysfunction associated with IBS.
Femtosecond laser ablation ICP‐MS measurement of otolith Sr:Ca and Ba:Ca composition reveal differential use of freshwater habitats for three amphidromous Sicyopterus (Teleostei: Gobioidei: Sicydiinae) species
Authors: Lord C. , Tabouret H. , Claverie F. , Pécheyran C. , Keith P.
Published: October 2011

The use of freshwater habitats was examined in three amphidromous goby species of the genus Sicyopterus using otolith microchemistry. Two species were endemic to either New Caledonia or Vanuatu whilst the other was widely distributed. Depositional patterns of strontium (Sr) and barium (Ba) in the otolith of adults were analysed with femtosecond laser ablation inductively coupled plasma mass spectrometry (ICP‐MS). The Sr:Ca and Ba:Ca results uncovered three different adult behaviours within the freshwater habitat. Some fishes stayed in elevated locations (square profile); others undertook back‐and‐forth migrations between higher and lower reaches (up‐and‐down profile), and finally, others stayed in the lower reaches (constant profile). The consequences of these movements to larval survival or competition for food and territory are discussed. This work brings new knowledge on amphidromous behaviour, and it highlights the necessity of multi‐elemental analysis to study amphidromy in freshwater systems.
EXPRESSION OF CONCERN: Subtype‐specific alterations of the Wnt signaling pathway in breast cancer: Clinical and prognostic significance
Authors: Mukherjee Nupur , Bhattacharya Nilanjana , Alam Neyaz , Roy Anup , Roychoudhury Susanta , Panda Chinmay K.
Published: October 2011

The aim of the study is to understand the importance of the Wnt/β‐catenin pathway in the development of breast cancer (BC) and its association with different clinicopathological parameters. Alterations (deletion/methylation/expression) of some Wnt/β‐catenin pathway antagonists like APC, SFRP1/2, CDH1 and activator β‐catenin (CTNNB1) were analyzed in primary BC in Indian patients. High frequencies (65–70%) of overall alterations (deletion/methylation) of the antagonists were seen in the BC samples. Also, 99% (156/158) of the samples showed alterations in any one of the genes, indicating the importance of this pathway in the development of this tumor. Co‐alterations of these genes were observed in 30% of samples, with significantly high alterations in late‐onset (37%) and estrogen receptor (ER)−/progesterone receptor (PR)− (37%) BC compared with early onset (21%) and ER/PR+ (18%) BC samples, respectively. Significantly high (P‐value = 0.001–0.02) alterations of APC and CDH1 genes were seen in ER−/PR− BC compared with ER/PR+ BC. Immunohistochemical analysis showed reduced expression of the Wnt antagonists in BC concordant with their molecular alterations. Nuclear localization of β‐catenin showed significant association with alterations in the antagonists and was also significantly high in the ER−/PR− BC samples. Alterations of SFRP2 coupled with a late clinical stage and low/nulliparity predicted the worst prognosis in BC patients. Therefore, the present study suggests that cumulative alterations in more than one Wnt antagonist along with increased nuclear accumulation of β‐catenin play an important role in the development of BC and have significant clinical as well as prognostic importance. (Cancer Sci 2012; 103: 210–220)
The pharmacogenetics of the response to warfarin in Chinese
Authors: Lam May P. S. , Cheung Bernard M. Y.
Published: October 2011

Warfarin is a commonly used oral anticoagulant with a narrow therapeutic range and large interindividual variability in daily dose. Compared with Caucasians, Chinese are known to require lower doses of warfarin. Differences between Caucasians and Chinese in the allelic frequencies of two genes, CYP2C9 and VKORC1, largely explain the difference in dose requirement. There are other genetic polymorphisms that may further explain the response to warfarin. The VKORC1 genotype is an important determinant of response to warfarin in Chinese, but some genetic variants found in other ethnic groups that have a large effect on warfarin response and dosing are not commonly found in Chinese. Therefore, it is important to recognize and beware of ethnic differences in the pharmacogenetics of the response to warfarin, especially in the design of algorithms to aid dosing in clinical practice.
The fibrosis marker galectin‐3 and outcome in the general population
Authors: de Boer R. A. , van Veldhuisen D. J. , Gansevoort R. T. , Muller Kobold A. C. , van Gilst W. H. , Hillege H. L. , Bakker S. J. L. , van der Harst P.
Published: October 2011

Abstract.  de Boer RA, van Veldhuisen DJ, Gansevoort RT, Muller Kobold AC, van Gilst WH, Hillege HL, Bakker SJL, van der Harst P (University of Groningen). The fibrosis marker galectin‐3 and outcome in the general population. J Intern Med 2012; 272: 55–64.

Objective.  Galectin‐3 is involved in fibrosis and inflammation and plays a role in heart failure, renal disease, obesity and cancer. We aimed to establish the relationship between galectin‐3 and cardiovascular (CV) risk factors and mortality in the general population.

Design and subjects.  This study included 7968 subjects from the Prevention of REnal and Vascular ENd‐stage Disease (PREVEND) cohort, with a median follow‐up of approximately 10 years. Plasma galectin‐3 was measured in baseline samples.

Main outcome measures.  We investigated the relationships between galectin‐3 levels, demographic characteristics and risk factors of CV disease. We determined the prognostic value for all‐cause, CV and cancer mortality.

Results.  The mean age of the population was 50 ± 13 years. Mean blood pressure was 129/74 mmHg, mean cholesterol was 5.7 ± 1.1 mmol L−1 and median galectin‐3 was 10.9 ng mL−1 [interquartile range (IQR) 9.0–13.1]. Galectin‐3 levels correlated with a wide range of risk factors of CV disease, including blood pressure, serum lipids, body mass index, renal function and N‐terminal pro‐B‐type natriuretic peptide (P < 0.0001). We observed a strong association between galectin‐3 and age. Furthermore, we found a gender interaction, with female subjects (n = 4001) having higher median galectin‐3 levels (11.0 ng mL−1, IQR 9.1–13.4 vs. men (n = 3967) 10.7 ng mL−1, IQR 8.9–12.8; P < 0.0001), and galectin‐3 levels in women more strongly correlated with risk factors of CV disease. After correction for the classical CV risk factors (smoking, blood pressure, cholesterol and diabetes), galectin‐3 levels independently predicted all‐cause mortality (hazard ratio per SD galectin‐3 1.09, 95% CI 1.01–1.19; P = 0.036), but not CV and cancer mortality separately.

Conclusions.  Galectin‐3 is associated with age and risk factors of CV disease, with a strong gender interaction for these correlations. Galectin‐3 predicts all‐cause mortality in the general population.
Platelet‐activating Factor in Iberian Pig Spermatozoa: Receptor Expression and Role as Enhancer of the Calcium‐Induced Acrosome Reaction
Authors: Bragado MJ , Gil MC , Garcia‐Marin LJ
Published: October 2011

Contents

Platelet‐activating factor (PAF) is a phospholipid involved in reproductive physiology. PAF receptor is expressed in some mammalian spermatozoa species where it plays a role in these germ‐cell‐specific processes. The aim of this study is to identify PAF receptor in Iberian pig spermatozoa and to evaluate PAF’s effects on motility, viability and acrosome reaction. Semen samples from Iberian boars were used. PAF receptor identification was performed by Western blotting. Spermatozoa motility was analysed by computer‐assisted sperm analysis system, whereas spermatozoa viability and acrosome reaction were evaluated by flow cytometry. Different PAF concentrations added to non‐capacitating medium during 60 min have no effect on any spermatozoa motility parameter measured. Acrosome reaction was rapid and potently induced by 1 μm calcium ionophore A23187 showing an effect at 60 min and maximum at 240 min. PAF added to a capacitating medium is not able to induce spermatozoa acrosome reaction at any time studied. However, PAF, in the presence of A23187, significantly accelerates and enhances the calcium‐induced acrosome reaction in a concentration‐dependent manner in Iberian boar spermatozoa. Exogenous PAF does not affect at all spermatozoa viability, whereas slightly exacerbated the A23187‐induced loss in viability. This work demonstrates that PAF receptor is expressed in Iberian pig spermatozoa and that its stimulation by PAF regulates the calcium‐induced acrosome reaction. This work contributes to further elucidate the physiological regulation of the most relevant spermatozoa functions for successful fertilization: acrosome reaction.
Leverage, executive incentives and corporate governance
Authors: Agha Mahmoud
Published: October 2011

This paper analyses the effect of executive incentives and internal governance on capital structure. Using a large sample of non‐financial US‐listed firms over the period 1999–2005, it is found that managers have different attitudes towards leverage when offered different incentive schemes; leverage initially decreases in bonuses and stock incentives and then increases in these incentives after a certain incentive level, suggesting the existence of the entrenchment–alignment effects under these incentive schemes. In contrast, leverage initially increases in option incentives and then decreases after a certain option incentive level. When all of these incentive schemes are combined together into a single incentive package, the entrenchment–alignment effects prevail. It is also found that leverage increases in internal governance and managers behave differently under different governance regimes such that the entrenchment–alignment effects prevail under weak governance firms, whereas the alignment–entrenchment effects prevail under strong governance firms. The results also suggest that managers’ target leverage ratio is less than the one predicted by theory or preferred by firm shareholders.
Angiotensin‐(1–7) through Mas receptor up‐regulates neuronal norepinephrine transporter via Akt and Erk1/2‐dependent pathways
Authors: Lopez Verrilli María A. , Rodriguez Fermepín Martín , Longo Carbajosa Nadia , Landa Silvina , Cerrato Bruno D. , García Silvia , Fernandez Belisario E. , Gironacci Mariela M.
Published: October 2011

J. Neurochem. (2012) 120, 46–55.

As angiotensin (Ang) (1–7) decreases norepinephrine (NE) content in the synaptic cleft, we investigated the effect of Ang‐(1–7) on NE neuronal uptake in spontaneously hypertensive rats. [3H]‐NE neuronal uptake was measured in isolated hypothalami. NE transporter (NET) expression was evaluated in hypothalamic neuronal cultures by western‐blot. Ang‐(1–7) lacked an acute effect on neuronal NE uptake. Conversely, Ang‐(1–7) caused an increase in NET expression after 3 h incubation (40 ± 7%), which was blocked by the Mas receptor antagonist, a PI3‐kinase inhibitor or a MEK1/2 inhibitor suggesting the involvement of Mas receptor and the PI3‐kinase/Akt and MEK1/2‐ERK1/2 pathways in the Ang‐(1–7)‐stimulated NET expression. Ang‐(1–7) through Mas receptors stimulated Akt and ERK1/2 activities in spontaneously hypertensive rat neurons. Cycloheximide attenuated Ang‐(1–7) stimulation of NET expression suggesting that Ang‐(1–7) stimulates NET synthesis. In fact, Ang‐(1–7) increased NET mRNA levels. Thus, we evaluated the long‐term effect of Ang‐(1–7) on neuronal NE uptake after 3 h incubation. Under this condition, Ang‐(1–7) increased neuronal NE uptake by 60 ± 14% which was blocked by cycloheximide and the Mas receptor antagonist. Neuronal NE uptake and NET expression were decreased after 3 h incubation with an anti‐Ang‐(1–7) antibody. Ang‐(1–7) induces a chronic stimulatory effect on NET expression. In this way, Ang‐(1–7) may regulate a pre‐synaptic mechanism in maintaining appropriate synaptic NE levels during hypertensive conditions.
Appraisal of New Product Development Success Indicators in the Aerospace Industry
Authors: Moatari Kazerouni Afrooz , Achiche Sofiane , Hisarciklilar Onur , Thomson Vincent
Published: October 2011

Assessing performance in developing new aerospace products is essential. However, choosing an accurate set of success indicators to measure the performance of complex products is a nontrivial task. Moreover, the most useful success indicators can change over the life of the product; therefore, different metrics need to be used at different phases of the product lifecycle (PLC). This paper describes the research undertaken to determine success measurement metrics for new product development (NPD) processes. The goal of this research was to ascertain an appropriate set of metrics used by aerospace companies for assessing success during different phases of the PLC. Furthermore, an evaluation of the differences and similarities of NPD success measurement was carried out between aerospace companies and the nonaerospace companies practicing in the business-to-business (B2B) market. Practical case studies were carried out for 16 Canadian and Danish companies. Seven companies belong to the aerospace sector, while nine are nonaerospace companies that are in the B2B market. The data were gathered from relevant product managers at participating companies. The outcomes of this research indicate that: (1) the measurement of success of aerospace NPD practices depends on the PLC phase being measured, (2) product and process management performance are the more important indicators of success in the early PLC phases with revenue and market share indicators being important during late phases, and (3) there are reasonable similarities in success measurement between aerospace and nonaerospace B2B companies. Sets of metrics for measuring success during each PLC phase of aerospace products are proposed, which can guide companies in determining their ideal practices.
Biphasic Finite Element Modeling of Hydrated Soft Tissue Contact Using an Augmented Lagrangian Method
Authors: Guo Hongqiang , Spilker Robert L.
Published: October 2011

A study of biphasic soft tissues contact is fundamental to understanding the biomechanical behavior of human diarthrodial joints. To date, biphasic-biphasic contact has been developed for idealized geometries and not been accessible for more general geometries. In this paper a finite element formulation is developed for contact of biphasic tissues. The augmented Lagrangian method is used to enforce the continuity of contact traction and fluid pressure across the contact interface, and the resulting method is implemented in the commercial software COMSOL Multiphysics. The accuracy of the implementation is verified using 2D axisymmetric problems, including indentation with a flat-ended indenter, indentation with spherical-ended indenter, and contact of glenohumeral cartilage layers. The biphasic finite element contact formulation and its implementation are shown to be robust and able to handle physiologically relevant problems.
Use of a high-flow diaphragm valve in the exhaust line of atomic layer deposition reactors
Authors: Dasgupta Neil P. , Trejo Orlando , Prinz Fritz B.
Published: October 2011

In many atomic layer deposition (ALD) reactors, a stop valve is placed between the reaction chamber and the vacuum pump to allow for long precursor exposure times. This valve can lead to a reduction in conductance to the pump, lowering pumping efficiency and increasing the required purging time. In this study, a prototype high-flow (flow coefficient Cv = 1.7) diaphragm valve designed for ALD compatibility was inserted into the exhaust line of an ALD reactor and compared to a standard ALD diaphragm valve (Cv = 0.62). The results show that the chamber base pressure was reduced by 66% with the high-flow valve, which has implications for precursor delivery and mass transport. Furthermore, ZnO films were deposited via ALD, and the variation in thickness across a 100 mm diameter Si wafer was shown to be lower for the high-flow valve, especially with short purging times. These results suggest that the use of a high-flow ALD valve in the exhaust line can be beneficial when attempting to reduce the purging time and improve uniformity in research-scale reactors, and it could eventually be utilized in larger production-scale reactors.
Mechanisms Decreasing
In Vitro
Susceptibility to the LpxC Inhibitor CHIR-090 in the Gram-Negative Pathogen Pseudomonas aeruginosa
Authors: Caughlan Ruth E. , Jones Adriana K. , DeLucia Angela M. , Woods Angela L. , Xie Lili , Ma Bing , Barnes S. Whitney , Walker John R. , Sprague Elizabeth R. , Yang Xia , Dean Charles R.
Published: October 2011

Testing
P. aeruginosa
efflux pump mutants showed that the LpxC inhibitor CHIR-090 is a substrate for MexAB-OprM, MexCD-OprJ, and MexEF-OprN. Utilizing
P. aeruginosa
PAO1 with a chromosomal
mexC
::
luxCDABE
fusion, luminescent mutants arose on medium containing 4 μg/ml CHIR-090, indicating upregulation of MexCD-OprJ. These mutants were less susceptible to CHIR-090 (MIC, 4 μg/ml) and had mutations in the
mexCD-oprJ
repressor gene
nfxB
. Nonluminescent mutants (MIC, 4 μg/ml) that had mutations in the
mexAB-oprM
regulator gene
mexR
were also observed. Plating the clinical isolate K2153 on 4 μg/ml CHIR-090 selected mutants with alterations in
mexS
(immediately upstream of
mexT
), which upregulates MexEF-OprN. A mutant altered in the putative1ribosomal binding site (RBS) upstream of
lpxC
and overexpressing LpxC was selected on a related LpxC inhibitor and exhibited reduced susceptibility to CHIR-090. Overexpression of LpxC from a plasmid reduced susceptibility to CHIR-090, and introduction of the altered RBS in this construct further increased expression of LpxC and decreased susceptibility to CHIR-090. Using a
mutS
(hypermutator) strain, a mutant with an altered
lpxC
target gene (LpxC L18V) was also selected. Purified LpxC L18V had activity similar to that of wild-type LpxC in an
in vitro
assay but had reduced inhibition by CHIR-090. Finally, an additional class of mutant, typified by an extreme growth defect, was identified. These mutants had mutations in
fabG
, indicating that alteration in fatty acid synthesis conferred resistance to LpxC inhibitors. Passaging experiments showed progressive decreases in susceptibility to CHIR-090. Therefore,
P. aeruginosa
can employ several strategies to reduce susceptibility to CHIR-090
in vitro
.
MyD88-Dependent Recruitment of Monocytes and Dendritic Cells Required for Protection from Pulmonary Burkholderia mallei Infection
Authors: Goodyear Andrew , Troyer Ryan , Bielefeldt-Ohmann Helle , Dow Steven
Published: October 2011

The Gram-negative bacterium
Burkholderia mallei
causes rapidly fatal illness in equines and humans when contracted by inhalation and also has the potential to be used as a bioweapon. However, little is known regarding the early innate immune responses and signaling mechanisms required to generate protection from pneumonic
B. mallei
infection. We showed previously that monocyte chemoattractant protein 1 (MCP-1) was a critical chemokine required for protection from pneumonic
B. mallei
infection. We have now extended those studies to identify key Toll-like receptor (TLR) signaling pathways, effector cells, and cytokines required for protection from respiratory
B. mallei
infection. We found that MyD88
−/−
mice were highly susceptible to pulmonary challenge with
B. mallei
and had significantly short survival times, increased bacterial burdens, and severe organ pathology compared to wild-type mice. Notably, MyD88
−/−
mice had significantly fewer monocytes and dendritic cells (DCs) in lung tissues and airways than infected wild-type mice despite markedly higher bacterial burdens. The MyD88
−/−
mice were also completely unable to produce gamma interferon (IFN-γ) at any time points following infection. In wild-type mice, NK cells were the primary cells producing IFN-γ in the lungs following
B. mallei
infection, while DCs and monocytes were the primary cellular sources of interleukin-12 (IL-12) production. Treatment with recombinant IFN-γ (rIFN-γ) was able to significantly restore protective immunity in MyD88
−/−
mice. Thus, we conclude that the MyD88-dependent recruitment of inflammatory monocytes and DCs to the lungs and the local production of IL-12, followed by NK cell production of IFN-γ, are the key initial cellular responses required for early protection from
B. mallei
infection.
INNOVATION OF PROCESS TECHNOLOGY: EXPLORING DETERMINANTS FOR ORGANIZATIONAL DESIGN
Authors: BERGFORS MARKUS , LAGER THOMAS
Published: October 2011

At present, R&D managers have little guidance on how to design organizations with respect to organizational affiliation of process innovation. While process innovation in the process industries traditionally accounts for a large share of the company's total development resources it has nevertheless not received much attention in academic studies. In this paper four variables: (1) Industry category, (2) Size of R&D organization, (3) Process innovation intensity and (4) Newness of process innovation are statistically tested against the organizational affiliation of process innovation, based within either R&D or production. The study provides new empirical support for the positive association between the degree of newness and the organization of process innovations. By extensively analysing and discussing the findings in terms of both pros and cons for different organizational structural choices for process innovation, the paper also offers managers practical guidance in making organizational design decisions.
P
–
T
constraints and timing of Barrovian metamorphism in the Shetland Islands, Scottish Caledonides: implications for the structural setting of the Unst ophiolite
Authors: Cutts K.A. , Hand M. , Kelsey D.E. , Strachan R.A.
Published: October 2011

An integrated
in situ
monazite laser-ablation inductively coupled plasma mass spectrometry and metamorphic equilibria study is used to establish the
P
–
T
conditions and timing of Barrovian metamorphism in the Shetland Islands, Scottish Caledonides. The results have implications for the structural setting of the Unst ophiolite, which was obducted onto metasedimentary rocks of the Dalradian Supergroup. Metapelites in the footwall of the ophiolite yield U–Pb ages between 462 and 451 Ma with
P
–
T
conditions varying from
c
. 7.5 kbar and 550 °C directly below the ophiolite to
c
. 10 kbar and 775 °C at structurally deeper levels. The timing of peak metamorphism corresponds closely to that of Grampian (
c
. 450–470 Ma) metamorphism in mainland Scotland and Ireland, and Taconic (
c
. 450–460 Ma) metamorphism in the Appalachians, thus confirming the near-synchroneity of this important arc accretion event along the Laurentian margin. There is a significant metamorphic contrast between the low-grade rocks associated with the Unst ophiolite and the
P
–
T
conditions recorded in its footwall. If published K–Ar ages of
c.
470 Ma broadly record obduction of the ophiolite, its present basal contact is probably a younger tectonic break that was associated with the excision of at least
c
. 10 km of crustal section.

Supplementary material:

Electron microporobe chemical analyses of garnet grains are available at
www.geolsoc.org.uk/SUP18494