bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of yield and oil from a series of canola breeding trials. Part II. Exploring variety by environment interaction using factor analysisThis article is one of a selection of papers from the conference “Exploiting Genome-wide Association in Oilseed Brassicas: a model for genetic improvement of major OECD crops for sustainable farming”.
Authors: Cullis B.R. , Smith A.B. , Beeck C.P. , Cowling W.A.
Published: November 2010

Exploring and exploiting variety by environment (V × E) interaction is one of the major challenges facing plant breeders. In paper I of this series, we presented an approach to modelling V × E interaction in the analysis of complex multi-environment trials using factor analytic models. In this paper, we develop a range of statistical tools which explore V × E interaction in this context. These tools include graphical displays such as heat-maps of genetic correlation matrices as well as so-called E-scaled uniplots that are a more informative alternative to the classical biplot for large plant breeding multi-environment trials. We also present a new approach to prediction for multi-environment trials that include pedigree information. This approach allows meaningful selection indices to be formed either for potential new varieties or potential parents.
Design of aBrassica rapacore collection for association mapping studiesThis article is one of a selection of papers from the conference “Exploiting Genome-wide Association in Oilseed Brassicas: a model for genetic improvement of major OECD crops for sustainable farming”.
Authors: Zhao Jianjun , Artemyeva Anna , Del Carpio Dunia Pino , Basnet Ram Kumar , Zhang Ningwen , Gao Jie , Li Fei , Bucher Johan , Wang Xiaowu , Visser Richard G.F. , Bonnema Guusje
Published: November 2010

A Brassica rapa collection of 239 accessions, based on two core collections representing different morphotypes from different geographical origins, is presented and its use for association mapping is illustrated for flowering time. We analyzed phenotypic variation of leaf and seed pod traits, plant architecture, and flowering time using data collected from three field experiments and evaluated the genetic diversity with a set of SSR markers. The Wageningen University and Research Centre (WUR) and the Vavilov Research Institute of Plant Industry (VIR) core collections had similar representations of most morphotypes, as illustrated by the phenotypic and genetic variation within these groups. The analysis of population structure revealed five subgroups in the collection, whereas previous studies of the WUR core collection indicated four subgroups; the fifth group identified consisted mainly of oil accessions from the VIR core collection, winter oils from Pakistan, and a number of other types. A very small group of summer oils is described, that is not related to other oil accessions. A candidate gene approach was chosen for association mapping of flowering time with a BrFLC1 biallelic CAPS marker and a BrFLC2 multiallelic SSR marker. The two markers were significantly associated with flowering time, but their effects were confined to certain morphotypes and (or) alleles. Based on these results, we discuss the optimal design for an association mapping population and the need to fix the heterogeneous accessions to facilitate phenotyping and genotyping.
Carbonation of fly ash concrete: laboratory and field data
Authors: Bouzoubaâ N. , Bilodeau A. , Tamtsia B. , Foo S.
Published: November 2010

The present study consists of investigating the carbonation resistance of two series of concrete mixtures designed for three classes of concrete (25, 35, and 45 MPa compressive strength at 28 d) and using American Society for Testing and Materials (ASTM) type I Portland cement and two commercially used fly ashes meeting the ASTM standards at the level of 20%, 35%, and 50% of the total weight of cementitious materials. The carbonation resistance was determined on samples moist cured for 3, 7, and 10 d and exposed to a CO2-enriched environment (3% CO2 at 23 °C and 65% relative humidity) for 140 d to accelerate the carbonation; it was also determined on samples moist cured for 7 d and exposed to an indoor and outdoor natural environments for 4 years. A mathematical model allowing the prediction of the depth of accelerated carbonation of fly ash concrete mixtures is presented.
CONVEXITY PROPERTIES AND COMPLETE HYPERBOLICITY OF LEMPERT'S ELLIPTIC TUBES
Authors: ALESSANDRINI DANIELE , SARACCO ALBERTO
Published: November 2010

We prove that elliptic tubes over properly convex domains D ⊂ ℝℙn are ℂ-convex and complete Kobayashi-hyperbolic. We also study a natural construction of complexification of convex real projective manifolds.
ON RAMIFIED COVERS OF THE PROJECTIVE PLANE I: INTERPRETING SEGRE'S THEORY (WITH AN APPENDIX BY EUGENII SHUSTIN)
Authors: FRIEDMAN MICHAEL , LEYENSON MAXIM , SHUSTIN EUGENII
Published: November 2010

We study ramified covers of the projective plane ℙ2. Given a smooth surface S in ℙN and a generic enough projection ℙN → ℙ2, we get a cover π: S → ℙ2, which is ramified over a plane curve B. The curve B is usually singular, but is classically known to have only cusps and nodes as singularities for a generic projection. The main question that arises is with respect to the geometry of branch curves; i.e. how can one distinguish a branch curve from a non-branch curve with the same numerical invariants? For example, a plane sextic with six cusps is known to be a branch curve of a generic projection iff its six cusps lie on a conic curve, i.e. form a special 0-cycle on the plane. The classical work of Beniamino Segre gives a complete answer to the second question in the case when S is a smooth surface in ℙ3. We give an interpretation of the work of Segre in terms of relation between Picard and Chow groups of 0-cycles on a singular plane curve B. In addition, the appendix written by E. Shustin shows the existence of new Zariski pairs.
A CLASSIFICATION OF SMOOTH EMBEDDINGS OF FOUR-MANIFOLDS IN SEVEN-SPACE, II
Authors: CROWLEY DIARMUID , SKOPENKOV ARKADIY
Published: November 2010

Let N be a closed connected smooth four-manifold with H1(N; ℤ) = 0. Our main result is the following classification of the set E7(N) of smooth embeddings N → ℝ7up to smooth isotopy. Haefliger proved that E7(S4) together with the connected sum operation is a group isomorphic to ℤ12. This group acts on E7(N) by an embedded connected sum. Boéchat and Haefliger constructed an invariant ℵ: E7(N) → H2(N;ℤ) which is injective on the orbit space of this action; they also described im (ℵ). We determine the orbits of the action: for u ∈ im (ℵ) the number of elements in ℵ-1(u) is GCD (u/2, 12) if u is divisible by 2, or is GCD(u, 3) if u is not divisible by 2. The proof is based on Kreck's modified formulation of surgery.
RELATIONAL TOPOLOGICAL MAP
Authors: LABIOD LAZHAR , GROZAVU NISTOR , BENNANI YOUNÈS
Published: November 2010

This paper introduces a relational topological map model, dedicated to multidimensional categorial data (or qualitative data) arising in the form of a binary matrix or a sum of binary matrices. This approach is based on the principle of Kohonen's model (conservation of topological order) and uses the Relational Analysis formalism by maximizing a modified Condorcet criterion. This proposed method is developed from the classical Relational Analysis approach by adding a neighborhood constraint to the Condorcet criterion. We propose a hybrid algorithm, which deals linearly with large data sets, provides a natural clusters identification and allows a visualization of the clustering result on a two-dimensional grid while preserving the a priori topological order of this data. The proposed approach called Relational Topological Map (RTM) was validated on several databases and the experimental results showed very promising performances.
A brief survey on sequence classification
Authors: Xing Zhengzheng , Pei Jian , Keogh Eamonn
Published: November 2010

Sequence classification has a broad range of applications such as genomic analysis, information retrieval, health informatics, finance, and abnormal detection. Different from the classification task on feature vectors, sequences do not have explicit features. Even with sophisticated feature selection techniques, the dimensionality of potential features may still be very high and the sequential nature of features is difficult to capture. This makes sequence classification a more challenging task than classification on feature vectors. In this paper, we present a brief review of the existing work on sequence classification. We summarize the sequence classification in terms of methodologies and application domains. We also provide a review on several extensions of the sequence classification problem, such as early classification on sequences and semi-supervised learning on sequences.
Apples-to-apples in cross-validation studies
Authors: Forman George , Scholz Martin
Published: November 2010

Cross-validation is a mainstay for measuring performance and progress in machine learning. There are subtle differences in how exactly to compute accuracy, F-measure and Area Under the ROC Curve (AUC) in cross-validation studies. However, these details are not discussed in the literature, and incompatible methods are used by various papers and software packages. This leads to inconsistency across the research literature. Anomalies in performance calculations for particular folds and situations go undiscovered when they are buried in aggregated results over many folds and datasets, without ever a person looking at the intermediate performance measurements. This research note clarifies and illustrates the differences, and it provides guidance for how best to measure classification performance under cross-validation. In particular, there are several divergent methods used for computing F-measure, which is often recommended as a performance measure under class imbalance, e.g., for text classification domains and in one-vs.-all reductions of datasets having many classes. We show by experiment that all but one of these computation methods leads to biased measurements, especially under high class imbalance. This paper is of particular interest to those designing machine learning software libraries and researchers focused on high class imbalance.
Survey on social tagging techniques
Authors: Gupta Manish , Li Rui , Yin Zhijun , Han Jiawei
Published: November 2010

Social tagging on online portals has become a trend now. It has emerged as one of the best ways of associating metadata with web objects. With the increase in the kinds of web objects becoming available, collaborative tagging of such objects is also developing along new dimensions. This popularity has led to a vast literature on social tagging. In this survey paper, we would like to summarize different techniques employed to study various aspects of tagging. Broadly, we would discuss about properties of tag streams, tagging models, tag semantics, generating recommendations using tags, visualizations of tags, applications of tags and problems associated with tagging usage. We would discuss topics like why people tag, what influences the choice of tags, how to model the tagging process, kinds of tags, different power laws observed in tagging domain, how tags are created, how to choose the right tags for recommendation, etc. We conclude with thoughts on future work in the area.
Characterization of silent afferents in the pelvic and splanchnic innervations of the mouse colorectum
Authors: Feng Bin , Gebhart G. F.
Published: November 2010

Hypersensitivity in inflammatory/irritable bowel syndrome is contributed to in part by changes in the receptive properties of colorectal afferent endings, likely including mechanically insensitive afferents (MIAs; silent afferents) that have the ability to acquire mechanosensitivity. The proportion and attributes of colorectal MIAs, however, have not previously been characterized. The distal ∼3 cm of colorectum with either pelvic (PN) or lumbar splanchnic (LSN) nerve attached was removed, opened longitudinally, pinned flat in a recording chamber, and perfused with oxygenated Krebs solution. Colorectal receptive endings were located by electrical stimulation and characterized as mechanosensitive or not by blunt probing, mucosal stroking, and circumferential stretch. MIA endings were tested for response to and acquisition of mechanosensitivity by localized exposure to an inflammatory soup (IS). Colorectal afferents were also tested with twin-pulse and repetitive electrical stimulation paradigms. PN MIAs represented 23% of 211 afferents studied, 71% (30/42) of which acquired mechanosensitivity after application of IS to their receptive ending. LSN MIAs represented 33% of 156 afferents studied, only 23% (11/48) of which acquired mechanosensitivity after IS exposure. Mechanosensitive PN endings uniformly exhibited significant twin-pulse slowing whereas LSN endings showed no significant twin-pulse difference. PN MIAs displayed significantly greater activity-dependent slowing than LSN MIAs. In conclusion, significant proportions of MIAs are present in the colorectal innervation; significantly more in the PN than LSN acquire mechanosensitivity in an inflammatory environment. This knowledge contributes to our understanding of the possible roles of MIAs in colon-related disorders like inflammatory/irritable bowel syndrome.
Balance of meprin A and B in mice affects the progression of experimental inflammatory bowel disease
Authors: Banerjee Sanjita , Jin Ge , Bradley S. Gaylen , Matters Gail L. , Gailey Ryan D. , Crisman Jacqueline M. , Bond Judith S.
Published: November 2010

MEP1A, which encodes the α subunit of meprin metalloproteinases, is a susceptibility gene for inflammatory bowel disease (IBD), and decreased intestinal meprin-α expression is associated with enhanced IBD in humans. Mice lacking meprin α (α knockout, αKO) have more severe colitis induced by dextran sulfate sodium (DSS) than wild-type (WT) mice, indicating an anti-inflammatory role for meprin A. Previous studies and those herein indicate the meprin B has proinflammatory activities. Therefore, mice lacking both meprin A and B (dKO mice) were generated to determine how their combined absence alters the inflammatory response to DSS. Unchallenged dKO mice grow and reproduce normally and have no obvious abnormal phenotype, except for a slightly elevated plasma albumin in both males and females and a lower urine creatinine level in dKO males. Upon oral administration of 3.5% DSS, the dKO mice have more severe colitis than the WT and βKO mice but significantly less than the αKO mice. The dKO mice lose more weight and have elevated MPO and IL-6 activities in the colon compared with WT mice. Systemic inflammation, monitored by plasma nitric oxide levels, is absent in DSS-treated dKO mice, unlike WT mice. The severity of experimental IBD in dKO mice is intermediate between αKO and WT mice. The data indicate that the absence of meprin A aggravates chronic inflammation and the lack of meprin B affords some protection from injury. Manipulation of the expression of meprin gene products may have therapeutic potential.
Cerebral vascular adaptation to pregnancy and its role in the neurological complications of eclampsia
Authors: Cipolla Marilyn J. , Sweet Julie G. , Chan Siu-Lung
Published: November 2010

The cerebral circulation has a central role in mediating the neurological complications of eclampsia, yet our understanding of how pregnancy and preeclampsia affect this circulation is severely limited. Here, we show that pregnancy causes outward remodeling of penetrating arterioles and increased capillary density in the brain due to activation of peroxisome proliferator-activated receptor-γ (PPARγ), a transcription factor involved in cerebrovascular remodeling and highly activated in pregnancy. Pregnancy-induced PPARγ activation also significantly affected cerebral hemodynamics, decreasing vascular resistance and increasing cerebral blood flow by ∼40% in response to acute hypertension that caused breakthrough of autoregulation. These structural and hemodynamic changes in the brain during pregnancy were associated with substantially increased blood-brain barrier permeability, an effect that could promote passage of damaging proteins into the brain and cause the neurological complications of eclampsia, including seizure.
The MIF Homologue D-Dopachrome Tautomerase Promotes COX-2 Expression through β-Catenin–Dependent and –Independent Mechanisms
Authors: Xin Dan , Rendon Beatriz E. , Zhao Ming , Winner Millicent , Coleman Arlixer McGhee , Mitchell Robert A.
Published: November 2010

The cytokine/growth factor, macrophage migration inhibitory factor (MIF), contributes to pathologies associated with immune, inflammatory, and neoplastic disease processes. Several studies have shown an important contributing role for MIF-dependent COX-2 expression in the progression of these disorders. We now report that the MIF homologue, D-dopachrome tautomerase (D-DT), is both sufficient and necessary for maximal COX-2 expression in colorectal adenocarcinoma cell lines. D-DT–dependent COX-2 transcription is mediated in part by β-catenin protein stabilization and subsequent transcription. Also contributing to D-DTs regulation of COX-2 expression are the activities of both c-jun-N-terminal kinase and the MIF-interacting protein, Jab1/CSN5. Interestingly, D-DT–dependent β-catenin stabilization is regulated by COX-2 expression, suggesting the existence of an amplification loop between COX-2- and β-catenin–mediated transcription in these cells. Because both COX-2- and β-catenin–mediated transcription are important contributors to colorectal cancer (CRC) disease maintenance and progression, these findings suggest a unique and novel regulatory role for MIF family members in CRC pathogenesis. Mol Cancer Res; 8(12); 1601–9. ©2010 AACR.
Acyclic Retinoid Inhibits Diethylnitrosamine-Induced Liver Tumorigenesis in Obese and Diabetic C57BLKS/J- +Leprdb/+Leprdb Mice
Authors: Shimizu Masahito , Sakai Hiroyasu , Shirakami Yohei , Iwasa Junpei , Yasuda Yoichi , Kubota Masaya , Takai Koji , Tsurumi Hisashi , Tanaka Takuji , Moriwaki Hisataka
Published: November 2010

Obesity and the related metabolic abnormalities are associated with increased risk of hepatocellular carcinoma (HCC). Malfunctioning of retinoid X receptor (RXR) α due to phosphorylation by Ras/MAPK also plays a critical role in liver carcinogenesis. In the present study, we examined the effects of acyclic retinoid (ACR), which targets RXRα, on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BLKS/J- +Leprdb/+Leprdb (db/db) obese mice. Male db/db mice were given tap water containing 40 ppm DEN for 2 weeks, after which they were fed a diet containing 0.03% or 0.06% of ACR throughout the experiment. In mice treated with either dose of ACR for 34 weeks, the development of liver cell adenomas was significantly inhibited as compared with basal diet-fed mice. ACR markedly inhibited the activation of Ras and phosphorylation of the ERK (extracellular signal-regulated kinase) and RXRα proteins in the livers of experimental mice. It also increased the expression of RAR β and p21CIP1 mRNA while decreasing the expression of cyclin D1, c-Fos, and c-Jun mRNA in the liver, thereby restoring RXRα function. Administration of ACR improved liver steatosis and activated the AMPK protein. The serum levels of insulin decreased by ACR treatment, whereas the quantitative insulin sensitivity check index (QUICKI) values increased, indicating improved insulin sensitivity. The serum levels of TNF-α and the expression levels of TNF- α, IL-6, and IL-1 β mRNA in the livers of DEN-treated db/db mice were decreased by ACR treatment, suggesting attenuation of the chronic inflammation induced by excessive fatty deposits. ACR may be, therefore, useful in the chemoprevention of obesity-related HCC. Cancer Prev Res; 4(1); 128–36. ©2010 AACR.
MicroRNAs 221/222 and Genistein-Mediated Regulation of ARHI Tumor Suppressor Gene in Prostate Cancer
Authors: Chen Yi , Zaman Mohd Saif , Deng Guoren , Majid Shahana , Saini Shranjot , Liu Jan , Tanaka Yuichiro , Dahiya Rajvir
Published: November 2010

ARHI is an imprinted tumor suppressor gene and is downregulated in various malignancies. However, ARHI expression, function, and mechanisms of action in prostate cancer have not been reported. Here, we report that ARHI mRNA and protein levels were downregulated in prostate cancer tissues compared with adjacent normal tissues. Overexpression of ARHI inhibited cell proliferation, colony formation, invasion, and induced apoptosis. Further studies on a new mechanism of ARHI downregulation showed a significant inverse relationship between ARHI and miR-221 and 222, which were upregulated in prostate cancer cell lines. Transfection of miR-221 and 222 inhibitors into PC-3 cells caused a significant induction of ARHI expression. A direct interaction of miR-221 or 222 with a target site on the 3′UTR of ARHI was confirmed by a dual luciferase pMIR-REPORT assay. Finally, we also found that genistein upregulates ARHI by downregulating miR-221 and 222 in PC-3 cells. In conclusion, ARHI is a tumor suppressor gene downregulated in prostate cancer, and overexpression of ARHI can inhibit cell proliferation, colony formation, and invasion. This study demonstrates for the first time that prostate cancer cells have decreased level of ARHI which could be caused by direct targeting of 3′UTR of ARHI by miR221/222. Genistein, a potential nontoxic chemopreventive agent, restores expression of ARHI and may be an important dietary therapeutic agent for treating prostate cancer. Cancer Prev Res; 4(1); 76–86. ©2010 AACR. Cancer Prev Res; 4(1); 76–86. ©2010 AACR.
Efficacy and Safety of Iron Administration in Juvenile Populations
Authors: Schümann Klaus , Solomons Noel W.
Published: November 2010

Infantile iron deficiency anemia (IDA) reduces maximal lifetime cognitive capacity and can threaten the life of an adolescent mother in childbirth. Administration of iron is a component of strategies for preventing or reversing iron deficiency (ID) and iron can be given parenterally or as oral supplements or fortified food. Safety issues can arise at the point of administration, i.e. in the gut lumen, and as a consequence of excessive iron stores arising from the interventions. Recent improvements in the pharmacology of parenteral iron compounds open the way to greater consideration of the intravenous route in pediatric therapy, and even public health. Oral iron supplementation, usually with folic acid, is the main treatment of IDA in the clinical setting. It is often combined with multiple micronutrients and is also used for resolution of severe anemia at the community level and for prophylaxis in the nonanemic population. Fortification of staple food (such as flour), or age-specific foods (infant formula, complementary foods) and beverages are the usual methods for ID prophylaxis. Special iron-rich preparations (powders, crushable tablets, edible spreads) are available for home fortification. Biofortification, i.e. enriching the iron content of crops during cultivation, is a novel approach, yet to be fully implemented or evaluated for children. Side effects and toxicity after oral iron intake are seen in the gut lumen. After oral and parenteral iron intake, the rise in circulating iron can increase the risk of complications from coexisting infections, notably with malaria, and when individual iron status is adequate. Growth impairment occurs with exposure of iron-sufficient children to iron interventions, so that targeting of iron to ID individuals seems advisable. Numerous adverse consequences from accumulation of excessive total body iron stores show up as a consequence of iron-mediated oxidative stress. Incomplete maturation of iron homoeostasis may permit higher iron absorption before 6 months of age.
Fisiología del embarazo: Interacción materno-infantil
Authors: Cetin Irene , Cardellicchio Manuela
Published: November 2010

En los últimos años los datos han demostrado de qué manera el bienestar vitalicio depende considerablemente del crecimiento y el desarrollo intrauterinos durante la vida dentro del útero. El crecimiento fetal puede alcanzar únicamente su potencial íntegro mediante una interacción adecuada y armonizada entre la madre, la placenta y el feto. Este delicado equilibrio puede ser alterado por varios factores ambientales y maternos, como la dieta, la composición corporal y la situación endocrina maternas. Por otra parte, la función y el metabolismo de la placenta contribuyen y regulan la disponibilidad de nutrientes fetales. Los cambios en este mecanismo complejo pueden comprometer el desenlace del embarazo. En este capítulo pretendemos aclarar los mecanismos fisiológicos que regulan esta interacción y de qué modo, incluso pequeñas modificaciones pueden predisponer a patologías como la limitación del crecimiento intrauterino y la diabetes gravídica, con importantes consecuencias sobre la salud fetal y adulta.
Detection of Markers of Cardiovascular and Renal Risk in Cuba: Isle of Youth Study (ISYS)
Authors: Herrera R. , Almaguer M. , Chipi J. , Toirac X. , Martínez O. , Castellanos O. , Bacallao J. , Licourt R.M. , Mulet P. , Velásquez I. , Diéguez L. , Hernández M.C. , Caballero W. , Urra P. , Rodríguez-Triana N.
Published: November 2010

Chronic vascular diseases constitute a growing global health problem. Objectives: To (a) determine marker positivity for renovascular damage in the total adult population of the Isle of Youth, Cuba; (b) describe marker association with common risk factors for renal and related chronic vascular conditions, and (c) identify best predictors of renovascular damage. Methods: Previous informed consent was obtained, the population studied was 55,646, and subjects were aged ≧20 years. Blood pressure, weight and height were measured and a questionnaire applied. Urine markers for renovascular damage (hematuria, proteinuria and microalbuminuria) were also determined. Results: Positive markers were detected in 21.3%: hematuria (12.6%), microalbuminuria (6.8%), proteinuria (0.9%), and proteinuria + hematuria (0.9%). Risk factors were highly prevalent: 15.1% were aged ≧60 years; 32.3% overweight, 13.9% obese, and 25.1% smokers. Prevalence of high blood pressure (30%), diabetes mellitus (5.4%) and cardiovascular disease (5%) was also high, while cerebrovascular disease registered 0.9%. Markers were more prevalent in older people and in those suffering from diabetes mellitus, high blood pressure, cardiovascular and cerebrovascular disease, overweight or obesity. Risk factor regression tree analysis identified hypertension as the best predictor of renovascular damage. Conclusions: Adult population-wide screening revealed hidden morbidity and permitted better risk stratification. Results serve to inform community-based multidisciplinary and intersectoral disease prevention and management.
Neurology in the People’s Republic of China – An Update
Authors: Wang Xiao-Ping , Zhang Wei-Feng , Huang Hsuan-Ying , Preter Maurice
Published: November 2010

The present note provides an overview of the historical development of neurology and its current status in the People’s Republic of China, against the backdrop of the current massive transformation of Chinese society. We trace the origins of neurology in China to missionary medicine during the Republican period (1911–1949), and describe how the discipline grows with difficulty throughout the subsequent decades (1950–1976). We then introduce an influential legacy of the post-revolutionary period, the ideal of integrating traditional Chinese medicine (TCM) and Western medicine, and briefly describe recent efforts to modernize medical education and training. Finally, we provide a brief overview of topics in neurology and neuropsychiatry that have a ‘Chinese face’, last but not least the successful integration of TCM and Western medicine in the treatment of hepatolenticular degeneration/Wilson’s disease.
Ticagrelor Effectively and Reversibly Blocks Murine Platelet P2Y
12
-Mediated Thrombosis and Demonstrates a Requirement for Sustained P2Y
12
Inhibition to Prevent Subsequent Neointima
Authors: Patil Shankar B. , Jackman Laura E. , Francis Sheila E. , Judge Heather M. , Nylander Sven , Storey Robert F.
Published: November 2010

Objective—

Our goal was to study the effects of ticagrelor on murine platelet function and thrombosis and characterize the time course of P2Y
12
inhibition required to inhibit neointima formation following vascular injury.

Methods and Results—

Mice were treated with ticagrelor or vehicle. Platelet aggregation and P-selectin expression were assessed over time, and thrombus formation was assessed in laser-injured cremasteric arterioles of P2Y
12
+/+ and P2Y
12
−/− mice. Neointima formation in FeCl
3
-injured carotid artery was assessed in C57BL/6 mice treated with different regimens of ticagrelor. Ticagrelor inhibited platelet aggregation and P-selectin expression in a dose-dependent, reversible manner. Ticagrelor inhibited thrombus formation to the same extent as seen in P2Y
12
−/− mice. Neointima formation was markedly reduced in mice treated with ticagrelor before and 4 hours after injury (neointima area: control, 39 921±22 749 μm
2
, versus ticagrelor, 3705±2600 μm
2
;
P
<0.01), whereas administration of ticagrelor either before injury only or from 4 hours postinjury was ineffective.

Conclusion—

Ticagrelor effectively and reversibly inhibits P2Y
12
-mediated platelet function and thrombosis in mice. P2Y
12
inhibition is required both at the time of and after injury to effectively inhibit neointima formation. Additional studies are warranted to evaluate the role of P2Y
12
inhibition in preventing restenosis.
P-Selectin–Mediated Platelet-Neutrophil Aggregate Formation Activates Neutrophils in Mouse and Human Sickle Cell Disease
Authors: Polanowska-Grabowska Renata , Wallace Kori , Field Joshua J. , Chen Lanlin , Marshall Melissa A. , Figler Robert , Gear Adrian R.L. , Linden Joel
Published: November 2010

Objective—

To determine the role of platelets in stimulating mouse and human neutrophil activation and pulmonary injury in sickle cell disease (SCD).

Methods and Results—

Both platelet and neutrophil activation occur in SCD, but the interdependence of these events is unknown. Platelet activation and binding to leukocytes were measured in mice and patients with SCD and in controls. Relative to controls, blood obtained from mice or patients with SCD contained significantly elevated platelet-neutrophil aggregates (PNAs). Both platelets and neutrophils found in sickle PNAs were activated. Multispectral imaging (ImageStream) and conventional flow cytometry revealed a subpopulation of activated neutrophils with multiple adhered platelets that expressed significantly more CD11b and exhibited greater oxidative activity than single neutrophils. On average, wild-type and sickle PNAs contained 1.1 and 2.6 platelets per neutrophil, respectively. Hypoxia/reoxygenation induced a further increase in PNAs in mice with SCD and additional activation of both platelets and neutrophils. The pretreatment of mice with SCD with clopidogrel or P-selectin antibody reduced the formation of PNAs and neutrophil activation and decreased lung vascular permeability.

Conclusion—

Our findings suggest that platelet binding activates neutrophils and contributes to a chronic inflammatory state and pulmonary dysfunction in SCD. The inhibition of platelet activation may be useful to decrease tissue injury in SCD, particularly during the early stages of vaso-occlusive crises.
Regulation of Functionally Active P2Y12 ADP Receptors by Thrombin in Human Smooth Muscle Cells and the Presence of P2Y12 in Carotid Artery Lesions
Authors: Rauch Bernhard H. , Rosenkranz Anke C. , Ermler Swen , Böhm Andreas , Driessen Julia , Fischer Jens W. , Sugidachi Atsuhiro , Jakubowski Joseph A. , Schrör Karsten
Published: November 2010

Objective—

The platelet P2Y12 ADP receptor is a well-known target of thienopyridine-type antiplatelet drugs. This study is the first to describe increased transcriptional expression of a functionally active P2Y12 in response to thrombin in human vascular smooth muscle cells (SMC).

Methods and Results—

On exposure to thrombin, P2Y12 mRNA was transiently increased, whereas total protein and cell surface expression of P2Y12 were markedly increased within 6 hours and remained elevated over 24 hours. This effect was mediated by activation of nuclear factor κB. Preincubation with thrombin significantly enhanced the efficacy of the P2Y receptor agonist 2-methylthio-ADP to induce interleukin 6 expression and SMC mitogenesis. Effects induced by 2-methylthio-ADP were prevented by RNA interference-mediated knockdown of P2Y12 and a selective P2Y12-antagonist R-138727, the active metabolite of prasugrel. In addition, positive P2Y12 immunostaining was shown in SMC of human carotid artery plaques and was found to colocalize with tissue factor, the rate-limiting factor of thrombin formation in vivo.

Conclusion—

These data suggest that the P2Y12 receptor not only is central to ADP-induced platelet activation but also may mediate platelet-independent responses, specifically under conditions of enhanced thrombin formation, such as local vessel injury and atherosclerotic plaque rupture.
Compartmentalized Connexin 43
S
-Nitrosylation/Denitrosylation Regulates Heterocellular Communication in the Vessel Wall
Authors: Straub Adam C. , Billaud Marie , Johnstone Scott R. , Best Angela K. , Yemen Sean , Dwyer Scott T. , Looft-Wilson Robin , Lysiak Jeffery J. , Gaston Ben , Palmer Lisa , Isakson Brant E.
Published: November 2010

Objective—

To determine whether
S
-nitrosylation of connexins (Cxs) modulates gap junction communication between endothelium and smooth muscle.

Methods and Results—

Heterocellular communication is essential for endothelium control of smooth muscle constriction; however, the exact mechanism governing this action remains unknown. Cxs and NO have been implicated in regulating heterocellular communication in the vessel wall. The myoendothelial junction serves as a conduit to facilitate gap junction communication between endothelial cells and vascular smooth muscle cells within the resistance vasculature. By using isolated vessels and a vascular cell coculture, we found that Cx43 is constitutively
S
-nitrosylated on cysteine 271 because of active endothelial NO synthase compartmentalized at the myoendothelial junction. Conversely, we found that stimulation of smooth muscle cells with the constrictor phenylephrine caused Cx43 to become denitrosylated because of compartmentalized
S
-nitrosoglutathione reductase, which attenuated channel permeability. We measured
S
-nitrosoglutathione breakdown and NO
x
concentrations at the myoendothelial junction and found
S
-nitrosoglutathione reductase activity to precede NO release.

Conclusion—

This study provides evidence for compartmentalized
S
-nitrosylation/denitrosylation in the regulation of smooth muscle cell to endothelial cell communication.
Enhanced Levels of Soluble CD40 Ligand Exacerbate Platelet Aggregation and Thrombus Formation Through a CD40-Dependent Tumor Necrosis Factor Receptor–Associated Factor-2/Rac1/p38 Mitogen-Activated Protein Kinase Signaling Pathway
Authors: Yacoub Daniel , Hachem Ahmed , Théorêt Jean-François , Gillis Marc-Antoine , Mourad Walid , Merhi Yahye
Published: November 2010

Objective—

CD40 ligand is a thromboinflammatory molecule that predicts cardiovascular events. Platelets constitute the major source of soluble CD40 ligand (sCD40L), which has been shown to influence platelet activation, although its exact functional impact on platelets and the underlying mechanisms remain undefined. We aimed to determine the impact and the signaling mechanisms of sCD40L on platelets.

Methods and Results—

sCD40L strongly enhances platelet activation and aggregation. Human platelets treated with a mutated form of sCD40L that does not bind CD40, and CD40
−/−
mouse platelets failed to elicit such responses. Furthermore, sCD40L stimulation induces the association of the tumor necrosis factor receptor–associated factor-2 with platelet CD40. Notably, sCD40L primes platelets through activation of the small GTPase Rac1 and its downstream target p38 mitogen-activated protein kinase, which leads to platelet shape change and actin polymerization. Moreover, sCD40L exacerbates thrombus formation and leukocyte infiltration in wild-type mice but not in CD40
−/−
mice.

Conclusion—

sCD40L enhances agonist-induced platelet activation and aggregation through a CD40-dependent tumor necrosis factor receptor–associated factor-2/Rac1/p38 mitogen-activated protein kinase signaling pathway. Thus, sCD40L is an important platelet primer predisposing platelets to enhanced thrombus formation in response to vascular injury. This may explain the link between circulating levels of sCD40L and cardiovascular diseases.
TRIB1
and
GCKR
Polymorphisms, Lipid Levels, and Risk of Ischemic Heart Disease in the General Population
Authors: Varbo Anette , Benn Marianne , Tybjærg-Hansen Anne , Grande Peer , Nordestgaard Børge G.
Published: November 2010

Objective—

The goal of this study was to test whether
TRIB1
-rs2954029 and
GCKR
-rs1260326 associate with lipid levels and risk of ischemic heart disease (IHD) and myocardial infarction (MI) in the general population.

Methods and Results—

We genotyped >71 000 individuals. Lipid levels were studied cross-sectionally. Risk of IHD and MI was examined prospectively, cross-sectionally, and in a case-control study, and a metaanalysis was performed.
TRIB1
TA (50%) and AA (27%) versus TT (23%) genotypes were associated with increased levels of triglycerides (total increase, +0.16 mmol/L; trend,
P
<0.001), remnant cholesterol (+0.07 mmol/L;
P
<0.001), apolipoprotein B (+5.7 mg/dL;
P
<0.001), and low-density lipoprotein cholesterol (+0.11 mmol/L;
P
<0.001) and with decreased levels of high-density lipoprotein cholesterol (−0.04 mmol/L;
P
<0.001). In metaanalyses of the 3 studies combined,
TRIB1
TA and AA versus TT genotypes were associated with 13% (95% CI, 5% to 20%) and 15% (7% to 23%) increased risk of IHD, and 11% (1% to 21%) and 17% (6% to 30%) increased risk of MI, respectively. Although
GCKR
CT (46%) and TT (14%) versus CC (40%) genotypes had effects on triglycerides (+0.17 mmol/L; trend,
P
<0.001), remnant cholesterol (+0.07 mmol/L;
P
<0.001), and apolipoprotein B (+4.6 mg/dL;
P
<0.001) similar to those of
TRIB1
,
GCKR
did not influence low-density lipoprotein cholesterol levels or risk of IHD or MI. Risks of IHD were similar after stratification for gender, age, body mass index, hypertension, diabetes mellitus, smoking, statin use, alcohol intake, and physical activity.

Conclusion—

In the general population, both
TRIB1
-
rs2954029 and
GCKR
-
rs1260326 were associated with lipid levels, whereas
TRIB1
was also associated with increased risk of IHD and MI.
The Prostaglandin E2Receptor EP4 Is Expressed by Human Platelets and Potently Inhibits Platelet Aggregation and Thrombus Formation
Authors: Philipose Sonia , Konya Viktoria , Sreckovic Ivana , Marsche Gunther , Lippe Irmgard T. , Peskar Bernhard A. , Heinemann Akos , Schuligoi Rufina
Published: November 2010

Objective—Low concentrations of prostaglandin (PG) E2enhance platelet aggregation, whereas high concentrations inhibit it. The effects of PGE2are mediated through 4 G protein-coupled receptors, termed E-type prostaglindin (EP) receptor EP1, EP2, EP3, and EP4. The platelet-stimulating effect of PGE2has been suggested to involve EP3 receptors. Here we analyzed the receptor usage relating to the inhibitory effect of PGE2.

Methods and Results—Using flow cytometry, we found that human platelets expressed EP4 receptor protein. A selective EP4 agonist (ONO AE1-329) potently inhibited the platelet aggregation as induced by ADP or collagen. This effect could be completely reversed by an EP4 antagonist, but not by PGI2, PGD2, and thromboxane receptor antagonists or cyclooxygenase inhibition. Moreover, an EP4 antagonist enhanced the PGE2-induced stimulation of platelet aggregation, indicating a physiological antiaggregatory activity of EP4 receptors. The inhibitory effect of the EP4 agonist was accompanied by attenuated Ca2+flux, inhibition of glycoprotein IIb/IIIa, and downregulation of P-selectin. Most importantly, adhesion of platelets to fibrinogen under flow and in vitro thrombus formation were effectively prevented by the EP4 agonist. In this respect, the EP4 agonist synergized with acetylsalicylic acid.

Conclusion—These results are suggestive of EP4 receptor activation as a novel antithrombotic strategy.
A Systematic Assessment of Causes of Death After Heart Failure Onset in the Community
Authors: Lee Douglas S. , Gona Philimon , Albano Irene , Larson Martin G. , Benjamin Emelia J. , Levy Daniel , Kannel William B. , Vasan Ramachandran S.
Published: November 2010

Background—

The high mortality rate in patients with heart failure (HF) is influenced by presence of multiple comorbidities. Data are limited on the relative contributions of cardiovascular versus noncardiovascular diseases to death in individuals with HF in the community.

Methods and Results—

We examined the incidence and predictors of cardiovascular versus noncardiovascular death in participants with HF in the Framingham Heart Study. Underlying, immediate, and contributing causes of death (3 key elements of the World Health Organization classification) were adjudicated by a 3-physician review panel. During 1971 to 2004, 1025 participants with HF died (499 men, mean [SD] age at death 79 [11] years), including 463 participants with left ventricular ejection fraction (LVEF) data. Cardiovascular disease was the cause of death in 66.1% overall. Stratified by LVEF, cardiovascular deaths occurred in 44.5% and 69.9% of those with preserved and reduced LVEF, respectively. Presence of reduced LVEF increased the risk of cardiovascular death, with odds ratios of 3.16 (95% confidence interval [CI], 1.73 to 5.78) in men and 2.39 (95% CI, 1.39 to 4.08) in women. Prior myocardial infarction was associated with increased cardiovascular death in women with HF (odds ratio, 1.87; 95% CI, 1.10 to 3.16) but not in men. The risk of cardiovascular disease death decreased in women (odds ratio after 1980, 0.41; 95% CI, 0.24 to 0.69) and men (odds ratio, 0.66; 95% CI, 0.41 to 1.07,
P
=0.095) with HF over time. Infections and kidney disease emerged as key immediate and contributing causes of death, respectively.

Conclusions—

Individuals with HF in the community often experience cardiovascular death, but noncardiovascular disease also contributes significantly especially among those with preserved LVEF.
Reduced Tongue Pressure Against the Hard Palate on the Paralyzed Side During Swallowing Predicts Dysphagia in Patients With Acute Stroke
Authors: Hirota Nobuko , Konaka Kuni , Ono Takahiro , Tamine Kenichi , Kondo Jugo , Hori Kazuhiro , Yoshimuta Yoko , Maeda Yoshinobu , Sakoda Saburo , Naritomi Hiroaki
Published: November 2010

Background and Purpose—

Dysphagia is important for prognosis in patients with stroke because this condition can cause aspiration pneumonia or nutritional deficits. The present study investigated the relationship between tongue motor deficits and dysphagia in patients with acute stroke.

Methods—

Maximal tongue pressure on the hard palate when swallowing 5 mL of water was measured using a T-shaped sensor sheet with 5 measuring points in 33 dysphagic and 31 nondysphagic patients with acute stroke. Maximum tongue pressures at each measuring point were compared between dysphagic and nondysphagic groups and between paralyzed and nonparalyzed sides.

Results—

Tongue pressure at each measuring point was significantly smaller in dysphagic patients than in nondysphagic patients with the largest significant difference on the paralyzed side. The magnitude of tongue pressure to predict dysphagia was calculated as 4.6 kPa on the paralyzed side, offering 71.4% sensitivity and 72.3% specificity.

Conclusions—

Reduced tongue pressure on the paralyzed side may predict dysphagia in patients with acute stroke.
New Polyphonies: Score Streams, Improvisation and Telepresence
Authors: Dessen Michael
Published: November 2010

The author discusses “score streams,” a compositional method in which notations are displayed dynamically on computer screens and interpreted by improvisers. These works are informed by contemporary explorations in telematic performance and by the many methods devised over the past half century in composer-improviser traditions, where works by individuals are understood as catalysts for profoundly collaborative real-time acts of creation. Referencing polyphony both literally and metaphorically, the author points to a richly generative dialogue between recent histories of improvised music and new forms of digital networking technologies.
The Building of Boutique Effects Pedals—The “Where” of Improvisation
Authors: Fenn John
Published: November 2010

Based on 2 years of ethnographic fieldwork with builders of boutique music effects boxes, this essay explores the ways in which improvisation figures into the creation of music technology. The author argues that expanding the rubric of improvisation to encompass the processes of designing and building effects boxes pushes scholars to understand relationships between music and improvisation as existing beyond the boundaries of performance. Ultimately he posits that improvisatory behavior and exploratory engagement with material at hand is central to building pedals, and should be assessed as part of the continuum of social-aesthetic practices composing music making.
Music of Its Own Accord
Authors: Satz Aura
Published: November 2010

The disembodied hands of spiritualist sittings touched people and levitated objects but also strummed guitars, rang bells, played closed pianos and accordions in cages. Likewise, the mechanical music machines of the time (orchestrions, pianolas, etc.) seemed animated by invisible fingers. Highlighting the historical and haptic parallels between these manifestations, the author addresses the lack of a visible performing body, which remains implicit through the invisible animating agency. She looks at the moment before music became abstracted into the grooves of the gramophone, when music still looked like instruments, though without the gestural presence of the performer. The article is illustrated with images from the author's project Automamusic.
Let's Dance Architecture: Improvisation, Technology and Form
Authors: Impett Jonathan
Published: November 2010

The author considers the technology-enabled improvisation of musical form—the projection of the dynamics of structure on the unfolding of improvised performance. Improvisation with technology has been largely concerned with its potential for more complex activity in the present. He proposes reclaiming the radical potential of technological improvisation by subverting the “permanent present.” Technology importantly affords a dynamical temporal prosthesis. Following a re-examination of times and forms in music and performance, the imagining and projection of future events is predicated on the same architecture as memory. Finally, brief consideration is given to the technological challenges of such an approach.
Are the Father and Son Different in Kind? Scotus and Ockham on Different Kinds of Things, Univocal and Equivocal Production, and Subordination in the Trinity
Authors: Paasch JT
Published: November 2010

In this paper, I examine how Scotus and Ockham try to solve the following problem. If different kinds of constituents contribute some difference in kind to the things they constitute, then the divine Father and Son should be different in kind because they are constituted by at least some constituents that are different in kind (namely, fatherhood and sonship). However, if the Father and Son are different in kind, the Son’s production will be equivocal, and equivocal products are typically less perfect than their producers. Therefore, the Son must be subordinate to the Father. In response, Scotus argues that different kinds of constituents do not necessarily result in different kinds of things, but Ockham rejects this, arguing instead that although the Father and Son are different in kind, they are still equal in perfection because of their identity with the divine essence.