scispace - formally typeset
Search or ask a question

Showing papers by "Ludwig Maximilian University of Munich published in 2009"


Journal ArticleDOI
Denise Harold1, Richard Abraham2, Paul Hollingworth2, Rebecca Sims2, Amy Gerrish2, Marian L. Hamshere3, Jaspreet Singh Pahwa2, Valentina Moskvina2, Kimberley Dowzell2, Amy L. Williams2, Nicola L. Jones2, Charlene Thomas2, Alexandra Stretton2, Angharad R. Morgan2, Simon Lovestone4, John Powell5, Petroula Proitsi5, Michelle K. Lupton5, Carol Brayne6, David C. Rubinsztein7, Michael Gill6, Brian A. Lawlor6, Aoibhinn Lynch6, Kevin Morgan8, Kristelle Brown8, Peter Passmore9, David Craig9, Bernadette McGuinness9, Stephen Todd9, Clive Holmes10, David M. A. Mann11, A. David Smith12, Seth Love3, Patrick G. Kehoe3, John Hardy, Simon Mead13, Nick C. Fox13, Martin N. Rossor13, John Collinge13, Wolfgang Maier14, Frank Jessen14, Britta Schürmann14, Hendrik van den Bussche15, Isabella Heuser16, Johannes Kornhuber17, Jens Wiltfang18, Martin Dichgans19, Lutz Frölich20, Harald Hampel19, Harald Hampel21, Michael Hüll22, Dan Rujescu19, Alison Goate23, John S. K. Kauwe24, Carlos Cruchaga23, Petra Nowotny23, John C. Morris23, Kevin Mayo23, Kristel Sleegers25, Karolien Bettens25, Sebastiaan Engelborghs25, Peter Paul De Deyn25, Christine Van Broeckhoven25, Gill Livingston26, Nicholas Bass26, Hugh Gurling26, Andrew McQuillin26, Rhian Gwilliam27, Panagiotis Deloukas27, Ammar Al-Chalabi28, Christopher Shaw28, Magda Tsolaki29, Andrew B. Singleton30, Rita Guerreiro30, Thomas W. Mühleisen14, Markus M. Nöthen14, Susanne Moebus18, Karl-Heinz Jöckel18, Norman Klopp, H-Erich Wichmann19, Minerva M. Carrasquillo31, V. Shane Pankratz31, Steven G. Younkin31, Peter Holmans2, Michael Conlon O'Donovan2, Michael John Owen2, Julie Williams2 
TL;DR: A two-stage genome-wide association study of Alzheimer's disease involving over 16,000 individuals, the most powerful AD GWAS to date, produced compelling evidence for association with Alzheimer's Disease in the combined dataset.
Abstract: We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 10-157) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 10-9) and 5' to the PICALM gene (rs3851179, P = 1.9 10-8). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 10-10, odds ratio = 0.86; rs3851179, P = 1.3 10-9, odds ratio = 0.86).

2,956 citations


Journal ArticleDOI
TL;DR: The aim of this work is to introduce the principles of the standard recursive partitioning methods as well as recent methodological improvements, to illustrate their usage for low and high-dimensional data exploration, but also to point out limitations of the methods and potential pitfalls in their practical application.
Abstract: Recursive partitioning methods have become popular and widely used tools for nonparametric regression and classification in many scientific fields. Especially random forests, which can deal with large numbers of predictor variables even in the presence of complex interactions, have been applied successfully in genetics, clinical medicine, and bioinformatics within the past few years. High-dimensional problems are common not only in genetics, but also in some areas of psychological research, where only a few subjects can be measured because of time or cost constraints, yet a large amount of data is generated for each subject. Random forests have been shown to achieve a high prediction accuracy in such applications and to provide descriptive variable importance measures reflecting the impact of each variable in both main effects and interactions. The aim of this work is to introduce the principles of the standard recursive partitioning methods as well as recent methodological improvements, to illustrate their usage for low and high-dimensional data exploration, but also to point out limitations of the methods and potential pitfalls in their practical application. Application of the methods is illustrated with freely available implementations in the R system for statistical computing.

2,001 citations


Journal ArticleDOI
TL;DR: Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
Abstract: Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.

1,710 citations


Journal ArticleDOI
TL;DR: A meta-analysis of randomised controlled trials to compare the effects of second-generation antipsychotic drugs in patients with schizophrenia provided data for individualised treatment based on efficacy, side-effects, and cost.

1,682 citations


Journal ArticleDOI
Hreinn Stefansson1, Hreinn Stefansson2, Roel A. Ophoff2, Roel A. Ophoff3, Roel A. Ophoff4, Stacy Steinberg2, Stacy Steinberg1, Ole A. Andreassen5, Sven Cichon6, Dan Rujescu7, Thomas Werge8, Olli Pietilainen9, Ole Mors10, Preben Bo Mortensen11, Engilbert Sigurdsson12, Omar Gustafsson1, Mette Nyegaard11, Annamari Tuulio-Henriksson13, Andres Ingason1, Thomas Hansen8, Jaana Suvisaari13, Jouko Lönnqvist13, Tiina Paunio, Anders D. Børglum10, Anders D. Børglum11, Annette M. Hartmann7, Anders Fink-Jensen8, Merete Nordentoft14, David M. Hougaard, Bent Nørgaard-Pedersen, Yvonne Böttcher1, Jes Olesen15, René Breuer16, Hans-Jürgen Möller7, Ina Giegling7, Henrik B. Rasmussen8, Sally Timm8, Manuel Mattheisen6, István Bitter17, János Réthelyi17, Brynja B. Magnusdottir12, Thordur Sigmundsson12, Pall I. Olason1, Gisli Masson1, Jeffrey R. Gulcher1, Magnús Haraldsson12, Ragnheidur Fossdal1, Thorgeir E. Thorgeirsson1, Unnur Thorsteinsdottir1, Unnur Thorsteinsdottir12, Mirella Ruggeri18, Sarah Tosato18, Barbara Franke19, Eric Strengman3, Lambertus A. Kiemeney19, Ingrid Melle5, Srdjan Djurovic5, Lilia I. Abramova20, Kaleda Vg20, Julio Sanjuán21, Rosa de Frutos21, Elvira Bramon22, Evangelos Vassos22, Gillian Fraser23, Ulrich Ettinger22, Marco Picchioni22, Nicholas Walker, T. Toulopoulou22, Anna C. Need24, Dongliang Ge24, Joeng Lim Yoon4, Kevin V. Shianna24, Nelson B. Freimer4, Rita M. Cantor4, Robin M. Murray22, Augustine Kong1, Vera Golimbet20, Angel Carracedo25, Celso Arango26, Javier Costas, Erik G. Jönsson27, Lars Terenius27, Ingrid Agartz27, Hannes Petursson12, Markus M. Nöthen6, Marcella Rietschel16, Paul M. Matthews28, Pierandrea Muglia29, Leena Peltonen9, David St Clair23, David Goldstein24, Kari Stefansson12, Kari Stefansson1, David A. Collier30, David A. Collier22 
06 Aug 2009-Nature
TL;DR: Findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.
Abstract: Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

1,625 citations


Journal ArticleDOI
TL;DR: In this article, improved versions of the relations between supermassive black hole mass (M BH) and host-galaxy bulge velocity dispersion (σ) and luminosity (L; the M-σ and M-L relations), based on 49 M BH measurements and 19 upper limits, were derived.
Abstract: We derive improved versions of the relations between supermassive black hole mass (M BH) and host-galaxy bulge velocity dispersion (σ) and luminosity (L; the M-σ and M-L relations), based on 49 M BH measurements and 19 upper limits. Particular attention is paid to recovery of the intrinsic scatter (e0) in both relations. We find log(M BH/M) = α + βlog(σ/200 km s-1) with (α, β, e0) = (8.12 0.08, 4.24 0.41, 0.44 0.06) for all galaxies and (α, β, e0) = (8.23 0.08, 3.96 0.42, 0.31 0.06) for ellipticals. The results for ellipticals are consistent with previous studies, but the intrinsic scatter recovered for spirals is significantly larger. The scatter inferred reinforces the need for its consideration when calculating local black hole mass function based on the M-σ relation, and further implies that there may be substantial selection bias in studies of the evolution of the M-σ relation. We estimate the M-L relationship as log(M BH/M) = α + βlog(LV /1011 L V) of (α, β, e0) = (8.95 0.11, 1.11 0.18, 0.38 0.09); using only early-type galaxies. These results appear to be insensitive to a wide range of assumptions about the measurement errors and the distribution of intrinsic scatter. We show that culling the sample according to the resolution of the black hole's sphere of influence biases the relations to larger mean masses, larger slopes, and incorrect intrinsic residuals. © 2009. The American Astronomical Society.

1,528 citations


Journal ArticleDOI
TL;DR: This article derived improved versions of the relations between supermassive black hole mass and host-galaxy bulge velocity dispersion (sigma) and luminosity (L) (the M-sigma and M-L relations), based on 49 M_BH measurements and 19 upper limits.
Abstract: We derive improved versions of the relations between supermassive black hole mass (M_BH) and host-galaxy bulge velocity dispersion (sigma) and luminosity (L) (the M-sigma and M-L relations), based on 49 M_BH measurements and 19 upper limits. Particular attention is paid to recovery of the intrinsic scatter (epsilon_0) in both relations. We find log(M_BH / M_sun) = alpha + beta * log(sigma / 200 km/s) with (alpha, beta, epsilon_0) = (8.12 +/- 0.08, 4.24 +/- 0.41, 0.44 +/- 0.06) for all galaxies and (alpha, beta, epsilon_0) = (8.23 +/- 0.08, 3.96 +/- 0.42, 0.31 +/- 0.06) for ellipticals. The results for ellipticals are consistent with previous studies, but the intrinsic scatter recovered for spirals is significantly larger. The scatter inferred reinforces the need for its consideration when calculating local black hole mass function based on the M-sigma relation, and further implies that there may be substantial selection bias in studies of the evolution of the M-sigma relation. We estimate the M-L relationship as log(M_BH / M_sun) = alpha + beta * log(L_V / 10^11 L_sun,V) of (alpha, beta, epsilon_0) = (8.95 +/- 0.11, 1.11 +/- 0.18, 0.38 +/- 0.09); using only early-type galaxies. These results appear to be insensitive to a wide range of assumptions about the measurement errors and the distribution of intrinsic scatter. We show that culling the sample according to the resolution of the black hole's sphere of influence biases the relations to larger mean masses, larger slopes, and incorrect intrinsic residuals.

1,522 citations


Journal ArticleDOI
TL;DR: This survey tries to clarify the different problem definitions related to subspace clustering in general; the specific difficulties encountered in this field of research; the varying assumptions, heuristics, and intuitions forming the basis of different approaches; and how several prominent solutions tackle different problems.
Abstract: As a prolific research area in data mining, subspace clustering and related problems induced a vast quantity of proposed solutions. However, many publications compare a new proposition—if at all—with one or two competitors, or even with a so-called “naive” ad hoc solution, but fail to clarify the exact problem definition. As a consequence, even if two solutions are thoroughly compared experimentally, it will often remain unclear whether both solutions tackle the same problem or, if they do, whether they agree in certain tacit assumptions and how such assumptions may influence the outcome of an algorithm. In this survey, we try to clarify: (i) the different problem definitions related to subspace clustering in general; (ii) the specific difficulties encountered in this field of research; (iii) the varying assumptions, heuristics, and intuitions forming the basis of different approaches; and (iv) how several prominent solutions tackle different problems.

1,206 citations


Journal ArticleDOI
TL;DR: In this paper, the association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2(P = 1 × 10-23), FGF5 (P=1 × 10 -21), SH2B3(P= 3 × 10−18), MTHFR(MTHFR), c10orf107(P), ZNF652(ZNF652), PLCD3 (P,P = 5 × 10 −9),
Abstract: Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

1,205 citations


Journal ArticleDOI
Sekar Kathiresan1, Benjamin F. Voight1, Shaun Purcell2, Kiran Musunuru1, Diego Ardissino, Pier Mannuccio Mannucci3, Sonia S. Anand4, James C. Engert5, Nilesh J. Samani6, Heribert Schunkert7, Jeanette Erdmann7, Muredach P. Reilly8, Daniel J. Rader8, Thomas M. Morgan9, John A. Spertus10, Monika Stoll11, Domenico Girelli12, Pascal P. McKeown13, Christopher Patterson13, David S. Siscovick14, Christopher J. O'Donnell15, Roberto Elosua, Leena Peltonen16, Veikko Salomaa17, Stephen M. Schwartz14, Olle Melander18, David Altshuler1, Pier Angelica Merlini, Carlo Berzuini19, Luisa Bernardinelli19, Flora Peyvandi3, Marco Tubaro, Patrizia Celli, Maurizio Ferrario, Raffaela Fetiveau, Nicola Marziliano, Giorgio Casari20, Michele Galli, Flavio Ribichini12, Marco Rossi, Francesco Bernardi21, Pietro Zonzin, Alberto Piazza22, Jean Yee14, Yechiel Friedlander23, Jaume Marrugat, Gavin Lucas, Isaac Subirana, Joan Sala24, Rafael Ramos, James B. Meigs1, Gordon H. Williams1, David M. Nathan1, Calum A. MacRae1, Aki S. Havulinna17, Göran Berglund18, Joel N. Hirschhorn1, Rosanna Asselta, Stefano Duga, Marta Spreafico25, Mark J. Daly1, James Nemesh2, Joshua M. Korn1, Steven A. McCarroll1, Aarti Surti2, Candace Guiducci2, Lauren Gianniny2, Daniel B. Mirel2, Melissa Parkin2, Noël P. Burtt2, Stacey Gabriel2, John R. Thompson6, Peter S. Braund6, Benjamin J. Wright6, Anthony J. Balmforth26, Stephen G. Ball26, Alistair S. Hall26, Patrick Linsel-Nitschke7, Wolfgang Lieb7, Andreas Ziegler7, Inke R. König7, Christian Hengstenberg27, Marcus Fischer27, Klaus Stark27, Anika Grosshennig7, Michael Preuss7, H-Erich Wichmann28, Stefan Schreiber29, Willem H. Ouwehand19, Panos Deloukas30, Michael Scholz, François Cambien31, Mingyao Li8, Zhen Chen8, Robert L. Wilensky8, William H. Matthai8, Atif Qasim8, Hakon Hakonarson8, Joe Devaney32, Mary-Susan Burnett32, Augusto D. Pichard32, Kenneth M. Kent32, Lowell F. Satler32, Joseph M. Lindsay32, Ron Waksman32, Stephen E. Epstein32, Thomas Scheffold, Klaus Berger11, Andreas Huge11, Nicola Martinelli12, Oliviero Olivieri12, Roberto Corrocher12, Hilma Holm33, Gudmar Thorleifsson33, Unnur Thorsteinsdottir34, Kari Stefansson34, Ron Do5, Changchun Xie4, David S. Siscovick14 
TL;DR: SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with my Cardiovascular Infarction risk.
Abstract: We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls We carried out replication in an independent sample with an effective sample size of up to 19,492 SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations1, 2, 3, 4 (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9) We tested 554 common copy number polymorphisms (>1% allele frequency) and none met the pre-specified threshold for replication (P < 10-3) We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk

1,092 citations


Journal ArticleDOI
TL;DR: This review describes many examples of how modern molecular-biological methods can enable us to understand the various synergistic mechanisms underlying these effects of herbal drug combinations.

Journal ArticleDOI
TL;DR: In this paper, a theoretical model linking achievement goals and achievement emotions to academic performance was proposed, which was tested in a prospective study with undergraduates, using exam-specific assessments of both goals and emotions as predictors of exam performance in an introductory-level psychology course.
Abstract: The authors propose a theoretical model linking achievement goals and achievement emotions to academic performance. This model was tested in a prospective study with undergraduates (N = 213), using exam-specific assessments of both goals and emotions as predictors of exam performance in an introductory-level psychology course. The findings were consistent with the authors' hypotheses and supported all aspects of the proposed model. In multiple regression analysis, achievement goals (mastery, performance approach, and performance avoidance) were shown to predict discrete achievement emotions (enjoyment, boredom, anger, hope, pride, anxiety, hopelessness, and shame), achievement emotions were shown to predict performance attainment, and 7 of the 8 focal emotions were documented as mediators of the relations between achievement goals and performance attainment. All of these findings were shown to be robust when controlling for gender, social desirability, positive and negative trait affectivity, and scholastic ability. The results are discussed with regard to the underdeveloped literature on discrete achievement emotions and the need to integrate conceptual and applied work on achievement goals and achievement emotions.

Posted Content
TL;DR: In this article, the authors provide evidence that the robust association between cognitive skills and economic growth reflects a causal effect of cognitive skills, and support the economic benefits of effective school policy and develop a new common metric that allows tracking student achievement across countries, over time, and along the within-country distribution.
Abstract: We provide evidence that the robust association between cognitive skills and economic growth reflects a causal effect of cognitive skills and supports the economic benefits of effective school policy. We develop a new common metric that allows tracking student achievement across countries, over time, and along the within-country distribution. Extensive sensitivity analyses of cross-country growth regressions generate remarkably stable results across specifications, time periods, and country samples. In addressing causality, we find, first, significant growth effects of cognitive skills when instrumented by institutional features of school systems. Second, home-country cognitive-skill levels strongly affect the earnings of immigrants on the U.S. labor market in a difference-in-differences model that compares home-educated to U.S.-educated immigrants from the same country of origin. Third, countries that improved their cognitive skills over time experienced relative increases in their growth paths. From a policy perspective, the shares of basic literates and high performers have independent significant effects on growth that are complementary to each other, and the high-performer effect is larger in poorer countries.

Journal ArticleDOI
TL;DR: A detailed Raman investigation of graphene flakes with edges oriented at different crystallographic directions is presented and a real space theory for Raman scattering is developed to analyze the general case of disordered edges.
Abstract: Graphene edges are of particular interest since their orientation determines the electronic properties. Here we present a detailed Raman investigation of graphene flakes with edges oriented at different crystallographic directions. We also develop a real space theory for Raman scattering to analyze the general case of disordered edges. The position, width, and intensity of G and D peaks are studied as a function of the incident light polarization. The D-band is strongest for polarization parallel to the edge and minimum for perpendicular. Raman mapping shows that the D peak is localized in proximity of the edge. For ideal edges, the D peak is zero for zigzag orientation and large for armchair, allowing in principle the use of Raman spectroscopy as a sensitive tool for edge orientation. However, for real samples, the D to G ratio does not always show a significant dependence on edge orientation. Thus, even though edges can appear macroscopically smooth and oriented at well-defined angles, they are not necessarily microscopically ordered.

Journal ArticleDOI
TL;DR: Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency and effective protection against infections and improvement in physical development made a normal lifestyle possible.
Abstract: Background We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency. Methods We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells. Results All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxificati...

Journal ArticleDOI
TL;DR: In this article, a review of work on graphene monolayers adsorbed on metal surfaces is presented, with a focus on the metal/graphene interaction. But the authors do not consider the effect of the metal-graphenes interaction on the electronic structure.

Journal ArticleDOI
TL;DR: A link comprising the gp130/Stat3 transcription factor signaling axis is established comprising the common tumor cell-autonomous mechanism that bridges chronic inflammation to tumor promotion in colitis-associated cancer models.

Journal ArticleDOI
04 Feb 2009-JAMA
TL;DR: In this article, a cross-sectional, international, multicenter, observational study was conducted to estimate the radiation dose of CCTA in routine clinical practice as well as the association of currently available strategies with dose reduction.
Abstract: Context Cardiac computed tomography (CT) angiography (CCTA) has emerged as a useful diagnostic imaging modality in the assessment of coronary artery disease. However, the potential risks due to exposure to ionizing radiation associated with CCTA have raised concerns. Objectives To estimate the radiation dose of CCTA in routine clinical practice as well as the association of currently available strategies with dose reduction and to identify the independent factors contributing to radiation dose. Design, Setting, and Patients A cross-sectional, international, multicenter, observational study (50 study sites: 21 university hospitals and 29 community hospitals) of estimated radiation dose in 1965 patients undergoing CCTA between February and December 2007. Linear regression analysis was used to identify independent predictors associated with dose. Main Outcome Measure Dose-length product (DLP) of CCTA. Results The median DLP of 1965 CCTA examinations performed at 50 study sites was 885 mGy × cm (interquartile range, 568-1259 mGy × cm), which corresponds to an estimated radiation dose of 12 mSv (or 1.2 × the dose of an abdominal CT study or 600 chest x-rays). A high variability in DLP was observed between study sites (range of median DLPs per site, 331-2146 mGy × cm). Independent factors associated with radiation dose were patient weight (relative effect on DLP, 5%; 95% confidence interval [CI], 4%-6%), absence of stable sinus rhythm (10%; 95% CI, 2%-19%), scan length (5%; 95% CI, 4%-6%), electrocardiographically controlled tube current modulation (−25%; 95% CI, −23% to −28%; applied in 73% of patients), 100-kV tube voltage (−46%; 95% CI, −42% to −51%; applied in 5% of patients), sequential scanning (−78%; 95% CI, −77% to −79%; applied in 6% of patients), experience in cardiac CT (−1%; 95% CI, −1% to 0%), number of CCTAs per month (0%; 95% CI, 0%-1%), and type of 64-slice CT system (for highest vs lowest dose system, 97%; 95% CI, 88%-106%). Algorithms for dose reduction were not associated with deteriorated diagnostic image quality in this observational study. Conclusions Median doses of CCTA differ significantly between study sites and CT systems. Effective strategies to reduce radiation dose are available but some strategies are not frequently used. The comparable diagnostic image quality may support an increased use of dose-saving strategies in adequately selected patients.

Journal ArticleDOI
TL;DR: Recent insights into the structure, function, and cellular regulation of HCN channels are summarized and evidence on the role of individual HCN channel types arising from the analysis ofHCN knockout mouse models is discussed.
Abstract: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels comprise a small subfamily of proteins within the superfamily of pore-loop cation channels. In mammals, the HCN channel family com...

Journal ArticleDOI
TL;DR: It is shown that a high-salt diet in rats leads to interstitial hypertonic Na+ accumulation in skin, resulting in increased density and hyperplasia of the lymphcapillary network and VEGFC is identified as an osmosensitive, hypertonicity-driven gene intimately involved in salt-induced hypertension.
Abstract: In salt-sensitive hypertension, the accumulation of Na(+) in tissue has been presumed to be accompanied by a commensurate retention of water to maintain the isotonicity of body fluids We show here that a high-salt diet (HSD) in rats leads to interstitial hypertonic Na(+) accumulation in skin, resulting in increased density and hyperplasia of the lymphcapillary network The mechanisms underlying these effects on lymphatics involve activation of tonicity-responsive enhancer binding protein (TonEBP) in mononuclear phagocyte system (MPS) cells infiltrating the interstitium of the skin TonEBP binds the promoter of the gene encoding vascular endothelial growth factor-C (VEGF-C, encoded by Vegfc) and causes VEGF-C secretion by macrophages MPS cell depletion or VEGF-C trapping by soluble VEGF receptor-3 blocks VEGF-C signaling, augments interstitial hypertonic volume retention, decreases endothelial nitric oxide synthase expression and elevates blood pressure in response to HSD Our data show that TonEBP-VEGF-C signaling in MPS cells is a major determinant of extracellular volume and blood pressure homeostasis and identify VEGFC as an osmosensitive, hypertonicity-driven gene intimately involved in salt-induced hypertension

Journal ArticleDOI
21 May 2009-Nature
TL;DR: The results demonstrate the molecular basis for IL-1β production after fungal infection and identify a crucial function for the Nlrp3 inflammasome in mammalian host defence in vivo.
Abstract: Immunocompromised individuals are at high risk from fungal infection, yet the molecular mechanisms that govern host defence against fungi are not well understood. Gross et al. now show that Candida albicans infection in mice activates the NALP3 inflammasome via a mechanism involving Sky-induced production of reactive oxygen induced by the tyrosine kinase Syk.

Journal ArticleDOI
TL;DR: The paper presents the architecture and functionality of the principal networking agent?the SECOQC node module, which enables the authentic classical communication required for key distillation, manages the generated key material, determines a communication path between any destinations in the network, and realizes end-to-end secure transport of key material between these destinations.
Abstract: In this paper, we present the quantum key distribution (QKD) network designed and implemented by the European project SEcure COmmunication based on Quantum Cryptography (SECOQC) (2004?2008), unifying the efforts of 41 research and industrial organizations. The paper summarizes the SECOQC approach to QKD networks with a focus on the trusted repeater paradigm. It discusses the architecture and functionality of the SECOQC trusted repeater prototype, which has been put into operation in Vienna in 2008 and publicly demonstrated in the framework of a SECOQC QKD conference held from October 8 to 10, 2008. The demonstration involved one-time pad encrypted telephone communication, a secure (AES encryption protected) video-conference with all deployed nodes and a number of rerouting experiments, highlighting basic mechanisms of the SECOQC network functionality.The paper gives an overview of the eight point-to-point network links in the prototype and their underlying technology: three plug and play systems by id Quantique, a one way weak pulse system from Toshiba Research in the UK, a coherent one-way system by GAP Optique with the participation of id Quantique and the AIT Austrian Institute of Technology (formerly ARC), an entangled photons system by the University of Vienna and the AIT, a continuous-variables system by Centre National de la Recherche Scientifique (CNRS) and THALES Research and Technology with the participation of Universit? Libre de Bruxelles, and a free space link by the Ludwig Maximillians University in Munich connecting two nodes situated in adjacent buildings (line of sight 80?m). The average link length is between 20 and 30?km, the longest link being 83?km.The paper presents the architecture and functionality of the principal networking agent?the SECOQC node module, which enables the authentic classical communication required for key distillation, manages the generated key material, determines a communication path between any destinations in the network, and realizes end-to-end secure transport of key material between these destinations.The paper also illustrates the operation of the network in a number of typical exploitation regimes and gives an initial estimate of the network transmission capacity, defined as the maximum amount of key that can be exchanged, or alternatively the amount of information that can be transmitted with information theoretic security, between two arbitrary nodes.

Journal ArticleDOI
TL;DR: This review gives a short outline of currently discussed pathways and induction methods for protein aggregation and describes currently employed set of analytical techniques and emerging technologies for aggregate detection, characterization and quantification.

Journal ArticleDOI
TL;DR: In this review, basic concepts of hair follicle biology are presented and important recent advances in the field are summarized.

Journal ArticleDOI
TL;DR: In this paper, a parameterized stellar-to-halo mass (SHM) relation was derived by populating halos and subhalos in an N-body simulation with galaxies and requiring that the observed stellar mass function be reproduced.
Abstract: We use a statistical approach to determine the relationship between the stellar masses of galaxies and the masses of the dark matter halos in which they reside. We obtain a parameterized stellar-to-halo mass (SHM) relation by populating halos and subhalos in an N-body simulation with galaxies and requiring that the observed stellar mass function be reproduced. We find good agreement with constraints from galaxy-galaxy lensing and predictions of semi-analytic models. Using this mapping, and the positions of the halos and subhalos obtained from the simulation, we find that our model predictions for the galaxy two-point correlation function (CF) as a function of stellar mass are in excellent agreement with the observed clustering properties in the SDSS at z=0. We show that the clustering data do not provide additional strong constraints on the SHM function and conclude that our model can therefore predict clustering as a function of stellar mass. We compute the conditional mass function, which yields the average number of galaxies with stellar masses in the range [m, m+dm] that reside in a halo of mass M. We study the redshift dependence of the SHM relation and show that, for low mass halos, the SHM ratio is lower at higher redshift. The derived SHM relation is used to predict the stellar mass dependent galaxy CF and bias at high redshift. Our model predicts that not only are massive galaxies more biased than low mass ones at all redshifts, but the bias increases more rapidly with increasing redshift for massive galaxies than for low mass ones. We present convenient fitting functions for the SHM relation as a function of redshift, the conditional mass function, and the bias as a function of stellar mass and redshift.

Journal ArticleDOI
TL;DR: In this paper, the authors compared the probability of survival in patients with blunt trauma who had whole-body CT during resuscitation with those who had not, and found that the use of CT for early assessment of primary trauma is increasing.

Journal ArticleDOI
TL;DR: The European Psychiatric Association (EPA) supported by the European Association for the Study of Diabetes (EASD) and the European Society of Cardiology (ESC) published a statement with the aim of improving the care of patients suffering from severe mental illness as mentioned in this paper.

Journal ArticleDOI
TL;DR: In this article, the authors present measurements of the Hubble diagram for 103 Type Ia supernovae with redshifts 0.04 < z < 0.42, discovered during the first season (Fall 2005) of the Sloan Digital Sky Survey-II (SDSS-II) Supernova Survey.
Abstract: We present measurements of the Hubble diagram for 103 Type Ia supernovae (SNe) with redshifts 0.04 < z < 0.42, discovered during the first season (Fall 2005) of the Sloan Digital Sky Survey-II (SDSS-II) Supernova Survey. These data fill in the redshift "desert" between low- and high-redshift SN Ia surveys. Within the framework of the MLCS2K2 light-curve fitting method, we use the SDSS-II SN sample to infer the mean reddening parameter for host galaxies, RV = 2.18 ± 0.14stat ± 0.48syst, and find that the intrinsic distribution of host-galaxy extinction is well fitted by an exponential function, P(AV ) = exp(–AV /τV), with τV = 0.334 ± 0.088 mag. We combine the SDSS-II measurements with new distance estimates for published SN data from the ESSENCE survey, the Supernova Legacy Survey (SNLS), the Hubble Space Telescope (HST), and a compilation of Nearby SN Ia measurements. A new feature in our analysis is the use of detailed Monte Carlo simulations of all surveys to account for selection biases, including those from spectroscopic targeting. Combining the SN Hubble diagram with measurements of baryon acoustic oscillations from the SDSS Luminous Red Galaxy sample and with cosmic microwave background temperature anisotropy measurements from the Wilkinson Microwave Anisotropy Probe, we estimate the cosmological parameters w and ΩM, assuming a spatially flat cosmological model (FwCDM) with constant dark energy equation of state parameter, w. We also consider constraints upon ΩM and ΩΛ for a cosmological constant model (ΛCDM) with w = –1 and non-zero spatial curvature. For the FwCDM model and the combined sample of 288 SNe Ia, we find w = –0.76 ± 0.07(stat) ± 0.11(syst), ΩM = 0.307 ± 0.019(stat) ± 0.023(syst) using MLCS2K2 and w = –0.96 ± 0.06(stat) ± 0.12(syst), ΩM = 0.265 ± 0.016(stat) ± 0.025(syst) using the SALT-II fitter. We trace the discrepancy between these results to a difference in the rest-frame UV model combined with a different luminosity correction from color variations; these differences mostly affect the distance estimates for the SNLS and HST SNe. We present detailed discussions of systematic errors for both light-curve methods and find that they both show data-model discrepancies in rest-frame U band. For the SALT-II approach, we also see strong evidence for redshift-dependence of the color-luminosity parameter (β). Restricting the analysis to the 136 SNe Ia in the Nearby+SDSS-II samples, we find much better agreement between the two analysis methods but with larger uncertainties: w = –0.92 ± 0.13(stat)+0.10 –0.33(syst) for MLCS2K2 and w = –0.92 ± 0.11(stat)+0.07 –0.15 (syst) for SALT-II.

Journal ArticleDOI
Inga Prokopenko1, Claudia Langenberg2, Jose C. Florez3, Jose C. Florez4, Richa Saxena3, Richa Saxena4, Nicole Soranzo5, Nicole Soranzo6, Gudmar Thorleifsson7, Ruth J. F. Loos2, Alisa K. Manning8, Anne U. Jackson9, Yurii S. Aulchenko10, Simon C. Potter6, Michael R. Erdos11, Serena Sanna, Jouke-Jan Hottenga12, Eleanor Wheeler6, Marika Kaakinen13, Valeriya Lyssenko14, Wei-Min Chen15, Kourosh R. Ahmadi5, Jacques S. Beckmann16, Jacques S. Beckmann17, Richard N. Bergman18, Murielle Bochud16, Lori L. Bonnycastle11, Thomas A. Buchanan18, Antonio Cao, Alessandra C. L. Cervino5, Lachlan J. M. Coin19, Francis S. Collins11, Laura Crisponi, Eco J. C. de Geus12, Abbas Dehghan10, Panos Deloukas6, Alex S. F. Doney20, Paul Elliott19, Nelson B. Freimer21, Vesela Gateva9, Christian Herder22, Albert Hofman10, Thomas Edward Hughes23, Sarah E. Hunt6, Thomas Illig, Michael Inouye6, Bo Isomaa, Toby Johnson17, Toby Johnson24, Toby Johnson16, Augustine Kong7, Maria Krestyaninova25, Johanna Kuusisto26, Markku Laakso26, Noha Lim27, Ulf Lindblad14, Cecilia M. Lindgren1, O. T. McCann6, Karen L. Mohlke28, Andrew D. Morris20, Silvia Naitza, Marco Orru, Colin N. A. Palmer20, Anneli Pouta29, Joshua C. Randall1, Wolfgang Rathmann22, Jouko Saramies, Paul Scheet9, Laura J. Scott9, Angelo Scuteri11, Stephen J. Sharp2, Eric J.G. Sijbrands10, Jan H. Smit30, Kijoung Song27, Valgerdur Steinthorsdottir7, Heather M. Stringham9, Tiinamaija Tuomi31, Jaakko Tuomilehto, André G. Uitterlinden10, Benjamin F. Voight3, Benjamin F. Voight4, Dawn M. Waterworth27, H-Erich Wichmann32, Gonneke Willemsen12, Jacqueline C.M. Witteman10, Xin Yuan27, Jing Hua Zhao2, Eleftheria Zeggini1, David Schlessinger11, Manjinder S. Sandhu33, Manjinder S. Sandhu2, Dorret I. Boomsma12, Manuela Uda, Tim D. Spector5, Brenda W.J.H. Penninx34, Brenda W.J.H. Penninx33, Brenda W.J.H. Penninx35, David Altshuler3, David Altshuler4, Peter Vollenweider16, Marjo-Riitta Järvelin19, Marjo-Riitta Järvelin13, Edward G. Lakatta11, Gérard Waeber16, Caroline S. Fox11, Caroline S. Fox36, Leena Peltonen37, Leena Peltonen6, Leif Groop14, Vincent Mooser27, L. Adrienne Cupples8, Unnur Thorsteinsdottir38, Unnur Thorsteinsdottir7, Michael Boehnke9, Inês Barroso6, Cornelia M. van Duijn10, Josée Dupuis8, Richard M. Watanabe18, Kari Stefansson38, Kari Stefansson7, Mark I. McCarthy39, Mark I. McCarthy1, Nicholas J. Wareham2, James B. Meigs4, Gonçalo R. Abecasis9 
TL;DR: Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten genome-wide association scans, and previous associations of fasting glucose with variants at the G6PC2 and GCK loci are confirmed.
Abstract: To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06-0.08) mmol/l in fasting glucose levels (P = 3.2 x 10(-50)) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 x 10(-15)). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05-1.12), per G allele P = 3.3 x 10(-7)) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 x 10(-57)) and GCK (rs4607517, P = 1.0 x 10(-25)) loci.

Journal ArticleDOI
17 Apr 2009-Cell
TL;DR: It is shown that the nuclear architecture of rod photoreceptor cells differs fundamentally in nocturnal and diurnal mammals and suggests that the conventional architecture prevails in eukaryotic nuclei because it results in more flexible chromosome arrangements, facilitating positional regulation of nuclear functions.