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Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits (2013)

Joshua C. Randall Thomas W. Winkler Zoltán Kutalik Sonja I. Berndt Anne U. Jackson Keri L. Monda Tuomas O. Kilpeläinen Tõnu Esko Reedik Mägi Shengxu Li Tsegaselassie Workalemahu Mary F. Feitosa Damien C. Croteau-Chonka Felix R. Day Tove Fall Teresa Ferreira Stefan Gustafsson Adam E. Locke Iain Mathieson Andre Scherag Sailaja Vedantam Andrew R. Wood Liming Liang Valgerdur Steinthorsdottir Gudmar Thorleifsson Emmanouil T. Dermitzakis Antigone S. Dimas Fredrik Karpe Josine L. Min George Nicholson Deborah J. Clegg Thomas Person Jon P. Krohn Sabrina Bauer Christa Buechler Kristina Eisinger DIAGRAM Consortium Amélie Bonnefond Philippe Froguel MAGIC Investigators Jouke-Jan Hottenga Inga Prokopenko Lindsay L. Waite Tamara B. Harris Albert Vernon Smith Alan R. Shuldiner Wendy L. McArdle Mark J. Caulfield Patricia B. Munroe Henrik Grönberg Yii-Der Ida Chen Guo Li Jacques S. Beckmann Toby Johnson Unnur Thorsteinsdottir Maris Teder-Laving Kay-Tee Khaw Nicholas J. Wareham Jing Hua Zhao Najaf Amin Ben A. Oostra Aldi T. Kraja Michael A. Province L. Adrienne Cupples Nancy L. Heard-Costa Jaakko Kaprio Samuli Ripatti Ida Surakka Francis S. Collins Jouko Saramies Jaakko Tuomilehto Antti Jula Veikko Salomaa Jeanette Erdmann Christian Hengstenberg Christina Loley Heribert Schunkert Claudia Lamina H. Erich Wichmann Eva Albrecht Christian Gieger Andrew A. Hicks Åsa Johansson Peter P. Pramstaller Sekar Kathiresan Elizabeth K. Speliotes Brenda Penninx Anna-Liisa Hartikainen Marjo-Riitta Jarvelin Ulf Gyllensten Dorret I. Boomsma Harry Campbell James F. Wilson Stephen J. Chanock Martin Farrall Anuj Goel Carolina Medina-Gomez Fernando Rivadeneira Karol Estrada André G. Uitterlinden Albert Hofman M. Carola Zillikens Martin den Heijer Lambertus A. Kiemeney Andrea Maschio Per Hall Jonathan Tyrer Alexander Teumer Henry Völzke Peter Kovacs Anke Tönjes Massimo Mangino Tim D. Spector Caroline Hayward Igor Rudan Alistair S. Hall Nilesh J. Samani Antony Paul Attwood Jennifer G. Sambrook Joseph Hung Lyle J. Palmer Marja-Liisa Lokki Juha Sinisalo Gabrielle Boucher Heikki Huikuri Mattias Lorentzon Claes Ohlsson Niina Eklund Johan G. Eriksson Cristina Barlassina Carlo Rivolta Ilja M. Nolte Harold Snieder Melanie M. van der Klauw Jana V. van Vliet-Ostaptchouk Pablo V. Gejman Jianxin Shi Kevin B. Jacobs Zhaoming Wang Stephan J. L. Bakker Irene Mateo Leach Gerjan Navis Pim van der Harst Nicholas G. Martin Sarah E. Medland Grant W. Montgomery Jian Yang Daniel I. Chasman Paul M. Ridker Lynda M. Rose Terho Lehtimäki Olli Raitakari Devin Absher Carlos Iribarren Hanneke Basart Kees G. Hovingh Elina Hyppönen Chris Power Chris Power Denise Anderson John P. Beilby Jennie Hui Jennifer Jolley Hendrik Sager Stefan R. Bornstein Peter E. H. Schwarz Kati Kristiansson Markus Perola Jaana Lindström Amy J. Swift Matti Uusitupa Mustafa Atalay Timo A. Lakka Rainer Rauramaa Jennifer L. Bolton Gerry Fowkes Ross M. Fraser Jackie F. Price Krista Fischer Kaarel KrjutÅ¡kov Andres Metspalu Evelin Mihailov Claudia Langenberg Jian'an Luan Ken K. Ong Peter S. Chines Sirkka M. Keinanen-Kiukaanniemi Timo E. Saaristo Sarah Edkins Paul W. Franks Göran Hallmans Dmitry Shungin Andrew David Morris Colin N. A. Palmer Raimund Erbel Susanne Moebus Markus M. Nöthen Sonali Pechlivanis Kristian Hveem Narisu Narisu Anders Hamsten Steve E. Humphries Rona J. Strawbridge Elena Tremoli Harald Grallert Barbara Thorand Thomas Illig Wolfgang Koenig Martina Müller-Nurasyid Annette Peters Bernhard O. Boehm Marcus E. Kleber Winfried März Bernhard R. Winkelmann Johanna Kuusisto Markku Laakso Dominique Arveiler Giancarlo Cesana Kari Kuulasmaa Jarmo Virtamo John W. G. Yarnell Diana Kuh Andrew Wong Lars Lind Ulf de Faire Bruna Gigante Patrik K. E. Magnusson Nancy L. Pedersen George Dedoussis Maria Dimitriou Genovefa Kolovou Stavroula Kanoni Kathleen Stirrups Lori L. Bonnycastle Inger Njølstad Tom Wilsgaard Andrea Ganna Emil Rehnberg Aroon Hingorani Mika Kivimaki Meena Kumari Themistocles L. Assimes Inês Barroso Michael Boehnke Ingrid B. Borecki Panos Deloukas Caroline S. Fox Timothy Frayling Leif C. Groop Talin Haritunians David Hunter Erik Ingelsson Robert Kaplan Karen L. Mohlke Jeffrey R. O'Connell Kari E. North Cecilia M. Lindgren Ruth J. F. Loos Lu Qi Joel N. Hirschhorn Gonçalo R. Abecasis Cornelia M. van Duijn Kari Stefansson David P. Strachan David Schlessinger Iris M. Heid Mark I. McCarthy

Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.

Are V1 Simple Cells Optimized for Visual Occlusions? A Comparative Study (2013)

Jörg Bornschein Marc Henniges Jörg Lücke

Abstract: Simple cells in primary visual cortex were famously found to respond to low-level image components such as edges. Sparse coding and independent component analysis (ICA) emerged as the standard computational models for simple cell coding because they linked their receptive fields to the statistics of visual stimuli. However, a salient feature of image statistics, occlusions of image components, is not considered by these models. Here we ask if occlusions have an effect on the predicted shapes of simple cell receptive fields. We use a comparative approach to answer this question and investigate two models for simple cells: a standard linear model and an occlusive model. For both models we simultaneously estimate optimal receptive fields, sparsity and stimulus noise. The two models are identical except for their component superposition assumption. We find the image encoding and receptive fields predicted by the models to differ significantly. While both models predict many Gabor-like fields, the occlusive model predicts a much sparser encoding and high percentages of ‘globular’ receptive fields. This relatively new center-surround type of simple cell response is observed since reverse correlation is used in experimental studies. While high percentages of ‘globular’ fields can be obtained using specific choices of sparsity and overcompleteness in linear sparse coding, no or only low proportions are reported in the vast majority of studies on linear models (including all ICA models). Likewise, for the here investigated linear model and optimal sparsity, only low proportions of ‘globular’ fields are observed. In comparison, the occlusive model robustly infers high proportions and can match the experimentally observed high proportions of ‘globular’ fields well. Our computational study, therefore, suggests that ‘globular’ fields may be evidence for an optimal encoding of visual occlusions in primary visual cortex. Author Summary: The statistics of our visual world is dominated by occlusions. Almost every image processed by our brain consists of mutually occluding objects, animals and plants. Our visual cortex is optimized through evolution and throughout our lifespan for such stimuli. Yet, the standard computational models of primary visual processing do not consider occlusions. In this study, we ask what effects visual occlusions may have on predicted response properties of simple cells which are the first cortical processing units for images. Our results suggest that recently observed differences between experiments and predictions of the standard simple cell models can be attributed to occlusions. The most significant consequence of occlusions is the prediction of many cells sensitive to center-surround stimuli. Experimentally, large quantities of such cells are observed since new techniques (reverse correlation) are used. Without occlusions, they are only obtained for specific settings and none of the seminal studies (sparse coding, ICA) predicted such fields. In contrast, the new type of response naturally emerges as soon as occlusions are considered. In comparison with recent in vivo experiments we find that occlusive models are consistent with the high percentages of center-surround simple cells observed in macaque monkeys, ferrets and mice.

BACL Is a Novel Brain-Associated, Non-NKC-Encoded Mammalian C-Type Lectin-Like Receptor of the CLEC2 Family (2013)

Olga Lysenko Dorothea Schulte Michel Mittelbronn Alexander Steinle

Natural Killer Gene Complex (NKC)–encoded C-type lectin-like receptors (CTLRs) are expressed on various immune cells including T cells, NK cells and myeloid cells and thereby contribute to the orchestration of cellular immune responses. Some NKC-encoded CTLRs are grouped into the C-type lectin family 2 (CLEC2 family) and interact with genetically linked CTLRs of the NKRP1 family. While many CLEC2 family members are expressed by hematopoietic cells (e.g. CD69 (CLEC2C)), others such as the keratinocyte-associated KACL (CLEC2A) are specifically expressed by other tissues. Here we provide the first characterization of the orphan gene CLEC2L. In contrast to other CLEC2 family members, CLEC2L is conserved among mammals and located outside of the NKC. We show that CLEC2L-encoded CTLRs are expressed as non-glycosylated, disulfide-linked homodimers at the cell surface. CLEC2L expression is fairly tissue-restricted with a predominant expression in the brain. Thus CLEC2L-encoded CTLRs were designated BACL (brain-associated C-type lectin). Combining in situ hybridization and immunohistochemistry, we show that BACL is expressed by neurons in the CNS, with a pronounced expression by Purkinje cells. Notably, the CLEC2L locus is adjacent to another orphan CTLR gene (KLRG2), but reporter cell assays did neither indicate interaction of BACL with the KLRG2 ectodomain nor with human NK cell lines or lymphocytes. Along these lines, growth of BACL-expressing tumor cell lines in immunocompetent mice did not provide evidence for an immune-related function of BACL. Altogether, the CLEC2L gene encodes a homodimeric cell surface CTLR that stands out among CLEC2 family members by its conservation in mammals, its biochemical properties and the predominant expression in the brain. Future studies will have to reveal insights into the functional relevance of BACL in the context of its neuronal expression.

Postoperative Neurocognitive Dysfunction in Patients Undergoing Cardiac Surgery after Remote Ischemic Preconditioning: A Double-Blind Randomized Controlled Pilot Study (2013)

Patrick Meybohm Jochen Renner Ole Broch Dorothee Caliebe Martin Albrecht Jochen Cremer Nils Haake Jens Scholz Kai Zacharowski Berthold Bein

Background: Remote ischemic preconditioning (RIPC) has been shown to enhance the tolerance of remote organs to cope with a subsequent ischemic event. We hypothesized that RIPC reduces postoperative neurocognitive dysfunction (POCD) in patients undergoing complex cardiac surgery. Methods: We conducted a prospective, randomized, double-blind, controlled trial including 180 adult patients undergoing elective cardiac surgery with cardiopulmonary bypass. Patients were randomized either to RIPC or to control group. Primary endpoint was postoperative neurocognitive dysfunction 5–7 days after surgery assessed by a comprehensive test battery. Cognitive change was assumed if the preoperative to postoperative difference in 2 or more tasks assessing different cognitive domains exceeded more than one SD (1 SD criterion) or if the combined Z score was 1.96 or greater (Z score criterion). Results: According to 1 SD criterion, 52% of control and 46% of RIPC patients had cognitive deterioration 5–7 days after surgery (p = 0.753). The summarized Z score showed a trend to more cognitive decline in the control group (2.16±5.30) compared to the RIPC group (1.14±4.02; p = 0.228). Three months after surgery, incidence and severity of neurocognitive dysfunction did not differ between control and RIPC. RIPC tended to decrease postoperative troponin T release at both 12 hours [0.60 (0.19–1.94) µg/L vs. 0.48 (0.07–1.84) µg/L] and 24 hours after surgery [0.36 (0.14–1.89) µg/L vs. 0.26 (0.07–0.90) µg/L]. Conclusions: We failed to demonstrate efficacy of a RIPC protocol with respect to incidence and severity of POCD and secondary outcome variables in patients undergoing a wide range of cardiac surgery. Therefore, definitive large-scale multicenter trials are needed. Trial Registration: ClinicalTrials.gov NCT00877305

Robust Automated Detection of Microstructural White Matter Degeneration in Alzheimer’s Disease Using Machine Learning Classification of Multicenter DTI Data (2013)

Martin Dyrba Michael Ewers Martin Wegrzyn Ingo Kilimann Claudia Plant Annahita Oswald Thomas Meindl Michela Pievani Arun L. W. Bokde Andreas Fellgiebel Massimo Filippi Harald Hampel Stefan Klöppel Karlheinz Hauenstein Thomas Kirste Stefan J. Teipel

Diffusion tensor imaging (DTI) based assessment of white matter fiber tract integrity can support the diagnosis of Alzheimer’s disease (AD). The use of DTI as a biomarker, however, depends on its applicability in a multicenter setting accounting for effects of different MRI scanners. We applied multivariate machine learning (ML) to a large multicenter sample from the recently created framework of the European DTI study on Dementia (EDSD). We hypothesized that ML approaches may amend effects of multicenter acquisition. We included a sample of 137 patients with clinically probable AD (MMSE 20.6±5.3) and 143 healthy elderly controls, scanned in nine different scanners. For diagnostic classification we used the DTI indices fractional anisotropy (FA) and mean diffusivity (MD) and, for comparison, gray matter and white matter density maps from anatomical MRI. Data were classified using a Support Vector Machine (SVM) and a Naïve Bayes (NB) classifier. We used two cross-validation approaches, (i) test and training samples randomly drawn from the entire data set (pooled cross-validation) and (ii) data from each scanner as test set, and the data from the remaining scanners as training set (scanner-specific cross-validation). In the pooled cross-validation, SVM achieved an accuracy of 80% for FA and 83% for MD. Accuracies for NB were significantly lower, ranging between 68% and 75%. Removing variance components arising from scanners using principal component analysis did not significantly change the classification results for both classifiers. For the scanner-specific cross-validation, the classification accuracy was reduced for both SVM and NB. After mean correction, classification accuracy reached a level comparable to the results obtained from the pooled cross-validation. Our findings support the notion that machine learning classification allows robust classification of DTI data sets arising from multiple scanners, even if a new data set comes from a scanner that was not part of the training sample.

Sustainable consumption: towards action and impact. : International scientific conference November 6th-8th 2011, Hamburg - European Green Capital 2011, Germany: abstract volume (2011)

This volume contains the abstracts of all oral and poster presentations of the international scientific conference „Sustainable Consumption – Towards Action and Impact“ held in Hamburg (Germany) on November 6th-8th 2011. This unique conference aims to promote a comprehensive academic discourse on issues concerning sustainable consumption and brings together scholars from a wide range of academic disciplines.

Nonthermal phase transitions in semiconductors induced by a femtosecond extreme ultraviolet laser pulse (2013)

Nikita Medvedev Harald O. Jeschke Beata Ziaja

Part of Focus on High Energy Density Physics. In this paper, we present a novel theoretical approach, which allows the study of nonequilibrium dynamics of both electrons and atoms/ions within free-electron laser excited semiconductors at femtosecond time scales. The approach consists of the Monte-Carlo method treating photoabsorption, high-energy-electron and core-hole kinetics and relaxation processes. Low-energy electrons localized within the valence and conduction bands of the target are treated with a temperature equation, including source terms, defined by the exchange of energy and particles with high-energy electrons and atoms. We follow the atomic motion with the molecular dynamics method on the changing potential energy surface. The changes of the potential energy surface and of the electron band structure are calculated at each time step with the help of the tight-binding method. Such a combination of methods enables investigation of nonequilibrium structural changes within materials under extreme ultraviolet (XUV) femtosecond irradiation. Our analysis performed for diamond irradiated with an XUV femtosecond laser pulse predicts for the first time in this wavelength regime the nonthermal phase transition from diamond to graphite. Similar to the case of visible light irradiation, this transition takes place within a few tens of femtoseconds and is caused by changes of the interatomic potential induced by ultrafast electronic excitations. It thus occurs well before the heating stimulated by electron–phonon coupling starts to play a role. This allows us to conclude that this transition is nonthermal and represents a general mechanism of the response of solids to ultrafast electron excitations.

Integer point sets minimizing average pairwise L1 distance: What is the optimal shape of a town? (2010)

Erik D. Demaine Sándor P. Fekete Günter Rote Nils Schweer Daria Schymura Mariano Zelke

An n-town, n[is an element of]N , is a group of n buildings, each occupying a distinct position on a 2-dimensional integer grid. If we measure the distance between two buildings along the axis-parallel street grid, then an n-town has optimal shape if the sum of all pairwise Manhattan distances is minimized. This problem has been studied for cities, i.e., the limiting case of very large n. For cities, it is known that the optimal shape can be described by a differential equation, for which no closed-form solution is known. We show that optimal n-towns can be computed in O(n[superscript 7.5]) time. This is also practically useful, as it allows us to compute optimal solutions up to n=80.

CAST constraints on the axion-electron coupling (2013)

Klaus Barth Alexander Belov Berta Beltran Heinrich Bräuninger José Manuel Carmona Juan I. Collar Theopisti Dafni Martyn Davenport Luigi Di Lella Christos Eleftheriadis Jakob Englhauser George Fanourakis Ester Ferrer-Ribas Horst Fischer Jürgen Franz Peter Friedrich Javier Galán J. A. García Theodoros Geralis Ioanis Giomataris Sergei Gninenko Héctor Gómez Michael D. Hasinoff Fritz Herbert Heinsius Dieter H.H. Hoffmann Igor Garcia Irastorza Joachim Jacoby Kresimir Jakovčić Donghwa Kang Kay Königsmann Rainer Kotthaus Konstantinos Kousouris Milica Krčmar M. Kuster Biljana Lakić Anastasios Liolios Ante Ljubičić Gerhard Lutz Gloria Luzón David W. Miller Thomas Papaevangelou Mike J. Pivovaroff Georg Raffelt Javier Redondo Hans Riege A. Rodríguez Jaime Ruz Ilias Savvidis Yannis Semertzidis Laura Stewart Karl van Bibber Joaquin D. Vieira José A. Villar Julia K. Vogel Louis Walckiers Konstantin Zioutas

In non-hadronic axion models, which have a tree-level axion-electron interaction, the Sun produces a strong axion flux by bremsstrahlung, Compton scattering, and axiorecombination, the “BCA processes.” Based on a new calculation of this flux, including for the first time axio-recombination, we derive limits on the axion-electron Yukawa coupling gae and axion-photon interaction strength ga using the CAST phase-I data (vacuum phase). For ma <~ 10 meV/c2 we find ga gae < 8.1 × 10−23 GeV−1 at 95% CL. We stress that a next-generation axion helioscope such as the proposed IAXO could push this sensitivity into a range beyond stellar energy-loss limits and test the hypothesis that white-dwarf cooling is dominated by axion emission.

4-Nitrophenyl 2-chlorobenzoate (2012)

Asma Iqbal Toheed Akhter Humaira Masood Siddiqi Zareen Akhter Michael Bolte

The aromatic rings in the title compound, C13H8ClNO4, enclose a dihedral angle of 39.53 (3)°. The nitro group is almost coplanar with the ring to which it is attached [dihedral angle = 4.31 (1)°]. In the crystal, molecules are connected by C-H...O hydrogen bonds into chains running along [001]. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 A°; R factor = 0.044; wR factor = 0.105; data-to-parameter ratio = 18.9.

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