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Showing papers by "Trinity College, Dublin published in 2009"


Journal ArticleDOI
TL;DR: An Explanation and Elaboration of the PRISMA Statement is presented and updated guidelines for the reporting of systematic reviews and meta-analyses are presented.
Abstract: Systematic reviews and meta-analyses are essential to summarize evidence relating to efficacy and safety of health care interventions accurately and reliably. The clarity and transparency of these reports, however, is not optimal. Poor reporting of systematic reviews diminishes their value to clinicians, policy makers, and other users. Since the development of the QUOROM (QUality Of Reporting Of Meta-analysis) Statement—a reporting guideline published in 1999—there have been several conceptual, methodological, and practical advances regarding the conduct and reporting of systematic reviews and meta-analyses. Also, reviews of published systematic reviews have found that key information about these studies is often poorly reported. Realizing these issues, an international group that included experienced authors and methodologists developed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) as an evolution of the original QUOROM guideline for systematic reviews and meta-analyses of evaluations of health care interventions. The PRISMA Statement consists of a 27-item checklist and a four-phase flow diagram. The checklist includes items deemed essential for transparent reporting of a systematic review. In this Explanation and Elaboration document, we explain the meaning and rationale for each checklist item. For each item, we include an example of good reporting and, where possible, references to relevant empirical studies and methodological literature. The PRISMA Statement, this document, and the associated Web site (http://www.prisma-statement.org/) should be helpful resources to improve reporting of systematic reviews and meta-analyses.

25,711 citations


Journal ArticleDOI
TL;DR: This Explanation and Elaboration document explains the meaning and rationale for each checklist item and includes an example of good reporting and, where possible, references to relevant empirical studies and methodological literature.

8,021 citations


Journal ArticleDOI
Shaun Purcell1, Shaun Purcell2, Naomi R. Wray3, Jennifer Stone2, Jennifer Stone1, Peter M. Visscher, Michael Conlon O'Donovan4, Patrick F. Sullivan5, Pamela Sklar2, Pamela Sklar1, Douglas M. Ruderfer, Andrew McQuillin, Derek W. Morris6, Colm O'Dushlaine6, Aiden Corvin6, Peter Holmans4, Stuart MacGregor3, Hugh Gurling, Douglas Blackwood7, Nicholas John Craddock5, Michael Gill6, Christina M. Hultman8, Christina M. Hultman9, George Kirov4, Paul Lichtenstein8, Walter J. Muir7, Michael John Owen4, Carlos N. Pato10, Edward M. Scolnick1, Edward M. Scolnick2, David St Clair, Nigel Williams4, Lyudmila Georgieva4, Ivan Nikolov4, Nadine Norton4, Hywel Williams4, Draga Toncheva, Vihra Milanova, Emma Flordal Thelander8, Patrick Sullivan11, Elaine Kenny6, Emma M. Quinn6, Khalid Choudhury12, Susmita Datta12, Jonathan Pimm12, Srinivasa Thirumalai13, Vinay Puri12, Robert Krasucki12, Jacob Lawrence12, Digby Quested14, Nicholas Bass12, Caroline Crombie15, Gillian Fraser15, Soh Leh Kuan, Nicholas Walker, Kevin A. McGhee7, Ben S. Pickard16, P. Malloy7, Alan W Maclean7, Margaret Van Beck7, Michele T. Pato10, Helena Medeiros10, Frank A. Middleton17, Célia Barreto Carvalho10, Christopher P. Morley17, Ayman H. Fanous, David V. Conti10, James A. Knowles10, Carlos Ferreira, António Macedo18, M. Helena Azevedo18, Andrew Kirby2, Andrew Kirby1, Manuel A. R. Ferreira1, Manuel A. R. Ferreira2, Mark J. Daly2, Mark J. Daly1, Kimberly Chambert1, Finny G Kuruvilla1, Stacey Gabriel1, Kristin G. Ardlie1, Jennifer L. Moran1 
06 Aug 2009-Nature
TL;DR: The extent to which common genetic variation underlies the risk of schizophrenia is shown, using two analytic approaches, and the major histocompatibility complex is implicate, which is shown to involve thousands of common alleles of very small effect.
Abstract: Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%(1,2). We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.

4,573 citations


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
Lorenzo Galluzzi1, Lorenzo Galluzzi2, Lorenzo Galluzzi3, Stuart A. Aaronson4, John M. Abrams5, Emad S. Alnemri6, David W. Andrews7, Eric H. Baehrecke8, Nicolas G. Bazan9, Mikhail V. Blagosklonny10, Klas Blomgren11, Klas Blomgren12, Christoph Borner13, Dale E. Bredesen14, Dale E. Bredesen15, Catherine Brenner16, Maria Castedo2, Maria Castedo3, Maria Castedo1, John A. Cidlowski17, Aaron Ciechanover18, Gerald M. Cohen19, V De Laurenzi20, R De Maria21, Mohanish Deshmukh22, Brian David Dynlacht23, Wafik S. El-Deiry24, Richard A. Flavell25, Richard A. Flavell26, Simone Fulda27, Carmen Garrido28, Carmen Garrido3, Pierre Golstein16, Pierre Golstein3, Pierre Golstein29, Marie-Lise Gougeon30, Douglas R. Green, Hinrich Gronemeyer16, Hinrich Gronemeyer3, Hinrich Gronemeyer31, György Hajnóczky6, J. M. Hardwick32, Michael O. Hengartner33, Hidenori Ichijo34, Marja Jäättelä, Oliver Kepp1, Oliver Kepp2, Oliver Kepp3, Adi Kimchi35, Daniel J. Klionsky36, Richard A. Knight37, Sally Kornbluth38, Sharad Kumar, Beth Levine5, Beth Levine26, Stuart A. Lipton, Enrico Lugli17, Frank Madeo39, Walter Malorni21, Jean-Christophe Marine40, Seamus J. Martin41, Jan Paul Medema42, Patrick Mehlen16, Patrick Mehlen43, Gerry Melino19, Gerry Melino44, Ute M. Moll45, Ute M. Moll46, Eugenia Morselli2, Eugenia Morselli3, Eugenia Morselli1, Shigekazu Nagata47, Donald W. Nicholson48, Pierluigi Nicotera19, Gabriel Núñez36, Moshe Oren35, Josef M. Penninger49, Shazib Pervaiz50, Marcus E. Peter51, Mauro Piacentini44, Jochen H. M. Prehn52, Hamsa Puthalakath53, Gabriel A. Rabinovich54, Rosario Rizzuto55, Cecília M. P. Rodrigues56, David C. Rubinsztein57, Thomas Rudel58, Luca Scorrano59, Hans-Uwe Simon60, Hermann Steller26, Hermann Steller61, J. Tschopp62, Yoshihide Tsujimoto63, Peter Vandenabeele64, Ilio Vitale2, Ilio Vitale3, Ilio Vitale1, Karen H. Vousden65, Richard J. Youle17, Junying Yuan66, Boris Zhivotovsky67, Guido Kroemer3, Guido Kroemer1, Guido Kroemer2 
Institut Gustave Roussy1, University of Paris-Sud2, French Institute of Health and Medical Research3, Icahn School of Medicine at Mount Sinai4, University of Texas Southwestern Medical Center5, Thomas Jefferson University6, McMaster University7, University of Massachusetts Medical School8, LSU Health Sciences Center New Orleans9, Roswell Park Cancer Institute10, Boston Children's Hospital11, University of Gothenburg12, University of Freiburg13, Buck Institute for Research on Aging14, University of California, San Francisco15, Centre national de la recherche scientifique16, National Institutes of Health17, Technion – Israel Institute of Technology18, University of Leicester19, University of Chieti-Pescara20, Istituto Superiore di Sanità21, University of North Carolina at Chapel Hill22, New York University23, University of Pennsylvania24, Yale University25, Howard Hughes Medical Institute26, University of Ulm27, University of Burgundy28, Aix-Marseille University29, Pasteur Institute30, University of Strasbourg31, Johns Hopkins University32, University of Zurich33, University of Tokyo34, Weizmann Institute of Science35, University of Michigan36, University College London37, Duke University38, University of Graz39, Ghent University40, Trinity College, Dublin41, University of Amsterdam42, University of Lyon43, University of Rome Tor Vergata44, Stony Brook University45, University of Göttingen46, Kyoto University47, Merck & Co.48, Austrian Academy of Sciences49, National University of Singapore50, University of Chicago51, Royal College of Surgeons in Ireland52, La Trobe University53, University of Buenos Aires54, University of Padua55, University of Lisbon56, University of Cambridge57, University of Würzburg58, University of Geneva59, University of Bern60, Rockefeller University61, University of Lausanne62, Osaka University63, University of California, San Diego64, University of Glasgow65, Harvard University66, Karolinska Institutet67
TL;DR: A nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls is provided and the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells is emphasized.
Abstract: Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios Thus far, dozens of methods have been proposed to quantify cell death-related parameters However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells

2,218 citations


Journal ArticleDOI
TL;DR: A method to disperse and exfoliate graphite to give graphene suspended in water-surfactant solutions and suggests the flakes to be largely free of defects and oxides, although X-ray photoelectron spectroscopy shows evidence of a small oxide population.
Abstract: We have demonstrated a method to disperse and exfoliate graphite to give graphene suspended in water−surfactant solutions. Optical characterization of these suspensions allowed the partial optimization of the dispersion process. Transmission electron microscopy showed the dispersed phase to consist of small graphitic flakes. More than 40% of these flakes had <5 layers with ∼3% of flakes consisting of monolayers. Atomic resolution transmission electron microscopy shows the monolayers to be generally free of defects. The dispersed graphitic flakes are stabilized against reaggregation by Coulomb repulsion due to the adsorbed surfactant. We use DLVO and Hamaker theory to describe this stabilization. However, the larger flakes tend to sediment out over ∼6 weeks, leaving only small flakes dispersed. It is possible to form thin films by vacuum filtration of these dispersions. Raman and IR spectroscopic analysis of these films suggests the flakes to be largely free of defects and oxides, although X-ray photoelect...

2,086 citations


Journal ArticleDOI
24 Jun 2009-ACS Nano
TL;DR: These nanowire films are electromechanically very robust, with all but the thinnest films showing no change in sheet resistance when flexed over >1000 cycles, which makes these films ideal as replacements for indium tin oxide as transparent electrodes.
Abstract: We have used aqueous dispersions of silver nanowires to prepare thin, flexible, transparent, conducting films. The nanowires are of length and diameter close to 6.5 μm and 85 nm, respectively. At low thickness, the films consist of networks but appear to become bulk-like for mean film thicknesses above ∼160 nm. These films can be very transparent with optical transmittance reaching as high as 92% for low thickness. The transmittance (550 nm) decreases with increasing thickness, consistent with an optical conductivity of 6472 S/m. The films are also very uniform; the transmittance varies spatially by typically <2%. The sheet resistance decreases with increasing thickness, falling below 1 Ω/◻ for thicknesses above 300 nm. The DC conductivity increases from 2 × 105 S/m for very thin films before saturating at 5 × 106 S/m for thicker films. Similarly, the ratio of DC to optical conductivity increases with increasing thickness from 25 for the thinnest films, saturating at ∼500 for thicknesses above ∼160 nm. We...

1,530 citations


Journal ArticleDOI
21 Aug 2009-Immunity
TL;DR: It is shown that gammadelta T cells express IL-23R and the transcription factor RORgammat and produce IL-17, IL-21, and IL-22 in response to IL-1beta andIL-23, without T cell receptor engagement.

1,410 citations


Journal ArticleDOI
TL;DR: In this paper, the authors investigated the relationship between stocks, bonds and gold and found that gold is a hedge against stocks on average and a safe haven in extreme stock market conditions.
Abstract: Is gold a hedge against sudden changes in stock and bond returns, or does it instead have a subtly different property, that of being a safe haven? This paper addresses these two interlinked questions. A safe haven is defined as a security that is uncorrelated with stocks and bonds in case of a market crash. This is counterpoised against a hedge, defined as a security that is uncorrelated with stocks or bonds on average. We study constant and time-varying relationships between stocks, bonds and gold in order to investigate the existence of a hedge and a safe haven. The empirical analysis examines US, UK and German stock and bond returns and their relationship with gold returns. We find that gold is a hedge against stocks on average and a safe haven in extreme stock market conditions. This finding suggests that the existence of a safe haven enhances the stability and resiliency of financial markets since it reduces investors' losses at times when a reduction is needed the most. A portfolio analysis further shows that the safe haven property is extremely short-lived so that an investor buying gold one day after a shock loses money.

1,255 citations


Journal ArticleDOI
24 Apr 2009-Science
TL;DR: To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage and provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.
Abstract: To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.

1,144 citations


Journal ArticleDOI
13 Nov 2009-Science
TL;DR: Electric field–dependent studies show that a tetragonal-like phase can be reversibly converted into a rhombohedral- like phase, accompanied by measurable displacements of the surface, making this new lead-free system of interest for probe-based data storage and actuator applications.
Abstract: Piezoelectric materials, which convert mechanical to electrical energy and vice versa, are typically characterized by the intimate coexistence of two phases across a morphotropic phase boundary. Electrically switching one to the other yields large electromechanical coupling coefficients. Driven by global environmental concerns, there is currently a strong push to discover practical lead-free piezoelectrics for device engineering. Using a combination of epitaxial growth techniques in conjunction with theoretical approaches, we show the formation of a morphotropic phase boundary through epitaxial constraint in lead-free piezoelectric bismuth ferrite (BiFeO3) films. Electric field-dependent studies show that a tetragonal-like phase can be reversibly converted into a rhombohedral-like phase, accompanied by measurable displacements of the surface, making this new lead-free system of interest for probe-based data storage and actuator applications.

Journal ArticleDOI
TL;DR: In this article, the authors prove that the nonlinear dispersive partial differential equations (NPDPDE) and Korteweg-de Vries (KDE) arise in the modeling of the propagation of shallow water waves over a flat bed.
Abstract: In recent years two nonlinear dispersive partial differential equations have attracted a lot of attention due to their integrable structure. We prove that both equations arise in the modeling of the propagation of shallow water waves over a flat bed. The equations capture stronger nonlinear effects than the classical nonlinear dispersive Benjamin-Bona-Mahoney and Korteweg-de Vries equations. In particular, they accomodate wave breaking phenomena.

Journal ArticleDOI
TL;DR: The contribution of cognitive neuroscience, molecular genetics and clinical investigations to understanding how response inhibition is mediated in the human brain is reviewed.

Journal ArticleDOI
Richard A. Gibbs1, Jeremy F. Taylor2, Curtis P. Van Tassell3, William Barendse4, William Barendse5, Kellye Eversole, Clare A. Gill6, Ronnie D. Green3, Debora L. Hamernik3, Steven M. Kappes3, Sigbjørn Lien7, Lakshmi K. Matukumalli3, Lakshmi K. Matukumalli8, John C. McEwan9, Lynne V. Nazareth1, Robert D. Schnabel2, George M. Weinstock1, David A. Wheeler1, Paolo Ajmone-Marsan10, Paul Boettcher11, Alexandre Rodrigues Caetano12, José Fernando Garcia13, José Fernando Garcia11, Olivier Hanotte14, Paola Mariani15, Loren C. Skow6, Tad S. Sonstegard3, John L. Williams16, John L. Williams15, Boubacar Diallo, Lemecha Hailemariam17, Mário Luiz Martinez12, C. A. Morris9, Luiz Otávio Campos da Silva12, Richard J. Spelman18, Woudyalew Mulatu14, Keyan Zhao19, Colette A. Abbey6, Morris Agaba14, Flábio R. Araújo12, Rowan J. Bunch5, Rowan J. Bunch4, James O. Burton16, C. Gorni15, Hanotte Olivier15, Blair E. Harrison5, Blair E. Harrison4, Bill Luff, Marco Antonio Machado12, Joel Mwakaya14, Graham Plastow20, Warren Sim5, Warren Sim4, Timothy P. L. Smith3, Merle B Thomas5, Merle B Thomas4, Alessio Valentini21, Paul D. Williams5, James E. Womack6, John Woolliams16, Yue Liu1, Xiang Qin1, Kim C. Worley1, Chuan Gao6, Huaiyang Jiang1, Stephen S. Moore20, Yanru Ren1, Xingzhi Song1, Carlos Bustamante19, Ryan D. Hernandez19, Donna M. Muzny1, Shobha Patil1, Anthony San Lucas1, Qing Fu1, Matthew Peter Kent7, Richard Vega1, Aruna Matukumalli3, Sean McWilliam5, Sean McWilliam4, Gert Sclep15, Katarzyna Bryc19, Jung-Woo Choi6, Hong Gao19, John J. Grefenstette8, Brenda M. Murdoch20, Alessandra Stella15, Rafael Villa-Angulo8, Mark G. Wright19, Jan Aerts22, Jan Aerts16, Oliver C. Jann16, Riccardo Negrini10, Michael E. Goddard23, Michael E. Goddard24, Ben J. Hayes24, Daniel G. Bradley25, Marcos V.B. da Silva3, Marcos V.B. da Silva12, Lilian P.L. Lau25, George E. Liu3, David J. Lynn26, David J. Lynn25, Francesca Panzitta15, Ken G. Dodds9 
24 Apr 2009-Science
TL;DR: Data show that cattle have undergone a rapid recent decrease in effective population size from a very large ancestral population, possibly due to bottlenecks associated with domestication, selection, and breed formation.
Abstract: The imprints of domestication and breed development on the genomes of livestock likely differ from those of companion animals. A deep draft sequence assembly of shotgun reads from a single Hereford female and comparative sequences sampled from six additional breeds were used to develop probes to interrogate 37,470 single-nucleotide polymorphisms (SNPs) in 497 cattle from 19 geographically and biologically diverse breeds. These data show that cattle have undergone a rapid recent decrease in effective population size from a very large ancestral population, possibly due to bottlenecks associated with domestication, selection, and breed formation. Domestication and artificial selection appear to have left detectable signatures of selection within the cattle genome, yet the current levels of diversity within breeds are at least as great as exists within humans.

Journal ArticleDOI
TL;DR: This work provides a mechanism for the coordinate repression of let-7 miRNAs observed in a subset of human cancers, and associates activation of LIN28 and LIN28B with poor clinical prognosis.
Abstract: Multiple members of the let-7 family of miRNAs are often repressed in human cancers, thereby promoting oncogenesis by derepressing targets such as HMGA2, K-Ras and c-Myc. However, the mechanism by which let-7 miRNAs are coordinately repressed is unclear. The RNA-binding proteins LIN28 and LIN28B block let-7 precursors from being processed to mature miRNAs, suggesting that their overexpression might promote malignancy through repression of let-7. Here we show that LIN28 and LIN28B are overexpressed in primary human tumors and human cancer cell lines (overall frequency approximately 15%), and that overexpression is linked to repression of let-7 family miRNAs and derepression of let-7 targets. LIN28 and LIN28b facilitate cellular transformation in vitro, and overexpression is associated with advanced disease across multiple tumor types. Our work provides a mechanism for the coordinate repression of let-7 miRNAs observed in a subset of human cancers, and associates activation of LIN28 and LIN28B with poor clinical prognosis.

Journal ArticleDOI
TL;DR: Recent human genetic studies strongly suggest that perturbation of skin barrier function as a result of reduction or complete loss of filaggrin expression leads to enhanced percutaneous transfer of allergens.
Abstract: Recently, loss-of-function mutations in FLG, the human gene encoding profilaggrin and filaggrin, have been identified as the cause of the common skin condition ichthyosis vulgaris (which is characterised by dry, scaly skin). These mutations, which are carried by up to 10% of people, also represent a strong genetic predisposing factor for atopic eczema, asthma and allergies. Profilaggrin is the major component of the keratohyalin granules within epidermal granular cells. During epidermal terminal differentiation, the ∼400 kDa profilaggrin polyprotein is dephosphorylated and rapidly cleaved by serine proteases to form monomeric filaggrin (37 kDa), which binds to and condenses the keratin cytoskeleton and thereby contributes to the cell compaction process that is required for squame biogenesis. Within the squames, filaggrin is citrullinated, which promotes its unfolding and further degradation into hygroscopic amino acids, which constitute one element of natural moisturising factor. Loss of profilaggrin or filaggrin leads to a poorly formed stratum corneum (ichthyosis), which is also prone to water loss (xerosis). Recent human genetic studies strongly suggest that perturbation of skin barrier function as a result of reduction or complete loss of filaggrin expression leads to enhanced percutaneous transfer of allergens. Filaggrin is therefore in the frontline of defence, and protects the body from the entry of foreign environmental substances that can otherwise trigger aberrant immune responses.


Journal ArticleDOI
TL;DR: A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia, bipolar disorder, and autism, while the reciprocal microdeletion was associated only with autism and developmental disorders.
Abstract: Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders1, 2, 3. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 10-5, OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 10-7), bipolar disorder (P = 0.017) and autism (P = 1.9 10-7). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 10-13). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).

Posted Content
01 Jan 2009
TL;DR: In this article, the effects of stochastic wind and load on the unit commitment and dispatch of power systems with high levels of wind power are examined, by comparing the costs, planned operation and performance of the schedules produced.
Abstract: The stochastic nature of wind alters the unit commitment and dispatch problem. By accounting for this uncertainty when scheduling the system, more robust schedules are produced, which should, on average, reduce expected costs. In this paper, the effects of stochastic wind and load on the unit commitment and dispatch of power systems with high levels of wind power are examined. By comparing the costs, planned operation and performance of the schedules produced, it is shown that stochastic optimization results in less costly, of the order of 0.25%, and better performing schedules than deterministic optimization. The impact of planning the system more frequently to account for updated wind and load forecasts is then examined. More frequent planning means more up to date forecasts are used, which reduces the need for reserve and increases performance of the schedules. It is shown that mid merit and peaking units and the interconnection are the most affected parts of the system where uncertainty of wind is concerned

Journal ArticleDOI
TL;DR: It is shown that extensive training on a free‐operant task reduces the sensitivity of participants’ behavior to a reduction in outcome value, and suggested that cue‐driven activation in a specific region of dorsolateral posterior putamen may contribute to the habitual control of behavior in humans.
Abstract: Habits are characterized by an insensitivity to their consequences and, as such, can be distinguished from goal-directed actions. The neural basis of the development of demonstrably outcome-insensitive habitual actions in humans has not been previously characterized. In this experiment, we show that extensive training on a free-operant task reduces the sensitivity of participants' behavior to a reduction in outcome value. Analysis of functional magnetic resonance imaging data acquired during training revealed a significant increase in task-related cue sensitivity in a right posterior putamen-globus pallidus region as training progressed. These results provide evidence for a shift from goal-directed to habit-based control of instrumental actions in humans, and suggest that cue-driven activation in a specific region of dorsolateral posterior putamen may contribute to the habitual control of behavior in humans.

Journal ArticleDOI
TL;DR: In this paper, the effects of stochastic wind and load on the unit commitment and dispatch of power systems with high levels of wind power are examined, by comparing the costs, planned operation and performance of the schedules produced.
Abstract: The stochastic nature of wind alters the unit commitment and dispatch problem. By accounting for this uncertainty when scheduling the system, more robust schedules are produced, which should, on average, reduce expected costs. In this paper, the effects of stochastic wind and load on the unit commitment and dispatch of power systems with high levels of wind power are examined. By comparing the costs, planned operation and performance of the schedules produced, it is shown that stochastic optimization results in less costly, of the order of 0.25%, and better performing schedules than deterministic optimization. The impact of planning the system more frequently to account for updated wind and load forecasts is then examined. More frequent planning means more up to date forecasts are used, which reduces the need for reserve and increases performance of the schedules. It is shown that mid-merit and peaking units and the interconnection are the most affected parts of the system where uncertainty of wind is concerned.

Journal ArticleDOI
17 Jul 2009-Immunity
TL;DR: It is shown that IL-33 was processed by caspases activated during apoptosis but was not a physiological substrate for caspasing associated with inflammation, and caspase-mediated proteolysis acts as a switch to dampen the proinflammatory properties of IL- 33.

Journal ArticleDOI
TL;DR: In this paper, a review of recent work in this area is presented, focusing on results from the author's group, and it is concluded that functionalized nanotubes can be exfoliated to the greatest degree.
Abstract: Many applications of carbon nanotubes require the exfoliation of the nanotubes to give individual tubes in the liquid phase. This requires the dispersion, exfoliation, and stabilization of nanotubes in a variety of liquids. In this paper recent work in this area is reviewed, focusing on results from the author's group. It begins by reviewing stabilization mechanisms before exploring research into the exfoliation of nanotubes in solvents, by using surfactants or biomolecules and by covalent attachment of molecules. The concentration dependence of the degree of exfoliation in each case will be highlighted. In addition research into the dispersion mechanism for each dispersant type is discussed. Most importantly, dispersion quality metrics for all dispersants are compared. From this analysis, it is concluded that functionalized nanotubes can be exfoliated to the greatest degree. Finally, the extension of this work to the liquid phase exfoliation of graphite to give graphene is reviewed.

Journal ArticleDOI
Lauren A. Weiss1, Lauren A. Weiss2, Dan E. Arking3, Mark J. Daly2  +211 moreInstitutions (54)
08 Oct 2009-Nature
TL;DR: A linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms in a common set of 1,031 multiplex autism families, implicating SEMA5A as an autism susceptibility gene.
Abstract: Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 x 10(-7)). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.

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TL;DR: The emerging roles of long non-coding RNAs and a subset of transcription factors in the regulation of PcG association with target genes are discussed and how their deregulation contributes to tumorigenesis is speculated about.
Abstract: The Polycomb group (PcG) proteins are transcriptional repressors that regulate lineage choices during development and differentiation. Recent studies have advanced our understanding of how the PcG proteins regulate cell fate decisions and how their deregulation potentially contributes to cancer. In this Review we discuss the emerging roles of long non-coding RNAs (ncRNAs) and a subset of transcription factors, which we call cell fate transcription factors, in the regulation of PcG association with target genes. We also speculate about how their deregulation contributes to tumorigenesis.

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TL;DR: Activity in a key brain region previously implicated in encoding goal-values: the ventromedial prefrontal cortex (vmPFC) was correlated with the subjects' value for each category of good, providing evidence that the brain encodes a “common currency” that allows for a shared valuation for different categories of goods.
Abstract: To make economic choices between goods, the brain needs to compute representations of their values. A great deal of research has been performed to determine the neural correlates of value representations in the human brain. However, it is still unknown whether there exists a region of the brain that commonly encodes decision values for different types of goods, or if, in contrast, the values of different types of goods are represented in distinct brain regions. We addressed this question by scanning subjects with functional magnetic resonance imaging while they made real purchasing decisions among different categories of goods (food, nonfood consumables, and monetary gambles). We found activity in a key brain region previously implicated in encoding goal-values: the ventromedial prefrontal cortex (vmPFC) was correlated with the subjects' value for each category of good. Moreover, we found a single area in vmPFC to be correlated with the subjects' valuations for all categories of goods. Our results provide evidence that the brain encodes a "common currency" that allows for a shared valuation for different categories of goods.

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TL;DR: This work examines the similarities and differences between RNAi and small-molecule screens, highlighting particular characteristics of RNAi screen data that must be addressed during analysis and provides guidance on selection of analysis techniques in the context of a sample workflow.
Abstract: RNA interference (RNAi) has become a powerful technique for reverse genetics and drug discovery, and in both of these areas large-scale high-throughput RNAi screens are commonly performed. The statistical techniques used to analyze these screens are frequently borrowed directly from small-molecule screening; however, small-molecule and RNAi data characteristics differ in meaningful ways. We examine the similarities and differences between RNAi and small-molecule screens, highlighting particular characteristics of RNAi screen data that must be addressed during analysis. Additionally, we provide guidance on selection of analysis techniques in the context of a sample workflow.

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TL;DR: This perspective with the role of the insula in interoception, self-awareness and drug craving, the anterior cingulate in behavioral monitoring and response selection and drug-related stimuli that predict emotional behavior in addicted individuals are integrated.


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TL;DR: This tutorial review surveys the covalent modification of SWCNTs with organic moieties, and illustrates the major analytical techniques routinely used to characterise the functionalised materials.
Abstract: Since carbon nanotubes (CNTs) display unique structures and remarkable physical properties, a variety of applications have emerged in both materials and life sciences. In terms of applications, the functionalisation of nanotubes is extremely important, as it increases their solubility and processability, and combines the unique properties of single-walled carbon nanotubes (SWCNTs) with those of other classes of materials. A number of methods have been developed, which can be divided into two major approaches: (1) non-covalent supramolecular modifications, and (2) covalent functionalisation. In this tutorial review, we survey the covalent modification of SWCNTs with organic moieties, and illustrate the major analytical techniques routinely used to characterise the functionalised materials.