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Showing papers by "University of Oxford published in 2012"


Journal ArticleDOI
Stephen S Lim1, Theo Vos, Abraham D. Flaxman1, Goodarz Danaei2  +207 moreInstitutions (92)
TL;DR: In this paper, the authors estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010.

9,324 citations


Journal ArticleDOI
Georges Aad1, T. Abajyan2, Brad Abbott3, Jalal Abdallah4  +2964 moreInstitutions (200)
TL;DR: In this article, a search for the Standard Model Higgs boson in proton-proton collisions with the ATLAS detector at the LHC is presented, which has a significance of 5.9 standard deviations, corresponding to a background fluctuation probability of 1.7×10−9.

9,282 citations


Journal ArticleDOI
02 Nov 2012-Science
TL;DR: A low-cost, solution-processable solar cell, based on a highly crystalline perovskite absorber with intense visible to near-infrared absorptivity, that has a power conversion efficiency of 10.9% in a single-junction device under simulated full sunlight is reported.
Abstract: The energy costs associated with separating tightly bound excitons (photoinduced electron-hole pairs) and extracting free charges from highly disordered low-mobility networks represent fundamental losses for many low-cost photovoltaic technologies. We report a low-cost, solution-processable solar cell, based on a highly crystalline perovskite absorber with intense visible to near-infrared absorptivity, that has a power conversion efficiency of 10.9% in a single-junction device under simulated full sunlight. This "meso-superstructured solar cell" exhibits exceptionally few fundamental energy losses; it can generate open-circuit photovoltages of more than 1.1 volts, despite the relatively narrow absorber band gap of 1.55 electron volts. The functionality arises from the use of mesoporous alumina as an inert scaffold that structures the absorber and forces electrons to reside in and be transported through the perovskite.

9,158 citations


Journal ArticleDOI
01 Nov 2012-Nature
TL;DR: It is shown that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites.
Abstract: By characterizing the geographic and functional spectrum of human genetic variation, the 1000 Genomes Project aims to build a resource to help to understand the genetic contribution to disease. Here we describe the genomes of 1,092 individuals from 14 populations, constructed using a combination of low-coverage whole-genome and exome sequencing. By developing methods to integrate information across several algorithms and diverse data sources, we provide a validated haplotype map of 38 million single nucleotide polymorphisms, 1.4 million short insertions and deletions, and more than 14,000 larger deletions. We show that individuals from different populations carry different profiles of rare and common variants, and that low-frequency variants show substantial geographic differentiation, which is further increased by the action of purifying selection. We show that evolutionary conservation and coding consequence are key determinants of the strength of purifying selection, that rare-variant load varies substantially across biological pathways, and that each individual contains hundreds of rare non-coding variants at conserved sites, such as motif-disrupting changes in transcription-factor-binding sites. This resource, which captures up to 98% of accessible single nucleotide polymorphisms at a frequency of 1% in related populations, enables analysis of common and low-frequency variants in individuals from diverse, including admixed, populations.

7,710 citations


Journal ArticleDOI
Theo Vos, Abraham D. Flaxman1, Mohsen Naghavi1, Rafael Lozano1  +360 moreInstitutions (143)
TL;DR: Prevalence and severity of health loss were weakly correlated and age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010, but population growth and ageing have increased YLD numbers and crude rates over the past two decades.

7,021 citations


Journal ArticleDOI
Christopher J L Murray1, Theo Vos2, Rafael Lozano1, Mohsen Naghavi1  +366 moreInstitutions (141)
TL;DR: The results for 1990 and 2010 supersede all previously published Global Burden of Disease results and highlight the importance of understanding local burden of disease and setting goals and targets for the post-2015 agenda taking such patterns into account.

6,861 citations


Journal ArticleDOI
Kaoru Hagiwara, Ken Ichi Hikasa1, Koji Nakamura, Masaharu Tanabashi1, M. Aguilar-Benitez, Claude Amsler2, R. M. Barnett3, P. R. Burchat4, C. D. Carone5, C. Caso6, G. Conforto7, Olav Dahl3, Michael Doser8, Semen Eidelman9, Jonathan L. Feng10, L. K. Gibbons11, M. C. Goodman12, Christoph Grab13, D. E. Groom3, Atul Gurtu14, Atul Gurtu8, K. G. Hayes15, J.J. Hernández-Rey16, K. Honscheid17, Christopher Kolda18, Michelangelo L. Mangano8, D. M. Manley19, Aneesh V. Manohar20, John March-Russell8, Alberto Masoni, Ramon Miquel3, Klaus Mönig, Hitoshi Murayama3, Hitoshi Murayama21, S. Sánchez Navas13, Keith A. Olive22, Luc Pape8, C. Patrignani6, A. Piepke23, Matts Roos24, John Terning25, Nils A. Tornqvist24, T. G. Trippe3, Petr Vogel26, C. G. Wohl3, Ron L. Workman27, W-M. Yao3, B. Armstrong3, P. S. Gee3, K. S. Lugovsky, S. B. Lugovsky, V. S. Lugovsky, Marina Artuso28, D. Asner29, K. S. Babu30, E. L. Barberio8, Marco Battaglia8, H. Bichsel31, O. Biebel32, P. Bloch8, Robert N. Cahn3, Ariella Cattai8, R.S. Chivukula33, R. Cousins34, G. A. Cowan35, Thibault Damour36, K. Desler, R. J. Donahue3, D. A. Edwards, Victor Daniel Elvira37, Jens Erler38, V. V. Ezhela, A Fassò8, W. Fetscher13, Brian D. Fields39, B. Foster40, Daniel Froidevaux8, Masataka Fukugita41, Thomas K. Gaisser42, L. A. Garren37, H J Gerber13, Frederick J. Gilman43, Howard E. Haber44, C. A. Hagmann29, J.L. Hewett4, Ian Hinchliffe3, Craig J. Hogan31, G. Höhler45, P. Igo-Kemenes46, John David Jackson3, Kurtis F Johnson47, D. Karlen48, B. Kayser37, S. R. Klein3, Konrad Kleinknecht49, I.G. Knowles50, P. Kreitz4, Yu V. Kuyanov, R. Landua8, Paul Langacker38, L. S. Littenberg51, Alan D. Martin52, Tatsuya Nakada53, Tatsuya Nakada8, Meenakshi Narain33, Paolo Nason, John A. Peacock54, H. R. Quinn55, Stuart Raby17, Georg G. Raffelt32, E. A. Razuvaev, B. Renk49, L. Rolandi8, Michael T Ronan3, L.J. Rosenberg54, C.T. Sachrajda55, A. I. Sanda56, Subir Sarkar57, Michael Schmitt58, O. Schneider53, Douglas Scott59, W. G. Seligman60, M. H. Shaevitz60, Torbjörn Sjöstrand61, George F. Smoot3, Stefan M Spanier4, H. Spieler3, N. J. C. Spooner62, Mark Srednicki63, Achim Stahl, Todor Stanev42, M. Suzuki3, N. P. Tkachenko, German Valencia64, K. van Bibber29, Manuella Vincter65, D. R. Ward66, Bryan R. Webber66, M R Whalley52, Lincoln Wolfenstein43, J. Womersley37, C. L. Woody51, Oleg Zenin 
Tohoku University1, University of Zurich2, Lawrence Berkeley National Laboratory3, Stanford University4, College of William & Mary5, University of Genoa6, University of Urbino7, CERN8, Budker Institute of Nuclear Physics9, University of California, Irvine10, Cornell University11, Argonne National Laboratory12, ETH Zurich13, Tata Institute of Fundamental Research14, Hillsdale College15, Spanish National Research Council16, Ohio State University17, University of Notre Dame18, Kent State University19, University of California, San Diego20, University of California, Berkeley21, University of Minnesota22, University of Alabama23, University of Helsinki24, Los Alamos National Laboratory25, California Institute of Technology26, George Washington University27, Syracuse University28, Lawrence Livermore National Laboratory29, Oklahoma State University–Stillwater30, University of Washington31, Max Planck Society32, Boston University33, University of California, Los Angeles34, Royal Holloway, University of London35, Université Paris-Saclay36, Fermilab37, University of Pennsylvania38, University of Illinois at Urbana–Champaign39, University of Bristol40, University of Tokyo41, University of Delaware42, Carnegie Mellon University43, University of California, Santa Cruz44, Karlsruhe Institute of Technology45, Heidelberg University46, Florida State University47, Carleton University48, University of Mainz49, University of Edinburgh50, Brookhaven National Laboratory51, Durham University52, University of Lausanne53, Massachusetts Institute of Technology54, University of Southampton55, Nagoya University56, University of Oxford57, Northwestern University58, University of British Columbia59, Columbia University60, Lund University61, University of Sheffield62, University of California, Santa Barbara63, Iowa State University64, University of Alberta65, University of Cambridge66
TL;DR: The Particle Data Group's biennial review as mentioned in this paper summarizes much of particle physics, using data from previous editions, plus 2658 new measurements from 644 papers, and lists, evaluates, and average measured properties of gauge bosons, leptons, quarks, mesons, and baryons.
Abstract: This biennial Review summarizes much of particle physics. Using data from previous editions, plus 2658 new measurements from 644 papers, we list, evaluate, and average measured properties of gauge bosons, leptons, quarks, mesons, and baryons. We summarize searches for hypothetical particles such as Higgs bosons, heavy neutrinos, and supersymmetric particles. All the particle properties and search limits are listed in Summary Tables. We also give numerous tables, figures, formulae, and reviews of topics such as the Standard Model, particle detectors, probability, and statistics. Among the 112 reviews are many that are new or heavily revised including those on Heavy-Quark and Soft-Collinear Effective Theory, Neutrino Cross Section Measurements, Monte Carlo Event Generators, Lattice QCD, Heavy Quarkonium Spectroscopy, Top Quark, Dark Matter, V-cb & V-ub, Quantum Chromodynamics, High-Energy Collider Parameters, Astrophysical Constants, Cosmological Parameters, and Dark Matter. A booklet is available containing the Summary Tables and abbreviated versions of some of the other sections of this full Review. All tables, listings, and reviews (and errata) are also available on the Particle Data Group website: http://pdg.lbl.gov.

4,465 citations


Journal ArticleDOI
TL;DR: These guidelines are presented for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

4,316 citations


Journal ArticleDOI
TL;DR: Properties of currently available glucose-lowering agents that may guide treatment choice in individual patients with type 2 diabetes mellitus are explored.
Abstract: Erratum to: DiabetologiaDOI 10.1007/s00125-012-2534-0In the text box ‘Properties of currently available glucose-lowering agents that may guide treatment choice in individualpatients with type 2 diabetes mellitus ’ vildagliptin was incor-rectly assigned footnote ‘a’ (Limited use in the USA/Europe)instead of footnote ‘b’ (Not licensed in the USA).

4,126 citations


Journal ArticleDOI
TL;DR: A comprehensive survey of recent work on modified theories of gravity and their cosmological consequences can be found in this article, where the authors provide a reference tool for researchers and students in cosmology and gravitational physics, as well as a selfcontained, comprehensive and up-to-date introduction to the subject as a whole.

3,674 citations


Journal ArticleDOI
TL;DR: These interventions were more effective in people at higher risk of falling, including those with severe visual impairment, and home safety interventions appear to be more effective when delivered by an occupational therapist.
Abstract: As people get older, they may fall more often for a variety of reasons including problems with balance, poor vision, and dementia. Up to 30% may fall in a year. Although one in five falls may require medical attention, less than one in 10 results in a fracture. This review looked at the healthcare literature to establish which fall prevention interventions are effective for older people living in the community, and included 159 randomised controlled trials with 79,193 participants. Group and home-based exercise programmes, usually containing some balance and strength training exercises, effectively reduced falls, as did Tai Chi. Overall, exercise programmes aimed at reducing falls appear to reduce fractures. Multifactorial interventions assess an individual's risk of falling, and then carry out treatment or arrange referrals to reduce the identified risks. Overall, current evidence shows that this type of intervention reduces the number of falls in older people living in the community but not the number of people falling during follow-up. These are complex interventions, and their effectiveness may be dependent on factors yet to be determined. Interventions to improve home safety appear to be effective, especially in people at higher risk of falling and when carried out by occupational therapists. An anti-slip shoe device worn in icy conditions can also reduce falls. Taking vitamin D supplements does not appear to reduce falls in most community-dwelling older people, but may do so in those who have lower vitamin D levels in the blood before treatment. Some medications increase the risk of falling. Three trials in this review failed to reduce the number of falls by reviewing and adjusting medications. A fourth trial involving family physicians and their patients in medication review was effective in reducing falls. Gradual withdrawal of a particular type of drug for improving sleep, reducing anxiety, and treating depression (psychotropic medication) has been shown to reduce falls. Cataract surgery reduces falls in women having the operation on the first affected eye. Insertion of a pacemaker can reduce falls in people with frequent falls associated with carotid sinus hypersensitivity, a condition which causes sudden changes in heart rate and blood pressure. In people with disabling foot pain, the addition of footwear assessment, customised insoles, and foot and ankle exercises to regular podiatry reduced the number of falls but not the number of people falling. The evidence relating to the provision of educational materials alone for preventing falls is inconclusive.

Journal ArticleDOI
TL;DR: This statement has been written incorporating the best available evidence and, where solid support does not exist, using the experience and insight of the writing group, incorporating an extensive review by additional experts (acknowledged below).
Abstract: Glycemic management in type 2 diabetes mellitus has become increasingly complex and, to some extent, controversial, with a widening array of pharmacological agents now available (1–5), mounting concerns about their potential adverse effects and new uncertainties regarding the benefits of intensive glycemic control on macrovascular complications (6–9). Many clinicians are therefore perplexed as to the optimal strategies for their patients. As a consequence, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) convened a joint task force to examine the evidence and develop recommendations for antihyperglycemic therapy in nonpregnant adults with type 2 diabetes. Several guideline documents have been developed by members of these two organizations (10) and by other societies and federations (2,11–15). However, an update was deemed necessary because of contemporary information on the benefits/risks of glycemic control, recent evidence concerning efficacy and safety of several new drug classes (16,17), the withdrawal/restriction of others, and increasing calls for a move toward more patient-centered care (18,19). This statement has been written incorporating the best available evidence and, where solid support does not exist, using the experience and insight of the writing group, incorporating an extensive review by additional experts (acknowledged below). The document refers to glycemic control; yet this clearly needs to be pursued within a multifactorial risk reduction framework. This stems from the fact that patients with type 2 diabetes are at increased risk of cardiovascular morbidity and mortality; the aggressive management of cardiovascular …

Journal ArticleDOI
TL;DR: Delamination of LDHs is an interesting route for producing positively charged thin platelets with a thickness of a few atomic layers, which can be used as nanocomposites for polymers or as building units for making new designed organic- inorganic or inorganic-inorganic nanomaterials.
Abstract: Layered double hydroxides (LDHs) are a class of ionic lamellar compounds made up of positively charged brucite-like layers with an interlayer region containing charge compensating anions and solvation molecules. Delamination of LDHs is an interesting route for producing positively charged thin platelets with a thickness of a few atomic layers, which can be used as nanocomposites for polymers or as building units for making new designed organic-inorganic or inorganic-inorganic nanomaterials. The synthesis of nanosized LDH platelets can be generally classified into two approaches, bottom-up and top-down. It requires modification of the LDH interlamellar environment and then selection of an appropriate solvent system. In DDS intercalated LDHs, the aliphatic tails of the DDS- anions exhibit a high degree of interdigitation in order to maximize guest-guest dispersive interactions. Bellezza reported that the LDH colloids can also been obtained by employing a reverse microemulsion approach.

Journal ArticleDOI
12 Apr 2012-Nature
TL;DR: It is argued that nascent fungal infections will cause increasing attrition of biodiversity, with wider implications for human and ecosystem health, unless steps are taken to tighten biosecurity worldwide.
Abstract: The past two decades have seen an increasing number of virulent infectious diseases in natural populations and managed landscapes. In both animals and plants, an unprecedented number of fungal and fungal-like diseases have recently caused some of the most severe die-offs and extinctions ever witnessed in wild species, and are jeopardizing food security. Human activity is intensifying fungal disease dispersal by modifying natural environments and thus creating new opportunities for evolution. We argue that nascent fungal infections will cause increasing attrition of biodiversity, with wider implications for human and ecosystem health, unless steps are taken to tighten biosecurity worldwide.

Journal ArticleDOI
TL;DR: In this paper, the authors present a survey of the use of Wannier functions in the context of electronic-structure theory, including their applications in analyzing the nature of chemical bonding, or as a local probe of phenomena related to electric polarization and orbital magnetization.
Abstract: The electronic ground state of a periodic system is usually described in terms of extended Bloch orbitals, but an alternative representation in terms of localized "Wannier functions" was introduced by Gregory Wannier in 1937. The connection between the Bloch and Wannier representations is realized by families of transformations in a continuous space of unitary matrices, carrying a large degree of arbitrariness. Since 1997, methods have been developed that allow one to iteratively transform the extended Bloch orbitals of a first-principles calculation into a unique set of maximally localized Wannier functions, accomplishing the solid-state equivalent of constructing localized molecular orbitals, or "Boys orbitals" as previously known from the chemistry literature. These developments are reviewed here, and a survey of the applications of these methods is presented. This latter includes a description of their use in analyzing the nature of chemical bonding, or as a local probe of phenomena related to electric polarization and orbital magnetization. Wannier interpolation schemes are also reviewed, by which quantities computed on a coarse reciprocal-space mesh can be used to interpolate onto much finer meshes at low cost, and applications in which Wannier functions are used as efficient basis functions are discussed. Finally the construction and use of Wannier functions outside the context of electronic-structure theory is presented, for cases that include phonon excitations, photonic crystals, and cold-atom optical lattices.

Journal ArticleDOI
20 Sep 2012-Nature
TL;DR: A transcriptional atlas of the adult human brain is described, comprising extensive histological analysis and comprehensive microarray profiling of ∼900 neuroanatomically precise subdivisions in two individuals, to form a high-resolution transcriptional baseline for neurogenetic studies of normal and abnormal human brain function.
Abstract: Neuroanatomically precise, genome-wide maps of transcript distributions are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture. Here we describe the generation and analysis of a transcriptional atlas of the adult human brain, comprising extensive histological analysis and comprehensive microarray profiling of ~900 neuroanatomically precise subdivisions in two individuals. Transcriptional regulation varies enormously by anatomical location, with different regions and their constituent cell types displaying robust molecular signatures that are highly conserved between individuals. Analysis of differential gene expression and gene co-expression relationships demonstrates that brain-wide variation strongly reflects the distributions of major cell classes such as neurons, oligodendrocytes, astrocytes and microglia. Local neighbourhood relationships between fine anatomical subdivisions are associated with discrete neuronal subtypes and genes involved with synaptic transmission. The neocortex displays a relatively homogeneous transcriptional pattern, but with distinct features associated selectively with primary sensorimotor cortices and with enriched frontal lobe expression. Notably, the spatial topography of the neocortex is strongly reflected in its molecular topography—the closer two cortical regions, the more similar their transcriptomes. This freely accessible online data resource forms a high-resolution transcriptional baseline for neurogenetic studies of normal and abnormal human brain function.

Journal ArticleDOI
TL;DR: Reduction of LDL cholesterol with a statin reduced the risk of major vascular events, largely irrespective of age, sex, baseline LDL cholesterol or previous vascular disease, and of vascular and all-cause mortality.

Journal ArticleDOI
TL;DR: In this article, the effectiveness of different forms of nicotine replacement therapy (chewing gum, transdermal patches, nasal spray, inhalers and tablets) in achieving abstinence from cigarettes, or a sustained reduction in amount smoked; to determine whether the effect is influenced by the clinical setting in which the smoker is recruited and treated, the dosage and form of the NRT used, or the intensity of additional advice and support offered to the smoker.
Abstract: BACKGROUND: The aim of nicotine replacement therapy (NRT) is to replace nicotine from cigarettes. This reduces withdrawal symptoms associated with smoking cessation thus helping resist the urge to smoke cigarettes. OBJECTIVES: The aims of this review were to determine the effectiveness of the different forms of nicotine replacement therapy (chewing gum, transdermal patches, nasal spray, inhalers and tablets) in achieving abstinence from cigarettes, or a sustained reduction in amount smoked; to determine whether the effect is influenced by the clinical setting in which the smoker is recruited and treated, the dosage and form of the NRT used, or the intensity of additional advice and support offered to the smoker; to determine whether combinations of NRT are more effective than one type alone; and to determine its effectiveness compared to other pharmacotherapies. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group trials register in July 2002. SELECTION CRITERIA: Randomized trials in which NRT was compared to placebo or no treatment, or where different doses of NRT were compared. We excluded trials which did not report cessation rates, and those with follow-up of less than six months. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the type of subjects, the dose and duration and form of nicotine therapy, the outcome measures, method of randomization, and completeness of follow-up. The main outcome measure was abstinence from smoking after at least six months of follow-up. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. Where appropriate, we performed meta-analysis using a fixed effects model (Peto). MAIN RESULTS: We identified 110 trials; 96 with a non NRT control group. The odds ratio for abstinence with NRT compared to control was 1.74 (95% confidence interval 1.64 - 1.86), The odds ratios for the different forms of NRT were 1.66 for gum, 1.74 for patches, 2.27 for nasal spray, 2.08 for inhaled nicotine and 2.08 for nicotine sublingual tablet/lozenge. These odds were largely independent of the duration of therapy, the intensity of additional support provided or the setting in which the NRT was offered. In highly dependent smokers there was a significant benefit of 4 mg gum compared with 2mg gum (odds ratio 2.67, 95% confidence interval 1.69 - 4.22). There was weak evidence that combinations of forms of NRT are more effective. Higher doses of nicotine patch may produce small increases in quit rates. Only one study directly compared NRT to another pharmacotherapy, in which bupropion was significantly more effective than nicotine patch or placebo. REVIEWER'S CONCLUSIONS: All of the commercially available forms of NRT (nicotine gum, transdermal patch, the nicotine nasal spray, nicotine inhaler and nicotine sublingual tablets/lozenges) are effective as part of a strategy to promote smoking cessation. They increase quit rates approximately 1.5 to 2 fold regardless of setting. The effectiveness of NRT appears to be largely independent of the intensity of additional support provided to the smoker. Provision of more intense levels of support, although beneficial in facilitating the likelihood of quitting, is not essential to the success of NRT. There is promising evidence that bupropion may be more effective than NRT (either alone or in combination). However, its most appropriate place in the therapeutic armamentarium requires further study and consideration.

Journal ArticleDOI
TL;DR: The Human Connectome Project (HCP) as discussed by the authors is a 5-year effort to characterize brain connectivity and function and their variability in healthy adults using diffusion imaging (dMRI), resting-state fMRI, task-evoked fMRI (T-fMRI), T1-and T2-weighted MRI for structural and myelin mapping, plus combined magnetoencephalography (MEG/EEG).

Journal ArticleDOI
TL;DR: This article conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent, and identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association.
Abstract: To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.


Journal ArticleDOI
Benjamin F. Voight1, Benjamin F. Voight2, Benjamin F. Voight3, Gina M. Peloso4, Gina M. Peloso5, Marju Orho-Melander6, Ruth Frikke-Schmidt7, Maja Barbalić8, Majken K. Jensen2, George Hindy6, Hilma Holm9, Eric L. Ding2, Toby Johnson10, Heribert Schunkert11, Nilesh J. Samani12, Nilesh J. Samani13, Robert Clarke14, Jemma C. Hopewell14, John F. Thompson13, Mingyao Li1, Gudmar Thorleifsson9, Christopher Newton-Cheh, Kiran Musunuru3, Kiran Musunuru2, James P. Pirruccello2, James P. Pirruccello3, Danish Saleheen15, Li Chen16, Alexandre F.R. Stewart16, Arne Schillert11, Unnur Thorsteinsdottir9, Unnur Thorsteinsdottir17, Gudmundur Thorgeirsson17, Sonia S. Anand18, James C. Engert19, Thomas M. Morgan20, John A. Spertus21, Monika Stoll22, Klaus Berger22, Nicola Martinelli23, Domenico Girelli23, Pascal P. McKeown24, Christopher Patterson24, Stephen E. Epstein25, Joseph M. Devaney25, Mary Susan Burnett25, Vincent Mooser26, Samuli Ripatti27, Ida Surakka27, Markku S. Nieminen27, Juha Sinisalo27, Marja-Liisa Lokki27, Markus Perola4, Aki S. Havulinna4, Ulf de Faire28, Bruna Gigante28, Erik Ingelsson28, Tanja Zeller29, Philipp S. Wild29, Paul I.W. de Bakker, Olaf H. Klungel30, Anke-Hilse Maitland-van der Zee30, Bas J M Peters30, Anthonius de Boer30, Diederick E. Grobbee30, Pieter Willem Kamphuisen31, Vera H.M. Deneer, Clara C. Elbers30, N. Charlotte Onland-Moret30, Marten H. Hofker31, Cisca Wijmenga31, W. M. Monique Verschuren, Jolanda M. A. Boer, Yvonne T. van der Schouw30, Asif Rasheed, Philippe M. Frossard, Serkalem Demissie5, Serkalem Demissie4, Cristen J. Willer32, Ron Do2, Jose M. Ordovas33, Jose M. Ordovas34, Gonçalo R. Abecasis32, Michael Boehnke32, Karen L. Mohlke35, Mark J. Daly3, Mark J. Daly2, Candace Guiducci3, Noël P. Burtt3, Aarti Surti3, Elena Gonzalez3, Shaun Purcell2, Shaun Purcell3, Stacey Gabriel3, Jaume Marrugat, John F. Peden14, Jeanette Erdmann11, Patrick Diemert11, Christina Willenborg11, Inke R. König11, Marcus Fischer36, Christian Hengstenberg36, Andreas Ziegler11, Ian Buysschaert37, Diether Lambrechts37, Frans Van de Werf37, Keith A.A. Fox38, Nour Eddine El Mokhtari39, Diana Rubin, Jürgen Schrezenmeir, Stefan Schreiber39, Arne Schäfer39, John Danesh15, Stefan Blankenberg29, Robert Roberts16, Ruth McPherson16, Hugh Watkins14, Alistair S. Hall40, Kim Overvad41, Eric B. Rimm2, Eric Boerwinkle8, Anne Tybjærg-Hansen7, L. Adrienne Cupples4, L. Adrienne Cupples5, Muredach P. Reilly1, Olle Melander6, Pier Mannuccio Mannucci42, Diego Ardissino, David S. Siscovick43, Roberto Elosua, Kari Stefansson17, Kari Stefansson9, Christopher J. O'Donnell2, Christopher J. O'Donnell4, Veikko Salomaa4, Daniel J. Rader1, Leena Peltonen44, Leena Peltonen27, Stephen M. Schwartz43, David Altshuler, Sekar Kathiresan 
11 Aug 2012
TL;DR: In this paper, a Mendelian randomisation analysis was performed to compare the effect of HDL cholesterol, LDL cholesterol, and genetic score on risk of myocardial infarction.
Abstract: Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. – ¹³) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with noncarriers. This diff erence in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45–1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69–2·69, p=2×10

Journal ArticleDOI
04 Oct 2012-Nature
TL;DR: The sequencing and assembly of the oyster genome using short reads and a fosmid-pooling strategy and transcriptomes of development and stress response and the proteome of the shell are reported, showing that shell formation in molluscs is more complex than currently understood and involves extensive participation of cells and their exosomes.
Abstract: The Pacific oyster Crassostrea gigas belongs to one of the most species-rich but genomically poorly explored phyla, the Mollusca. Here we report the sequencing and assembly of the oyster genome using short reads and a fosmid-pooling strategy, along with transcriptomes of development and stress response and the proteome of the shell. The oyster genome is highly polymorphic and rich in repetitive sequences, with some transposable elements still actively shaping variation. Transcriptome studies reveal an extensive set of genes responding to environmental stress. The expansion of genes coding for heat shock protein 70 and inhibitors of apoptosis is probably central to the oyster's adaptation to sessile life in the highly stressful intertidal zone. Our analyses also show that shell formation in molluscs is more complex than currently understood and involves extensive participation of cells and their exosomes. The oyster genome sequence fills a void in our understanding of the Lophotrochozoa.

Journal ArticleDOI
TL;DR: This work introduces a strategy called 'pre-phasing' that maintains the accuracy of leading methods while reducing computational costs in genome-wide association studies (GWAS), and will be particularly valuable for repeated imputation as reference panels evolve.
Abstract: Goncalo Abecasis, Jonathan Marchini and colleagues report a pre-phasing strategy for genotype imputation in GWAS, which they show maintains accuracy while substantially lowering computational costs. Their approach has been implemented in both MACH and IMPUTE 2.0 software.

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TL;DR: A method for estimating haplotypes, using genotype data from unrelated samples or small nuclear families, that leads to improved accuracy and speed compared to several widely used methods is presented.
Abstract: An efficient haplotype-estimation algorithm that features linear complexity allows the rapid and accurate phasing of diploid genomes from trios, duos and unrelated samples.

Journal Article
TL;DR: Schulz et al. as discussed by the authors investigated whether adult macrophages all share a common developmental origin and found that a population of yolk-sac-derived, tissue-resident macophages was able to develop and persist in adult mice in the absence of hematopoietic stem cells.
Abstract: Macrophage Development Rewritten Macrophages provide protection against a wide variety of infections and critically shape the inflammatory environment in many tissues. These cells come in many flavors, as determined by differences in gene expression, cell surface phenotype and specific function. Schulz et al. (p. 86, published online 22 March) investigated whether adult macrophages all share a common developmental origin. Immune cells, including most macrophages, are widely thought to arise from hematopoietic stem cells (HSCs), which require the transcription factor Myb for their development. Analysis of Myb-deficient mice revealed that a population of yolk-sac–derived, tissue-resident macrophages was able to develop and persist in adult mice in the absence of HSCs. Importantly, yolk sac–derived macrophages also contributed substantially to the tissue macrophage pool even when HSCs were present. In mice, a population of tissue-resident macrophages arises independently of bone marrow–derived stem cells. Macrophages and dendritic cells (DCs) are key components of cellular immunity and are thought to originate and renew from hematopoietic stem cells (HSCs). However, some macrophages develop in the embryo before the appearance of definitive HSCs. We thus reinvestigated macrophage development. We found that the transcription factor Myb was required for development of HSCs and all CD11bhigh monocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80bright macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, and microglia—cell populations that all can persist in adult mice independently of HSCs. These results define a lineage of tissue macrophages that derive from the YS and are genetically distinct from HSC progeny.

Journal ArticleDOI
TL;DR: In this paper, the impacts of global climate change on food systems are expected to be widespread, complex, geographically and temporally variable, and profoundly influenced by socioeconomic conditions, and some synergies among food security, adaptati...
Abstract: Food systems contribute 19%–29% of global anthropogenic greenhouse gas (GHG) emissions, releasing 9,800–16,900 megatonnes of carbon dioxide equivalent (MtCO2e) in 2008. Agricultural production, including indirect emissions associated with land-cover change, contributes 80%–86% of total food system emissions, with significant regional variation. The impacts of global climate change on food systems are expected to be widespread, complex, geographically and temporally variable, and profoundly influenced by socioeconomic conditions. Historical statistical studies and integrated assessment models provide evidence that climate change will affect agricultural yields and earnings, food prices, reliability of delivery, food quality, and, notably, food safety. Low-income producers and consumers of food will be more vulnerable to climate change owing to their comparatively limited ability to invest in adaptive institutions and technologies under increasing climatic risks. Some synergies among food security, adaptati...

Journal ArticleDOI
26 Oct 2012-Science
TL;DR: A new method, based on nonlinear state space reconstruction, that can distinguish causality from correlation is introduced, and extends to nonseparable weakly connected dynamic systems (cases not covered by the current Granger causality paradigm).
Abstract: Identifying causal networks is important for effective policy and management recommendations on climate, epidemiology, financial regulation, and much else. We introduce a method, based on nonlinear state space reconstruction, that can distinguish causality from correlation. It extends to nonseparable weakly connected dynamic systems (cases not covered by the current Granger causality paradigm). The approach is illustrated both by simple models (where, in contrast to the real world, we know the underlying equations/relations and so can check the validity of our method) and by application to real ecological systems, including the controversial sardine-anchovy-temperature problem.

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TL;DR: In this article, the authors present an overview of the achievements and the status of integrability in the context of the AdS/CFT correspondence as of the year 2010.
Abstract: This is the introductory chapter of a review collection on integrability in the context of the AdS/CFT correspondence. In the collection we present an overview of the achievements and the status of this subject as of the year 2010.

Journal ArticleDOI
TL;DR: How high-throughput genomic methods are revealing the importance of the kinetics of cytokine gene expression and the remarkable degree of redundancy and overlap in cytokine signaling is highlighted.
Abstract: The cytokine storm has captured the attention of the public and the scientific community alike, and while the general notion of an excessive or uncontrolled release of proinflammatory cytokines is well known, the concept of a cytokine storm and the biological consequences of cytokine overproduction are not clearly defined. Cytokine storms are associated with a wide variety of infectious and noninfectious diseases. The term was popularized largely in the context of avian H5N1 influenza virus infection, bringing the term into popular media. In this review, we focus on the cytokine storm in the context of virus infection, and we highlight how high-throughput genomic methods are revealing the importance of the kinetics of cytokine gene expression and the remarkable degree of redundancy and overlap in cytokine signaling. We also address evidence for and against the role of the cytokine storm in the pathology of clinical and infectious disease and discuss why it has been so difficult to use knowledge of the cytokine storm and immunomodulatory therapies to improve the clinical outcomes for patients with severe acute infections.