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Showing papers by "Cardiff University published in 2012"


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: Molpro (available at http://www.molpro.net) is a general-purpose quantum chemical program as discussed by the authors, which uses local approximations combined with explicit correlation treatments, highly accurate coupled-cluster calculations are now possible for molecules with up to approximately 100 atoms.
Abstract: Molpro (available at http://www.molpro.net) is a general-purpose quantum chemical program. The original focus was on high-accuracy wave function calculations for small molecules, but using local approximations combined with explicit correlation treatments, highly accurate coupled-cluster calculations are now possible for molecules with up to approximately 100 atoms. Recently, multireference correlation treatments were also made applicable to larger molecules. Furthermore, an efficient implementation of density functional theory is available.

2,999 citations


Journal ArticleDOI
09 Aug 2012-Nature
TL;DR: The data support a relationship between diet, microbiota and health status, and indicate a role for diet-driven microbiota alterations in varying rates of health decline upon ageing.
Abstract: Alterations in intestinal microbiota composition are associated with several chronic conditions, including obesity and inflammatory diseases. The microbiota of older people displays greater inter-individual variation than that of younger adults. Here we show that the faecal microbiota composition from 178 elderly subjects formed groups, correlating with residence location in the community, day-hospital, rehabilitation or in long-term residential care. However, clustering of subjects by diet separated them by the same residence location and microbiota groupings. The separation of microbiota composition significantly correlated with measures of frailty, co-morbidity, nutritional status, markers of inflammation and with metabolites in faecal water. The individual microbiota of people in long-stay care was significantly less diverse than that of community dwellers. Loss of community-associated microbiota correlated with increased frailty. Collectively, the data support a relationship between diet, microbiota and health status, and indicate a role for diet-driven microbiota alterations in varying rates of health decline upon ageing.

2,622 citations


Journal ArticleDOI
TL;DR: A model of how to do shared decision making that is based on choice, option and decision talk is proposed that is practical, easy to remember, and can act as a guide to skill development.
Abstract: The principles of shared decision making are well documented but there is a lack of guidance about how to accomplish the approach in routine clinical practice. Our aim here is to translate existing conceptual descriptions into a three-step model that is practical, easy to remember, and can act as a guide to skill development. Achieving shared decision making depends on building a good relationship in the clinical encounter so that information is shared and patients are supported to deliberate and express their preferences and views during the decision making process. To accomplish these tasks, we propose a model of how to do shared decision making that is based on choice, option and decision talk. The model has three steps: a) introducing choice, b) describing options, often by integrating the use of patient decision support, and c) helping patients explore preferences and make decisions. This model rests on supporting a process of deliberation, and on understanding that decisions should be influenced by exploring and respecting “what matters most” to patients as individuals, and that this exploration in turn depends on them developing informed preferences.

2,596 citations


Journal ArticleDOI
TL;DR: Concentrating on recent advances, this article covers industrial aspects, inorganic materials, organic synthesis, cocrystallisation, pharmaceutical aspects, metal complexes, supramolecular aspects and characterization methods.
Abstract: The aim of this critical review is to provide a broad but digestible overview of mechanochemical synthesis, i.e. reactions conducted by grinding solid reactants together with no or minimal solvent. Although mechanochemistry has historically been a sideline approach to synthesis it may soon move into the mainstream because it is increasingly apparent that it can be practical, and even advantageous, and because of the opportunities it provides for developing more sustainable methods. Concentrating on recent advances, this article covers industrial aspects, inorganic materials, organic synthesis, cocrystallisation, pharmaceutical aspects, metal complexes (including metal–organic frameworks), supramolecular aspects and characterization methods. The historical development, mechanistic aspects, limitations and opportunities are also discussed (314 references).

2,102 citations



Journal ArticleDOI
TL;DR: Unipolar depressive disorder in adolescence is common worldwide but often unrecognised, and the incidence, notably in girls, rises sharply after puberty and, by the end of adolescence, the 1 year prevalence rate exceeds 4%.

1,556 citations


Journal ArticleDOI
TL;DR: In this paper, a multi-disciplinary review explores past attempts to define wellbeing and provides an overview of the main theoretical perspectives, from the work of Aristotle to the present day, concluding that it would be appropriate for a new definition of wellbeing to centre on a state of equilibrium or balance that can be affected by life events or challenges.
Abstract: Wellbeing is a growing area of research, yet the question of how it should be defined remains unanswered. This multi-disciplinary review explores past attempts to define wellbeing and provides an overview of the main theoretical perspectives, from the work of Aristotle to the present day. The article argues that many attempts at expressing its nature have focused purely on dimensions of wellbeing, rather than on definition. Among these theoretical perspectives, we highlight the pertinence of dynamic equilibrium theory of wellbeing (Headey & Wearing, 1989), the effect of life challenges on homeostasis (Cummins, 2010) and the lifespan model of development (Hendry & Kloep, 2002). Consequently, we conclude that it would be appropriate for a new definition of wellbeing to centre on a state of equilibrium or balance that can be affected by life events or challenges. The article closes by proposing this new definition, which we believe to be simple, universal in application, optimistic and a basis for measurement. This definition conveys the multi-faceted nature of wellbeing and can help individuals and policy makers move forward in their understanding of this popular term.

1,286 citations


Journal ArticleDOI
TL;DR: It is confirmed that abiraterone acetate significantly prolongs overall survival in patients with metastatic castration-resistant prostate cancer who have progressed after docetaxel treatment.
Abstract: Background Abiraterone acetate improved overall survival in metastatic castration-resistant prostate cancer at a preplanned interim analysis of the COU-AA-301 double-blind, placebo-controlled phase 3 study. Here, we present the final analysis of the study before crossover from placebo to abiraterone acetate (after 775 of the prespecified 797 death events). Methods Between May 8, 2008, and July 28, 2009, this study enrolled 1195 patients at 147 sites in 13 countries. Patients were eligible if they had metastatic castration-resistant prostate cancer progressing after docetaxel. Patients were stratified according to baseline Eastern Cooperative Oncology Group (ECOG) performance status, worst pain over the past 24 h on the Brief Pain Inventory-Short Form, number of previous chemotherapy regimens, and type of progression. Patients were randomly assigned (ratio 2:1) to receive either abiraterone acetate (1000 mg, once daily and orally) plus prednisone (5 mg, orally twice daily) or placebo plus prednisone with a permuted block method via an interactive web response system. The primary endpoint was overall survival, analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00638690. Findings Of the 1195 eligible patients, 797 were randomly assigned to receive abiraterone acetate plus prednisone (abiraterone group) and 398 to receive placebo plus prednisone (placebo group). At median follow-up of 20·2 months (IQR 18·4—22·1), median overall survival for the abiraterone group was longer than in the placebo group (15·8 months [95% CI 14·8—17·0] vs 11·2 months [10·4—13·1]; hazard ratio [HR] 0·74, 95% CI 0·64—0·86; p<0·0001). Median time to PSA progression (8·5 months, 95% CI 8·3—11·1, in the abiraterone group vs 6·6 months, 5·6—8·3, in the placebo group; HR 0·63, 0·52—0·78; p<0·0001), median radiologic progression-free survival (5·6 months, 5·6—6·5, vs 3·6 months, 2·9—5·5; HR 0·66, 0·58—0·76; p<0·0001), and proportion of patients who had a PSA response (235 [29·5%] of 797 patients vs 22 [5·5%] of 398; p<0·0001) were all improved in the abiraterone group compared with the placebo group. The most common grade 3—4 adverse events were fatigue (72 [9%] of 791 patients in the abiraterone group vs 41 [10%] of 394 in the placebo group), anaemia (62 [8%] vs 32 [8%]), back pain (56 [7%] vs 40 [10%]), and bone pain (51 [6%] vs 31 [8%]). Interpretation This final analysis confirms that abiraterone acetate significantly prolongs overall survival in patients with metastatic castration-resistant prostate cancer who have progressed after docetaxel treatment. No new safety signals were identified with increased follow-up. Funding Janssen Research & Development.

1,189 citations


Journal ArticleDOI
17 Feb 2012-Science
TL;DR: Functional and evolutionary differences between LoF-tolerant and recessive disease genes and a method for using these differences to prioritize candidate genes found in clinical sequencing studies are described.
Abstract: Genome-sequencing studies indicate that all humans carry many genetic variants predicted to cause loss of function (LoF) of protein-coding genes, suggesting unexpected redundancy in the human genome. Here we apply stringent filters to 2951 putative LoF variants obtained from 185 human genomes to determine their true prevalence and properties. We estimate that human genomes typically contain ~100 genuine LoF variants with ~20 genes completely inactivated. We identify rare and likely deleterious LoF alleles, including 26 known and 21 predicted severe disease-causing variants, as well as common LoF variants in nonessential genes. We describe functional and evolutionary differences between LoF-tolerant and recessive disease genes and a method for using these differences to prioritize candidate genes found in clinical sequencing studies.

1,186 citations


Journal ArticleDOI
TL;DR: Vesiclepedia is a community-annotated compendium of molecular data on extracellular vesicles that aims to provide a single authoritative source for information on vesicle structure and function.
Abstract: Extracellular vesicles (EVs) are membraneous vesicles released by a variety of cells into their microenvironment. Recent studies have elucidated the role of EVs in intercellular communication, pathogenesis, drug, vaccine and gene-vector delivery, and as possible reservoirs of biomarkers. These findings have generated immense interest, along with an exponential increase in molecular data pertaining to EVs. Here, we describe Vesiclepedia, a manually curated compendium of molecular data (lipid, RNA, and protein) identified in different classes of EVs from more than 300 independent studies published over the past several years. Even though databases are indispensable resources for the scientific community, recent studies have shown that more than 50% of the databases are not regularly updated. In addition, more than 20% of the database links are inactive. To prevent such database and link decay, we have initiated a continuous community annotation project with the active involvement of EV researchers. The EV research community can set a gold standard in data sharing with Vesiclepedia, which could evolve as a primary resource for the field.

Journal ArticleDOI
TL;DR: Empirical approaches have yielded new hypotheses about aetiology and now provide data on the often debated genetic architectures of these conditions, which have implications for future research strategies.
Abstract: Psychiatric disorders are among the most intractable enigmas in medicine In the past 5 years, there has been unprecedented progress on the genetics of many of these conditions In this Review, we discuss the genetics of nine cardinal psychiatric disorders (namely, Alzheimer's disease, attention-deficit hyperactivity disorder, alcohol dependence, anorexia nervosa, autism spectrum disorder, bipolar disorder, major depressive disorder, nicotine dependence and schizophrenia) Empirical approaches have yielded new hypotheses about aetiology and now provide data on the often debated genetic architectures of these conditions, which have implications for future research strategies Further study using a balanced portfolio of methods to assess multiple forms of genetic variation is likely to yield many additional new findings

Journal ArticleDOI
29 Nov 2012-Nature
TL;DR: It is shown that metabolites of vitamin B represent a class of antigen that are presented by MR1 for MAIT-cell immunosurveillance, and data suggest that MAIT cells use these metabolites to detect microbial infection.
Abstract: Antigen-presenting molecules, encoded by the major histocompatibility complex (MHC) and CD1 family, bind peptide- and lipid-based antigens, respectively, for recognition by T cells. Mucosal-associated invariant T (MAIT) cells are an abundant population of innate-like T cells in humans that are activated by an antigen(s) bound to the MHC class I-like molecule MR1. Although the identity of MR1-restricted antigen(s) is unknown, it is present in numerous bacteria and yeast. Here we show that the structure and chemistry within the antigen-binding cleft of MR1 is distinct from the MHC and CD1 families. MR1 is ideally suited to bind ligands originating from vitamin metabolites. The structure of MR1 in complex with 6-formyl pterin, a folic acid (vitamin B9) metabolite, shows the pterin ring sequestered within MR1. Furthermore, we characterize related MR1-restricted vitamin derivatives, originating from the bacterial riboflavin (vitamin B2) biosynthetic pathway, which specifically and potently activate MAIT cells. Accordingly, we show that metabolites of vitamin B represent a class of antigen that are presented by MR1 for MAIT-cell immunosurveillance. As many vitamin biosynthetic pathways are unique to bacteria and yeast, our data suggest that MAIT cells use these metabolites to detect microbial infection.

Journal ArticleDOI
TL;DR: The power and pitfalls of NGS diet methods are reviewed, the critical factors to take into account when choosing or designing a suitable barcode are presented and the validation of data accuracy including the viability of producing quantitative data is discussed.
Abstract: The analysis of food webs and their dynamics facilitates understanding of the mechanistic processes behind community ecology and ecosystem functions. Having accurate techniques for determining dietary ranges and components is critical for this endeavour. While visual analyses and early molecular approaches are highly labour intensive and often lack resolution, recent DNA-based approaches potentially provide more accurate methods for dietary studies. A suite of approaches have been used based on the identification of consumed species by characterization of DNA present in gut or faecal samples. In one approach, a standardized DNA region (DNA barcode) is PCR amplified, amplicons are sequenced and then compared to a reference database for identification. Initially, this involved sequencing clones from PCR products, and studies were limited in scale because of the costs and effort required. The recent development of next generation sequencing (NGS) has made this approach much more powerful, by allowing the direct characterization of dozens of samples with several thousand sequences per PCR product, and has the potential to reveal many consumed species simultaneously (DNA metabarcoding). Continual improvement of NGS technologies, on-going decreases in costs and current massive expansion of reference databases make this approach promising. Here we review the power and pitfalls of NGS diet methods. We present the critical factors to take into account when choosing or designing a suitable barcode. Then, we consider both technical and analytical aspects of NGS diet studies. Finally, we discuss the validation of data accuracy including the viability of producing quantitative data.

Journal ArticleDOI
TL;DR: A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD, suggesting a one-off expansion occurring about 1500 years ago.
Abstract: Background We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Methods We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. Findings In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. Interpretation A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. Funding Full funding sources listed at end of paper (see Acknowledgments).

Journal ArticleDOI
TL;DR: Findings clearly point to the utility of risk communication techniques designed to reduce psychological distance, and highlighting the potentially very serious distant impacts of climate change may also be useful in promoting sustainable behavior, even among those already concerned.
Abstract: Avoiding dangerous climate change is one of the most urgent social risk issues we face today and understanding related public perceptions is critical to engaging the public with the major societal transformations required to combat climate change. Analyses of public perceptions have indicated that climate change is perceived as distant on a number of different dimensions. However, to date there has been no in-depth exploration of the psychological distance of climate change. This study uses a nationally representative British sample in order to systematically explore and characterize each of the four theorized dimensions of psychological distance—temporal, social, and geographical distance, and uncertainty—in relation to climate change. We examine how each of these different aspects of psychological distance relate to each other as well as to concerns about climate change and sustainable behavior intentions. Results indicate that climate change is both psychologically distant and proximal in relation to different dimensions. Lower psychological distance was generally associated with higher levels of concern, although perceived impacts on developing countries, as an indicator of social distance, was also significantly related to preparedness to act on climate change. Our findings clearly point to the utility of risk communication techniques designed to reduce psychological distance. However, highlighting the potentially very serious distant impacts of climate change may also be useful in promoting sustainable behavior, even among those already concerned.

Journal ArticleDOI
Stephen Kaptoge1, Emanuele Di Angelantonio1, Lisa Pennells1, Angela M. Wood1, Ian R. White2, Pei Gao1, Matthew G. Walker1, Alexander M. W. Cargill Thompson1, Nadeem Sarwar1, Muriel J. Caslake3, Adam S. Butterworth1, Philippe Amouyel4, Gerd Assmann, Stephan J. L. Bakker5, Elizabeth L M Barr6, Elizabeth Barrett-Connor7, Emelia J. Benjamin8, Cecilia Björkelund9, Hermann Brenner10, Eric J. Brunner11, Robert Clarke12, Jackie A. Cooper11, Peter Cremer13, Mary Cushman14, Gilles R. Dagenais, Ralph B. D'Agostino8, Rachel Dankner, George Davey-Smith15, Dorly J. H. Deeg16, Jacqueline M. Dekker16, Gunnar Engström17, Aaron R. Folsom18, F. Gerry R. Fowkes19, John Gallacher20, J. Michael Gaziano21, Simona Giampaoli22, Richard F. Gillum23, Albert Hofman24, Barbara V. Howard25, Erik Ingelsson26, Hiroyasu Iso27, Torben Jørgensen28, Stefan Kiechl29, Akihiko Kitamura, Yutaka Kiyohara30, Wolfgang Koenig31, Daan Kromhout32, Lewis H. Kuller33, Debbie A Lawlor15, Tom W. Meade34, Aulikki Nissinen35, Børge G. Nordestgaard28, Altan Onat36, Demosthenes B. Panagiotakos37, Bruce M. Psaty38, Beatriz L. Rodriguez39, Annika Rosengren9, Veikko Salomaa35, Jussi Kauhanen40, Jukka T. Salonen41, Jonathan A. Shaffer42, Steven Shea42, Ian Ford3, Coen D.A. Stehouwer43, Timo E. Strandberg44, Robert W. Tipping45, Alberto Tosetto, Sylvia Wassertheil-Smoller46, Patrik Wennberg47, Rudi G. J. Westendorp48, Peter H. Whincup49, Lars Wilhelmsen9, Mark Woodward50, Gordon D.O. Lowe3, Nicholas J. Wareham2, Kay-Tee Khaw1, Naveed Sattar3, Chris J. Packard3, Vilmundur Gudnason51, Paul M. Ridker21, Mark B. Pepys11, Simon G. Thompson1, John Danesh1 
TL;DR: It is estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened.
Abstract: Background There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events. Methods We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen. Results The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P = 20%) (P = 20% and for those with certain other risk factors, such as diabetes, irrespective of their 10-year predicted risk), additional targeted assessment of CRP or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years. Conclusions In a study of people without known cardiovascular disease, we estimated that under current treatment guidelines, assessment of the CRP or fibrinogen level in people at intermediate risk for a cardiovascular event could help prevent one additional event over a period of 10 years for every 400 to 500 people screened. (Funded by the British Heart Foundation and others.)

Journal ArticleDOI
TL;DR: A specific objective of this review article is to motivate researchers to synthesize some of the "designer" bimetallic catalysts with specific nanostructures, inspired from recent advances in the area of materials chemistry, and to utilize them for the transformation of biomass derived materials that are very complex and pose different challenges compared to those of simple organic molecules.
Abstract: This Critical Review provides an overview of the recent developments in the synthesis and characterization of bimetallic nanoparticles. Initially the review follows a materials science perspective on preparing bimetallic nanoparticles with designer morphologies, after which the emphasis shifts towards recent developments in using these bimetallic particles for catalysing either oxidation or reduction. In the final part of this review we present an overview of the utilization of bimetallic catalyst systems for the transformation of bio-renewable substrates and reactions related to the realization of a bio-refinery. Because of the sheer number of examples of transformations in this area, a few key examples, namely selective oxidation, hydrogenation/hydrogenolysis and reforming of biomass derived molecules, have been chosen for this review. Reports of bimetallic catalysts being used for the aforementioned transformations are critically analysed and the potential for exploiting such bimetallic catalysts have also been highlighted. A specific objective of this review article is to motivate researchers to synthesize some of the “designer” bimetallic catalysts with specific nanostructures, inspired from recent advances in the area of materials chemistry, and to utilize them for the transformation of biomass derived materials that are very complex and pose different challenges compared to those of simple organic molecules. We consider that supported bimetallic nanoparticles have an important role to play as catalysts in our quest for a more green and sustainable society.

Journal ArticleDOI
Daniel I. Swerdlow1, Michael V. Holmes1, Karoline Kuchenbaecker2, Engmann Jel.1, Tina Shah1, Reecha Sofat1, Yiran Guo, C Chung1, Anne Peasey1, Roman Pfister3, Simon P. Mooijaart4, Helen Ireland1, Maarten Leusink5, Claudia Langenberg3, KaWah Li1, Jutta Palmen1, Phil Howard1, Jackie A. Cooper1, Fotios Drenos1, John Hardy1, Mike A. Nalls6, Yun Li7, Gordon D.O. Lowe8, Marlene C. W. Stewart9, S. J. Bielinski10, Julian Peto11, Nicholas J. Timpson12, John Gallacher13, Malcolm G. Dunlop9, Richard S. Houlston, Ian Tomlinson14, Ioanna Tzoulaki15, Jian'an Luan2, Boer Jma.2, Nita G. Forouhi2, N. C. Onland-Moret5, Y. T. van der Schouw16, Renate B. Schnabel16, Jaroslav A. Hubacek, Růžena Kubínová, Migle Baceviciene17, Abdonas Tamosiunas17, Andrzej Pajak18, Roman Topor-Madry18, Sofia Malyutina19, Damiano Baldassarre, Bengt Sennblad20, Elena Tremoli, U de Faire21, Luigi Ferrucci21, S Bandenelli, Tetsu Tanaka21, James F. Meschia10, AB Singleton6, Gerjan Navis22, I. Mateo Leach22, Bakker Sjl.22, Ron T. Gansevoort, Ian Ford8, Stephen E. Epstein23, Mary-Susan Burnett23, Joe Devaney23, Johan Wouter Jukema4, Westendorp Rgj.5, G Jan de Borst5, Y. van der Graaf5, P A de Jong5, Mailand-van der Zee A-H.5, Olaf H. Klungel5, A. de Boer5, P. A. Doevendans5, Jeffrey W. Stephens24, Charles B. Eaton25, Jennifer G. Robinson26, JoAnn E. Manson27, F G Fowkes28, Timothy M. Frayling28, Jenna Price9, Peter H. Whincup11, Richard W Morris1, Debbie A Lawlor12, George Davey Smith12, Yoav Ben-Shlomo12, Susan Redline27, Leslie A. Lange29, Meena Kumari1, Nicholas J. Wareham2, Verschuren Wmm.30, Emelia J. Benjamin30, John C. Whittaker11, Anders Hamsten20, Frank Dudbridge11, Delaney Jac.31, Andrew Wong31, Diana Kuh31, Rebecca Hardy31, Berta Almoguera Castillo7, John Connolly7, P. van der Harst, Eric J. Brunner1, Michael Marmot1, Christina L. Wassel32, Steve E. Humphries1, P.J. Talmud1, Mika Kivimäki1, Folkert W. Asselbergs5, Mikhail I. Voevoda19, Martin Bobak1, Hynek Pikhart1, James G. Wilson33, Hakon Hakonarson7, Alexander P. Reiner34, Brendan J. Keating7, Naveed Sattar8, Aroon D. Hingorani1, Juan P. Casas11 
TL;DR: IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials and could help to validate and prioritise novel drug targets or to repurpose existing agents and targets for new therapeutic uses.

Journal ArticleDOI
Seb Oliver1, James J. Bock2, James J. Bock3, Bruno Altieri4, Alexandre Amblard5, V. Arumugam6, Herve Aussel7, Tom Babbedge8, Alexandre Beelen9, Matthieu Béthermin9, Matthieu Béthermin7, Andrew Blain3, Alessandro Boselli10, C. Bridge3, Drew Brisbin11, V. Buat10, Denis Burgarella10, N. Castro-Rodríguez12, N. Castro-Rodríguez13, Antonio Cava14, P. Chanial7, Michele Cirasuolo15, David L. Clements8, A. Conley16, L. Conversi4, Asantha Cooray3, Asantha Cooray17, C. D. Dowell2, C. D. Dowell3, Elizabeth Dubois1, Eli Dwek18, Simon Dye19, Stephen Anthony Eales20, David Elbaz7, Duncan Farrah1, A. Feltre21, P. Ferrero13, P. Ferrero12, N. Fiolet9, N. Fiolet22, M. Fox8, Alberto Franceschini21, Walter Kieran Gear20, E. Giovannoli10, Jason Glenn16, Yan Gong17, E. A. González Solares23, Matthew Joseph Griffin20, Mark Halpern24, Martin Harwit, Evanthia Hatziminaoglou, Sebastien Heinis10, Peter Hurley1, Ho Seong Hwang7, A. Hyde8, Edo Ibar15, O. Ilbert10, K. G. Isaak25, Rob Ivison15, Rob Ivison6, Guilaine Lagache9, E. Le Floc'h7, L. R. Levenson3, L. R. Levenson2, B. Lo Faro21, Nanyao Y. Lu3, S. C. Madden7, Bruno Maffei26, Georgios E. Magdis7, G. Mainetti21, Lucia Marchetti21, G. Marsden24, J. Marshall2, J. Marshall3, A. M. J. Mortier8, Hien Nguyen2, Hien Nguyen3, B. O'Halloran8, Alain Omont22, Mat Page27, P. Panuzzo7, Andreas Papageorgiou20, H. Patel8, Chris Pearson28, Chris Pearson29, Ismael Perez-Fournon13, Ismael Perez-Fournon12, Michael Pohlen20, Jonathan Rawlings27, Gwenifer Raymond20, Dimitra Rigopoulou29, Dimitra Rigopoulou30, L. Riguccini7, D. Rizzo8, Giulia Rodighiero21, Isaac Roseboom1, Isaac Roseboom6, Michael Rowan-Robinson8, M. Sanchez Portal4, Benjamin L. Schulz3, Douglas Scott24, Nick Seymour31, Nick Seymour27, D. L. Shupe3, A. J. Smith1, Jamie Stevens32, M. Symeonidis27, Markos Trichas33, K. E. Tugwell27, Mattia Vaccari21, Ivan Valtchanov4, Joaquin Vieira3, Marco P. Viero3, L. Vigroux22, Lifan Wang1, Robyn L. Ward1, Julie Wardlow17, G. Wright15, C. K. Xu3, Michael Zemcov3, Michael Zemcov2 
TL;DR: The Herschel Multi-tiered Extragalactic Survey (HerMES) is a legacy program designed to map a set of nested fields totalling ∼380deg^2 as mentioned in this paper.
Abstract: The Herschel Multi-tiered Extragalactic Survey (HerMES) is a legacy programme designed to map a set of nested fields totalling ∼380 deg^2. Fields range in size from 0.01 to ∼20 deg^2, using the Herschel-Spectral and Photometric Imaging Receiver (SPIRE) (at 250, 350 and 500 μm) and the Herschel-Photodetector Array Camera and Spectrometer (PACS) (at 100 and 160 μm), with an additional wider component of 270 deg^2 with SPIRE alone. These bands cover the peak of the redshifted thermal spectral energy distribution from interstellar dust and thus capture the reprocessed optical and ultraviolet radiation from star formation that has been absorbed by dust, and are critical for forming a complete multiwavelength understanding of galaxy formation and evolution. The survey will detect of the order of 100 000 galaxies at 5σ in some of the best-studied fields in the sky. Additionally, HerMES is closely coordinated with the PACS Evolutionary Probe survey. Making maximum use of the full spectrum of ancillary data, from radio to X-ray wavelengths, it is designed to facilitate redshift determination, rapidly identify unusual objects and understand the relationships between thermal emission from dust and other processes. Scientific questions HerMES will be used to answer include the total infrared emission of galaxies, the evolution of the luminosity function, the clustering properties of dusty galaxies and the properties of populations of galaxies which lie below the confusion limit through lensing and statistical techniques. This paper defines the survey observations and data products, outlines the primary scientific goals of the HerMES team, and reviews some of the early results.

Journal ArticleDOI
02 Mar 2012-Science
TL;DR: This paper reviewed events exhibiting evidence for elevated atmospheric CO2, global warming, and ocean acidification over the past ~300 million years of Earth's history, some with contemporaneous extinction or evolutionary turnover among marine calcifiers.
Abstract: Ocean acidification may have severe consequences for marine ecosystems; however, assessing its future impact is difficult because laboratory experiments and field observations are limited by their reduced ecologic complexity and sample period, respectively. In contrast, the geological record contains long-term evidence for a variety of global environmental perturbations, including ocean acidification plus their associated biotic responses. We review events exhibiting evidence for elevated atmospheric CO2, global warming, and ocean acidification over the past ~300 million years of Earth’s history, some with contemporaneous extinction or evolutionary turnover among marine calcifiers. Although similarities exist, no past event perfectly parallels future projections in terms of disrupting the balance of ocean carbonate chemistry—a consequence of the unprecedented rapidity of CO2 release currently taking place.

Journal ArticleDOI
TL;DR: The data indicate that defects in NMDAR postsynaptic signalling and, possibly, ARC complexes, which are known to be important in synaptic plasticity and cognition, play a significant role in the pathogenesis of schizophrenia.
Abstract: A small number of rare, recurrent genomic copy number variants (CNVs) are known to substantially increase susceptibility to schizophrenia. As a consequence of the low fecundity in people with schizophrenia and other neurodevelopmental phenotypes to which these CNVs contribute, CNVs with large effects on risk are likely to be rapidly removed from the population by natural selection. Accordingly, such CNVs must frequently occur as recurrent de novo mutations. In a sample of 662 schizophrenia proband–parent trios, we found that rare de novo CNV mutations were significantly more frequent in cases (5.1% all cases, 5.5% family history negative) compared with 2.2% among 2623 controls, confirming the involvement of de novo CNVs in the pathogenesis of schizophrenia. Eight de novo CNVs occurred at four known schizophrenia loci (3q29, 15q11.2, 15q13.3 and 16p11.2). De novo CNVs of known pathogenic significance in other genomic disorders were also observed, including deletion at the TAR (thrombocytopenia absent radius) region on 1q21.1 and duplication at the WBS (Williams– Beuren syndrome) region at 7q11.23. Multiple de novos spanned genes encoding members of the DLG (discs large) family of membrane-associated guanylate kinases (MAGUKs) that are components of the postsynaptic density (PSD). Two de novos also affected EHMT1, a histone methyl transferase known to directly regulate DLG family members. Using a systems biology approach and merging novel CNV and proteomics data sets, systematic analysis of synaptic protein complexes showed that, compared with control CNVs, case de novos were significantly enriched for the PSD proteome (P=1.72 � 10 � 6 ). This was largely explained by enrichment for members of the N-methyl-D-aspartate receptor (NMDAR) (P=4.24 � 10 � 6 ) and neuronal activity-regulated cytoskeleton-associated protein (ARC) (P=3.78 � 10 � 8 ) postsynaptic signalling complexes. In an analysis of 18492 subjects (7907 cases and 10585 controls), case CNVs were enriched for members of the NMDAR complex (P=0.0015) but not ARC (P=0.14). Our data indicate that defects in NMDAR postsynaptic signalling and, possibly, ARC complexes, which are known to be important in synaptic plasticity and cognition, play a significant role in the pathogenesis of schizophrenia. Molecular Psychiatry (2012) 17, 142–153; doi:10.1038/mp.2011.154; published online 15 November 2011

Journal ArticleDOI
Lam C. Tsoi1, Sarah L. Spain2, Sarah L. Spain1, Jo Knight1  +212 moreInstitutions (52)
TL;DR: A meta-analysis of genome-wide association studies and independent data sets genotyped on the Immunochip identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals, and identified five independent signals within previously known loci.
Abstract: To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.

Journal ArticleDOI
27 Jan 2012-BMJ
TL;DR: Although many clinicians feel they already use shared decision making, research shows a perception-reality gap and A M Stiggelbout and colleagues discuss why it is important and highlight some best practices.
Abstract: Although many clinicians feel they already use shared decision making, research shows a perception-reality gap. A M Stiggelbout and colleagues discuss why it is important and highlight some best practices

Journal ArticleDOI
TL;DR: Information is provided on the current state of knowledge on the biology, identification, epidemiology, pathogenicity and antifungal resistance of C. glabrata, C. parapsilosis and C. tropicalis.
Abstract: The incidence of infections caused by Candida species (candidosis) has increased considerably over the past three decades, mainly due to the rise of the AIDS epidemic, an increasingly aged population, higher numbers of immunocompromised patients and the more widespread use of indwelling medical devices. Candida albicans is the main cause of candidosis; however, non-C. albicans Candida (NCAC) species such as Candida glabrata, Candida tropicalis and Candida parapsilosis are now frequently identified as human pathogens. The apparent increased emergence of these species as human pathogens can be attributed to improved identification methods and also associated with the degree of diseases of the patients, the interventions that they were subjected and the drugs used. Candida pathogenicity is facilitated by a number of virulence factors, most importantly adherence to host surfaces including medical devices, biofilm formation and secretion of hydrolytic enzymes (e.g. proteases, phospholipases and haemolysins). Furthermore, despite extensive research to identify pathogenic factors in fungi, particularly in C. albicans, relatively little is known about NCAC species. This review provides information on the current state of knowledge on the biology, identification, epidemiology, pathogenicity and antifungal resistance of C. glabrata, C. parapsilosis and C. tropicalis.

Journal ArticleDOI
TL;DR: Psilocybin caused a significant decrease in the positive coupling between the mPFC and PCC, which strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain's key connector hubs, enabling a state of unconstrained cognition.
Abstract: Psychedelic drugs have a long history of use in healing ceremonies, but despite renewed interest in their therapeutic potential, we continue to know very little about how they work in the brain. Here we used psilocybin, a classic psychedelic found in magic mushrooms, and a task-free functional MRI (fMRI) protocol designed to capture the transition from normal waking consciousness to the psychedelic state. Arterial spin labeling perfusion and blood-oxygen level-dependent (BOLD) fMRI were used to map cerebral blood flow and changes in venous oxygenation before and after intravenous infusions of placebo and psilocybin. Fifteen healthy volunteers were scanned with arterial spin labeling and a separate 15 with BOLD. As predicted, profound changes in consciousness were observed after psilocybin, but surprisingly, only decreases in cerebral blood flow and BOLD signal were seen, and these were maximal in hub regions, such as the thalamus and anterior and posterior cingulate cortex (ACC and PCC). Decreased activity in the ACC/medial prefrontal cortex (mPFC) was a consistent finding and the magnitude of this decrease predicted the intensity of the subjective effects. Based on these results, a seed-based pharmaco-physiological interaction/functional connectivity analysis was performed using a medial prefrontal seed. Psilocybin caused a significant decrease in the positive coupling between the mPFC and PCC. These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain's key connector hubs, enabling a state of unconstrained cognition.

Journal ArticleDOI
Seb Oliver1, James J. Bock2, James J. Bock3, Bruno Altieri4, Alexandre Amblard5, V. Arumugam6, Herve Aussel7, Tom Babbedge8, Alexandre Beelen, Matthieu Béthermin7, Andrew Blain3, Alessandro Boselli9, C. Bridge3, Drew Brisbin10, V. Buat9, Denis Burgarella9, N. Castro-Rodríguez11, N. Castro-Rodríguez12, Antonio Cava13, P. Chanial7, Michele Cirasuolo14, David L. Clements8, A. Conley15, L. Conversi4, Asantha Cooray16, Asantha Cooray3, C. D. Dowell3, C. D. Dowell2, Elizabeth Dubois1, Eli Dwek17, Simon Dye18, Stephen Anthony Eales19, David Elbaz7, Duncan Farrah1, A. Feltre20, P. Ferrero12, P. Ferrero11, N. Fiolet21, M. Fox8, Alberto Franceschini20, Walter Kieran Gear19, E. Giovannoli9, Jason Glenn15, Yan Gong16, E. A. González Solares22, Matthew Joseph Griffin19, Mark Halpern23, Martin Harwit, Evanthia Hatziminaoglou, Sebastien Heinis9, Peter Hurley1, Ho Seong Hwang7, A. Hyde8, Edo Ibar14, O. Ilbert9, K. G. Isaak24, Rob Ivison14, Rob Ivison6, Guilaine Lagache, E. Le Floc'h7, L. R. Levenson3, L. R. Levenson2, B. Lo Faro20, Nanyao Y. Lu3, S. C. Madden7, Bruno Maffei25, Georgios E. Magdis7, G. Mainetti20, Lucia Marchetti20, G. Marsden23, J. Marshall3, J. Marshall2, A. M. J. Mortier8, Hien Nguyen3, Hien Nguyen2, B. O'Halloran8, Alain Omont21, Mat Page26, P. Panuzzo7, Andreas Papageorgiou19, H. Patel8, Chris Pearson27, Chris Pearson28, Ismael Perez-Fournon11, Ismael Perez-Fournon12, Michael Pohlen19, Jonathan Rawlings26, Gwenifer Raymond19, Dimitra Rigopoulou29, Dimitra Rigopoulou27, L. Riguccini7, D. Rizzo8, Giulia Rodighiero20, Isaac Roseboom6, Isaac Roseboom1, Michael Rowan-Robinson8, M. Sanchez Portal4, Benjamin L. Schulz3, Douglas Scott23, Nick Seymour26, Nick Seymour30, D. L. Shupe3, A. J. Smith1, Jamie Stevens31, M. Symeonidis26, Markos Trichas32, K. E. Tugwell26, Mattia Vaccari20, Ivan Valtchanov4, Joaquin Vieira3, Marco P. Viero3, L. Vigroux21, Lifan Wang1, Robyn L. Ward1, Julie Wardlow16, G. Wright14, C. K. Xu3, Michael Zemcov3, Michael Zemcov2 
TL;DR: The Herschel Multi-tiered Extragalactic Survey (HerMES) is a legacy program designed to map a set of nested fields totalling ~380 deg^2 as mentioned in this paper.
Abstract: The Herschel Multi-tiered Extragalactic Survey, HerMES, is a legacy program designed to map a set of nested fields totalling ~380 deg^2. Fields range in size from 0.01 to ~20 deg^2, using Herschel-SPIRE (at 250, 350 and 500 \mu m), and Herschel-PACS (at 100 and 160 \mu m), with an additional wider component of 270 deg^2 with SPIRE alone. These bands cover the peak of the redshifted thermal spectral energy distribution from interstellar dust and thus capture the re-processed optical and ultra-violet radiation from star formation that has been absorbed by dust, and are critical for forming a complete multi-wavelength understanding of galaxy formation and evolution. The survey will detect of order 100,000 galaxies at 5\sigma in some of the best studied fields in the sky. Additionally, HerMES is closely coordinated with the PACS Evolutionary Probe survey. Making maximum use of the full spectrum of ancillary data, from radio to X-ray wavelengths, it is designed to: facilitate redshift determination; rapidly identify unusual objects; and understand the relationships between thermal emission from dust and other processes. Scientific questions HerMES will be used to answer include: the total infrared emission of galaxies; the evolution of the luminosity function; the clustering properties of dusty galaxies; and the properties of populations of galaxies which lie below the confusion limit through lensing and statistical techniques. This paper defines the survey observations and data products, outlines the primary scientific goals of the HerMES team, and reviews some of the early results.

Journal ArticleDOI
08 Mar 2012-Nature
TL;DR: A comparison of protein coding genes reveals approximately 500 genes showing accelerated evolution on each of the gorilla, human and chimpanzee lineages, and evidence for parallel acceleration, particularly of genes involved in hearing.
Abstract: Gorillas are humans' closest living relatives after chimpanzees, and are of comparable importance for the study of human origins and evolution. Here we present the assembly and analysis of a genome sequence for the western lowland gorilla, and compare the whole genomes of all extant great ape genera. We propose a synthesis of genetic and fossil evidence consistent with placing the human-chimpanzee and human-chimpanzee-gorilla speciation events at approximately 6 and 10 million years ago. In 30% of the genome, gorilla is closer to human or chimpanzee than the latter are to each other; this is rarer around coding genes, indicating pervasive selection throughout great ape evolution, and has functional consequences in gene expression. A comparison of protein coding genes reveals approximately 500 genes showing accelerated evolution on each of the gorilla, human and chimpanzee lineages, and evidence for parallel acceleration, particularly of genes involved in hearing. We also compare the western and eastern gorilla species, estimating an average sequence divergence time 1.75 million years ago, but with evidence for more recent genetic exchange and a population bottleneck in the eastern species. The use of the genome sequence in these and future analyses will promote a deeper understanding of great ape biology and evolution.

Journal ArticleDOI
Trevor Jones1
TL;DR: The politics of the police, 4th ed., by Robert Reiner, Oxford, Oxford University Press, 2010, 336 pp., £25.99 (paperback), ISBN 978-0-19-928339-2 Even prior to the outbreak of serious rioting acros...
Abstract: The politics of the police, 4th ed., by Robert Reiner, Oxford, Oxford University Press, 2010, 336 pp., £25.99 (paperback), ISBN 978-0-19-928339-2 Even prior to the outbreak of serious rioting acros...

Journal ArticleDOI
TL;DR: A bacterial driver–passenger model for microbial involvement in the development of colorectal cancer is proposed and it is suggested that this model be incorporated into the genetic paradigm of cancer progression.
Abstract: Cancer has long been considered a genetic disease. However, accumulating evidence supports the involvement of infectious agents in the development of cancer, especially in those organs that are continuously exposed to microorganisms, such as the large intestine. Recent next-generation sequencing studies of the intestinal microbiota now offer an unprecedented view of the aetiology of sporadic colorectal cancer and have revealed that the microbiota associated with colorectal cancer contains bacterial species that differ in their temporal associations with developing tumours. Here, we propose a bacterial driver–passenger model for microbial involvement in the development of colorectal cancer and suggest that this model be incorporated into the genetic paradigm of cancer progression.