Ollscoil na Gaillimhe – University of Galway

Although geospatial question answering systems have received increasing attention in recent years, existing prototype systems struggle to properly answer qualitative spatial questions. In this work, we propose a unique framework for answering qualitative spatial questions, which comprises three main components: a geoparser that takes the input questions and extracts place semantic information from text, a reasoning system which is embedded with a crisp reasoner, and finally, answer extraction, which refines the solution space and generates final answers. We present an experimental design to evaluate our framework for point-based cardinal direction calculus (CDC) relations by developing an automated approach for generating three types of synthetic qualitative spatial questions. The initial evaluations of generated answers in our system are promising because a high proportion of answers were labelled correct.

AUTORES: Daniel J Klionsky1745,1749*, Kotb Abdelmohsen840, Akihisa Abe1237, Md Joynal Abedin1762, Hagai Abeliovich425,
\nAbraham Acevedo Arozena789, Hiroaki Adachi1800, Christopher M Adams1669, Peter D Adams57, Khosrow Adeli1981,
\nPeter J Adhihetty1625, Sharon G Adler700, Galila Agam67, Rajesh Agarwal1587, Manish K Aghi1537, Maria Agnello1826,
\nPatrizia Agostinis664, Patricia V Aguilar1960, Julio Aguirre-Ghiso784,786, Edoardo M Airoldi89,422, Slimane Ait-Si-Ali1376,
\nTakahiko Akematsu2010, Emmanuel T Akporiaye1097, Mohamed Al-Rubeai1394, Guillermo M Albaiceta1294,
\nChris Albanese363, Diego Albani561, Matthew L Albert517, Jesus Aldudo128, Hana Alg€ul1164, Mehrdad Alirezaei1198,
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\nGiuseppina Amadoro860, Atsuo Amano930, Consuelo Amantini1554, Santiago Ambrosio1458, Ivano Amelio756,
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\nAgnieszka Bagniewska-Zadworna2, Hua Bai90, Jie Bai667, Xue-Yuan Bai1133, Yannick Bailly884,
\nKithiganahalli Narayanaswamy Balaji473, Walter Balduini2002, Andrea Ballabio316, Rena Balzan1711, Rajkumar Banerjee239,
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\nK Ulrich Bayer1594, Rupert Beale1553, Jean-Fran¸cois Beaulieu1360, George R. Beck Jr48,294, Christoph Becker336,
\nJ David Beckham1595, Pierre-Andr e B edard749, Patrick J Bednarski301, Thomas J Begley1135, Christian Behl1419,
\nChristian Behrends757, Georg MN Behrens406, Kevin E Behrns1627, Eloy Bejarano26, Amine Belaid490,
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\nShalmoli Bhattacharyya973, Sujit K Bhutia838, Caroline Biagosch1159, Michele Wolfe Bianchi520,1378,1381,
\nMartine Biard-Piechaczyk210, Viktor Billes298, Claudia Bincoletto1314, Baris Bingol350, Sara W Bird1128, Marc Bitoun1112,
\nIvana Bjedov1258, Craig Blackstone843, Lionel Blanc1183, Guillermo A Blanco1496, Heidi Kiil Blomhoff1812,
\nEmilio Boada-Romero1297, Stefan B€ockler1464, Marianne Boes1423, Kathleen Boesze-Battaglia1835, Lawrence H Boise286,287,
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\nNathan Brady374, Vania MM Braga469, Claudio Brancolini1997, Gerhard H Braus353, Jos e M Bravo-San Pedro299,393,508,1374,
\nLisa A Brennan322, Emery H Bresnick2022, Patrick Brest490, Dave Bridges1939, Marie-Agn es Bringer124, Marisa Brini1822,
\nGlauber C Brito1311, Bertha Brodin631, Paul S Brookes1872, Eric J Brown352, Karen Brown1690, Hal E Broxmeyer480,
\nAlain Bruhat486,1339, Patricia Chakur Brum1893, John H Brumell446, Nicola Brunetti-Pierri315,1171,
\nRobert J Bryson-Richardson781, Shilpa Buch1777, Alastair M Buchan1819, Hikmet Budak1022, Dmitry V Bulavin118,505,1789,
\nScott J Bultman1792, Geert Bultynck665, Vladimir Bumbasirevic1470, Yan Burelle1356, Robert E Burke216,217,
\nMargit Burmeister1750, Peter B€utikofer1473, Laura Caberlotto1987, Ken Cadwell896, Monika Cahova112, Dongsheng Cai24,
\nJingjing Cai2099, Qian Cai1018, Sara Calatayud2007, Nadine Camougrand1343, Michelangelo Campanella1700,
\nGrant R Campbell1525, Matthew Campbell1249, Silvia Campello556,1876, Robin Candau1769, Isabella Caniggia1983,
\nLavinia Cantoni560, Lizhi Cao116, Allan B Caplan1656, Michele Caraglia1051, Claudio Cardinali1043, Sandra Morais Cardoso1579, Jennifer S Carew208, Laura A Carleton874, Cathleen R Carlin101, Silvia Carloni2002,
\nSven R Carlsson1267, Didac Carmona-Gutierrez1643, Leticia AM Carneiro312, Oliana Carnevali971, Serena Carra1318,
\nAlice Carrier120, Bernadette Carroll900, Caty Casas1324, Josefina Casas1116, Giuliana Cassinelli324, Perrine Castets1462,
\nSusana Castro-Obregon214, Gabriella Cavallini1841, Isabella Ceccherini568, Francesco Cecconi253,555,1884,
\nArthur I Cederbaum459, Valent ın Ce~na199,1281, Simone Cenci1323,2064, Claudia Cerella444, Davide Cervia1996,
\nSilvia Cetrullo1478, Hassan Chaachouay2028, Han-Jung Chae187, Andrei S Chagin634, Chee-Yin Chai626,628,
\nGopal Chakrabarti1502, Georgios Chamilos1601, Edmond YW Chan1142, Matthew TV Chan181, Dhyan Chandra1003,
\nPallavi Chandra548, Chih-Peng Chang818, Raymond Chuen-Chung Chang1653, Ta Yuan Chang345, John C Chatham1434,
\nSaurabh Chatterjee1910, Santosh Chauhan527, Yongsheng Che62, Michael E Cheetham1263, Rajkumar Cheluvappa1783,
\nChun-Jung Chen1153, Gang Chen598,1676, Guang-Chao Chen9, Guoqiang Chen1078, Hongzhuan Chen1077, Jeff W Chen1514,
\nJian-Kang Chen370,371, Min Chen249, Mingzhou Chen2104, Peiwen Chen1823, Qi Chen1674, Quan Chen172,
\nShang-Der Chen138, Si Chen325, Steve S-L Chen10, Wei Chen2125, Wei-Jung Chen829, Wen Qiang Chen979, Wenli Chen1113,
\nXiangmei Chen1133, Yau-Hung Chen1157, Ye-Guang Chen1250, Yin Chen1447, Yingyu Chen953,955, Yongshun Chen2135,
\nYu-Jen Chen712, Yue-Qin Chen1145, Yujie Chen1208, Zhen Chen339, Zhong Chen2123, Alan Cheng1702,
\nChristopher HK Cheng184, Hua Cheng1728, Heesun Cheong814, Sara Cherry1836, Jason Chesney1703,
\nChun Hei Antonio Cheung817, Eric Chevet1359, Hsiang Cheng Chi140, Sung-Gil Chi656, Fulvio Chiacchiera308,
\nHui-Ling Chiang958, Roberto Chiarelli1826, Mario Chiariello235,567,577, Marcello Chieppa835, Lih-Shen Chin290,
\nMario Chiong1285, Gigi NC Chiu878, Dong-Hyung Cho676, Ssang-Goo Cho650, William C Cho982, Yong-Yeon Cho105,
\nYoung-Seok Cho1064, Augustine MK Choi2095, Eui-Ju Choi656, Eun-Kyoung Choi387,400,685, Jayoung Choi1563,
\nMary E Choi2093, Seung-Il Choi2116, Tsui-Fen Chou412, Salem Chouaib395, Divaker Choubey1574, Vinay Choubey1936,
\nKuan-Chih Chow822, Kamal Chowdhury730, Charleen T Chu1856, Tsung-Hsien Chuang827, Taehoon Chun657,
\nHyewon Chung652, Taijoon Chung978, Yuen-Li Chung1194, Yong-Joon Chwae18, Valentina Cianfanelli254,
\nRoberto Ciarcia1775, Iwona A Ciechomska886, Maria Rosa Ciriolo1876, Mara Cirone1042, Sofie Claerhout1694,
\nMichael J Clague1698, Joan Cl aria1457, Peter GH Clarke1687, Robert Clarke361, Emilio Clementi1045,1398, C edric Cleyrat1781,
\nMiriam Cnop1366, Eliana M Coccia574, Tiziana Cocco1459, Patrice Codogno1375, J€orn Coers271, Ezra EW Cohen1533,
\nDavid Colecchia235,567,577, Luisa Coletto25, N uria S Coll123, Emma Colucci-Guyon516, Sergio Comincini1829,
\nMaria Condello578, Katherine L Cook2073, Graham H Coombs1929, Cynthia D Cooper2076, J Mark Cooper1395,
\nIsabelle Coppens601, Maria Tiziana Corasaniti1387, Marco Corazzari485,1884, Ramon Corbalan1566,
\nElisabeth Corcelle-Termeau251, Mario D Cordero1899, Cristina Corral-Ramos1289, Olga Corti507,1109, Andrea Cossarizza1767,
\nPaola Costelli1993, Safia Costes1518, Susan L Cotman721, Ana Coto-Montes946, Sandra Cottet566,1688, Eduardo Couve1301,
\nLori R Covey1015, L Ashley Cowart762, Jeffery S Cox1536, Fraser P Coxon1427, Carolyn B Coyne1846, Mark S Cragg1919,
\nRolf J Craven1679, Tiziana Crepaldi1995, Jose L Crespo1300, Alfredo Criollo1285, Valeria Crippa558, Maria Teresa Cruz1576,
\nAna Maria Cuervo26, Jose M Cuezva1277, Taixing Cui1907, Pedro R Cutillas987, Mark J Czaja27, Maria F Czyzyk-Krzeska1572,
\nRuben K Dagda2068, Uta Dahmen1404, Chunsun Dai800, Wenjie Dai1187, Yun Dai2059, Kevin N Dalby1940,
\nLuisa Dalla Valle1822, Guillaume Dalmasso1340, Marcello D’Amelio557, Markus Damme188, Arlette Darfeuille-Michaud1340,
\nCatherine Dargemont950, Victor M Darley-Usmar1433, Srinivasan Dasarathy205, Biplab Dasgupta202, Srikanta Dash1254,
\nCrispin R Dass242, Hazel Marie Davey8, Lester M Davids1560, David D avila227, Roger J Davis1731, Ted M Dawson604,
\nValina L Dawson606, Paula Daza1898, Jackie de Belleroche470, Paul de Figueiredo1180,1182,
\nRegina Celia Bressan Queiroz de Figueiredo135, Jos e de la Fuente1023, Luisa De Martino1775,
\nAntonella De Matteis1171, Guido RY De Meyer1443, Angelo De Milito631, Mauro De Santi2002,

Our growing awareness of the microbial world's importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth's microbial diversity.

BACKGROUND: Anemia, a common complication of chronic kidney disease, usually develops as a consequence of erythropoietin deficiency. Recombinant human erythropoietin (epoetin alfa) is indicated for the correction of anemia associated with this condition. However, the optimal level of hemoglobin correction is not defined. METHODS: In this open-label trial, we studied 1432 patients with chronic kidney disease, 715 of whom were randomly assigned to receive a dose of epoetin alfa targeted to achieve a hemoglobin level of 13.5 g per deciliter and 717 of whom were assigned to receive a dose targeted to achieve a level of 11.3 g per deciliter. The median study duration was 16 months. The primary end point was a composite of death, myocardial infarction, hospitalization for congestive heart failure (without renal replacement therapy), and stroke. RESULTS: A total of 222 composite events occurred: 125 events in the high-hemoglobin group, as compared with 97 events in the low-hemoglobin group (hazard ratio, 1.34; 95% confidence interval, 1.03 to 1.74; P=0.03). There were 65 deaths (29.3%), 101 hospitalizations for congestive heart failure (45.5%), 25 myocardial infarctions (11.3%), and 23 strokes (10.4%). Seven patients (3.2%) were hospitalized for congestive heart failure and myocardial infarction combined, and one patient (0.5%) died after having a stroke. Improvements in the quality of life were similar in the two groups. More patients in the high-hemoglobin group had at least one serious adverse event. CONCLUSIONS: The use of a target hemoglobin level of 13.5 g per deciliter (as compared with 11.3 g per deciliter) was associated with increased risk and no incremental improvement in the quality of life. (ClinicalTrials.gov number, NCT00211120 [ClinicalTrials.gov].).

, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

The WHO definition of health as complete wellbeing is no longer fit for purpose given the rise of chronic disease. <b>Machteld Huber and colleagues </b>propose changing the emphasis towards the ability to adapt and self manage in the face of social, physical, and emotional challenges

The metaverse has the potential to extend the physical world using augmented and virtual reality technologies allowing users to seamlessly interact within real and simulated environments using avatars and holograms. Virtual environments and immersive games (such as, Second Life, Fortnite, Roblox and VRChat) have been described as antecedents of the metaverse and offer some insight to the potential socio-economic impact of a fully functional persistent cross platform metaverse. Separating the hype and “meta…” rebranding from current reality is difficult, as “big tech” paints a picture of the transformative nature of the metaverse and how it will positively impact people in their work, leisure, and social interaction. The potential impact on the way we conduct business, interact with brands and others, and develop shared experiences is likely to be transformational as the distinct lines between physical and digital are likely to be somewhat blurred from current perceptions. However, although the technology and infrastructure does not yet exist to allow the development of new immersive virtual worlds at scale - one that our avatars could transcend across platforms, researchers are increasingly examining the transformative impact of the metaverse. Impacted sectors include marketing, education, healthcare as well as societal effects relating to social interaction factors from widespread adoption, and issues relating to trust, privacy, bias, disinformation, application of law as well as psychological aspects linked to addiction and impact on vulnerable people. This study examines these topics in detail by combining the informed narrative and multi-perspective approach from experts with varied disciplinary backgrounds on many aspects of the metaverse and its transformational impact. The paper concludes by proposing a future research agenda that is valuable for researchers, professionals and policy makers alike.

BACKGROUND: Widespread application of pulmonary rehabilitation (also known as respiratory rehabilitation) in chronic obstructive pulmonary disease (COPD) should be preceded by demonstrable improvements in function (health-related quality of life, functional and maximal exercise capacity) attributable to the programmes. This review updates the review reported in 2006. OBJECTIVES: To compare the effects of pulmonary rehabilitation versus usual care on health-related quality of life and functional and maximal exercise capacity in persons with COPD. SEARCH METHODS: We identified additional randomised controlled trials (RCTs) from the Cochrane Airways Group Specialised Register. Searches were current as of March 2014. SELECTION CRITERIA: We selected RCTs of pulmonary rehabilitation in patients with COPD in which health-related quality of life (HRQoL) and/or functional (FEC) or maximal (MEC) exercise capacity were measured. We defined 'pulmonary rehabilitation' as exercise training for at least four weeks with or without education and/or psychological support. We defined 'usual care' as conventional care in which the control group was not given education or any form of additional intervention. We considered participants in the following situations to be in receipt of usual care: only verbal advice was given without additional education; and medication was altered or optimised to what was considered best practice at the start of the trial for all participants. DATA COLLECTION AND ANALYSIS: We calculated mean differences (MDs) using a random-effects model. We requested missing data from the authors of the primary study. We used standard methods as recommended by The Cochrane Collaboration. MAIN RESULTS: Along with the 31 RCTs included in the previous version (2006), we included 34 additional RCTs in this update, resulting in a total of 65 RCTs involving 3822 participants for inclusion in the meta-analysis.We noted no significant demographic differences at baseline between members of the intervention group and those who received usual care. For the pulmonary rehabilitation group, the mean forced expiratory volume at one second (FEV1) was 39.2% predicted, and for the usual care group 36.4%; mean age was 62.4 years and 62.5 years, respectively. The gender mix in both groups was around two males for each female. A total of 41 of the pulmonary rehabilitation programmes were hospital based (inpatient or outpatient), 23 were community based (at community centres or in individual homes) and one study had both a hospital component and a community component. Most programmes were of 12 weeks' or eight weeks' duration with an overall range of four weeks to 52 weeks.The nature of the intervention made it impossible for investigators to blind participants or those delivering the programme. In addition, it was unclear from most early studies whether allocation concealment was undertaken; along with the high attrition rates reported by several studies, this impacted the overall risk of bias.We found statistically significant improvement for all included outcomes. In four important domains of quality of life (QoL) (Chronic Respiratory Questionnaire (CRQ) scores for dyspnoea, fatigue, emotional function and mastery), the effect was larger than the minimal clinically important difference (MCID) of 0.5 units (dyspnoea: MD 0.79, 95% confidence interval (CI) 0.56 to 1.03; N = 1283; studies = 19; moderate-quality evidence; fatigue: MD 0.68, 95% CI 0.45 to 0.92; N = 1291; studies = 19; low-quality evidence; emotional function: MD 0.56, 95% CI 0.34 to 0.78; N = 1291; studies = 19; mastery: MD 0.71, 95% CI 0.47 to 0.95; N = 1212; studies = 19; low-quality evidence). Statistically significant improvements were noted in all domains of the St. George's Respiratory Questionnaire (SGRQ), and improvement in total score was better than 4 units (MD -6.89, 95% CI -9.26 to -4.52; N = 1146; studies = 19; low-quality evidence). Sensitivity analysis using the trials at lower risk of bias yielded a similar estimate of the treatment effect (MD -5.15, 95% CI -7.95 to -2.36; N = 572; studies = 7).Both functional exercise and maximal exercise showed statistically significant improvement. Researchers reported an increase in maximal exercise capacity (mean Wmax (W)) in participants allocated to pulmonary rehabilitation compared with usual care (MD 6.77, 95% CI 1.89 to 11.65; N = 779; studies = 16). The common effect size exceeded the MCID (4 watts) proposed by Puhan 2011(b). In relation to functional exercise capacity, the six-minute walk distance mean treatment effect was greater than the threshold of clinical significance (MD 43.93, 95% CI 32.64 to 55.21; participants = 1879; studies = 38).The subgroup analysis, which compared hospital-based programmes versus community-based programmes, provided evidence of a significant difference in treatment effect between subgroups for all domains of the CRQ, with higher mean values, on average, in the hospital-based pulmonary rehabilitation group than in the community-based group. The SGRQ did not reveal this difference. Subgroup analysis performed to look at the complexity of the pulmonary rehabilitation programme provided no evidence of a significant difference in treatment effect between subgroups that received exercise only and those that received exercise combined with more complex interventions. However, both subgroup analyses could be confounded and should be interpreted with caution. AUTHORS' CONCLUSIONS: Pulmonary rehabilitation relieves dyspnoea and fatigue, improves emotional function and enhances the sense of control that individuals have over their condition. These improvements are moderately large and clinically significant. Rehabilitation serves as an important component of the management of COPD and is beneficial in improving health-related quality of life and exercise capacity. It is our opinion that additional RCTs comparing pulmonary rehabilitation and conventional care in COPD are not warranted. Future research studies should focus on identifying which components of pulmonary rehabilitation are essential, its ideal length and location, the degree of supervision and intensity of training required and how long treatment effects persist. This endeavour is important in the light of the new subgroup analysis, which showed a difference in treatment effect on the CRQ between hospital-based and community-based programmes but no difference between exercise only and more complex pulmonary rehabilitation programmes.

BACKGROUND: We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention. METHODS: In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months. RESULTS: The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=-4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group. CONCLUSIONS: Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424 .).

Aerosols serve as cloud condensation nuclei (CCN) and thus have a substantial effect on cloud properties and the initiation of precipitation. Large concentrations of human-made aerosols have been reported to both decrease and increase rainfall as a result of their radiative and CCN activities. At one extreme, pristine tropical clouds with low CCN concentrations rain out too quickly to mature into long-lived clouds. On the other hand, heavily polluted clouds evaporate much of their water before precipitation can occur, if they can form at all given the reduced surface heating resulting from the aerosol haze layer. We propose a conceptual model that explains this apparent dichotomy.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Abstract Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight 1 . Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories 2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones 3 , showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.

NOD2, a protein associated with susceptibility to Crohn's disease, confers responsiveness to bacterial preparations of lipopolysaccharide and peptidoglycan, but the precise moiety recognized remains elusive. Biochemical and functional analyses identified muramyl dipeptide (MurNAc-l-Ala-d-isoGln) derived from peptidoglycan as the essential structure in bacteria recognized by NOD2. Replacement of l-Ala for d-Ala ord-isoGln for l-isoGln eliminated the ability of muramyl dipeptide to stimulate NOD2, indicating stereoselective recognition. Muramyl dipeptide was recognized by NOD2 but not by TLR2 or co-expression of TLR2 with TLR1 or TLR6. NOD2 mutants associated with susceptibility to Crohn's disease were deficient in their recognition of muramyl dipeptide. Notably, peripheral blood mononuclear cells from individuals homozygous for the major disease-associated L1007fsinsC NOD2 mutation responded to lipopolysaccharide but not to synthetic muramyl dipeptide. Thus, NOD2 mediates the host response to bacterial muropeptides derived from peptidoglycan, an activity that is important for protection against Crohn's disease. Because muramyl dipeptide is the essential structure of peptidoglycan required for adjuvant activity, these results also have implications for understanding adjuvant function and effective vaccine development. NOD2, a protein associated with susceptibility to Crohn's disease, confers responsiveness to bacterial preparations of lipopolysaccharide and peptidoglycan, but the precise moiety recognized remains elusive. Biochemical and functional analyses identified muramyl dipeptide (MurNAc-l-Ala-d-isoGln) derived from peptidoglycan as the essential structure in bacteria recognized by NOD2. Replacement of l-Ala for d-Ala ord-isoGln for l-isoGln eliminated the ability of muramyl dipeptide to stimulate NOD2, indicating stereoselective recognition. Muramyl dipeptide was recognized by NOD2 but not by TLR2 or co-expression of TLR2 with TLR1 or TLR6. NOD2 mutants associated with susceptibility to Crohn's disease were deficient in their recognition of muramyl dipeptide. Notably, peripheral blood mononuclear cells from individuals homozygous for the major disease-associated L1007fsinsC NOD2 mutation responded to lipopolysaccharide but not to synthetic muramyl dipeptide. Thus, NOD2 mediates the host response to bacterial muropeptides derived from peptidoglycan, an activity that is important for protection against Crohn's disease. Because muramyl dipeptide is the essential structure of peptidoglycan required for adjuvant activity, these results also have implications for understanding adjuvant function and effective vaccine development. Innate immunity recognizes invading microbes and triggers a defense response in the host aimed at clearing the invading pathogen. Toll-like receptors (TLRs) 1The abbreviations used are: TLR, Toll-like receptor; LPS, lipopolysaccharide; MDP, muramyl dipeptide MurNAc-l-Ala-d-isoGln; NF-κB, nuclear factor-κB, PBMNC, peripheral blood mononuclear cells; PGN, peptidoglycan; sBLP, synthetic bacterial lipoprotein; HEK, human embryonic kidney; LRR, leucine-rich repeat; HA, hemagglutinin; IL, interleukin; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; EMSA, electrophoretic mobility shift assay; Mur, muramic acid expressed on the surface of myelomonocytic cells play an important role in the recognition of microbial components and activation of innate immunity (1Takeda K. Akira S. Genes Cells. 2001; 6: 733-742Google Scholar). Each membrane-associated TLR recognizes pathogen-associated molecular patterns that are expressed on infectious agents (1Takeda K. Akira S. Genes Cells. 2001; 6: 733-742Google Scholar). Nods, including NOD1 and NOD2, are members of another family of proteins that have been recently implicated in intracellular recognition of bacterial components (2Inohara N. Ogura T. Nuñez G. Curr. Opin. Microbiol. 2002; 5: 76-80Google Scholar, 3Girardin S.E. Sansonetti P.J. Philpott D.J. Trends Microbiol. 2002; 10: 193-199Google Scholar). NOD2 is composed of two NH2-terminal caspase-recruitment domains, a centrally located nucleotide-binding domain and multiple COOH-terminal leucine-rich repeats (LRRs), and is expressed in myelomonocytic and dendritic cells (4Ogura Y. Inohara N. Benito A. Chen F.F. Yamaoka S. Nuñez G. J. Biol. Chem. 2001; 276: 4812-4818Google Scholar, 5Gutierrez O. Pipaon C. Inohara N. Fontalba A. Ogura Y. Prosper F. Nuñez G. Fernandez-Luna J.L. J. Biol. Chem. 2002; 277: 41701-47705Google Scholar). Three genetic variants within the coding region of NOD2, L1007fsinsC, G908R, and R702W, have been genetically associated with susceptibility to Crohn's disease in European and American populations (6Hugot J.P. Chamaillard M. Zouali H. Lesage S. Cezard J.P. Belaiche J. Almer S. Tysk C. O'Morain C.A. Gassull M. Binder V. Finkel Y. Cortot A. Modigliani R. Laurent-Puig P. Gower-Rousseau C. Macry J. Colombel J.F. Sahbatou M. Thomas G. Nature. 2001; 411: 599-603Google Scholar, 7Ogura Y. Bonen D.K. Inohara N. Nicolae D.L. Chen F.F. Ramos R. Britton H. Moran T. Karaliuskas R. Duerr R.H. Achkar J.P. Brant S.R. Bayless T.M. Kirschner B.S. Hanauer S.B. Nuñez G. Cho J.H. Nature. 2001; 411: 603-606Google Scholar, 8Hampe J. Cuthbert A. Croucher P.J. Mirza M.M. Mascheretti S. Fisher S. Frenzel H. King K. Hasselmeyer A. MacPherson A.J. Bridger S. van Deventer S. Forbes A. Nikolaus S. Lennard-Jones J.E. Foelsch U.R. Krawczak M. Lewis C. Schreiber S. Mathew C.G. Lancet. 2001; 357: 1925-1928Google Scholar, 9Ahmad T. Armuzzi A. Bunce M. Mulcahy-Hawes K. Marshall S.E. Orchard T.R. Crawshaw J. Large O. de Silva A. Cook J.T. Barnardo M. Cullen S. Welsh K.I. Jewell D.P. Gastroenterology. 2002; 122: 854-866Google Scholar). NOD2 has been shown to recognize preparations of lipopolysaccharides (LPS) and peptidoglycan (PGN) through its COOH-terminal LRRs (10Inohara N. Ogura Y. Chen F.F. Muto A. Nuñez G. J. Biol. Chem. 2001; 276: 2551-2554Google Scholar), and this activity is deficient in the disease-associated variants (7Ogura Y. Bonen D.K. Inohara N. Nicolae D.L. Chen F.F. Ramos R. Britton H. Moran T. Karaliuskas R. Duerr R.H. Achkar J.P. Brant S.R. Bayless T.M. Kirschner B.S. Hanauer S.B. Nuñez G. Cho J.H. Nature. 2001; 411: 603-606Google Scholar). However, the precise bacterial structure recognized by NOD2 remains unknown. In this report we identified muramyl dipeptide (MDP) derived from peptidoglycan as the structure in bacteria recognized by NOD2. LPS from Escherichia coli O55:B5 prepared by the phenol extraction method, further purified by gel-filtration chromatography, detoxified LPS, and purified lipid A were obtained from Sigma. LPS from Salmonella typhimurium was obtained from Sigma. PGN from Staphylococcus aureus was from Fluka-Chemie (Buchs, Germany). PGN fromBacillus subtilis was purified as reported (11Hajjar A.M. O'Mahony D.S. Ozinsky A. Underhill D.M. Aderem A. Klebanoff S.J. Wilson C.B. J. Immunol. 2002; 166: 15-19Google Scholar). Pam3CysSerLys4, a synthetic bacterial lipoprotein analog (sBLP), was a gift of A. Zychlinsky (Max Planck Institute for Infection Biology, Berlin, Germany). MDP and their analogs MurNAc-l-alanyl-l-isoglutamine and MurNAc-d-alanyl-d-isoglutamine were obtained from Bachem (Torrance, CA). Molecules with two and four copies of GlcNAc-MurNAc attached to l-Ala-d-isoGln, and their counterparts lacking dipeptide were synthesized as reported (12Onishi M. Kinoshita S. Morikawa Y. Shibuya A. Phillips J. Lanier L.L. Gorman D.M. Nolan G.P. Miyajima A. Kitamura T. Exp. Hematol. 1996; 24: 324-329Google Scholar). Briefly, the disaccharide glucosaminyl-β (1Takeda K. Akira S. Genes Cells. 2001; 6: 733-742Google Scholar, 2Inohara N. Ogura T. Nuñez G. Curr. Opin. Microbiol. 2002; 5: 76-80Google Scholar, 3Girardin S.E. Sansonetti P.J. Philpott D.J. Trends Microbiol. 2002; 10: 193-199Google Scholar, 4Ogura Y. Inohara N. Benito A. Chen F.F. Yamaoka S. Nuñez G. J. Biol. Chem. 2001; 276: 4812-4818Google Scholar)-muramic acid was prepared by stereoselective glycosylation of an N-Troc muramic acid acceptor with N-Troc-glucosaminyl trichloroacetimidate. The disaccharide was converted to both disaccharide acceptor and donor, which was then coupled together by the same glycosylation method to give a tetrasaccharide. Octasaccharide was obtained in a good yield in a similar manner. Introduction of the dipeptide moiety ofl-alanyl-d-isoglutamine to 3-O-lactyl groups was performed by deprotection afforded by the peptidoglycan tetrasaccharide and octasaccharide fragments. The plasmids pcDNA3- NOD2, pcDNA3-TLR4, and pDNA3-MD2 have been described (10Inohara N. Ogura Y. Chen F.F. Muto A. Nuñez G. J. Biol. Chem. 2001; 276: 2551-2554Google Scholar). The plasmids expressing TLR1 and TLR6 have been reported (13Takeuchi O. Hoshino K. Kawai T. Sanjo H. Takada H. Ogawa T. Takeda K. Akira S. Immunity. 1999; 11: 443-451Google Scholar) and were generously provided by Dr. A. Hajjar (University of Washington, Seattle). Expression plasmids producing NH2-terminal HA-tagged NOD2 variants P268S, P268S/R702W, and P268S/G908R were generated by the QuikChange XL site-directed mutagenesis kit (Stratagene, La Jolla, CA). P268S/L1007fsinsC was generated by a PCR method using P268S DNA as a template. The generated PCR products were cloned into the pMX-puro expression plasmid (14Atrih A. Bacher G. Allmaier G. Williamson M.P. Foster S.J. J. Bacteriol. 1999; 181: 3956-3962Google Scholar). The authenticity of the constructs were confirmed by DNA sequencing. Expression of NOD2 proteins in transfected cells was determined by immunoblotting using monoclonal anti-HA antibody (Babco, La Jolla, CA) as described (5Gutierrez O. Pipaon C. Inohara N. Fontalba A. Ogura Y. Prosper F. Nuñez G. Fernandez-Luna J.L. J. Biol. Chem. 2002; 277: 41701-47705Google Scholar). NF-κB activation assays were performed as described (10Inohara N. Ogura Y. Chen F.F. Muto A. Nuñez G. J. Biol. Chem. 2001; 276: 2551-2554Google Scholar). LPS, PGN, and MDP derivaties were added to the cultures in the presence of calcium phosphate to allow their entry into the cells as reported (10Inohara N. Ogura Y. Chen F.F. Muto A. Nuñez G. J. Biol. Chem. 2001; 276: 2551-2554Google Scholar). Results were normalized for transfection efficiency with values obtained with pEF-BOS-βgal. Expression of NOD2 proteins in transfected cells was determined by immunoblotting using monoclonal anti-HA antibody (Babco, La Jolla, CA) as described (4Ogura Y. Inohara N. Benito A. Chen F.F. Yamaoka S. Nuñez G. J. Biol. Chem. 2001; 276: 4812-4818Google Scholar). PGN from B. subtilus (0.4 mg) was digested with mutanolysin (Sigma) for 24 h. After centrifugation at 100,000 × g for 10 min and filtration with a 0.22-μm nitrocellulose filter, digested PGN was fractionated by Superose 12 gel-filtration column chromatography with 10 mm HEPES, 100 mm NaCl, pH 7.4. Purified bovine serum albumine, chicken egg lysozyme, and bovine cytochromec were used as molecular size standards. Peripheral blood was obtained from normal donors and Crohn's disease patients after informed consent according to Guidelines from the Committee for the Protection of Human Subjects at the Hospital Universitario Marques de Valdecilla. DNA was tested for the 3020insC NOD2 mutation using the SNaPshot method (Applied Biosystems, Foster City, CA) based on the dideoxy single-base extension of an unlabeled oligonucleotide primer (5′-GCCCTCCTGCAGGCCC-3′). PBMNC were cultured for 1 h with 1 μg/ml LPS from S. typhimuriumor 10 ng/ml MDP. Then cells were lysed and nuclear extracts were analyzed for the presence of NF-κB binding activity as described previously (5Gutierrez O. Pipaon C. Inohara N. Fontalba A. Ogura Y. Prosper F. Nuñez G. Fernandez-Luna J.L. J. Biol. Chem. 2002; 277: 41701-47705Google Scholar). Total RNA was prepared using TRIZOL reagent (Invitrogen). To assess mRNA expression, a quantitative PCR method was used as described previously (5Gutierrez O. Pipaon C. Inohara N. Fontalba A. Ogura Y. Prosper F. Nuñez G. Fernandez-Luna J.L. J. Biol. Chem. 2002; 277: 41701-47705Google Scholar). The generated cDNA was amplified by using primers for human IL-1β, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (5Gutierrez O. Pipaon C. Inohara N. Fontalba A. Ogura Y. Prosper F. Nuñez G. Fernandez-Luna J.L. J. Biol. Chem. 2002; 277: 41701-47705Google Scholar), and A1 (5′-CGGATGTGGATACCTATAAGG-3′ and 5′-GTCATCCAGCCAGATTTAGG-3′). Quantitative real-time PCR was performed in a 7000 sequence detection system (Applied Biosystems). The ratio of the abundance of IL-1β and A1 transcripts to that of GAPDH transcripts was calculated as described (5Gutierrez O. Pipaon C. Inohara N. Fontalba A. Ogura Y. Prosper F. Nuñez G. Fernandez-Luna J.L. J. Biol. Chem. 2002; 277: 41701-47705Google Scholar). Specificity of the PCR products was determined by melting curve analysis. NOD2 was shown to mediate responsiveness to preparations of LPS and PGN (10Inohara N. Ogura Y. Chen F.F. Muto A. Nuñez G. J. Biol. Chem. 2001; 276: 2551-2554Google Scholar). To further characterize the bacterial moiety recognized by NOD2, we used human embryonic kidney (HEK293T) cells and a NF-κB-dependent luciferase reporter to compare the ability of NOD2 and TLR4 to recognize LPS and PGN. Because NOD2 is an intracellular protein, we assessed NOD2 activity under culture conditions that allow the internalization of the bacterial components into the cells (10Inohara N. Ogura Y. Chen F.F. Muto A. Nuñez G. J. Biol. Chem. 2001; 276: 2551-2554Google Scholar). Expression of NOD2 and TLR4 together with its co-factor MD2 conferred responsiveness to purified LPS prepared by phenol extraction as reported (7Ogura Y. Bonen D.K. Inohara N. Nicolae D.L. Chen F.F. Ramos R. Britton H. Moran T. Karaliuskas R. Duerr R.H. Achkar J.P. Brant S.R. Bayless T.M. Kirschner B.S. Hanauer S.B. Nuñez G. Cho J.H. Nature. 2001; 411: 603-606Google Scholar, 10Inohara N. Ogura Y. Chen F.F. Muto A. Nuñez G. J. Biol. Chem. 2001; 276: 2551-2554Google Scholar), whereas only NOD2 induced the response to PGN (Fig. 1 A). The lipid A moiety of LPS mediates TLR4/MD2 activation (15Glauner B. Höltje J.-V. Schwartz U. J. Biol. Chem. 1988; 263: 10088-10095Google Scholar). Consistent with the latter, NOD2, but not TLR4, did respond to lipid A-depleted detoxified LPS prepared by alkaline treatment (Fig. 1 A), whereas TLR4, but not NOD2, responded to purified lipid A (Fig.1 A). Notably, TLR4, but not NOD2, was stimulated by highly purified LPS prepared by gel-filtration chromatography (Fig.1 A). These results indicate that TLR4 and NOD2 recognize different bacterial components and suggest that PGN present in LPS preparations may contain the moiety recognized by NOD2. To further characterize the bacterial structure recognized by NOD2, we digested purified PGN with the muramidases mutanolysin or Cellosyl, which degrade the glycan chains and result in the generation of muropeptides which are composed of N-acetylglucosamine (GlcNAc) andN-acetylmuramic acid (MurNAc) linked to short peptides (16Inamura S. Fukase K. Kusumoto S. Tetrahedron Lett. 2001; 42: 7613-7619Google Scholar). Digested PGN was fractionated by gel-filtration chromatography. Analysis of each fraction revealed a major peak of NOD2-stimulating activity induced by mutanolysin digestion with a relative molecular mass of less than 12 kDa, consistent with that expected for muropeptides (Fig. 1 B). Similar results were observed when PGN was digested with Cellosyl, which revealed a single peak of NOD2 stimulatory activity of less than 12 kDa. 2N. Inohara, Y. Ogura, and G. Nuñez, unpublished results. PGN-derived muropeptides derived from most bacterial species are composed of GlcNAc-MurNAc linked to short peptides, which include the conserved dipeptide l-Ala and d-isoGln ord-Glu (Fig. 2 A). To determine more directly if muropeptides are recognized by NOD2, we used a panel of synthetic molecules with the structure of GlcNAc-MurNAc linked to l-Ala-d-isoGln, as well as muramyl dipeptide MurNAc-l-Ala-d-isoGln (MDP), which lacks GlcNAc (Fig. 2 A). GlcNAc-MurNAc-l-Ala-d-isoGln stimulated NF-κB in a NOD2-dependent manner, whereas disaccharide GlcNAc-MurNAc in dimeric or tetrameric forms did not (Fig.2 B), indicating that amino acid residues are required for stimulation of NOD2. However, we cannot formally rule out that the lack of NOD2 response to GlcNAc-MurNAc in dimeric or tetrameric forms is due to poor internalization of the synthetic molecules into the cells. MDP induced potent stimulation of NOD2 (Fig. 2 B), indicating that GlcNAc is not essential for stimulatory activity. To determine further the specificity of the recognition of MDP by NOD2, we tested the MDP analogs MurNAc-l-Ala-l-isoGln and MurNAc-d-Ala-d-isoGln. Notably, replacement ofl-Ala for d-Ala or d-isoGln forl-isoGln eliminated the ability of MDP to stimulate NOD2, indicating stereoselective recognition (Fig. 2 C). Thus, the core structure required for recognition of NOD2 is MurNAc attached tol-Ala and d-isoGln. TLR2 has been proposed to act as a surface receptor for PGN and certain bacterial lipoproteins including synthetic bacterial lipopeptide S. B. P. Zychlinsky A. 1999; Scholar, J. Immunol. 2002; Scholar). we tested the ability of TLR2 and NOD2 to respond to MDP and TLR2 a response to but not to MDP (Fig.2 MDP, but not sBLP, stimulated NOD2 activity (Fig. 2 In we tested co-expression of TLR2 with TLR1 TLR6 mediate recognition of MDP. TLR2 in with or did not NF-κB in response to MDP (Fig. 2 Thus, NOD2 and TLR2 recognize different bacterial The NOD2 variants associated with Crohn's disease, R702W, G908R, and L1007fsinsC, on the same which the P268S (6Hugot J.P. Chamaillard M. Zouali H. Lesage S. Cezard J.P. Belaiche J. Almer S. Tysk C. O'Morain C.A. Gassull M. Binder V. Finkel Y. Cortot A. Modigliani R. Laurent-Puig P. Gower-Rousseau C. Macry J. Colombel J.F. Sahbatou M. Thomas G. Nature. 2001; 411: 599-603Google Scholar, 7Ogura Y. Bonen D.K. Inohara N. Nicolae D.L. Chen F.F. Ramos R. Britton H. Moran T. Karaliuskas R. Duerr R.H. Achkar J.P. Brant S.R. Bayless T.M. Kirschner B.S. Hanauer S.B. Nuñez G. Cho J.H. Nature. 2001; 411: 603-606Google Scholar). To compare the ability of normal and NOD2 proteins to NF-κB activity in response to MDP, we expressed the NOD2 proteins in cells and their activity in a functional normal and P268S NOD2 induced similar of NF-κB activation in response to MDP A), which is consistent with the that P268S is not genetically associated with disease (6Hugot J.P. Chamaillard M. Zouali H. Lesage S. Cezard J.P. Belaiche J. Almer S. Tysk C. O'Morain C.A. Gassull M. Binder V. Finkel Y. Cortot A. Modigliani R. Laurent-Puig P. Gower-Rousseau C. Macry J. Colombel J.F. Sahbatou M. Thomas G. Nature. 2001; 411: 599-603Google Scholar, 7Ogura Y. Bonen D.K. Inohara N. Nicolae D.L. Chen F.F. Ramos R. Britton H. Moran T. Karaliuskas R. Duerr R.H. Achkar J.P. Brant S.R. Bayless T.M. Kirschner B.S. Hanauer S.B. Nuñez G. Cho J.H. Nature. 2001; 411: 603-606Google Scholar). In the P268S/R702W, and P268S/L1007fsinsC variants induced of NF-κB activation in response to MDP when with normal NOD2 A). Notably, whereas the and mutants ability to respond to MDP, the protein did not respond at of NOD2 and MDP tested (Fig. A). revealed that the normal and NOD2 mutants were expressed B), indicating that the observed in MDP not by expression of the NOD2 determined the role of NOD2 in the recognition of MDP by cells from normal and Crohn's disease A panel of and Crohn's disease individuals were for the disease-associated NOD2 and two individuals of disease and with Crohn's were homozygous for the L1007fsinsC mutation were The of individuals homozygous for L1007fsinsC is expected in that the of the L1007fsinsC mutation is not (6Hugot J.P. Chamaillard M. Zouali H. Lesage S. Cezard J.P. Belaiche J. Almer S. Tysk C. O'Morain C.A. Gassull M. Binder V. Finkel Y. Cortot A. Modigliani R. Laurent-Puig P. Gower-Rousseau C. Macry J. Colombel J.F. Sahbatou M. Thomas G. Nature. 2001; 411: 599-603Google Scholar, 7Ogura Y. Bonen D.K. Inohara N. Nicolae D.L. Chen F.F. Ramos R. Britton H. Moran T. Karaliuskas R. Duerr R.H. Achkar J.P. Brant S.R. Bayless T.M. Kirschner B.S. Hanauer S.B. Nuñez G. Cho J.H. Nature. 2001; 411: 603-606Google Scholar, 8Hampe J. Cuthbert A. Croucher P.J. Mirza M.M. Mascheretti S. Fisher S. Frenzel H. King K. Hasselmeyer A. MacPherson A.J. Bridger S. van Deventer S. Forbes A. Nikolaus S. Lennard-Jones J.E. Foelsch U.R. Krawczak M. Lewis C. Schreiber S. Mathew C.G. Lancet. 2001; 357: 1925-1928Google Scholar, 9Ahmad T. Armuzzi A. Bunce M. Mulcahy-Hawes K. Marshall S.E. Orchard T.R. Crawshaw J. Large O. de Silva A. Cook J.T. Barnardo M. Cullen S. Welsh K.I. Jewell D.P. Gastroenterology. 2002; 122: 854-866Google Scholar). PBMNC that are to NOD2 were with MDP or LPS, and NF-κB activation was assessed in nuclear extracts by an electrophoretic mobility shift of PBMNC from individuals normal or NOD2 with LPS or MDP in of the (Fig. C). In PBMNC from individuals homozygous for L1007fsinsC did respond to LPS, but not to MDP (Fig. C). The DNA binding induced by MDP was by of the nuclear extracts with an antibody for the of NF-κB indicating that the To further assess NF-κB the mRNA of IL-1β and two NF-κB expressed in PBMNC J.P. M.M. J.P. J. Immunol. Scholar, Chen C. J. C. Genes 1999; Scholar), were by quantitative real-time PCR analysis. IL-1β and A1 mRNA were induced by with LPS and MDP in cells from individuals normal or NOD2 (Fig. and In LPS but not MDP, the of both IL-1β and A1 mRNA in PBMNC from individuals homozygous for L1007fsinsC (Fig. Thus, PBMNC the expression of normal NOD2 for their response to MDP but not to The lack of response to MDP in normal individuals suggest that the presence of certain bacteria in the genetic may required for disease. MDP is the essential structure of bacterial peptidoglycan required for including activity in adjuvant H. S. The and of Scholar). MDP has been shown to through and S. R. S. O. Akira S. S. Takada H. 2001; Scholar, J. Biol. Chem. 2002; 277: Scholar), but the host recognition system for MDP has not been present that NOD2 mediates the recognition of MDP in cells. contain intracellular that bacterial PGN and PGN including J. F. J. Scholar, Scholar). These muropeptides derived from intracellular bacteria as well as PGN bacterial for recognition by NOD2. The synthetic MDP and the muropeptides induced NOD2-dependent activation of Thus, NOD2 is to by muropeptides derived from bacteria in NOD2 mediate the recognition of the is and remains to Because the LRRs are required for muropeptides directly with NOD2 through its LRRs or as to identified Crohn's disease-associated NOD2 variants and PBMNC from individuals homozygous for L1007fsinsC are in their response to muramyl dipeptide. result is consistent with the that for L1007fsinsC is for susceptibility to Crohn's disease (6Hugot J.P. Chamaillard M. Zouali H. Lesage S. Cezard J.P. Belaiche J. Almer S. Tysk C. O'Morain C.A. Gassull M. Binder V. Finkel Y. Cortot A. Modigliani R. Laurent-Puig P. Gower-Rousseau C. Macry J. Colombel J.F. Sahbatou M. Thomas G. Nature. 2001; 411: 599-603Google Scholar, 7Ogura Y. Bonen D.K. Inohara N. Nicolae D.L. Chen F.F. Ramos R. Britton H. Moran T. Karaliuskas R. Duerr R.H. Achkar J.P. Brant S.R. Bayless T.M. Kirschner B.S. Hanauer S.B. Nuñez G. Cho J.H. Nature. 2001; 411: 603-606Google Scholar). Because activation of NF-κB in response to bacterial components mediates protection of the host against susceptibility to disease may by a to a NF-κB in response to a response against certain bacterial products may result in the activation of NF-κB in by The results suggest that the activity against bacterial muropeptides may to Crohn's disease patients NOD2 are to T. for C. for A. Zychlinsky for sBLP, and A. Hajjar for P. for of the

The selection of appropriate outcomes or domains is crucial when designing clinical trials in order to compare directly the effects of different interventions in ways that minimize bias. If the findings are to influence policy and practice then the chosen outcomes need to be relevant and important to key stakeholders including patients and the public, health care professionals and others making decisions about health care. There is a growing recognition that insufficient attention has been paid to the outcomes measured in clinical trials. These issues could be addressed through the development and use of an agreed standardized collection of outcomes, known as a core outcome set, which should be measured and reported, as a minimum, in all trials for a specific clinical area. Accumulating work in this area has identified the need for general guidance on the development of core outcome sets. Key issues to consider in the development of a core outcome set include its scope, the stakeholder groups to involve, choice of consensus method and the achievement of a consensus.

BACKGROUND: Nonnegative Matrix Factorization (NMF) is an unsupervised learning technique that has been applied successfully in several fields, including signal processing, face recognition and text mining. Recent applications of NMF in bioinformatics have demonstrated its ability to extract meaningful information from high-dimensional data such as gene expression microarrays. Developments in NMF theory and applications have resulted in a variety of algorithms and methods. However, most NMF implementations have been on commercial platforms, while those that are freely available typically require programming skills. This limits their use by the wider research community. RESULTS: Our objective is to provide the bioinformatics community with an open-source, easy-to-use and unified interface to standard NMF algorithms, as well as with a simple framework to help implement and test new NMF methods. For that purpose, we have developed a package for the R/BioConductor platform. The package ports public code to R, and is structured to enable users to easily modify and/or add algorithms. It includes a number of published NMF algorithms and initialization methods and facilitates the combination of these to produce new NMF strategies. Commonly used benchmark data and visualization methods are provided to help in the comparison and interpretation of the results. CONCLUSIONS: The NMF package helps realize the potential of Nonnegative Matrix Factorization, especially in bioinformatics, providing easy access to methods that have already yielded new insights in many applications. Documentation, source code and sample data are available from CRAN.

) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

BACKGROUND: The past decade has seen considerable interest in the development and evaluation of complex interventions to improve health. Such interventions can only have a significant impact on health and health care if they are shown to be effective when tested, are capable of being widely implemented and can be normalised into routine practice. To date, there is still a problematic gap between research and implementation. The Normalisation Process Theory (NPT) addresses the factors needed for successful implementation and integration of interventions into routine work (normalisation). DISCUSSION: In this paper, we suggest that the NPT can act as a sensitising tool, enabling researchers to think through issues of implementation while designing a complex intervention and its evaluation. The need to ensure trial procedures that are feasible and compatible with clinical practice is not limited to trials of complex interventions, and NPT may improve trial design by highlighting potential problems with recruitment or data collection, as well as ensuring the intervention has good implementation potential. SUMMARY: The NPT is a new theory which offers trialists a consistent framework that can be used to describe, assess and enhance implementation potential. We encourage trialists to consider using it in their next trial.

Lists of authors and their affiliations appear in the online version of the paper Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry 1 . We identified 65 new loci that are associated with overall breast cancer risk at P < 5 10 -8 . The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genomewide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Cells can respond to stress in various ways ranging from the activation of survival pathways to the initiation of cell death that eventually eliminates damaged cells. Whether cells mount a protective or destructive stress response depends to a large extent on the nature and duration of the stress as well as the cell type. Also, there is often the interplay between these responses that ultimately determines the fate of the stressed cell. The mechanism by which a cell dies (i.e., apoptosis, necrosis, pyroptosis, or autophagic cell death) depends on various exogenous factors as well as the cell's ability to handle the stress to which it is exposed. The implications of cellular stress responses to human physiology and diseases are manifold and will be discussed in this review in the context of some major world health issues such as diabetes, Parkinson's disease, myocardial infarction, and cancer.