dataesr/scientific-paragraphs-categorization huggingface dataset:
MATERIALS AND METHODS Studies Samples contributing to this project and demographics by site are given in Supplementary Table  1. Participating sites were contacted to collaborate on this project through the ENIGMA Consortium, after advertising the goals of the project on the ENIGMA website and at numerous international conferences in neuroimaging and psychiatry; none of the sites contacted refused or were unable to participate in this project. In total, data from 4304 subjects including 1710 cases and 2594 healthy controls were available for analysis. Each participating site obtained approval from an institutional review board or local ethics committee, and all study participants signed informed consent documents at their local institution.
Analysis of differences in diagnosis subtype, mood state, age of illness onset and medications To investigate brain differences associated with the clinical phenotype we examined whether there were detectable differences between BD subtypes, focusing on patients diagnosed with BDI and BDII. Methods for determining subtype at each site are given in Supplementary Table  3. We performed three separate meta-analyses comparing: BDI patients with controls, BDII patients with controls and BDI with BDII patients following the same model as in the section described above. Similarly, we examined how mood state at the time of scanning influenced brain structure. Mood state data were available from 13 sites; patients were categorized into six different categories: euthymic, depressed, manic, hypomanic, mixed and unknown.
ACKNOWLEDGMENTS We acknowledge members of the  International Group for the Study of Lithium Treated Patients (IGSLi)  and  Costa Rica/Colombia Consortium for Genetic Investigation of Bipolar Endophenotypes. The Halifax studies have been supported by grants from  Canadian Institutes of Health Research  ( 103703 ,  106469  and  64410 ), the  Nova Scotia Health Research Foundation ,  Dalhousie Clinical Research Scholarship  to  T Hajek. We also acknowledge research funding sources: TOP is supported by the  Research Council of Norway , the  South East Norway Health Authority , the  Kristian Gerhard Jebsen Foundation  and the  European Community 's  Seventh Framework Programme  ( FP7/2007-2013 ), grant agreement no. 602450. Cardiff is supported by the  National Centre for Mental Health (NCMH)  and  Bipolar Disorder Research Network (BDRN).
Results and Discussion From benzene extract of L. nicou roots, two new compounds 1 and 2 were isolated together with the known maackian (3), flemichapparin-B (4) and rotenone (5) as described in Materials and Methods. Chemical structures of new compounds were elucidated as follows. Compound 1 was isolated as a yellow needle which exhibited an intense UV band at λ max (MeOH): 288 and 408 nm respectively, supposing a large conjugated system. The molecular formula C 8 H 8 O 4 was deduced from HRESMS (found: 169. 0491; calcd: 169. 0501 for [M+H] + ). The 13 C NMR data display only four signals respectively at δ 178. 9; 163. 7; 103. 0 and 57. 1, suggesting a symmetric compound. Indeed, δ 178. 9 was assigned to a carbonyl group whereas δ 163. 7 was attributed as O-bonded quaternary sp 2 C. Moreover, a shielded double bond carbon appears at δ 103.
• The LUISA modelling platform  (Baranzelli et al. 2014 ) was used to spatially identify different ecosystems based on land cover and land use. Thus, LUISA was used to assess the actual ES provision, translating processes and functions into services ( Fig. 1 ). The choice for these two models constrained the number of ecosystems and ecosystem services that could be covered in this assessment. As a result, we present the assessment for terrestrial ecosystems based on their capacity to deliver air quality regulation, soil retention (or soil erosion control) and water (quantity) regulation (capacity to regulate water flows which either supply or buffer water). Fig. 2  is a schematic representation of the main data sources and methods leading to assess ES provision and changes therein. In summary, we selected three regulating ES which we estimated using Bayesian Networks (BN) built with bio-physical components from the CLM.
Hormone receptor-positive breast cancer The Phase III trial of everolimus in combination with exemestane in ER-positive, HER2-negative advanced breast cancer (BOLERO-2; NCT00863655) demonstrated the value of PI3K-AKT-mTOR pathway inhibition in HR-positive advanced breast cancer. 11 However, retrospective molecular analyses of the BOLERO-2 study have not identified a subpopulation deriving greater clinical benefit. 12 Furthermore, a recent Phase IB study of buparlisib in combination with letrozole (a nonsteroidal aromatase inhibitor) has demonstrated the feasibility of combining a PI3K inhibitor with letrozole in patients with ER-positive, HER2-negative metastatic breast cancer refractory to endocrine therapy. 13 Of the 46 patients who were evaluable for response, there was one complete response, one partial response, and 25 patients with stable disease.
Clinical activity was not shown to correlate with PIK3CA mutation status, suggesting that alterations in other pathway components were responsible for PI3K pathway dependence. 13 n the pivotal Phase III BELLE-2 study of buparlisib and fulvestrant (a selective ER downregulator) in patients with HR-positive, HER2-negative advanced breast cancer that has progressed on/after aromatase inhibitor therapy, patient selection and stratification were designed to assess buparlisib efficacy in the full population and in the PI3K pathwayactivated subpopulation (defined as PIK3CA mutation and/or PTEN loss; NCT01610284). This study will assess the predictive value of single PI3K-AKT-mTOR pathway alterations in terms of clinical response to buparlisib. The study has completed enrollment, and data are expected in mid-2015.
Preclinical data have demonstrated that buparlisib in combination with fulvestrant can reverse resistance to mTOR inhibitors and/or fulvestrant (Novartis data on file). Therefore, the Phase III BELLE-3 study of buparlisib and fulvestrant is not using molecular preselection for enrollment, but mandates tissue collection and clinical selection for patients with HR-positive, HER2-negative, aromatase inhibitor-treated, locally advanced or metastatic breast cancer that has progressed on mTOR inhibitor therapy (NCT01633060). Due to associations between mTOR inhibitor resistance and PI3K-AKT-mTOR pathway activation, all patients are expected to have PI3K pathway-activated tumors. As such, tumor specimens will be assessed retrospectively for PI3K pathway activation status. Preclinical studies have also shown that breast cancer cell lines are sensitive to the PI3Kα inhibitor alpelisib in vitro,  2  and PIK3CA mutations and HER2 amplifications correlate with alpelisib sensitivity.
14 Targeting a single PI3K isoform in patients may allow administration at therapeutic doses without being limited by toxicities associated with inhibiting multiple isoforms. As such, alpelisib is being investigated in several breast cancer studies using targeted enrollment. The first-in-human Phase I study of single-agent alpelisib in advanced solid tumors with PIK3CA alterations, and a subsequent study in combination with fulvestrant in ER-positive metastatic breast cancer (PIK3CA-altered and PIK3CA wild-type tumors), used patient selection and mandatory tissue collection (NCT01219699). Promising preliminary antitumor activity in PIK3CA-altered tumors treated with alpelisib alone or with fulvestrant has been observed. 15, 16 urther analyses will reveal whether patients with PIK3CAaltered tumors display greater sensitivity to alpelisib, or whether PIK3CA-altered and wild-type tumors are equally sensitive.
The combination of alpelisib and fulvestrant is being investigated in a Phase III trial in postmenopausal women, or men, with HR-positive, HER2-negative advanced breast cancer that progressed after aromatase inhibitor treatment (SOLAR-1; NCT02437318). Patients will be screened and stratified based on PIK3CA mutation status, and randomized to receive fulvestrant in combination with either alpelisib or placebo. Abbreviations: NSCLC, non-small-cell lung carcinoma; GBM, glioblastoma multiforme. • • • • • • • • • • • • • Phase I studies are investigating alpelisib in combination with letrozole or exemestane in HR-positive, locally advanced, and/or metastatic breast cancer (NCT01791478, NCT01870505). The nonselective, mandatory tissue collection approach is also being used in these early dose-finding studies evaluating alpelisib in combination with aromatase inhibitors or taxanes.
In the study of alpelisib and letrozole, half of patients enrolled must have PIK3CA-mutated tumors, and the provision of tumor tissue for correlative studies is mandatory. Exploratory analyses of tumor samples will be performed to determine potential benefit or predictive value in PI3K pathway-activated tumors and to evaluate biomarkers of response. Phase I studies are also evaluating alpelisib plus paclitaxel in locally advanced or metastatic, chemotherapy-naïve, HER2-negative breast cancer and recurrent, metastatic head and neck squamous cell carcinoma (HNSCC; NCT02051751), as well as the triplet combination of alpelisib, everolimus, and exemestane in advanced breast cancer (NCT02077933). Enrollment for both studies is based on the availability of tumor tissue for biomarker analyses and determination of PI3K pathway activation status.
A neoadjuvant study of letrozole with or without buparlisib or alpelisib in HR-positive, HER2-negative breast cancer is employing targeted enrollment (NCT01923168). Two cohorts are being enrolled: patients with PIK3CAmutated tumors and those with PIK3CA wild-type disease. This study will enable the identification of the optimal strategy of PI3K pathway inhibition (ie, pan-PI3K vs PI3Kα-selective inhibition) in these molecular subtypes; the results will reveal whether alpelisib has superior efficacy in the PIK3CA-mutant population and whether buparlisib is more beneficial in tumors where PI3K is activated by other mechanisms, such as alteration of PTEN or INPP4B.
HeR2-positive breast cancer The PI3K-AKT-mTOR pathway is frequently activated in HER2-positive breast cancer. 9 The Phase III trial of combined trastuzumab and paclitaxel treatment with or without everolimus in HER2-positive advanced breast cancer (BOLERO-1; NCT00876395), showed no improvement in progression-free survival (PFS) in the full population; however, the 7. 2-month improvement in median PFS observed in HR-negative, HER2-positive patients, though not statistically significant, provided a rationale for further investigation of PI3K inhibitors in this indication. 17 Meanwhile, addition of everolimus to trastuzumab and vinorelbine in women with HER2-positive metastatic breast cancer in the Phase III BOLERO-3 trial (NCT01007942) achieved an increase in median PFS from 5. 78 to 7. 00 months.
10 Both BOLERO-1 and BOLERO-3 therefore demonstrate the clinical relevance of PI3K-AKT-mTOR pathway inhibition in HER2-positive disease. A combined analysis of BOLERO-1 and BOLERO-3 revealed a robust positive correlation between PI3K-AKT-mTOR pathway hyperactivity and PFS benefit (with a hazard ratio of 0. 61 vs 1. 38 for normal pathway activation), supporting further investigation of PI3K inhibitors in this patient population. 18 he CLEOPATRA study of pertuzumab, trastuzumab, and docetaxel in first-line metastatic breast cancer (NCT00567190) established PIK3CA mutation as a negative prognostic factor in HER2-positive breast cancer; patients with tumors harboring PIK3CA mutations had a significantly worse PFS than those with PIK3CA wild-type disease. 19 elective enrollment/target enrichment is therefore being used in a Phase II study of neoadjuvant buparlisib in combination with trastuzumab and paclitaxel in HER2-positive breast cancer with or without PIK3CA mutations (NeoPHOEBE; NCT01816594) to establish whether PIK3CA mutation status can predict a benefit from combination therapy with anti-HER2 chemotherapy and a PI3K inhibitor.
A Phase IB/II study has investigated buparlisib and trastuzumab in relapsed HER2-positive breast cancer that has previously failed on trastuzumab, with no selective enrollment/ target enrichment approach employed (NCT01132664). In the Phase IB part of the study, buparlisib and trastuzumab were well tolerated, and preliminary signs of clinical activity were observed (two partial responders, seven patients with stable disease, and a disease control rate [DCR] of 75%). 20 he Phase II part of the study has been completed, and further analyses will assess the ability of buparlisib and trastuzumab combinations to overcome trastuzumab resistance in patients with PIK3CA-activated and wild-type tumors. Buparlisib in combination with lapatinib is also being studied in a Phase IB/II trial in HER2-positive breast cancer that has failed following trastuzumab therapy, again using the selective enrollment/target enrichment approach (NCT01589861).
For example, an ongoing Phase II study is investigating single-agent buparlisib in recurrent or metastatic HNSCC after platinum failure (NCT01527877); the tissue samples collected will form part of an extensive translational research panel. PIK3CA amplifications and mutations are associated with resistance to cetuximab therapy. 25 Therefore, a Phase II study is assessing buparlisib in HNSCC that has progressed on platinum-and cetuximab-based chemotherapy in PIK3CAmutated and PIK3CA wild-type cohorts using the patient selection approach (NCT01737450). PI3K pathway activation is associated with chemotherapy resistance and resistance to targeted therapy. 5 To investigate this in the clinical setting, a nonselective, mandatory tissue collection approach has been implemented in the following studies conducted in recurrent/metastatic HNSCC resistant to platinum-based therapy, all of which require tissue specimens for biomarker analyses: a Phase II randomized study is exploring buparlisib in combination with paclitaxel (BERIL-1; NCT01852292); a Phase IB/II study is investigating alpelisib in combination with cetuximab (NCT01602315); and a Phase I study of alpelisib with paclitaxel is also ongoing (NCT02051751).
Early results from the study of alpelisib in combination with cetuximab have demonstrated promising preliminary antitumor activity in patients with recurrent HNSCC. 26 n-small cell lung carcinoma PI3K pathway alterations occur in a clinically significant proportion of patients with non-small cell lung carcinoma (NSCLC). 27 In a large data set of patients screened for the Phase II BASALT-1 study (NCT01297491), PI3K pathway activation (defined as PIK3CA mutation, PTEN mutation, and/or PTEN loss), was observed in 16% and 11% of squamous and nonsquamous tumors, respectively. 27 n this study, patients with relapsed, metastatic NSCLC received single-agent buparlisib, and were stratified according to squamous or nonsquamous histology. The study adopted the targeted enrollment approach, with PI3K pathway activation required for enrollment.
DCR was 47% and 46% in the squamous and nonsquamous groups, respectively, with a median PFS of 2. 8 months in both groups. 28 Both histological groups met the predefined futility criteria in Stage I, defined as a PFS rate ,50% at 12 weeks, and the randomized part of the study was therefore not initiated. The results are in line with previous observations of single-agent PI3K pathway inhibitors demonstrating modest activity in NSCLC. Preclinical data suggest that PI3K-AKT-mTOR pathway inhibition can sensitize cancer cells to chemotherapy,  29, 30  providing a rationale for buparlisib and chemotherapy combinations. As such, buparlisib is being studied in combination with docetaxel in second-line metastatic squamous NSCLC (NCT01911325), with provision of tumor tissue for biomarker analyses required for enrollment.
Preclinical studies suggest PI3K-AKT-mTOR pathway activation may drive resistance to EGFR tyrosine kinase inhibitors (TKIs). 8 PI3K inhibitors may act synergistically with EGFR TKIs, and may help overcome EGFR TKI resistance. Preliminary results of a Phase IB study of buparlisib and gefitinib demonstrated potential antitumor activity in EGFR TKI-resistant NSCLC (NCT01570296). 31  nonselective, mandatory tissue collection approach will therefore be employed in a Phase II study of buparlisib and erlotinib in advanced NSCLC that was previously sensitive to erlotinib (NCT01487265). Exploratory biomarker analyses will examine interactions between the two pathways.
Glioblastoma multiforme The PI3K-AKT-mTOR pathway is frequently activated by PTEN loss in glioblastoma multiforme (GBM). 35 Buparlisib holds promise for the treatment of GBM, due to its ability to penetrate the blood-brain barrier. 36 Indeed, in GBM cell lines and xenograft models, buparlisib demonstrated antitumor activity regardless of PTEN or EGFR status. 37 urthermore, synergistic activity was observed with buparlisib in combination with temozolomide in PTEN-null GBM mouse xenografts. 3 ingle-agent buparlisib has been investigated in a Phase II trial in patients with recurrent GBM using selective enrollment/target enrichment; inclusion in one of the cohorts was dependent on PI3K pathway activation (defined as PIK3CA or PTEN mutation, or PTEN deletion; NCT01339052). Among the 40 patients who underwent exome sequencing, there were four PIK3CA (10%), two PIK3R1 (5%), and 13 PTEN (33%) mutations.
The singleagent activity of buparlisib was marginal (median PFS of 1. 8 months), and no association between efficacy and pathway activation was observed. 38 andatory tissue collection is planned for the Phase II parts of the Phase IB/II studies of buparlisib in combination with carboplatin or lomustine (NCT01934361) or with bevacizumab (NCT01349660) in patients with recurrent GBM that has relapsed after standard therapy. The mandatory tissue collection approach is also being used in a Phase I trial of buparlisib with radiation therapy and temozolomide in newly diagnosed GBM (NCT01473901). Archival tumor biopsies will be used for determination of PI3K-AKT-mTOR pathway activation status and correlative testing.
Communication or mediation With the development of Online public access catalog (OPAC), catalogs diffuse their own content beyond the documentary space that they are supposed to represent. This deployment of the catalog beyond the document is at the heart of the new cataloging standard Resource Description and Access (RDA) based on the Functional Requirements for Bibliographic Records (FRBR), a relational conceptual model; this model is designed to pool the resources associated with a given work. "Designed for the digital world and an expanding universe of metadata users," 9 RDA succeeds the last Anglo-American Cataloguing Rules (AACR2): RDA is the result of a thorough deconstruction of AACR2 and a rebuilding into a new standard. RDA uses many of the old building blocks, but rearranges them in a new structure and context that is based on a sound and explicitly delineated theoretical framework, and thus quite different from AACR2.
« l'information n'est pas une donnée, c'est un ensemble de signes construits dans un contexte de production spécifique: ici un livre, là un article, là encore un discours, ou encore un film, une musique, une base de données, etc. Mais pour un bibliothécaire cette information n'accède à l'existence qu'à travers le sujet qui s'en est emparé et se l'est approprié. » (Calenge, 2012).
standard for therapeutic efficacy than merely slowing disability accumulation. Because disability is a primary contributor to the burden of MS,  [8] [9] [10]  restoring function in patients with previously acquired neurologic impairments may lead to improved long-term prognosis, greater productivity and quality of life, and reduced economic costs. CDI is a metric reflecting durable and clinically meaningful EDSS score changes. In the phase 2 trial of alemtuzumab for RRMS (CAMMS223; NCT00050778) and the phase 3 Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis II (CARE-MS II; NCT00548405) trial, CDI was more likely in alemtuzumab-treated patients than those receiving subcutaneous interferon-b-1a (SC IFN-b-1a). 11, 12 In CARE-MS II, alemtuzumab was also associated with significantly greater improvement in mean EDSS and Multiple Sclerosis Functional Composite (MSFC) scores vs SC IFN-b-1a.
Integrated disability score of AUC for EDSS to 2 years (post hoc analysis) was calculated using the trapezium rule with EDSS score at all preplanned scheduled visits. 21 EDSS AUC analysis used ranked analysis of covariance (ANCOVA) models with baseline EDSS and geographic region as covariates. Changes from baseline on MSFC component Z scores, overall MSFC score, and MSFC plus SLCLA scores were analyzed using the Wei-Lachin test and mixed model for repeated measures analyses with time-by-treatment interaction and covariate adjustment for geographic region and baseline score. The nonparametric Wei-Lachin multivariate test is used with repeated measures data using change from baseline at different timepoints to determine differences in score distribution over time between treatment groups. 24 SLCLA was analyzed by ranked ANCOVA with covariate adjustment for geographic region and baseline score.
2011 ) and its phylogenetic divergence occurred early in thaumarchaeotal diversification  (Gubry-Rangin et al. 2015). Sequences within this group are widely distributed in soil and other environments, but typically do not comprise the major proportion of amoA gene sequences in high throughput sequencing studies of soil (e. g. Gubry-Rangin et al. 2011). Pester et al. (2011)  found amoA gene sequences representative of this group in seven of nine soils sampled from four different continents, comprising up to 13% of all archaeal amoA gene sequences. In addition, a genome sequence of an unpublished soil enrichment culture has been deposited in GenBank (accession number CP012850. 1) and has provisionally been named 'Candidatus Nitrosocosmicus oleophilus', with the proposed genus name describing 'a widely distributed AO' (Rhee, pers.
Phylogenetic analysis PCR was performed with primer sets targeting the archaeal amoA gene (CrenamoA23f/CrenamoA616r) and 16S rRNA gene (A109f/1492r) (Table  2 ). PCR products were purified using a Macherey-Nagel NucleoSpin PCR Clean-up Kit (Fisher Scientific, Loughborough, UK) and sequenced, with assembled 16S rRNA and amoA gene sequences deposited in GenBank with accession numbers KU290365 and KU290366, respectively. Sequences were aligned with those from all previously cultivated AOA and a selection of environmental clones using the ClustalW function within the BioEdit software  (Hall 1999 ) before removing regions of ambiguous alignment. Phylogenetic analyses were performed using maximum-likelihood with General Time Reversible-correction (PhyML;  Guindon and Gascuel 2003) , Bayesian (MrBayes  (Ronquist et al.
[30]. The MC simulation of the CMS detector response is based on GEANT4  [31]. The data used in this study were recorded under special running conditions in which the beams were separated at the CMS interaction point, resulting in an average of 1. 3 pp interactions per bunch crossing. The integrated luminosity recorded was about 270 nb -1. As the average number of pp interactions per bunch crossing is small in the present data, minimum bias (MB) pp events were selected online by simply requiring that two proton bunches collide near the center of the CMS detector. Only a small fraction (∼10 -3 ) of all MB pp events were recorded (i. e. , the trigger was prescaled). In order to enhance the fraction of high-multiplicity events, additional samples were collected with a dedicated selection procedure that combined the CMS L1 and HLT systems.