dataesr/scientific-paragraphs-categorization huggingface dataset:
AEs were captured in both studies, with investigators being asked to record the relationship to study medication. In addition, clinical hematology and blood chemistry were assessed at baseline and at the end of dosing, with vital signs (systolic and diastolic blood pressure) and electrocardiogram (ECG) and 24 hours Holter ECG data captured at regular intervals. Lung function (FEV 1 ) was also assessed as a safety parameter in both parts of both studies to exclude the occurrence of post-dose bronchospasm. All subjects provided written informed consent prior to any study-related procedure. The studies were conducted at the same institution, were approved by the following independent ethics committees: Study.
2 or higher; SAS Institute Inc. , Cary, NC, USA). A model was developed to compare the PK characteristics of OD and BID dosing of CHF6001 administered via MDDPI. A two-compartment disposition model was found to best fit the data, with three-way parallel absorption pathways and first-order elimination from the central compartment. The model was built using NONMEM (Version 7. 3), supplemented with the PsN toolkit (Version 4. 4. 8). Simulations were run based on 100 subjects replicated 10 times per dose, performed using NONMEM Version 7. 4. 1 and processed using Phoenix WinNonlin (Version 7. 0) and GraphPad Prism (Version 7. 0). NONMEM data sets were prepared using SAS 9. 4.
1, Copenhurst Independent Research Ethics Committee, Wirral, UK (25 July 2011); Study 2, Wales Research Ethics Committee, Cardiff, UK (6 November 2014), and were performed in accordance with the principles of the declaration of Helsinki and the International Conference on Harmonization notes for guidance on Good Clinical Practice (ICH/CPMP/135/95). Both studies are registered in ClinicalTrials. gov (Study 1: NCT01703052; Study 2: NCT02386761). There were no substantial amendments to Study 2. Study 1 required two substantial amendments, both to Part 2 (one to permit escalation to the 1,200 µg dose, and one to permit escalation to the 1,600 µg dose).
Acknowledgments The authors would like to thank the investigators and subjects at the investigative site for their support of this study, and QuotientSciences for performing both studies. PK modeling support was provided by  Koen Jolling  and  Andreas Lindauer ,  SGS Exprimo NV (Belgium). Writing support was provided by  David Young  of  Young Medical Communications and Consulting Ltd. This support was funded by  Chiesi Farmaceutici SpA. These studies were funded by  Chiesi Farmaceutici SpA. An abstract summarizing the results of Study 1 was presented at the European Respiratory Society Annual Conference in 2013 as a poster presentation. The abstract was published in the European Respiratory Journal, Volume  42 (Supplement 57 ). Abstracts summarizing the results of Study 2 were presented at the American Thoracic Society Annual Conference in 2016 and the  European Respiratory Society Annual  Conference in 2016 as poster presentations.
However, no study compared SPG stimulation with the current standard abortive treatment, namely sumatriptan injection and/or oxygen inhalation, in terms of efficacy, delay between treatment administration and pain relief, amplitude of pain relief, respective constraints and safety, and costs. Further studies will have to address these points. Similarly, although a preventive effect has been suggested by the association of repeated SPG stimulation and decrease of attack frequency, no study compared SPG stimulation with CH prophylactic treatment or other surgical alternatives for refractory chronic CH, namely ONS and DBS. These data will be needed to determine the exact place of SPG stimulation in the management of CH. Moreover, all the previous data have been collected in refractory CH, and no published data are available regarding the interest of SPG stimulation in episodic CH.
Statistical analysis Cytokines levels, released by placebo-or active-treated cells, were normalized to levels released by LPS-control cells. A total of 100% is the normalized value of each donor response to LPS; indeed, each treated sample was compared with its own normalized control. The responses of the six donors were individually evaluated and the average of each duplicate was considered for statistical analysis. Statistical analysis was performed using GraphPad Prism version 7. 0 for Windows (GraphPad Software, La Jolla, CA, USA). Levels of IL-1β, TNF-α, and IL-6 secreted by active MI-treated cells were compared with the proper controls (placebo-treated cells and LPS-control cells) using paired t tests.
37 to 22 mM). The graphs in Figures  3  and 4  show that the active globules, at 3 tested lactose-saccharose concentrations (5. 5, 11, and 22 mM), exert significant anti-inflammatory effects compared with placebo and untreated LPS control on primary LPSstimulated enriched monocytes reducing IL-1β and TNF-α release of about 10%-30%. The observed effect on IL-6 Notes: Cultured human enriched monocytes from 6 donors, exposed to 10 ng/mL of LPS for 24 hours, were treated with placebo or active globules (from 1. 37 to 22 mM of lactose-saccharose concentrations). IL-6 release was evaluated by ELISA. Data were expressed as mean ± SD percentage of 6 donors, n=6 (vs LPS control, 100%). Cells treated with lactose-saccharose globules of 1 capsule of 2LARTH ® (magenta columns) have secreted lower levels of IL-6 compared with placebo control (gray columns).
Results Clustering cis-eQTL into regulatory modules. We generated transcriptome data for six circulating immune cell types (CD4+ T lymphocytes, CD8+ T lymphocytes, CD19+ B lymphocytes, CD14+ monocytes, CD15+ granulocytes, platelets) as well as ileal, colonic, and rectal biopsies (IL, TR, RE), collected from 323 healthy Europeans (141 men, 182 women, average age 56 years, visiting the clinic as part of a national screening campaign for colon cancer) using Illumina HT12 arrays (CEDAR data set; Methods). IBD being defined as an inappropriate mucosal immune response to a normal commensal gut flora  22  , these nine cell types can all be considered to be potentially disease relevant. Using standard methods based on linear regression and two megabase windows centered on the position of the interrogating probe (Methods), we identified significant cis-eQTL (FDR < 0.
Knowing that multigenic cRM represent 10% of all cRM (967/9720), 25/76 (i. e. , 33%) corresponds to a highly significant three-fold enrichment (p < 10 -9 ). To ensure that this apparent enrichment was not due to the fact that multigenic cRM have more chance to match DAP (as by definition multiple EAP are tested for multigenic cRM), we repeated the enrichment analysis by randomly sampling only one representative EAP per cRM in the 200 IBD risk loci. The frequency of multigenic cRM amongst DAP-matching cRM averaged 0. 22, and was never ≤0. 10 (p ≤ 10 -5 ) (Supplementary Fig. 4 ). In loci with high LD, EAP driven by distinct regulatory variants (yet in high LD) may erroneously be merged in the same cRM. To ensure that the observed enrichment in multigenic cRM was not due to higher levels of LD, we compared the LD-based recombination rate of the 63 cRM-matching IBD risk loci with that of the rest of the genome (https://github.
We added the well-established NOD2 and IL23R causative IBD genes as positive controls. We identified a total of 174 loss-of-function (LoF) variants, 2567 missense variants (of which 991 predicted by SIFT  25  to be damaging and Polyphen-2  26  to be either possibly or probably damaging), and 1434 synonymous variants (Fig. 8  and Supplementary Data 6). 1781 of these were also reported in the Genome Aggregation Database 27 with nearly identical allelic frequencies (Supplementary Fig. 6 ). We designed a gene-based burden test to simultaneously evaluate hypothesis (i): all disruptive variants enriched in cases (when ϑ < 0; risk variants) or all disruptive variants enriched in controls (when ϑ > 0; protective variants), and hypothesis (ii): some disruptive variants enriched in cases and others in controls.
Near identical results were obtained when classifying variants using the Combined Annotation Dependent Depletion (CADD) tool  30  instead of SIFT/PolyPhen-2 (Supplementary Data 7). We explored three approaches to increase the power of the burden test. The first built on the observation that cRM matching DAP are enriched in multigenic modules. This suggests that part of IBD risk loci harbor multiple co-regulated and hence functionally related genes, of which several (rather than one, as generally assumed) may be causally involved in disease predisposition. To test this hypothesis, we designed a module-rather than gene-based burden test (Methods). However, none of the 30 tested modules reached the experiment-wide significance threshold (p 0:05 2Ã30 % 0:0008). Moreover, the shift towards lower p values for the 30 modules was not more significant (p ¼ 2:3 10 À3 ) than for the gene-based test (Supplementary Fig.
Discussion We herein describe a novel dataset comprising array-based transcriptome data for six circulating immune cell types and intestinal biopsies at three locations collected on ∼300 healthy European individuals. We use this "Correlated Expression and Disease Association Research" data set (CEDAR) to identify 23,650 significant cis-eQTL, which fall into 9720 regulatory modules of which at least ∼889 affect more than one gene in more than one tissue. We provide strong evidence that 63 of 200 known IBD GWAS signals reflect the activity of common regulatory variants that preferentially drive multigenic modules. We perform an exon-based burden test for 45 positional candidate CD genes mapping to 33 modules, in 5500 CD cases and 6500 controls. By demonstrating a significant (p ¼ 6:9 10 À4 ) upwards shift of log(1/p) values for damaging when compared to synonymous variants, we show that the sequenced genes include new causative CD genes.
It suggests that cis-eQTL underlying disease predisposition operate in cell types, cell states (for instance, resting vs activated) or developmental stages that were not explored in this and other studies. It calls for the enlargement and extension of eQTL studies to more diverse and granular cellular panels  10, 33  , possibly by including single-cell sequencing or spatial transcriptomic approaches. By performing eQTL studies in a cohort of healthy individuals, we have made the reasonable assumption that the common regulatory variants that are driving the majority of GWAS signals are acting before disease onset, including in individuals that will never develop the disease. An added advantage of studying a healthy cohort, is that the corresponding dataset is "generic", usable for the study of perturbation of gene regulation for any common complex disease.
Nevertheless, a reasonable start may be to re-sequence the regions surrounding common regulatory variants that have been fine-mapped at near single base pair resolution  4. In conclusion, we hereby provide to the scientific community a collection of ∼24,000 cis-eQTL in nine cell types that are highly relevant for the study of inflammatory and immune-mediated diseases, particularly of the intestinal tract. The CEDAR dataset advantageously complements existing eQTL datasets including GTEx  10, 33. We propose a paradigm to rationally organize cis-eQTL effects in co-regulated clusters or regulatory modules. We identify ~100 candidate causative genes in 63 out of 200 analyzed risk loci, on the basis of correlated DAP and EAP. We have developed a web-based browser to share the ensuing results with the scientific community (http://cedar-web.
Informed consent was obtained prior to donation in agreement with the recommendations of the declaration of Helsinki for experiments involving human subjects. We refer to this cohort as CEDAR for Correlated Expression and Disease Association Research. SNP genotyping and imputation. Total DNA was extracted from EDTA-collected peripheral blood using the MagAttract DNA blood Midi M48 Kit on a QIAcube robot (Qiagen). DNA concentrations were measured using the Quant-iT Picogreen ds DNA Reagents (Invitrogen). Individuals were genotyped for >700 K SNPs using Illumina's Human OmniExpress BeadChips, an iScan system and the Genome Studio software following the guidelines of the manufacturer. We eliminated variants with call rate ≤0. 95, deviating from Hardy-Weinberg equilibrium (p ≤ 10 -4 ), or which were monomorphic.
For platelets, total RNA was extracted manually with the RNeasy Mini Kit (Qiagen). Whole genome expression data were generated using HT-12 Expression Beadchips following the instructions of the manufacturer (Illumina). Technical outliers were removed using controls recommended by Illumina and the Lumi package  38. We kept 29,464/47,323 autosomal probes (corresponding to 19,731 genes) mapped by Re-Annotator 39 to a single gene body with ≤2 mismatches and not spanning known variants with MAF>0. 05. Within cell types, we only considered probes (i. e. , "usable" probes) with detection p value ≤0. 05 in ≥25% of the samples. Fluorescence intensities were Log 2 transformed and Robust Spline Normalized (RSN) with Lumi  38. Normalized expression data were corrected for sex, age, smoking status and Sentrix Id using ComBat from the SVA R library  40.
e. , the fraction of the expression variance that is due to the cis-eQTL is therefore: h 2 eQTL ¼ σ 2 eQTL σ 2 T To simulate cis-eQTL explaining the same h 2 eQTL as the real eQTL in the CEDAR dataset, we sequentially considered all SNPs in the region. Each one of these SNPs would be characterized by n 11 individuals of genotype "11", n 12 of We would arbitrarily set z 11 , z 12 ; and z 22 at -1, 0, and +1. As a consequence, the variance due to this cis-eQTL equals: σ 2 eQTL ¼ n 11 À1 À z T ð Þ 2 þn 12 0 À z T ð Þ 2 þn 22 1 À z T ð Þ 2 n T in which z T ¼ n 22 À n 11 ð Þ =n T. Knowing σ 2 eQTL and h 2 eQTL , and knowing that h 2 eQTL ¼ σ 2 eQTL σ 2 eQTL þ σ 2 RES the residual variance σ 2 RES can be computed as σ 2 RES ¼ σ 2 eQTL 1 h 2 eQTL À 1 ! Individual expression data for the corresponding cis-eQTL (for all individuals of the CEDAR data set) were hence sampled from the normal distribution z i $ N z xx ; σ 2 RES À Á where z xx is -1, 0, or +1 depending on the genotype of the individual (11, 12, or  22).
The corresponding empirical p value accounts for the local LD structure between SNPs. Evaluating the enrichment of DAP-EAP matching. To evaluate whether DAP matched EAP more often than expected by chance alone, we analyzed 97 IBD risk loci interrogated by the Immunochip, (i) in order to allow for convenient comparison with Huang et al. 4  , and (ii) because we needed extensively QC genotypes for the IIBDGC data to perform the enrichment analysis with the ϑ-based method (see hereafter). Within these 97 IBD risk loci, we focused on 63 regions affecting CD  4  , encompassing at least one significant eQTL, and for which the lead CDassociated SNP had MAF > 0. 05. Indeed, eQTL analyses in the CEDAR dataset Fig. 9  QQ-plot for the gene-based burden test. Ranked log(1/p) values obtained when considering LoF and damaging variants (full circles), or synonymous variants (empty circles).
Acknowledgements This work was supported by grants to  Michel Georges  from  WELBIO (CAUSIBD) ,  BELSPO (BeMGI) , and  Horizon 2020  (SYSCID). Computational resources at ULg have been provided by  GIGA  and the  Consortium des Équipements de Calcul Intensif (CÉCI) , funded by the  Fonds de la Recherche Scientifique de Belgique (F. R. S. -FNRS)  under Grant No. 2. 5020. 11. This work was conducted as part of the  BioBank Japan Project  supported by the  Japan Agency for Medical Research and Development  and by the  Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government. The work of D. A. and I. A. was supported by  Russian Ministry of Science and Education  under 5- 100 Excellence Programme. R. K. Weersma  is supported by a  VIDI grant  ( 016. 136. 308 )from the  Netherlands Organisation for Scientific Research (NWO).
Data availability. The complete CEDAR eQTL dataset can be downloaded from the Array Express website (https://www. ebi. ac. uk/arrayexpress/), accession numbers E-MTAB-6666 (genotypes) and E-MTAB-6667 (expression data). The data, preprocessed as described in Methods, can be downloaded from the CEDAR website (http://cedar-web. giga. ulg. ac. be).
* S Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10. 1021/acs. chemmater. 8b02833. Full synthetic details, additional synthetic experiments and analysis for all materials, TGA, FT-IR, PXRD, gas sorption, UV/vis and photoluminescence spectra, SEM, TEM, energy-dispersive X-ray data, computational data, further photocatalysis data, time-correlated singlephoton counting data, selective laser sintering, and QENS data (PDF).
We thank the  Engineering and Physical Sciences Research Council (EPSRC)  for the financial support under Grant  EP/ N004884/1. Y. B. thanks the  China Scholarship Council  for a Ph. D. studentship. A. A. Y. G. thanks  EPSRC  for an  EPSRC Postdoctoral Fellowship  ( EP/P00928X/1 ). C. M. A. thanks the  EPSRC  for financial support through a  DTP grant. The  Institut Laue-Langevin (ILL) facility (Grenoble, France)  is acknowledged for providing beam time on the IN6 spectrometer. The  Imaging Centre at Liverpool (ICaL)  is acknowledged for performing TEM imaging. R. S. S. thanks  Dr. T. Hasell  for helpful discussions.
Systematic literature review 11 The GMO Panel assessed the applicant's literature searches on maize MON 87411, which include a scoping review, according to the guidelines given in EFSA (2010, 2017). A systematic review as referred to in the Regulation (EU) No 503/2013 has not been provided in support to the risk assessment of the application EFSA-GMO-NL-2015-124. Based on the outcome of the scoping review, the GMO Panel agrees that there is limited value of undertaking a systematic review for maize MON 87411 at present. Although the overall quality of the performed literature searches is acceptable, the GMO Panel considers that future searches on maize MON 87411 could be improved. The GMO Panel therefore recommends the applicant to: • design broader and more sensitive searches in the context of maize MON 87411, in order to identify as many relevant publications as possible; • ensure that enough search term variation is used (covering possible synonyms, related terms, acronyms, spelling variants, old and new terminology, brand and generic names, lay and scientific terminology, common typos, translation issues); • use truncation consistently; • adapt the search to the size of the identified publications (and thus not combine search sets when one of the search sets already yields only a small number of publications); • assess the relevance and risk assessment implications of publications retrieved via searches beyond electronic bibliographic databases.
In addition, updated bioinformatics analyses of the newly created open reading frames (ORFs) within the insert and spanning the junctions between the insert and genomic DNA did not indicate significant similarities to toxins and allergens. 15 ccording to Regulation (EU) No 503/2013, when silencing approaches by RNAi have been used in GM plant applications, a bioinformatics analysis to identify potential 'off target' genes is required. The applicants have followed the recommendations by the EFSA GMO Panel for an RNAi off-target search in the plant expressing the dsRNA. 16, 17 None of the maize transcript sequences present in the available databases showed perfect match to any of the siRNAs potentially produced. Few maize transcript sequences had regions matching to those siRNAs with one to four mismatches.
Cry3Bb1 protein characterisation and equivalence 18 Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis showed that both plant and microbe-derived Cry3Bb1 proteins had the expected molecular weight of ~74 kDa and were comparably immunoreactive to Cry3Bb1 protein-specific antibodies. An additional ~65 kDa truncated form of the Cry3Bb1 protein in the plant-derived sample was also identified by western blot analysis. Glycosylation detection analysis demonstrated that none of the Cry3Bb1 proteins were glycosylated. Amino acid sequence analysis of the intact plant-derived Cry3Bb1 protein by mass spectrometry (MS) methods showed that the protein matched the deduced sequence as defined by the cry3Bb1 gene. These sequence analysis data were consistent with the previously analysed microbederived intact Cry3Bb1 protein.
Functional equivalence was demonstrated by a biochemical in vitro activity assay that showed that both proteins had comparable activity. The protein characterisation data comparing the structural, biochemical and functional properties of plant and microbe-derived Cry3Bb1 and CP4 EPSPS proteins indicate that these proteins are equivalent. Therefore, the GMO Panel accepts the use of the Cry3Bb1 and CP4 EPSPS proteins produced in bacteria for the safety studies.
The representativeness of these sites was questioned (EFSA GMO Panel, 2015a) as it was doubtful whether they would capture the variability that may exist across potential receiving environments for the commercial cultivation of this GM maize line. Upon request of the EFSA GMO Panel, a rationale for the site selection 26 and one additional site from Argentina, 27 from the same growing season, was submitted for agronomic and phenotypic characteristics. The updated dataset was considered to conform to the EFSA guidance (2011a). At each site, the following materials were included: plots containing GM plants exposed to the intended herbicide (glyphosate) in addition to the conventional herbicides, plots with comparator plants treated with conventional herbicide management regimes and plots with GM plants treated with the same conventional herbicide management regimes.
Statistical analysis of field trial data The statistical analysis of the agronomic/phenotypic and compositional data from the 2011-2012 field trial study followed the recommendations of the GMO Panel (EFSA GMO Panel, 2010b, 2011a). This includes the application of a difference test (between the GM maize and its conventional counterpart) and an equivalence test (between the GM maize and the set of non-GM maize reference varieties). The results of the equivalence test are categorised into four possible outcomes (I-IV, ranging from equivalence to non-equivalence). Thirteen 30 agronomic and phenotypic endpoints, plus abiotic stressors, disease incidence and arthropod damage were collected from nine sites (Table  2 ). All endpoints were recorded appropriately at all sites. The endpoint dropped ear count was not categorised because the estimate of the variance among reference varieties was 0; however, no significant differences are identified for this endpoint.
Maize oil was excluded from the assessment since no proteins are expected to be present in the oil. Consumption data of the relevant commodities (corn bread, corn flakes, corn milling products, cornmeal porridge, corn grain, corn snacks, sweet corn and popcorn) were retrieved by the applicant from the available summary statistics of the EFSA Comprehensive European Food Consumption Database. 52 The EFSA consumption database contains information on food consumption data at individual level from the most recent national dietary surveys in different EU Member States (EFSA, 2011; Huybrechts et al. , 2011; Merten et al. , 2011). Acute dietary exposure was estimated using for each population group the food commodity with the highest acute consumption among consumers only (95th or 97. 5th percentile depending on the number of consumers), 53 and multiplying this value by the mean values of Cry3Bb1 and CP4 EPSPS proteins.