dataesr/scientific-paragraphs-categorization huggingface dataset:
After injection of the lentivectors and recovery from surgery, we assessed the aversive response of control and knockdown mice to a leucine-deficient meal. As expected, control mice injected with a scramble-shRNA lentivector (Ctr-shRNA) consumed significantly less imbalanced diet than the balanced one (-21. 7% over a 1 hr ΔLeu meal) (Figure  2A ). This aversive response was markedly blunted in mice injected with the lentivector carrying the GCN2 shRNA. Mice were sacrificed after the completion of food intake measurements in order to measure GCN2 mRNA expression specifically in ARC tissues. The delivery of GCN2specific shRNA molecules led to a significant reduction of GCN2 mRNA level by 40% in ARC extracts as compared to control mice (Figure  2B ). Although the injection of GCN2-shRNA lentivirus led to dispersion in both food intake response and GCN2 mRNA content, our data show that the magnitude of the aversive phenotype is correlated with GCN2 expression level in the ARC (Figure  2C ).
Four male mice were used per group. Signal intensity was quantified using ImageJ software. Results are given as mean ± SEM. The statistical difference between groups was assessed by a two-way ANOVA. **p < 0. 01. (C) IHC showed phospho-eIF2α labeling in the ARC. A representative mouse for each group (four male mice) is shown. Scale bar, 100 μm. (D) Western blot analysis showed increased ATF4 protein expression in the ARC following a ΔLeu meal. After overnight starvation, mice were fed either with a Ctr or a ΔLeu diet for 4 hr, then animals were sacrificed for analysis. Nuclear protein extracts were prepared from pooled ARC tissues of four mice per group. Histone H3 served as a loading Ctr. See also Figures  S1  and S2. Lentivectors encoding GCN2-specific shRNA or scramble sequence were delivered bilaterally into the ARC of wild-type male mice (see Figure  S3  for technical details).
Acknowledgments We thank  Dr. J. M. Friedman  ( Rockefeller University, New York ) for the generous gift of NPY-and POMC-GFP mice (Pinto et al. , 2004). We wish to acknowledge  Dr. Brigitte Gaillard-Martinie ,  Dr. Jean-Louis Couderc ,  Xavier Blanc ,  Anne Terrisse ,  Christophe Demartrin , and  Didier Nègre  for their technical assistance and  Drs. Jacques Mallet ,  Patrick Even , and  Christelle Boileau  for critical reading of this manuscript. This work was supported by grants from  "Fondation pour la Recherche Médicale ," " Société Française de Nutrition ,"  Ajinomoto Amino Acid Research Program  ( 3ARP ), and " Agence Nationale pour la Recherche. ".
Study population and data collection EPIC is a multicenter prospective cohort study designed to investigate the associations between diet, lifestyle, genetic and environmental factors and various types of cancer. The rationale and methods of the EPIC design have been published previously. 26, 27 In summary, 521,448 participants (aged 25-70 years; approximately 70% women) were enrolled between 1992-2000 in 23 sub-cohorts in ten European countries (Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden and United Kingdom). The present analysis is based on participant data from all centers except for Norway (blood samples only recently collected; few CRCs diagnosed after blood donation) and Sweden (no available serum samples). Detailed and validated dietary (country-specific questionnaires) and lifestyle data (standardized questionnaires), anthropometrics and biological samples were collected at the time of enrolment.
Epidemiology Hughes et al. tumors in the cecum, appendix, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending and sigmoid colon (C18. 0-C18. 7) and overlapping or unspecified origin tumors (C18. 8 and C18. 9). Rectal cancers were defined as tumors occurring at the recto-sigmoid junction (C19) or rectum (C20). Anal canal cancers (C21) were excluded. CRC is the combination of the colon and rectal cancer cases. All subjects with prior cancer diagnoses at any site (except non-melanoma skin cancer) or with missing values on any Se status biomarkers were excluded. The total number of samples processed for Se and SePP measurements in the laboratory was 2,192 (cases 5 1,096, controls 5 1,096), from which 130 case-control sets had missing biomarker measurements in either the case or matched control, due to insufficient availability of bio-sample for laboratory analysis, so that 1,932 individuals (cases 5 966, controls 5 966) were included in the final dataset and utilized in the present analyses.
It can be speculated that as fish and meat represent a good source of Se supply, they could, in that respect, confer some protection against CRC, although for men this may be slightly masked by the adverse effects of a high consumption of red and processed meat. 48 he study strengths include an appreciable sample size within a large, prospective study with extensive data on lifestyle and other dietary factors, and pre-diagnostic bloods. Use of blood samples taken at time points prior to CRC diagnoses and use of prospectively collected dietary and lifestyle data minimizes recall and reverse causality biases. A second major strength lies in the determination of the two most meaningful biomarkers of Se status, that is, total Se and SePP serum concentrations. 30, 33 The main limitations are the single time-point blood measure per subject, giving room for random error and the relatively short follow-up time (4 years).
Sampling agenda and laboratory analysis Milk was sampled at the morning milking at the delivery then at day 30 and 60 post-partum in a plastic bottle. Blood samples were collected in the dams just before injection then at the delivery. Blood samples were collected also on camel calves after parturition at the same time of their dam. Samples (blood and milk) were stored in deep freezer at -80°C until laboratory analysis. In blood and milk samples, copper and zinc were determined by Atomic Absorption Spectrophotometer (AA-6650, Shimadzu, Japan) at the IDAC laboratory, Kharj (Saudi Arabia). Selenium was determined in the same laboratory with Hybrid Vapor Generator (HVG-1, Shimadzu, Japan). The data are reported as ng/mL for selenium, and µg/100ml for copper and zinc.
Acknowledgements This study has been achieved within FAO camel project  UTF/SAU/021/SAU  with the support of  Camel and range Res. Center (CRRC). The authors thank  Mr. Sallal Issa Al-Mutairi , former head of the  CRRC  for his encouragements and support. We thank also the staff of the camel farm ( Mrs. Hassan  and  Surish ) for the monitoring of the camel feeding and milking. Thanks also to FAO team leader at Riyadh,  Dr. A. Oihabi  who supported this project.
Histologic disease activity Endoscopically collected, formalin-fixed, and paraffinembedded tissue biopsies were cut and H&E-stained in preparation for histological evaluation conforming to standard protocols at the respective institution. Tissues were evaluated and scored by a single, experienced pathologist at each center, using guidelines established by the WSAVA Gastrointestinal Standardization group  (Washabau et al. , 2010; Day et al. , 2008)  and with the pathologist being blinded to the results of fcA12, the severity of endoscopic lesions, and clinicopathologic data from these dogs. The severity of histopathologic lesions in each section of the GI tract was recorded using a 4-point grading system with 0 = normal, 1 = mild lesions, 2 = moderate changes, and 3 = severe histopathologic changes.
ACKNOWLEDGMENTS This work was performed within the  Département Hospitalo-Universitaire (DHU) AUToimmune and HORmonal diseases  and supported by grants from the  European Union 's  Seventh Framework Programme  ( FP7/2007-2013)  under grant agreement no. 241592  (to Ralf Jockers), the  Agence Nationale de la Recherche   ANR-12-JSV1-0011  (to  Julie Dam ), the " Who am I?" laboratory of excellence  no. ANR-11-LABX-0071  funded by the  French government  through its " Investments for the Future" program  operated by the  French National Research Agency (ANR)  under grant no. ANR-11-IDEX-0005-01  (to  Julie Dam  and  Ralf Jockers ), the  Institut National de la Santé et de la Recherche Médicale (INSERM)  and the  Centre National de la Recherche Scientifique (CNRS). Clara Roujeau  received a fellowship from the  French "Ministère de la Recherche et la Technologie (MRT).
4 milliunit each of heparin lyase I-III (for heparin or HS) at 37 °C overnight as described (  28 ) before heat inactivation of the enzymes. Products were separated by RPIP-HPLC and monitored by post-column fluorescence detection as described earlier  (28). Structure of the BT_1596 Sulfatase-The BT_1596 structure was solved by the Joint Center for Structural Genomics  (29)  and deposited in the PDB under code 3B5Q. Manual docking of the enzyme substrate was made using the disaccharide ⌬HexA2S-GalNAc4,6S derived from a structurally characterized heparin tetrasaccharide (PDB code 1BFB). The human cerebroside-3sulfate 3-sulfohydrolyase (ArsA) in interaction with a synthetic substrate (PDB code 1E2S) was superimposed with the BT_ 1596 structure using Coot and the SSM program. The heparin disaccharide was manually docked using ArsA substrate as reference.
NMR Analysis-NMR experiments were performed on a Bruker 600 MHz Avance III spectrometer using a 2. 5-mm 1 H/ 13 C inverse detection probe, a 5-mm 1 H/ 13 C/ 15 N/ 31 P inverse detection QCI probe, or a 5-mm 1 H/ 13 C/ 15 N/ 31 P cryoprobe all equipped with z-gradient and controlled by Topspin 2. 1 and 3. 0 software. The incubated samples were repeatedly exchanged with D 2 O with intermediate lyophilization. The residual HOD signal was suppressed by saturation of the water peak during the recycle delay or using the WATERGATE pulse sequence. For the one-dimensional NMR experiments with the substrates incubated with the enzymes, the diffusion-edited NMR experiment (ledbpgp2s1d) was used for effective suppression of the residual water and buffer signals while retaining the signals from the substrates.
ϳ8 units) and the internal IdoUA residues partially sulfated on position 2. NMR analysis showed AVE5026 to be an enzyme substrate (Fig. 2E ). It also demonstrated that BT_1596 exclusively hydrolyzes the ester sulfate at the 2-O-position of the ⌬4,5HexA2S nonreducing end of all oligosaccharides present in AVE5026. Furthermore, no change for the C2 chemical shifts and the H1 signal intensity of the internal IdoUA2S units was observed, confirming that they are not targets of the enzyme  (33). Our study thus establishes BT_1596 as a ⌬4,5-hexuronate-2-O-sulfatase connecting HS and CS metabolism in B. thetaiotaomicron, consistent with transcriptomic analysis showing its induction in presence of host glycans  (7). Structure of the ⌬4,5-Hexuronate-2-O-sulfatase BT_1596 -Investigation of public databases revealed that the structure of the BT_1596 enzyme has been solved by the Joint Center for Structural Genomics (29) (PDB code 3B5Q) and identified as a putative sulfatase.
Based on this analysis and using the ArsA substrate as a reference, we manually docked a disaccharide containing a ⌬4,5-HexA2S (PDB code 1BFB) inside the BT_1596-active site (Fig. 2G ). Interestingly, validations of our model are provided by the fact that the docked disaccharide superimposed with a sulfated piperazine crystallized within the enzymeactive site and that the four sulfate oxygen atoms coincide perfectly with four water molecules located inside the Functional Analysis of B. thetaiotaomicron GAG Sulfatases  AUGUST 29, 2014  • VOLUME 289 • NUMBER 35 enzyme-active site. In this model, two charged amino acids (i. e. Lys-296 and Lys-117) are ideally positioned to interact with the sulfate group, although Glu-378 and Asn-95 seem to be responsible for the correct orientation of the unsaturated unit inside the enzyme-active site.
The large upfield shift of H2 and smaller upfield shifts of the other signals from the nonreducing end unsaturated uronate residue (⌬) are indicative of desulfation at the C2 position. E, superimposition of 1 H- 13 C HSQC spectra of AVE5026 alone (red, CH and CH 3 groups, and blue, CH 2 groups) and incubated with BT_1596 (black, CH and CH 3 groups, and green, CH 2 groups) show the large shifts experienced by the carbon and proton signals of the nonreducing end residue upon desulfation at the C2 position, although signals for internal IdoUA2S remain unaltered. The upper spectrum displays the anomeric region and the lower spectrum the C2/H2 to C6/H6 region. F, overall structure of the BT_1596 sulfatase (PDB code 3B5Q) with the disaccharide ⌬HexA2S-GalNAc46S (PDB code 1BFB) manually docked into the active site.
The upper spectrum displays the anomeric region and the lower spectrum the C2/H2 to C6/H6 region. F, overall structure of the BT_1596 sulfatase (PDB code 3B5Q) with the disaccharide ⌬HexA2S-GalNAc46S (PDB code 1BFB) manually docked into the active site. G, zoom of the BT_1596 sulfatase showing conserved critical residues. Residues involved in cation coordination are shown in salmon, and residues involved in substrate coordination are shown in pink. Serine 64 is likely a C␣-formylglycine in the active enzyme. The green sphere represents a modeled cation.
Acknowledgments This work is a part of  Flore Dagorn 's Ph. D. thesis ( University of Nantes, Nantes, France, 2012 ) supported by a grant from the  Ministère de l'Education Nationale, de la Recherche et de la Technologie, Paris, France. Financial support for this work was provided by the  Syndicat mixte pour le dé veloppement de l'aquaculture et de la pêche (SMIDAP) ,  Région des Pays de la Loire, Nantes, France. The authors are grateful to  Yanic Marty ,  CNRS, University of West Brittany, Brest , for kindly donating pure samples of the authentic ceramide aminoethylphosphonate originated from C. fornicata and Pecten maximus, and to  Philippe Rosa  ( University of Nantes ) for technical assistance.
Real-time qPCR Total RNA was prepared from ileum (2 cm above the caecum) and distal colon with RNeasy mini kit (Quiagen, Courtaboeuf France). Total RNA was reverse-transcribed using the High Script reverse transcription Supermix (Biorad, Marnes-la-coquette, France). Primer set for GR was: forward 59TCTGGACTC-CATGCATGAGG3', reverse 59TCCAAAAATGTCTGGAAG-CAGT3' (annealing temperature 60uC). The qPCR assays were performed with IQ Syber Green Supermix (Biorad) on the CFX96 (Biorad). qPCR data were normalized by TATA-box binding protein (Tbp) expression levels and analyzed using 2 2DCt.
Statistics All analyses were done using GraphPad Prism 4 software (GraphPad; San Diego, USA). Intestinal permeability and plasma CORT in response to MS were expressed as the mean6SEM, and data analyzed by ANOVA and Tukey tests for post hoc comparisons. BT was expressed as the mean6SD and examined for significance using the chi square test and Fisher exact test. qPCR data were analyzed by Student t-tests. A P value ,0. 05 was considered significant.
In contrast, no significant change in epithelial permeability to Dextran 4 kDa or HPR 44 kDa was observed in the ileum of MS pups (Figure  3B ). h ), and after the pups were returned to their dams (T8 h, T12 h and T24 h). Note that only PND10 rats displayed increased IP in response to MS procedure. Data are mean6SEM (7-10 animals per group). **P,0. 01 ***P,0. 001 compared to corresponding sham controls. (B) Blood samples from MS and sham pups were obtained in rats throughout the MS procedure lasting for 4 h, then every 4 h for 8 to 12 h after the pups were returned to their dams. Note that basal plasma CORT levels in male and female PND10 were lower than in their PND20 counterparts. In both PND10 and PND20 rats, circulating CORT increased in MS rats soon after they were removed from their mother, and peaked at 4 h.
Figure2. Effect of a single MS for 4 h on IP and plasma CORT in PND10 and PND20 rats. (A) Data show in vivo IP to FD4 immediately after MS (T4 h), and after the pups were returned to their dams (T8 h, T12 h and T24 h). Note that only PND10 rats displayed increased IP in response to MS procedure. Data are mean6SEM (7-10 animals per group). **P,0. 01 ***P,0. 001 compared to corresponding sham controls. (B) Blood samples from MS and sham pups were obtained in rats throughout the MS procedure lasting for 4 h, then every 4 h for 8 to 12 h after the pups were returned to their dams. Note that basal plasma CORT levels in male and female PND10 were lower than in their PND20 counterparts. In both PND10 and PND20 rats, circulating CORT increased in MS rats soon after they were removed from their mother, and peaked at 4 h.
Recently, a direct functional link between the olfactory and hormonal systems in humans has been reported  [27]. Although promising, these studies remain confined to a few molecules and to a limited number of protein targets. With the availability of large-scale chemical bioactivity databases and the recent advances in chemoinformatics and bioinformatics, it has become possible to include the chemical space in systems biology, i. e. systems chemical biology  [28]. In addition, the application of global pharmacology profiles and network pharmacology of small molecules is emerging as a new paradigm in drug discovery  [29]. However, these concepts of multi targeting have primarily been implemented for drugs  [30]  but not in the context of environmental chemicals. This prompted us to investigate the global network pharmacology of odorant molecules, in addition to peculiar associations between odorant molecules and hORs.
It revealed several new functional proteins and biological pathways influenced by odorants. Lastly, we explored the potential pharmacological space of odorant compounds based on a large chemogenomics database. From the chemical structure of a large collection of odorant molecules, annotations and predictions of the activity profile against most known biological targets were gathered. The previously unknown activity for two sets of three odorants was evaluated and confirmed experimentally for the cannabinoid receptor 1 (CB1) and for the peroxisome proliferator-activated receptor gamma (PPARc). Thus, taking advantage of recent progress in computational chemical biology, we are able to propose new interactions, which are important for the understanding of the olfactory perception mechanism and -at the same time -highlight targets and pathways recognized by odorant compounds.
Odorant molecules data We extracted 2,927 compounds, their chemical structures and their respective flavor, odor or aroma descriptions from Flavor-Base (FLB) version 2004 (http://www. leffingwell. com/flavbase. htm). Flavor-Base is one of the most extensive collections of compounds related to natural and synthetic flavoring chemicals. All chemicals are listed on the U. S. Food and Drug Administration (FDA) and Flavor and Extracts Manufacturers Association (FEMA) Generally Regarded As Safe (GRAS) list. The flavor and odor descriptions provided by Dr. J. Leffingwell and Associates are also supported by several published studies sources such as Arctander  [34]. All the selected molecules possess at least one odorant component described as ''odor'', ''flavor'', or ''aroma'', excluding the molecule exclusively described as ''taste''.
Existing variations in organoleptic descriptions by various authors were taken into consideration. Note that no information about interactions between odorant molecules and ORs is provided in Flavor-Base. For the set of compounds extracted, we compiled odorant molecule-OR binding interactions from the literature and the Olfactory Receptor Database (ORDB)  [35]  for human, rat and mouse (Table  S1  in File S1). Only direct physical interactions were considered (i. e. binding data) and none of the gene expression was kept in this study.
Integrating the human interactome and the odorome Protein-protein interactions (PPIs) were extracted from a list of ORs and their first interactor proteins using an in-house human interactome network based on experimental data from human and model organisms  [32, 33]. The current interactome contains 507,142 unique PPIs linking 14,441 human proteins. PPIs of the 83 ORs allowed extending the odorome to 183 genes. This network was used for the disease and pathways enrichment analysis. Human disease information was extracted from the GeneCards database  [39]. We also determined the enriched terms among pathways using the KEGG and Reactome databases. Protein-disease relationships and gene-pathway links were independently evaluated in the odorome. P-values were calculated using hypergeometric testing with Bonferroni adjustment for multiple testing  [40].
Odor-target matrix A chemogenomic database, ChemProt, was used to explore the human pharmacological space with the FlavorBase odorant compounds. ChemProt is a chemical genomics platform that integrates chemical-protein interactions from various available data sources  [41]. The current version of ChemProt as of January 2013 contains 1,150,000 unique chemical structures with biological information for more than 15,290 proteins  [42]. We considered only compounds with binding activity in this study.
Results To improve knowledge of olfactory perception and biological roles of odors in human, odorant molecules were used to generate a predictive model to identify odor coding, and to explore the known pharmacological space. We integrated various data type such high confidence protein-protein interactions and large chemical biology database to underlie molecular mechanisms of odorant molecules and the biological pathways they perturb. Overall, the results show a global mapping of the human odorome. The key steps of our approach are illustrated in Figure  1.
A total of 183 new genes were identified and among them, 12 were connected to at least one of the 83 ORs with high confidence scores. In general, ORs appear to interact with three guanine nucleotide binding proteins: GNAL, GNGT1 and GNB1. OR1G1 is linked to a fourth protein, the odorant binding protein 2B (OBP2B). In a second step, disease enrichment data were included with the aim of prioritizing disease candidate genes. Among them, three disease groups are statistically significantly connected: hypertension, schizophrenia and mood disorders (list of genes and p-values can be found in Table  S3  in File S1). A previous study has explored the potential of olfactory dysfunction as a key component in early diagnostic strategies of Parkinson and Alzheimer diseases  [50]. The UPSIT (University of Pennsylvania Smell Identification Test) revealed abnormality more frequently for patients with neurological diseases than olfactory-evoked responses (http://emedicine.
medscape. com/article/861242overview). For hypertension, patients with smell impairment are reported to use larger quantities of sugar and salt to highlight flavors and thus increase the risk of developing hypertension  [51]. We analyzed also the functional properties of the olfactory system using two pathways repositories (KEGG and Reactome)  [52, 53]. From the KEGG database, we observed statistical significance for the calcium signaling pathway, the neuroactive ligand-receptor interaction pathway, the taste transduction pathway, the type 2 diabetes pathway and the long term depression pathway. From the Reactome database, three pathways were significantly linked to the global odorome, the 'opioid signaling', the 'integration of energy metabolism' and the 'GPCR signaling' pathways. A recent study supports our findings by showing that odoridentification deficit and memory impairment are closely associated with disease-specific metabolic changes  [54].