dataesr/scientific-paragraphs-categorization huggingface dataset:
Acknowledgements We gratefully acknowledge  M. Welham  for provision of BIO stock for preliminary experiments in this study,  S. Wilson  for supplying the Tg (top:GFP) fish,  N. Parkinson  and  Robert J. Burnside  for technical advice, and  H. Schwetlick  and  S. Mulnoz-Descalzo  for helpful comments on the manuscript. Funding was provided by  University of Bath Graduate Studentship (LV) , and  BBSRC  grant  BB/L00769X/1  (RNK) and  BBSRC  grant  BB/L007789/1  (GA and AR), as well as  NIH   R01 DE013828  (TFS). All data supporting this study are openly available from the  University of Bath  data archive at https://doi. org/10. 15125/BATH-00324. The authors declare they have no conflict of interest.
Liquid Chromatography Tandem Mass Spectrometry Proteins that eluted off Hupresin along with BChE or RBC AChE, as well as proteins from SDS gel bands were identified by liquid chromatography tandem mass spectrometry (LC-MS/MS). Data acquisition was performed with a Triple-TOF 6,600 mass spectrometer (ABI Sciex, Framingham, MA) fitted with a Nanospray III source (AB Sciex, Framingham, MA) and a Pico Tip emitter (# FS360-20-10-N-5-C12, New Objectives, Woburn, MA). The ion spray voltage was 2,700 V, declustering potential 60 V, curtain gas 30 psi, nebulizer gas 10 psi, and interface heater temperature 150 • C. Peptides were introduced into the mass spectrometer using ultra high pressure liquid chromatography. A splitless Ultra 1D Plus ultra-high pressure chromatography system (Eksigent, Dublin, CA) was coupled to the Triple-TOF via a cHiPLC Nanoflex microchip column system (Eksigent, Dublin, CA).
The Nanoflex system uses a replaceable microfluidic trap column and a replaceable separation column. Both are packed with ChromXP C 18 (3 µm, 120 Å particles; Trap: 200 µm × 0. 5 mm; Separation: 75 µm × 15 cm). Chromatography solvents were water/acetonitrile/formic acid (A: 100/0/0. 1%, B: 0/100/0. 1%). Picomole amounts of sample, in a 5 µl volume, were loaded. Trapping and desalting were carried out at 2 µL/min for 15 min with 100% mobile phase A. Separation was obtained with a linear gradient 5%A/95%B to 70%A/30% B over 60 min at a flow rate of 0. 3 µL/min. Peptides present in the data were identified by matching to the Swiss Prot or National Center for Biotechnology Information (NCBI) non-redundant databases, and corresponding proteins were identified. The Paragon algorithm in Protein Pilot v 5.
Minor BChE Isozymes BChE in plasma consists predominantly of tetramers. On nondenaturing gel electrophoresis bands for BChE monomers, dimers, and trimers are also seen, though their abundance is low (refer to the legend of Figure  3  for band annotation). Figure  3  shows that the minor BChE bands found in plasma are missing from BChE samples that have been chromatographed on Hupresin (lanes 1-7). Delipidated plasma in lane 6 developed a new band at the position of trimeric BChE. The position of albumin is indicated in Figure  3. It was identified by counterstaining the gel with Coomassie blue. a Protein molecular weights (MW) are taken from the UniProt database which includes the signal peptide, but excludes glycans and other posttranslational modifications. The molecular weight of the BChE monomer is actually 85 kDa when the 28 amino acid signal peptide is subtracted and 9 asparagine-linked glycans are added.
This state-of-the-art proteomic approach was applied to the cellular models in three independent SILAC experiments and led to the identification of 7 proteins down-phosphorylated and 24 proteins hyper-phosphorylated in HCV core expressing cells (Table  1 ). In addition, 16 out of the 35 differentially phosphorylated peptides exhibited a modulation of phosphorylation within the (Ser/Thr)-Pro motif, broadly recognized as potential MAP kinase and mTORC1 target sites  [14] , indicating that the (Ser/Thr)-Pro motif is essential for dynamic signaling transduction in HCVcore-expressing cells  [15]. A functional network was built by investigating the functions of the identified proteins into Go Elite database and visualized in Cytoscape program. This approach revealed that the phosphoproteins modulated by HCV core were prominently involved in metabolism (carbohydrate and lipid biosynthetic processes), insulin receptor signaling, protein transport, cell death, cellular component organization and translation (Figure  1 ).
The table encompasses the genes, protein names and their accession numbers according to the UniProt-SwissProt database. In the peptide sequences, (ph) after S/T/Y residue indicates the phosphorylated status. The probability for the site of phosphorylation was calculated by MaxQuant. The study was performed in biological triplicate (S 1 /S 2 /S 3 ) and Phosphorylated peptides were considered to be significantly regulated when exhibiting an abundance ratio core/WT exceeding mean + 1. 96 standard deviation in at least two replicates. www. impactjournals. com/oncotarget HCV core protein enhances the level of phosphorylated 4E-BP1 in human hepatoma cells and primary hepatocytes Among the proteins appearing substantially hyperphosphorylated in HCV core protein expressing cells compared to the control, several components involved in translation were identified such as the eukaryotic translation initiation factor 4B (EIF4B) and the eukaryotic translation initiation factors 4E-binding protein 1 (4E-BP1) and 2 (4E-BP2).
Column eluent was sprayed into the MS instrument operated with a lock mass of 445. 1200 for more accurate mass measurements in FTMS mode. Survey spectra were acquired over the mass range m/z 400-1400 at a resolution of 30,000 in the Orbitrap cell. In two separate runs, MS/MS data were acquired in data-dependent mode by selecting from the FTMS spectra the six most intense precursor ions for fragmentation by collision induced dissociation (CID) or electron transfer dissociation (ETD). Former target ions selected for MS 2 , within a mass window of +/-5 ppm, were dynamically excluded for 45s. In CID fragmentation mode, Multistage Activation (MSA) was applied, while considering the possible neutral losses of 32. 67, 49. 00, 65. 33 and 98. 00 to account for singly and doubly phosphorylated peptides  [35].
Assigning peptide sequences to MS/MS spectra and relative quantification Raw spectra were searched against the human SwissProt protein database (released on July 30th 2013) using the Andromeda search engine implemented in the MaxQuant software (version 1. 3. 0. 5) that includes features for SILAC-based quantitation and phosphosite localization. The SILAC label modifications and methylthio (C) for cysteine residues were set as fixed modifications in the database search. Methionine oxidation and phosphorylation on S, T and Y residues were added as variable modifications. The precursor and fragment ion mass tolerances were 5 ppm and 0. 6 Da, respectively. Up to two missed cleavages were allowed for trypsin digestion and the false discovery rate (FDR) was set to 1% for both peptide and protein identifications.
ACKNOWLEDGMENTS We thank  Charles Rice  for HuH7. 5 and FL/neo replicon cells,  Ralf Bartenschlager  for HuH9. 13 cells and  Francis Chisari  for HuH7. 5. 1 cells. We acknowledge  René Duchateau  at  Service des Animaux Transgéniques (SEAT)  for animal breedings. We are grateful to  Florence Petit ,  Véronique Legros  and  Taous Ait Saadi  for technical contribution. We acknowledge  François Guillonneau ,  Patrick Mayeux ,  France Demaugre  and  Marie-Annick Buendia  for helpful discussions.
FINANCIAL SUPPORT This work was supported by core funding from  Université Paris-Sud  and  Institut National de la Santé  et la  Recherche Médicale  (INSERM). Grants were obtained from l' Agence Nationale de Recherche sur le SIDA et les hépatites virales (ANRS), le comité Yvelines et le comité Ile de France de la Ligue Nationale Contre le Cancer and l'Institut National du Cancer (INCa, PAIR-CHC ). The Orbitrap XL-ETD instrument was funded by  CNRS, Genopole-France ,  Institut National de la Recherche Agronomique ,  Université d'Evry Val d'Essonne ,  Région Ile-de-France  and the  Agence Nationale de la Recherche (ANR). CA was recipient of a grant from  PRES UniverSud-Paris  and  ANRS , CL of a grant from  INCa.
Identification of Paralarvae and Morphological Measurements Dorsal mantle length (DML) was measured to the nearest 0. 05 mm on the dorsal side of all octopus and squid paralarvae using a Leica M205C stereomicroscope and Leica Application System image analysis software (Leica Microsystems, Germany). All octopus paralarvae (n = 492) were identified as O. vulgaris based on morphological characters following  Sweeney et al. (1992). Due to the difficulty of identifying squid paralarvae using morphological characters, all loliginid paralarvae (n = 163) were identified genetically. Molecular identification relies on previous work with adult specimens identified morphological and subsequently genetically. Briefly, DNA from the mantle of each loliginid paralarva was extracted with a QIAamp DNA Micro Kit (QIAGEN) following manufacturer's instructions, with the exception of two steps: Digestion at 56 • C was done overnight and the final elution was done in two steps using 15 µl buffer AE in each elution.
The barcoding region of the Cytochrome c Oxidase subunit I (COI) was amplified with the universal primers HCO2198 and LCO1490  (Folmer et al. , 1994)  and PCR products were sequenced by Sanger sequencing  (Stab Vida, Portugal). Each sequence was compared to the following GenBank reference sequences using the BLAST algorithm  (Altschul, 2014) : Alloteuthis media, EU668085  (Anderson et al. , 2008) ; A. subulata EU668098  (Anderson et al. , 2008) , and L. vulgaris, KF369142  (Lobo et al. , 2013). Loliginid paralarvae were identified as A. media (n = 93), A. subulata (n = 35), and L. vulgaris (n = 22)  (Olmos-Pérez et al. , unpublished data). For dietary analysis, a total of 64 O. vulgaris paralarvae (summer, n = 26; autumn, n = 38) and 32 A. media (summer, n = 16; autumn, n = 16) were selected.
Bioinformatic Analysis MiSeq reporter was used to separate and remove the adapters for the 96 samples. The software Fastq-Multx  (Aronesty, 2011)  was used to demultiplex amplicons according to the primer sequences. Due to the wildcard characters in the primer sequences, up to 7 base pair mismatches were permitted. Software SolexaQA++ 3. 1. 4 was used to ensure the reads were still paired  (Cox et al. , 2010). The paired end reads (read 1 and read 2) were merged using VSEARCH 1. 9. 5  (Rognes et al. , 2016). Paired reads that did not meet the following quality filtering were discarded  (Edgar and Flyvbjerg, 2015) : (i) reads with quality score over 3, (ii) reads longer than 140 bp, (iii) reads with less than one expected error in the primer sequence or barcodes. Unique sequences were clustered using a 97% identity threshold and remaining singleton Molecular Taxonomic Units (MOTUs) were discarded.
Chimeric sequences were then removed using UCHIME  (Edgar et al. , 2011). Using the final list of representative sequences, each MOTU was searched against the GenBank database using BLAST 3. 2. 31 (Camacho et al. , 2009). MOTUs with BLAST query coverage under 60% or BLAST identities lower than 74% were also deleted from the database. Potential contamination and predator MOTUs (i. e. , A. media and O. vulgaris) were removed from the database. Potential prey MOTUs were assigned using the following criteria to taxonomical categories: MOTUs with identity higher than 97% were determined at species level, MOTUs between 93 and 97% were assigned to genus, and MOTUs with identity below 93% were assigned to family.
Bioinformatic Analysis Of 8,274,658 raw reads, 5,734,163 were successfully demultiplexed and contained both read 1 and read 2. Then, 5,119,926 paired end reads were successfully merged, and 4,752,768 reads remained after quality filtering. A total of 4,124,464 reads was clustered into 1,155 MOTUs using a 97% threshold. Of the total reads, 3,189,247 corresponded to COI, 744,474 reads to the primers set 16Sa and 190,743 reads to the primer set 16Sb. Of these, 405 MOTUs (31,604 reads) did not match any GenBank sequence and 1,155 MOTUs, 750 (4,092,860 reads) had a match on GenBank database. After meeting the thresholds of query coverage and identity, 465 MOTUs (131,843 sequences) were removed and 285 MOTUs (3,961,017 reads) were classified as: contamination (48 MOTUs, 41,422 reads), O. vulgaris (60 MOTUs, 2,150,967 reads), and A.
DISCUSSION Overall, 107 MOTUs were successfully identified in O. vulgaris, which corresponded to 40 different families, 31 genera, and 32 species, while in A. media, 58 MOTUs were identified corresponding to 25 different families, 23 genera, and 21 species (Supplementary Material 1). The combination of the different primers targeting small DNA fragments, and comprehensive genetic databases, permitted us to identify up to 77 types of prey (Table  2 ). For the first time, a molecular approach was successfully applied to identify prey of wild A. media paralarvae, thereby increasing the range of known prey of wild O. vulgaris paralarvae during their first days of planktonic stage. Together, the results increased the knowledge of the prey predated by cephalopod paralarvae in their natural environment, suggesting more species to feed paralarvae in captivity conditions.
ACKNOWLEDGMENTS We are indebted to the captain, crew and technicians of  R/V Mytilus  ( IIM, CSIC Vigo ) for their assistance in collecting the zooplankton samples. We are grateful to  Mariana Cueto  for assisting with laboratory work,  Lara García Alves  for helping to sort the paralarvae,  Dr. Arsalan Emami-Khoyi  for assistance in primers selection and  Dr. Rob Cruickshank  ( Lincoln University, New Zealand ) for hosting LO-P in the molecular ecology laboratory. We would like to thank the two reviewers for their suggestions and comments that enormously improved the manuscript.
FUNDING This study was supported by the project  LARECO  ( CTM2011-25929 ) and  CALECO  ( CTM2015-69519-R ) funded by the  Spanish Ministry of Economy and Competitiveness. LO-P was supported with a  FPI grant  ( BES -2012-055651 ) and a mobility grant ( EEBB-I-15-10157 ) funded by the  Spanish Ministry of Economy and Competitiveness. ÁR was funded with a postdoctoral grant from the  "Fundación Barrié " and with RFWE funds from  La Trobe University (Australia). We acknowledge support of the publication fee by the  CSIC Open Access Publication Support Initiative  through its  Unit of Information Resources for Research (URICI).
For the ratiometric determination of the [Ca 2+ ] i the excitation light (monochromator IV, TILL Photonics, Gra ¨felfing, Germany) was alternated between 350 nm and 380 nm. The emitted fluorescence was detected with a photodiode and sampled using Pulse software (HEKA Elektronik, Lambrecht/Pfalz, Germany), which was also used for controlling the voltage in the pipette and performing capacitance measurements. The 350/380 fluorescence signal ratio was calibrated by infusion of cells with eight different solutions of known calcium concentrations. The standard intracellular solution contained (in mM): 100 Cs-glutamate, 8 NaCl, 4 CaCl 2 , 32 Cs-HEPES, 2 Mg-ATP, 0. 3 GTP, 5 NPE, 0. 4 fura-4F, 0. 4 furaptra, and 1 Vitamin C (to prevent UV-induced damage to the fura dyes), pH 7. 2 (osmolarity adjusted to ~295 mOsm).
Kinetic analysis and priming propensities Pool sizes and fusion rates were determined by fitting individual capacitance traces with a sum of three exponential functions, each of the form A(1-exp(-t/t)), representing the fast burst (time constant, t, 10-30 ms), the slow burst (time constant, t, 70-300 ms) and the sustained component (time constant, t, >1 s), respectively, using procedures written in IGOR Pro software. Since the time constant of the sustained component often approached or exceeded the measurement time (5 s), only the mean linear rate of sustained release within 5 s was reported. To understand the propensities for forward priming in the two sequential priming steps, priming 1 and priming 2 (Figure  10 ), we solved the two differential equations dSRP dt ¼ k 1 Depotþk À2 RRP À k À1 þ k 2 ð ÞSRP dRRP dt ¼ k 2 SRP À k À2 RRP under steady-state assumptions (i.
Quantitative image analysis Quantitative analysis of Fluoro-Jade B and NeuN staining was based on virtual microscopic slide technology, including the use of a slide scanner system (Olympus Dotslide system) equipped with a BX51 microscope with fluorescent applications and a computer-based workstation (Explora Nova using Mercator software). For both markers, five high-resolution brightfield or fluorescent (FITC filter) images, that included dorsal parts of the hippocampal and surrounding cortical areas, were taken at different positions along the sagittal lateromedial axis of the hemi-brain and analysed for each animal. Manual counting of Fluoro-Jade B-positive cells and measurement of the optical density of NeuN immuno-staining (used as an index of neuronal cell density) were performed in fixed subareas of the dentate gyrus, CA1 and CA3, and cortical layers II and VI using Mercator image analysis software (ExploraNova, France).
A 4-parameter logistic regression was performed to provide the best curve fit using Softmax® Pro software. Results are expressed as ng/L of CSF or serum. The detection level of the assay was around 1. 5 pg/well (corresponding to 31 ng/L when 50 μL was assayed). Spike recovery in human CSF has already been documented (see Instructions for Use version 2016/04 from NF-light® assay), with recovery yield of 88-99% in the interval 250-2500 ng/L. We also performed spike recovery testing in Wt mouse serum: following addition of known amounts of NF-L to 50 μL of serum per well, the recovery yield was 62-70% in the interval 1000-5000 ng/L (Supplementary data, Fig. S1 ).
Membranes were blocked with TBS/Tween 20 0. 1%/BSA 5% and incubated overnight at 4 °C with a rabbit polyclonal primary antibody raised against the C-terminal of p35 (C-19) (Santa Cruz) followed by an incubation with an anti-rabbit IgG HRP-conjugated secondary antibody (GE Healthcare) for 1 h at room temperature in TBS/Tween 20 0. 1%/milk 5%. Immuno-reactive proteins were revealed using an electrochemiluminescence detection kit (GE Healthcare). The electrochemiluminescent signal was captured with a high-resolution CCD camera LAS-3000 (Fujifilm) and densitometry measured with MultiGauge software. To allow quantification across several gels, one sample was used as an internal calibrator and was loaded on each gel and set to 100%.
Evaluation of CSF NF-L To enrich samples in NF-L before Western blot evaluation and to eliminate high amounts of albumin, which migrates very close to NF-L (data not shown), CSF NF-L or recombinant bovine NF-L was first immuno-captured by incubating samples for 1 h in the ELISA plate from the NF-light® assay which is coated with an antibody against-NF-L (capture monoclonal antibody 47:3). Then, after washing, 25 μL of boiled LDS buffer containing DTT was added to the wells for 10 min at 70 °C. Denatured samples containing the immuno-captured NF-L were then subjected to SDS-PAGE analysis. NF-L proteins were revealed using a rabbit monoclonal antibody raised against NF-L as a primary antibody (Cell Signaling, C28E10) and an anti-rabbit IgG HRP-conjugated as a secondary antibody (GE Healthcare).
ON-OFF study In the ON-OFF study (Figs. 2, 3 and 4), data from 12 Ctl (6 males and 6 females) and 60 p25 mice (30 males and 30 females) were analysed; 1 animal died before CSF sampling. The effect of the duration of p25 transgene induction and the impact of switching off p25 transgene expression were analysed in p25 male mice only. Further details on statistical analysis are provided in Supplementary methods. In addition, Spearman correlation coefficients were calculated between the parameter "CSF NF-L" and the parameters "brain weight", "p25-GFP", "serum NF-L", "NeuN" and "Fluoro-Jade B", respectively. Spearman correlation coefficients were also calculated between the parameter "Serum NF-L" and the parameters "NeuN" and "Fluoro-Jade B".
875 (Fig. 5B ). 3. 6. NF-L measured in CSF is not full-length NF-L To characterize which form of NF-L is present in the CSF of p25 mice, we performed an SDS-PAGE analysis of immuno-captured NF-L. We first validated our Western blot antibody, a monoclonal antibody (C28E10) from Cell Signaling, on brain homogenates from control and p25 mice. We easily detected full length NF-L in brain which was not modulated upon p25 induction (data not shown). Samples of recombinant bovine NF-L (ELISA standard, from 28 to 1000 pg) or CSF from p25 mice (300 pg NF-L as measured by ELISA) were then evaluated following immuno-capture on ELISA plates coated with a capture monoclonal NF-L antibody 47:3. The immuno-captured samples were evaluated by Western blot together with lysates from murine cerebral cortex (0.
By Western blot the fulllength NF-L signal decreased with incubation time and totally disappeared after 24 h. By contrast, when using an ELISA to detect NF-L there was only a 15% decrease of NF-L levels after incubating recombinant full-length NF-L in CSF for 24 h at 37 °C (Fig. 6B ). Taken together, these data suggest that NF-L measured by ELISA in the CSF of p25 mice is probably not full-length NF-L. Based on the antibodies used in this study, the cleaved form of NF-L most likely lacks the epitope recognized by the Cell Signaling antibody (around amino-acid residue 455, according to supplier information), whereas it can be detected by the two antibodies used in the UmanDiagnostics NF-light® assay. Similarly to our observations in p25 mice, high levels of CSF NF-L were also detected by ELISA in CSF from ThyTau22 mice, another The area under the ROC (AUROC) is equal to 1 (95% CI: [0.
We did not detect any change in full-length NF-L levels when measured by Western Blot in the hippocampus from p25 mice which could be due to a lack of sensitivity by analysing a whole homogenate. Very high levels of CSF NF-L (25,000 ng/L) are observed after only 4 weeks of transgene induction in male p25 mice. Such high levels of CSF NF-L have also been reported in three transgenic mouse models with different proteinopathy brain lesions, including α-synuclein A30P-αS, Tau P301S and APP/PS1 mice  (Bacioglu et al. , 2016). In TauP301S mice, CSF NF-L reached 40,000 ng/L in 10 to 12-month-old mice and reached 13,000 ng/L in 18-month-old APPPS1 mice. We have generated similar data in comparable transgenic mouse models, i. e. , ThyTau22 mice, APP/PS1 and APP mice (see Supplementary data in Fig. S4 ).
Acknowledgments We would like to thank  Li Huei Tsai  ( Massachusetts Institute of Technology ) for providing access to  CamKII-TetOp25  mice and  Niklas Norgren (UmanDiagnostics)  for the gracious gift of 2:1 antibody. At Sanofi , we also thank  Luc Esserméant  and  Dorothée Tamarelle  for statistical analyses,  Julie Durand  and  Patrick Juvet  for technical assistance during the in vivo phase and a special thanks to  Isabel A. Lefevre  for critical reading of the manuscript. We finally wish to thank  Marie Guillemot  and  François Autelitano (Evotec)  for technical support and assistance in the NanoLC-MS/MS analysis.
Placing EDC and ATS2 onto the WD2014 age scale To analyse the CO2 and ATS2 phase relationship, it is necessary to place them on the same chronology. Here we use the WD2014 chronology as a reference  (Buizert et al. , 2015; Sigl et al. , 2016). We therefore need to transfer ATS2 onto this chronology. To achieve this, we derived a volcanic synchronization between EDC and WD ice cores (Figure  2 ). The method of volcanic synchronization is explained in  Parrenin et al. (2012b). Here, we used the Electrical Conductivity Measurements (ECM). ECM data bring to light volcanic horizons by the detection of ice acidity. Acidity in the ice indicates volcanic fallout, which is found in several paleorecords including ice cores. It enables us to detect volcanic peaks in different ice cores, and by extension, the synchronisation between WAIS Divide and EDC ice core.