dataesr/scientific-paragraphs-categorization huggingface dataset:
We generated a 22 g mouse model as a 3D rectangular matrix of cubic voxels (20062006200 mm 3 ). The final 3D image dataset was composed of 25665506256 voxels and saved in a raw format (16-bit; unsigned integer; little-endian; 72 MB). Thyroid mass was reduced to 5. 4 mg by applying an erode mask implemented on ImageJ software. Soft tissues, lungs, bones and air density, and material composition  [28]  were also taken into account for radiation transport purposes. S-values were calculated using Monte Carlo modeling of radiation transport and energy deposition in the voxel-based mouse model. Up to 10 6 particles were simulated using GATE (version 6. 1), based on the GEANT4 toolkit (version 9. 04 patch01), both of which are well-established codes for radiation transport  [29, 30, 31]. The voxel-based mouse was implemented with the Compressed-Matrix option, the most suited function available for dosimetric purposes in that version, and regions of interest were defined using the range option.
Physics List Standard Option 3 was used to define physics processes. The deposited energy was scored at the voxel level of the phantom with the DoseActor, doseDistributionEdep. Statistical uncertainties were calculated using the associated UncertaintyEdep option. GATE was run with Mersenne Twister  [32]. The thyroid self S-value was calculated for 99m Tc. All detailed photon and electron emissions were based on the ''MIRD radionuclide data and decay schemes''  [33]. Cubic spline interpolation was applied to all continuous energy spectra used in simulations. The source was assumed to be distributed homogeneously within the thyroid and statistical uncertainties in self S-values were kept below 1%.
RNA Extraction, Quantitative RT-PCR and Microarrays Extraction of total RNA from mouse thyroid, and quantitative RT-PCR, were performed as previously described  [36, 37, 38]. Relative mRNA expression levels were determined using DCt values obtained by subtracting Ct control (mouse actin) from Ct target gene (mouse NIS), and expressed using the comparative CT method (2 2DCT ). For microarray analysis, RNA samples were labeled with Cy3 dye using the Low RNA Input QuickAmp Kit (Agilent), as recommended by the supplier. Labeled cRNA probes (400 ng) were hybridized on 8660K high-density SurePrint G3 gene mouse GE 8660K Agilent microarrays. Four biological replicates were performed for each experimental condition. The experimental data are deposited in the NCBI Gene Expression Omnibus (GEO) (http://www.
ncbi. nlm. nih. gov/geo/) under the record number, GSE46470. Normalization of microarray data was performed using the Limma package (http://www. bioconductor. org). Interslide normalization was performed using the quantile methods. Means of ratios from 99m Tc-treated versus control tissues were calculated and B-test analysis was performed. Differentially expressed genes were selected based on an adjusted p value of 0. 05. Data from expression microarrays were analyzed for enrichment in biological themes (Gene Ontology molecular function and canonical pathways) and biological networks were built using Ingenuity Pathway Analysis software (http://www. ingenuity. com/) and Mediante  [39].
To enrich the dataset, we performed a similar experiment on animals that were fed on a poor-iodide diet. Accumulation of 99m TcO 4 2 in the thyroid followed the same overall pattern (Figure  1B ) but the value at the peak averaged 6. 5 MBq with a low-iodide diet while it averaged 3. 5 MBq in mice fed a normal-iodide diet. Dosimetric calculations based on these pharmacokinetic data are detailed in Material S1. They indicate that the thyroid self S-value was 4. 55E 210 Gy. Bq 21. s 21. In these experimental conditions, the peak activity measured in the thyroid (ranging from 3 to 7 MBq) was strongly correlated (R 2 = 0. 985) with the cumulated activity, and hence with the absorbed dose to the thyroid at 24 hours (range 18. 9 to 49. 6 Gy) (Figure  1C ). Based on these kinetics and calculations, SPECT/CT analyses of thyroid activity throughout the study were systematically performed 60 minutes after radioisotope adminis- 2 , respectively.
Global pattern of gene expression in thyroids of 99m TcO 4 2 -exposed versus control mice To determine the impact of 99m TcO 4 2 exposure on the thyroid, total RNA, extracted from four untreated thyroids and four thyroids exposed to 30 Gy with 99m TcO 4 2 , was analyzed using whole genome mouse microarrays. Total RNA was collected 24 hours after radioisotope administration. The comparison between these two conditions showed a significant modulation of 2exposed thyroids (Table  S1  and Figure  7 ). These transcripts efficiently discriminated 99m TcO 4 2 -exposed from control thyroids. As expected from the data presented in Figure  4 , NIS (Slc5a5) mRNA appeared to be among the most significantly downregulated transcripts in 99m TcO 4 2 -exposed cells, while Pax8, a transcription factor regulating NIS, appeared to be unaffected (Figure  7 ).
Gene ontology analysis using the Mediante information system  [39]  and Ingenuity Pathway TM showed a very strong association of these modulated transcripts with ''p53 signaling'' (P = 1. 4610210) (Table  S2 ). Several genes regulated by p53 were strongly upregulated in 99mTcO42-exposed thyroids, including cyclin-dependent kinase inhibitor, p21 (p21/Cdkn1a/Waf1/ Cip1), reprimo/p53-dependent G2 arrest mediator candidate (Rprm), BCL2-associated X protein (Bax), p53 E3 ubiquitin protein ligase (Mdm2) and members of the TNF receptor family, Fas (Apo-1, Apt1, CD95, Fas1, Fastm, Tnfrsf6) (Table  S2 ).
Histological analysis of thyroid sections did not demonstrate any significant areas of cell death/necrosis in 99m TcO 4 2 -exposed compared with control animals. Altogether, these results are consistent with a stunning effect, defined as a marked diminution of 99m TcO 4 2 uptake by the thyroid, independent of any significant tissue destruction. The reversibility of this stunning within a few days confirms this hypothesis. The kinetics of residence of the radioisotope were determined by analysis of SPECT/CT images. Pharmacokinetic data showed that the peak 99m TcO 4 2 content in the thyroid was reached within 1 hour after intraperitoneal injection and strongly correlated with the cumulated dose at 24 hours. These data are in agreement with the previously published biodistribution of 99m TcO 4 2 measured by direct counting of radioactivity in biopsies collected at different times from different animals  [41].
Our dataset highlights the fact that small-animal SPECT imaging is a very powerful tool, capable of generating reliable data, whilst minimizing the number of experimental animals. Dosimetric calculations revealed that the 99m TcO 4 2 -mediated thyroid stunning effect requires an absorbed dose in the thyroid in the range of 20 Gy, observed in animals injected with an activity of 150 MBq. Activities from 74 to 370 MBq 99m TcO 4 2 are administered to patients during routine thyroid examination, leading to an absorbed dose to the thyroid below 20 mGy (Society of Nuclear Medicine Procedure Guideline for Thyroid Scintigraphy, http://interactive. snm. org/docs/ Thyroid_Scintigraphy_V3. pdf). This large difference in absorbed dose to the thyroid between humans and mice can be explained by the larger volume of distribution of the radioisotope in humans.
Analysis of the whole dataset indicates, with a very high statistical significance (P value in the range of 10 216 ), that the variation in gene expression observed in the thyroids of 99m TcO 4 2 -exposed animals is the result of activation of the p53 pathway. This pathway is typically activated when cells are subjected to stress  [43]. In our case, the stress is irradiation of the cells with an absorbed dose in the range of 20 Gy. A similar stress response was reported in thyroids subjected to 11 Gy 211 At  [44]. However, in this latter study NIS gene expression was not reported to vary, suggesting a differential regulation of NIS expression in thyroid cells subjected to a particles and to low-energy electrons. The 99m TcO 4 2 -mediated irradiation led to the induction of double-strand DNA break repair.
Foci of nuclear cH2AX staining were already visible in sections generated from thyroids exposed to 5 Gy, their numbers increased in sections from thyroids exposed to 30 Gy. In the salivary glands, NIS is expressed in ductal epithelial cells, and cH2AX nuclear foci are only detectable in these structures. The salivary gland dataset demonstrates that the biological events triggered by 99m TcO 4 2 exposure happen selectively in NIS-expressing cells capable of accumulating the radiotracer. The requirement for 99m TcO 4 2 to enter the cell in order to provoke maximal DNA damage and, if the dose is high enough, cell death, has been demonstrated in vitro using the NISexpressing PCCl3 thyroid cell line  [45, 46, 47, 48]. In these experiments, 99m TcO 4 2 -mediated toxicity was clearly magnified by 99m TcO 4 2 entry into the cells  [45, 46, 47]  and was further enhanced by 99m TcO 4 2 retention  [48].
Acknowledgments The authors would like to thank the radiopharmaceutical team of the  Centre Antoine Lacassagne  ( Didier Alberato ,  Stephane Espitallier ,  Guy Martinico ,  Isabelle Puy ,  Alison Richard ,  Nadine Sapin ) for their help with radioisotope production and handling. The authors acknowledge the excellent support of the  Nice-Sophia Antipolis Functional Genomics Platform  in which the microarray experiments were carried out.
For each channel, five sets of still images from different phases of the experiment are shown. Each set consists of 12 images recorded at 5-min time intervals. (B) Quantitative analysis of all 149 cells from this experiment. Every horizontal line represents data for an individual cell over 975 min. Dots mark the time points at which this cell divided. Cells are sorted according to ttss-1 expression during antibiotic exposure, measured as mean GFP fluorescence during that time interval. The cell index indicates the rank of a cell according to its mean GFP expression during antibiotic exposure; a lower cell index indicates lower GFP expression, and a higher cell index indicates higher GFP expression. The color of the lines indicates real-time GFP intensity. Shading indicates the data corresponding to the cells shown in (A).
Microscopy Microscopy was performed using an Olympus IX81 inverted microscope system with automated stage, shutters, and a laser-based ZDC autofocus system. Several different positions were monitored in parallel on the same device, and phase contrast and fluorescence images (where applicable) of every position were taken every 5 min. Images were acquired using an UPLFLN100xO2PH/1. 3 phase contrast oil immersion objective (Olympus) and a cooled CCD camera (Olympus XM10). For image acquisition, the CellM software package (Olympus) was used. Fluorescence images were acquired using a 120W mercury short arc lamp (Xcite 120PC Q) and the U-N41001 GFP filter set (450-490 nm ex/500-550 em/ 495 dichroic mirror, Chroma). The whole microscope was placed in an incubated box (Life Imaging Services, Reinach, Switzerland) at 37uC during all experiments.
Image Analysis Images were analyzed using the plugin MMJ (available at https://github. com/penamiller/mmJ) for ImageJ  [42]. It allows extracting of fluorescence intensities and cell length for the bottom cell of each channel during the course of the whole experiment, and scores division events based on cell length. For analysis of the experiments shown in Figure  1 , Figure  S2 , Figure  S3 , Figure  S4 , Figure  S8 , and for determining growth rates, the standard version of MMJ was used. For the experiments shown in Figure  2  and Figure  S6 , a modified version of MMJ (MMJAll) was used that allows the extraction of all cells on single frames. Data were then further processed and plots were generated using R  [43]. Cells were counted as surviving if they divided at least once after removal of antibiotic.
Determination of Single Cell Elongation Rates in Microscopy Experiments Data on cell length and divisions were extracted for a period of 100 min (20 frames)-75 min (15 frames) before and 25 min (5 frames) after addition of the antibiotic-and linear regression was performed on the natural logarithm of cell lengths between divisions, between the start of the period and the first division in the period, and between the last division in the period and the end of the period, respectively, to determine the slope of the length increase during every division. Arithmetic means of the slopes of every individual cell were then calculated and multiplied by 12 to get a number for length doublings per hour.
Flow Cytometry For the experiment in Figure  S10 , overnight cultures were diluted 1:20 in LB Lennox, and analyzed in a flow cytometer (LSRII, Becton Dickinson) at an OD 600 nm of 0. 9. Bacteria were identified by side scatter, and GFP emission was measured at 530 nm. Data were analyzed using FlowJo software (Tree Star, Inc. ). ) that open on one side into a main trench (approximately 100 mm in width, 20 mm in height, drawing not to scale). Medium is flowing through the main trench at 2 ml/h (as illustrated by grey arrows in the drawings). This design allows the observation of the bottom cell in the channel for the whole duration of an experiment, whereas its progeny will eventually be pushed into the main trench and flushed away. (TIF) Figure  S2  No antibiotic tolerance is observed in a genetically avirulent mutant.
Acknowledgments We thank  Johannes Wolf ,  Nela Nikolic ,  Alex Sturm ,  Daniel Angst ,  Olin Silander , and  Daan Kiviet  for helpful discussions;  Nela Nikolic ,  Johannes Wolf , and  Thomas Egli  for advice on chemostats; and  Suckjoon Jun  for sharing the drawings of the masks for the original mother machine and useful technical advice.
Laboratory Immune Monitoring. Laboratory monitoring was performed at baseline (T0), 12 weeks (T1), and 24 weeks (T2), respectively. Triplicate wells were pooled and stained with a mix of anti-CD4-APC-Cy7, anti-CD8-PE-Cy7, and anti-CD25-APC (BD Biosciences, San Jose, CA, USA). Cells were then washed twice with BD CellWash and analyzed by flow cytometry. The results were analyzed by the ModFit software (Verity Software House, Inc. ) and expressed as Proliferation Index (PI), after normalization for the number of acquired events, subtracted from the value of the control sample, and as fold increase (FI), calculated as the ratio of PI in the presence of the specific antigens and the PI values of control samples. Proliferative responses were considered positive when FI was 3 2.
Statistical Analysis. Statistical analysis was performed using the Graph Pad Software Prism 4 (GraphPad Software Inc. , San Diego, CA). One way ANOVA (and related nonparametric tests) for repeated measures was used to compare baseline measurements with those obtained during treatment. Comparisons between two groups were performed by -test. The Graph Pad Software Prism test for deviations from Gaussian distribution was performed using the Kolmogorov-Smirnov test (normality test).
Panel (c) shows an expanded view of the power spectrum revealing numerous weak peaks. ular frequencies was identified as suitable for a quantitative determination of the confidence level of our data and analysed to assess whether the intensity variation is stochastic. The signal height distribution was then investigated and the level at which a random event could be excluded with 99. 9 % certainty was determined. Details of the noise analysis are provided in the online-supplementary information. While this assessment of the noise level revealed a large number of lines exceeding the confidence level, focus was placed on the detailed analysis of the smallest complex, the C 2 H 2 -He complex. For this complex a potential energy surface and the energies of rotational states were calculated to guide the assignment.
Electronic structure calculations Total electronic energies for C 2 H 2 and C 2 H 2 -He were computed with the coupled cluster method with single and double substitutions and perturbative treatment of triples, CCSD(T), and all electrons were included in the correlation treatment. Core-optimised correlation consistent augmented (doubly augmented for He) basis sets, (d)aug-cc-pCVXZ, X=T,Q,5,6, as developed by Dunning and coworkers  93, 94  , were employed as implemented in the MOLPRO electronic structure package  95. Geometry optimisations carried out for the complex and isolated C 2 H 2 with basis set sizes up to sextuple zeta quality show that complexation with He changes the geometry of C 2 H 2 at most by 0. 0001 Å. The C 2 H 2 unit was consequently fixed at its experimental ground state expectation geometry,  88  r 0 (CC) = 1.
Acknowledgements The authors wish to thank  STFC  for access to the  Artemis facility  at the  Rutherford Appleton Laboratory  and the  University of Leicester  for funding to support the studentship for GG associated with this project. We would like to thank  S. Hook ,  P. Rice ,  N. Rodrigues  and  S. Thornton  for technical support during the experiment. KvH kindly acknowledges funding by  STFC  (seed corn fund for experiments using 4th generation light sources) and the  Leverhulme Trust  ( F/00212/AH ). LGML acknowledges financial support from the  Mexican Consejo Nacional de Ciencia y Tecnología  ( CONACYT ) Scholarship number  310668 , ID 215334. RSM would like to thank the  Royal Society  for a  University Research Fellowship  ( UF100047 ), ML and MM acknowledge computational resources funded through  ANR  grant  ANR-08-BLAN-0146-01.
Overall, a total of 684 plasma samples including 183 HCC patients, 274 CLD patients (including chronic active HB (CHB) and HC (CHC) patients), and 227 controls without liver symptoms were selected from the four studies and used in the validation step. In TLCS (Thailand) and in GLDS (The Gambia), all CLD patients had CHB. In contrast, in FLDS (France), only CLD patients with CHC were included. In the KLDS prospective cohort, the CLD group included patients with CHB, CHC as well as patients with liver cirrhosis developing in a context of either HB or HC carriage. All steps of the study (proteomics discovery, data mining and validation) were approved by national ethics review boards in Thailand, The Gambia, France and Korea, and by the Institutional Review Board of the International Agency for Research on Cancer.
Statistical analysis For each biomarker test, receiver operating characteristic (ROC) curves were plotted and area under the ROC curve (AUROC) was calculated as well as its 95% confidence intervals (CI) using PROC LOGISTIC program and %PLOTROC macro and comparison of area under the ROC curve was performed using the %ROC macro of the SAS statistical software package (SAS 9. 2, SAS Institute Inc, North Carolina, USA). Optimal cut-offs were calculated based on the minimum distance to the top-left corner of the ROC curve and the maximum likelihood ratio with highest achievable sensitivity and sensitivity. The sensitivity and specificity and corresponding 95% CI were calculated for AFP, LTBP2, and OPN utilizing Usage Note 24170 (http://support. sas. com/kb/24/170. html). All analyses were conducted with and without stratification for hepatitis virus aetiology and for AFP levels.
Grant Support: This work was supported by the European Union Collaborative Project Prolifica, 7th Framework Programme, FP7-AFRICA-2010, Health-F2-2011-265994 (Grant agreement no. 265994). ANdC was a recipient of a Postdoctoral Fellowship from the IARC, partially supported by the EC FP7 Marie Curie Actions -People -Cofunding of regional, national and international programmes (COFUND). Deep-plasma proteomics was used to identify candidate biomarkers for diagnosis of hepatocellular carcinoma (HCC), focusing on HBV-related HCC. Validation studies on a total of 684 samples showed that elevated levels of LTBP2 and/or OPN levels are highly specific and sensitive markers for distinguishing HCC from chronic liver disease, in particular in patients with low or undetectable levels of α-Fetoprotein. LTBP2 appears highly associated with HBV-related HCC, while OPN shows a robust and consistent association with HCC in both HBV and HCV contexts.
The study included three steps, with first plasma proteomics, second data mining to identify candidate markers and third validation in several cohorts of patients. First, biospecimens (plasma) were collected in two structured hospital-based case-control studies in two regions of high incidence of HB carriage and of HCC, The Gambia and Thailand, using protocols optimized from plasma proteomics. These case-control studies included control individuals (no liver symptoms), individuals with chronic liver disease patients (CLD, chronic active hepatitis B or hepatitis C), and patients with confirmed diagnosis of HCC. A small number of plasma specimens of cases (HCC, n=10), CLD (n=10) and controls (n=10) from each region were extensively analysed using a deep-plasma proteomic approach. Next, data generated from The Gambia and from Thailand were mined to identify candidate biomarkers that were differentially expressed in cases, CLD and controls in both regions.
Thus, the model does not smooth control variables directly. The adopted numerical assimilation scheme allows some compensation for model deficiencies  [Taguchi et al. , 2014]. 2. 1. 6. FES2012 FES2012 (FES12, for short) is the most recent of a series of global finite element tidal solutions, initiated by Le  Provost et al. [1994]. The FES12 atlas  [Carrère et al. , 2012]  is built upon altimetry-derived harmonic constant assimilation using the ensemble, frequency domain SpEnOI (Spectral Ensemble Optimal Interpolation) data assimilation software in T-UGOm (Toulouse-Unstructured Grid Ocean model) hydrodynamic tidal solutions. T-UGOm is a 2-D/3-D ocean hydrodynamics model based on unstructured meshes. It has been carried out in time-stepping mode and frequency domain mode. Frequency domain 2-D governing equations are derived from the classical shallow-water continuity and momentum equations, as described in  Lyard et al.
TPXO8 TPXO8 is the most recent in a series of tidal solutions (elevations plus barotropic currents) produced using the representer-based variational scheme described by  Egbert et al. [1994]  and  Egbert and Erofeeva [2002]  to assimilate altimetry (and other) data into a global shallow-water model. The TPXO8-atlas solution discussed in this paper represents a further refinement, with a series of over 30 regional assimilation solutions incorporated to increase resolution in coastal areas and shallow seas. The base global solution has a resolution of 1/6 • , with bathymetry for the dynamical model derived from the GEBCO 1 ′ database [GEBCO Digital  Atlas, 2003]  with some adjustments around Antarctica south of 57 • S. Primary data were harmonically analyzed along-track tidal constants from 685 T/P and Jason cycles (up to 2011), with load tide corrections based on the earlier assimilation solution TPXO6.
NSWC The most widely adopted global tidal model in the pre-T/P era was developed at the U. S. Naval Surface Weapons Center (NSWC) by  Schwiderski [1979]. He employed a large database of coastal and island harmonic constants and assimilated them into a 1 • barotropic tidal model using a method he called "hydrodynamic interpolation, " which seems to have been a variation of what is now understood as a relaxation or "nudging" method of assimilation  [Egbert and Bennett, 1996]. Where he had good data to guide the model, his results were quite good. However, in some wide expanses of the open ocean, such as the mid-Atlantic, errors in excess of 10 cm were later found [e. g. ,  Cartwright and Ray, 1990].