dataesr/scientific-paragraphs-categorization huggingface dataset:
They could be used in medical clinics to screen patients requiring a genetic counselling referral or in genetics clinics to document fh and to conduct a preliminary risk assessment before a formal genetic counselling interview. Nevertheless, non-electronic tools still have their place in cancer fh collection, given that not every clinical setting is equipped with an ehr system and not every health care provider has access to and can make use of the Internet and electronic devices. Validated paper-based questionnaires, automated telephone interviews, and telephone and faceto-face interviews can play a significant role in identifying at-risk individuals if they can guide health care providers in assessing risk and managing decisions, and if the data can be easily retrieved and updated. Otherwise, their contribution will remain partial and will continue to require additional human resources.
Wider use of the acce or an equivalent framework  104  should be encouraged when tools are being developed, especially if evidence-based recommendations are to be delivered to lay individuals and health professionals. Interpretation of the results of the present review should be considered in light of several potential limitations. First, our search was limited to reports published in French and English, which might have resulted in publication bias. However, we did not find additional relevant articles in other languages. Second, only 1 reviewer analyzed the papers and extracted the data. However, the latter limitation was mitigated through data cross-checking and repeated readings of relevant article sections. Third, the literature search might have missed papers of interest given that it ended in September 2016.
The maximum proposed level of intake is 1,200 mg/day (corresponding to 17 mg/kg body weight (bw) per day for a 70 kg person). It can be assumed that a large portion of the peptides would be hydrolysed to the individual constituent amino acids prior to absorption and only a small fraction would be available for systemic uptake. There are no concerns with regard to genotoxicity given the nature of the NF and on the basis of the studies provided by the applicant. The no observed adverse effect level (NOAEL) in a 90-day repeated-dose oral toxicity study was 2,000 mg/kg bw per day, the highest dose of the NF tested. Human data included two clinical trials which, as primary endpoints, assessed potential effects of the NF on blood pressure in subjects with mild or moderate hypertension. These studies also assessed safety-related end points such as biometrics, clinical biochemistry and urine analysis parameters as well as recordings of adverse events.
Compositional data The NF contains more than 87% peptides in the range of 2-24 amino acids, less than 1% both fat and carbohydrates, with minerals typical for shrimp shell and head material: sodium (< 35 mg/g), calcium (≤ 20 mg/g) and potassium (≤ 1. 5 mg/g). The total dry matter of the NF is more than 95%. The applicant provided results from seven production batches of the NF, which contained peptides with a MW < 2 kDa. The peptides separated by liquid chromatography (LC), were analysed using a Q-Exactive mass spectrometer. Data were collected in a data-dependent mode using a top10 method. De novo sequencing of peptides was performed using the PEAKS Studio 7 software, using an Average Local Confidence (ALC) score > 50% for identification. On the base of the results obtained, the applicant concluded that the NF contains more than 25,000 peptides in the range of 2-24 amino acids and that 670 peptides were identified as being common for all batches, (Unpublished study report, undated).
Human data The applicant provided study reports on two clinical trials which, as primary endpoints, assessed potential effects of the NF on blood pressure in subjects with mild or moderate hypertension. These studies also assessed safety-related end points such as clinical biochemistry and urine analysis parameters as well as recordings of adverse events (AEs)  (Unpublished study reports, 2013 (Unpublished study reports, , 2016)). In a randomised, double-blind, placebo-controlled trial (RCT), 68 adult subjects between 30 and 75 years of age and with mild or moderate hypertension, but overall healthy, received the NF at dose levels of 0 (control) or 1,200 mg/day, for 8 weeks (unpublished study report, 2013). The primary objective was to assess the effect of the NF on blood pressure by observing a change in systolic blood pressure (SBP), during the 8-week intervention.
Tree-Ring Data Tree cores from Fitzroya cupressoides at Glaciar Frías (GF) and Río Alerce (RA) were initially collected during the austral summers in the late 1980s to early 1990s and more recently in 2013. The two sites, at a distance of ~6 km from each other, are located in the Argentinean humid forests of northern Patagonia, between 950 and 1,050 m in elevation (41°09 0 S, 71°53 0 W; Figure  1 ). At each site, paired increment cores at breast height (1. 3 m above the ground) were extracted using a Pressler borer (5 mm diameter) from more than 30 trees showing similar competition and microsite conditions. Cores were dated to the calendar year of tree ring formation and cross-dated following  Stokes and Smiley (1968). Quality control of ring width measurements and cross dating were conducted with the program COFECHA  (Holmes, 1983).
, 2017). Therefore, for the period 1952-2011, we used the mean value of the two δ 13 C site chronologies already published (the data are available at the International Tree-Ring Data Bank (ITRDB) of the NOAA National Climate Date Center; https://www1. ncdc. noaa. gov/pub/data/paleo/treering/isotope/southamerica/argentina/). For the period 1800-1951, we selected the same F. cupressoides trees. They were old enough not to introduce any juvenile effects on δ 13 C. Annual tree rings were split using a scalpel. The wood samples were then chipped and grounded in a ball mill for homogenization. α-Cellulose was extracted from the wood according to the Soxhlet chemical method derived from  Leavitt and Danzer (1993). α-Cellulose was homogenized ultrasonically with a sonotrode apparatus and freeze-dried.
Cellulose samples of around 0. 10 mg were loaded in tin foil capsules. The δ 13 C was determined with an elemental analyzer (EA NC2500, Carlo Erba) coupled with a Finnigan MAT252 mass spectrometer. An internal laboratory reference of cellulose (Whatmann® CC31) was used to correct for instrument drift and to normalize the data to internationally accepted standards. Along the sequence analyses, the isotopic composition of CC31 was measured every three samples. The standard deviation (SD) obtained from the measurement of the isotopic composition of 10 consecutive CC31 standards was typically ±0. 1‰. The analyses on each sample were repeated at least once and up to three times. To assess the intertree isotopic variability, we compared annual δ 13 C variations from 12 individuals (six at each site) over the period  1920 -1951 (Figure S1 (Figure S1  in the supporting information).
BAI and iWUE Calculations Due to the persistent trend of decreasing ring width with increasing tree diameter and age, patterns of tree growth related to forest growth are better captured using BAI  (Rodríguez-Catón et al. , 2016). Here BAIs were estimated for each individual tree (a total of 374 trees) from the bark to the pith using the BAI. out( ) function of the R package "dplR" (Figure  S2 ). We considered only the 1800-2011 portion of the mean BAI series. We then calculated the intrinsic water-use efficiency (iWUE), that is, the ratio of net photosynthesis A to conductance for water vapor g, which is defined as follows  (Farquhar & Richards, 1984) : iWUE ¼ A=g ¼ c a À c i ð ÞÂ0:625 (1) where c a and c i are atmospheric and intercellular CO 2 concentrations, respectively, calculated from the isotopic discrimination Δ 13 C according to the following  (Farquhar et al.
To assess the predictive skill of the models, the coefficient of determination (r 2 ) of the regression models, reduction of error statistic (RE;  Fritts, 1976) , Journal of Geophysical Research: Biogeosciences   (Durbin & Watson, 1971). Regressions, AIC-BIC, and statistical tests were performed using the R software environment (lm( ) and predict( ) functions, the R package "MuMin," and skills( ) function of the R package "treeclim";  Zang & Biondi, 2015). The best models providing the more reliable estimation of summer temperature variability over the period 1931-2011 were applied in reconstructing temperature variations over the period 1800-2011.
Spectral Properties of the Summer Temperature Reconstructions We investigated the relation of the  ) over the same period. (c) Temporal variations of BAI residuals estimated using three different corrections (extracting iWUE or c a trends from BAI series, or using a 50% spline; gray, blue and black, respectively). The ** indicates that the correlation is significant at 99% confidence level. html). We also conducted time-space cross-wavelet analyses to identify the spectral properties of the reconstructions and their links to ENSO and SAM using the xwt( ) function of the R package "biwavelet. ".
Flow cytometry analysis Intracellular IFN-α staining was performed according to the intracellular staining protocol from BD Bioscience. Cells were treated with Brefeldin A (GolgiPlug, BD Bioscience, 555029) 6 h prior to harvesting and stained with an anti-human IFN-α antibody (Miltenyi Biotec, 130-092-602). RPE cells and monocyte-derived cells were distinguished by the expression of CD206 (anti-human CD206, biolegend, 321124) or CD163 (anti-human CD163, BD Bioscience, 556018) on monocyte-derived cells as well as CellTracker Violet BMQC (Invitrogen, C10094) staining of monocyte-derived cells prior to coculturing. Data were acquired on a LSRII flow cytometer (BD Biosciences) and analyzed with FlowJo software (Tree Star).
IFN-α2b either untreated or pretreated for 1 h with 100 ng/ml B18R was used to treat RPE cells that were infected with HCMV-GFP at MOI 0. 1 and subsequently incubated for 10 d while one fourth of the medium was replaced with fresh medium daily. Co-cultures of HCMV-infected RPE cells and monocytederived cells were established as described above and 100 ng/ml B18R was added daily by replacement of one tenth (4-day co-culture) or one fourth (10-day coculture) of medium with fresh medium containing B18R. qPCR RNA extraction (Macherey-Nagel, 740955. 250) and cDNA synthesis (Takara, RR036A) were performed according to the manufacturer's instructions. 5 ng of cDNA was analyzed by quantitative PCR using Sensi-FAST SYBR no-ROX Kit (Bioline, BIO-98020) in a LightCycler 480 (Roche). All data are presented as expression relative to hypoxanthine phosphoribosyl transferase 1 (HPRT1) mRNA.
Acknowledgments We are grateful to  Eva Borst  and  Martin Messerle  ( Hannover, Germany ), who generated and kindly provided HCMV-GFP as well as  Christian Sinzger  ( Ulm, Germany ), who generated and kindly provided RV-TB40-BAC KL7 -SE-EGFP. We also thank  Frank Klawonn  for advice concerning statistical analyses. Furthermore, we thank  Yvonne Knopp  and  Bibiana Costa  for help with several of the co-culture experiments. We especially thank the  Blutspendedienst NSTOB (Niedersachsen-Sachsen-Anhalt-Thüringen-Oldenburg-Bremen gGmbH, Institut Springe)  for providing buffy coats. This work was supported by  VISTRIE under Grant HGF grant   VH-VI-424  to L. C-S. and U. K. and the SFB900 under Grant  TP B2  to L. C-S. and U. K.
This has greatly facilitated the identification of the genes involved in the biosynthesis pathways, in particular with the help of trichome specific Express Sequence Tag (EST) and more recently next generation sequencing transcriptome databases. Thus, the biosynthesis of menthol in mint  (Croteau et al. , 2005) , of artemisin in Artemisia annua  (Brown, 2010) , of various terpenoids  (Sallaud et al. , 2009; Schilmiller et al. , 2009)  as well as acyl-sugars in tomato  (Fan et al. , 2016; Schilmiller et al. , 2016)  or diterpenes in tobacco or rosemary  (Sallaud et al. , 2012; Scheler et al. , 2016)  and monoterpenes in thyme  (Majdi et al. , 2017)  could be completely or partially elucidated. In contrast to the progress made in understanding trichome-specific biosynthesis pathways, very little is known about the genes controlling the development and differentiation of glandular trichomes.
Mapping Genomic DNA was isolated from 50 to 100 mg fresh leaf material using the Qiagen DNeasy Plant kit and 10 ng DNA was used for each mapping point. The backcross lines were genotyped for 192 markers by a combination of different techniques. Several markers were taken from the literature  (Dal Cin et al. , 2009)  but most markers were designed utilizing single nucleotide polymorphisms (SNPs) between the parental lines using the tomato genome (Tomato-Genome-Consortium, 2012) for the cultivated tomato and the Solanum trichome EST library  (McDowell et al. , 2011)  as well as our own unpublished RNA sequencing data for LA1777. The markers were chosen to cover the whole tomato genome and aligned to the published tomato genome version SL2. 40 annotation ITAG2. 3 by José M Jiménez-Gómez, Max Planck Institute for Plant Breeding Research, Cologne, Germany.
QTL Mapping QTL analysis was performed by composite interval mapping (CIM) using the Windows QTL Cartographer software V2. 5  (Wang et al. , 2012) , at 1 cM walk speed and with a 10 cM window size. Following the guidelines by  (Lander and Kruglyak, 1995)  a logarithm of odds (LOD) threshold of 2. 5, calculated from 1000 permutations at a probability of 0. 05, was used for declaring significant QTLs. Epistatic interactions were determined by using the QTLNetwork software version 2. 1  (Yang et al. , 2008). Window size, working speed and filtration window for the genome scan were set at 10, 1, and 10 cM, respectively. The F-test using Henderson method III was used to determine significance with 1,000 permutations.
The trichome scores were used in combination with the mapping data to perform a QTL analysis with the Windows QTL Cartographer software V2. 5 using composite interval mapping (CIM) algorithm. This revealed six QTLs on four different chromosomes (Figure  4  and Table  1 ). All QTLs provide an additive effect with the strong QTL on chromosome I being by far the strongest one and thus the major contributor. In order to see if epistatic interactions underlie the trichome shape we used the QTLNetwork software version 2. 1. No significant epistasis could be found.
DNA Copy Number Data DNA copy number data were collected from 671 high-risk neuroblastomas enrolled in the SIOPEN (cohort 1), GPOH (cohort 2), COG (cohort 3), and Japanese (cohort 4) treatment protocols. Parts of the SIOPEN cohort  (14, 15)  and the Japanese cohort  (10)  have been published previously. After quality control analyses (eg, excluding samples with normal cell contamination and/or silent profiles), 556 samples remained (Table  1 ; Supplementary Table  1 , available online). Data were segmented using SegAnnDB  (16)  and then converted into a regions-by-samples matrix at 1 kb resolution (using R) (see the Supplementary Methods, available online for details). The data have been deposited in GEO (accession number GSE103123).
Identifying Prognostic Copy Number Biomarkers The construction of a genome-wide classifier is described in the Supplementary Methods (available online). To select copy number aberrations associated with overall survival, the R statistical package was used to perform regression analyses for each of the 27 565 regions in the regions-by-samples matrix. The primary end point was binary: death from any cause within 18 months of diagnosis (¼case) vs survival with at least five years of follow-up (¼control). Logistic regression was performed on 83 case vs 53 control samples from the training set (cohort 1 and 2). A secondary end point was overall survival time, defined as the time from diagnosis until death from any cause, whereby patients who were alive were censored on the date of last contact.
Statistical Analysis and Data Visualization Kaplan-Meier estimates were calculated with the R package "survival" (default settings). P values reported with Kaplan-Meier plots result from log-rank tests. P values to test co-occurrences result from chi-square tests. All P values are two-sided and tested against an a of. 05; multiple testing correction relies on the Benjamini-Hochberg method. More details and additional methods for data visualization are described in the Supplementary Methods (available online).
Exploratory Analysis of Copy Number Aberrations in High-risk Neuroblastoma Patients In a first step, we explored the collected data by evaluating copy number aberrations known to be linked to high-risk neuroblastoma disease. Of interest, 2. 5% (14/556) of high-risk tumors presented with a copy number profile of only numerical aberrations that is typically observed in low-risk neuroblastoma  (12). Kaplan-Meier analysis confirmed a statistically significantly better outcome (P ¼. 001) for this small group of patients, with a 10-year survival probability of 92. 9% (95% confidence interval [CI] ¼ 80. 3% to 100%) for both overall (Figure  1A ) and event-free survival (P <. 001) (Supplementary Figure  3 , available online). Because these samples represent a different class of genomic aberrations, they were omitted from further analysis.
Amplifications in Regions Not Encompassing the MYCN Locus MYCN amplification is an important prognostic biomarker for neuroblastoma patients. In this data set of high-risk patients, the difference in survival of MYCN-amplified vs nonamplified cases is statistically significant (log-rank P ¼. 02), but the proportional hazards assumption is violated, and in the end the survival curves coincide (Figure  3, A  and B ). We then questioned whether the presence of amplifications in regions not encompassing the MYCN locus has prognostic potential in high-risk neuroblastoma. Importantly, not all copy number platforms could accurately identify the presence of MYCN amplification (Supplementary Figure  10 , available online), agreeing with published findings  (18). Copy number data generated on the Agilent array platform showed a large dynamic range at the MYCN locus.
Discussion As an international effort of the UHR working group of the INRC consortium, we collected an unprecedentedly large DNA copy number profiling data set of high-risk neuroblastoma tumors. After validation of this unique data set, we investigated different approaches to identify a prognostic multiregion classifier; (based on Cox regression) that met at least one of the following criteria: statistically significantly lower expression of the gene in neuroblastoma cell lines with vs without a 6q deletion (squares), at least one mutation in the gene as described in primary tumors (circles), and statistically significantly worse survival outcome when gene expression is low (lowest 10th percentile) in high-risk neuroblastoma tumors (triangles). SRO ¼ smallest region of overlap. however, this classifier could not be validated in independent cohorts.
Funding This work was supported by the  National Cancer Institute Pediatric and Adolescent Solid Tumor Steering Committee  for administrative support. PD was supported by the  Fund for Scientific Research Flanders  ( Research  project  GOD8815N  in the context of ERA-NET Transcan-2 cofound JTC 2014). VB was supported by the  ATIP-Avenir Program , the  ARC Foundation  (grant number  ARC-RAC16002KSA-R15093KS ),  Worldwide Cancer Research Foundation  (grant number  WCR16-1294 R16100KK ), and the " Who Am I?" laboratory of excellence   ANR-11-LABX-0071 , funded by the  French Government  through its " Investissement d'Avenir" program  operated by the  French National Research Agency (ANR ; grant number  ANR-11-IDEX-0005-02 ). RC was supported by the  Fund for Scientific Research Flanders. MF was supported by the  Federal German Ministry of Education and Research (BMBF ; grant numbers  01ZX1303A ,  01ZX1603A ,  01ZX1307D , and  01ZX1607D ) and the  German Cancer Aid  (grant number  110122 ).
image Data analysis Stacks 150-250 µm thick (Z steps of 3 µm) were acquired every 30 s to 1 min for 10-27 min. Movies were stabilized using Huygens Essential (SVI). Measurements were performed in at least three independent experiments. Average velocities and mean squared displacements (MSD) of individual T cells were obtained using Imaris (Bitplane). Directionality indexes (ratio between the distance between start and end time points in a straight line and the total length of the migratory path) were calculated using a routine programmed in MATLAB  (18). Similarly, T cell coordinates obtained using Imaris were imported in MATLAB to measure the displacement of T cells toward or away from islet centroids, to project T cell orientation of displacement vectors on a circle, to calculate angle differences between T cell displacement vector projections on the XY plane and the direction of vessels, and to generate graphs of XY projections of T cell tracks, using custom programs (available upon demand).
statistical analysis Values are represented as mean ± SEM. Statistical tests were performed using GraphPad Prism. Normality was tested using D' Agostino-Pearson test, and comparisons were made using either unpaired Student's t-test, or two-tailed Mann-Whitney U-test, as appropriate. Multiple comparisons were made using one-way ANOVA followed by Bonferroni's post hoc test. To analyze uniformity of distribution, the Hodjes-Ajne test for circular uniformity was used in MATLAB. P-values were considered significant at P < 0. 05*, 0. 01**, 0. 001***, and 0. 0001****.
Animal studies were conducted according to the European guidelines for animal welfare (2010/63/EU). Protocols were approved by the Institutional Animal Care and Use Committee (CEEA-LR-1190 and -12163) and the French Ministry of Agriculture (APAFIS#3874). aUThOr cOnTriBUTiOns GE-C, CS, JH, and MS designed experiments; GE-C, CS, AM, and MS performed experiments; GE-C, CS, PF, JH, and MS analyzed data; PM, JH, and MS wrote the manuscript. acKnOWleDgMenTs The authors declare no conflict of interest. The authors would like to thank C. Lafont, P. Samper, and E. Galibert, Institute of Functional Genomics, Montpellier, France, for technical assistance, the animal facility staff (RAM), and Montpellier Imaging Platforms [IPAM and MRI, members of the national infrastructure France-BioImaging supported by the French National Research Agency (ANR-10-INBS-04, "Investments for the future")].
EXPERIMENTAL PART All manipulations were realized in a dry, oxygen-free argon atmosphere using Schlenk-line and glove-box techniques. All the solvents were purified with a MBRAUN SBS-800 apparatus. The NMR spectra were recorded with a Bruker Avance II 300 apparatus: 1 H (300. 13 MHz), 13 C (75. 48 MHz), 31 P (121. 51 MHz, reference H 3 PO 4 ) at 298 K. High-resolution mass spectrometry (HRMS) spectra were measured with a GCT Premier Waters in DCI mode (CH 4 ). The X-ray data were collected at 193(2) K on a Bruker -AXS APEX II Quazar diffractometer, equipped with a 30 W air-cooled microfocus source using MoK α radiation (wavelength = 0. 71073 Å). Phi-and omega-scans were used. The data were integrated with SAINT  [41]  and an empirical absorption correction with SADABS  [42]  was applied. The structures were solved by direct methods using SHELXS-97  [43]  and refined using a least-squares method on F 2.