dataesr/scientific-paragraphs-categorization huggingface dataset:
Efficacy inputs Clinical data including PFS and OS were obtained from the KEYNOTE-024 trial (data cut-off May 9, 2016) and the NMA, considering PFS as a proxy for treatment duration. Observed data in KEYNOTE-024 were then extrapolated to project outcomes to the end of the 10-year time horizon. Hazard ratios from the NMA were used to extrapolate PFS and OS for interventions not included in the trial. Due to the low number of patients with squamous NSCLC in KEYNOTE-024 (n = 56 in squamous group and n = 249 in non-squamous group), extrapolations were performed in the ITT population and were then derived separately for squamous and non-squamous subgroups. The efficacy of pembrolizumab was assumed to be maintained after completing the 2-year maximum duration of treatment. A piecewise modeling approach was performed, utilizing PFS and OS Kaplan-Meier curves until a cut-off point, and extrapolating data beyond with exponential, Weibull, Gompertz, log-normal or generalized gamma distributions as recommended by the NICE Decision Support Unit (DSU)  [30]  (Table  2 ).
Cost inputs Resource use was derived from KEYNOTE-024, published literature and independent experts' opinions. Only direct medical costs (in 2017 Euros) were assessed, from a health system perspective, taking into account all stakeholders of the French health system (i. e. patients, compulsory and supplementary health insurance schemes, state, etc. ) (Table  2 )  [14]. Acquisition costs for drugs reimbursed in addition to the Diagnosis-Related Group (DRG), namely expensive and in-hospital use drugs (i. e. pembrolizumab; bevacizumab and pemetrexed) were obtained from the French National Tarif database (BdM IT). Wastage was not considered for any medication. DRG cost for a chemotherapy infusion was estimated based on public and private weighted tarifs from the technical agency for hospital information database (ATIH).
Transportation costs were obtained from data published by the Cour des Comptes (i. e. the supreme body for auditing the use of public funds in France). Premedication costs for drugs dispensed in retail pharmacies to prevent anemia (i. e. Erythropoietin) and nausea/vomiting (i. e. Aprepitant) were obtained from the National Tarif database and were applied at each chemotherapy infusion. It is really relevant to clarify that point. Erythropoietin cost was taken into account for only 20% of patients according to experts' opinions and included the injection by a home care nurse. These costs were applied at each infusion up to progression (mean PFS simulated by the model) and limited to 2-year maximum treatment duration for pembrolizumab, 6 treatment cycles for platinum; no treatment cap was considered for bevacizumab or pemetrexed maintenance (34.
The assumption of continued treatment effect after stopping pembrolizumab at 2 years was based on long-term results from the KEYNOTE-010 trial in previously treated NSCLC patients, and has not yet been documented for first-line treatment  [45]. Regarding the method used to take into account some inputs, the number of AEs may be underestimated due to exclusion of lower frequency AEs. Also, it would have been preferred to apply a unique disutility related to each AE. The sensitivity and scenario analyze showed that uncertainty around results was mainly driven by these limitations. At the time of the analysis, few elements allow robust validation of extrapolations for pembrolizumab and comparators. Long-term followup data for pembrolizumab (KEYNOTE-001), published literature and clinical trials for chemotherapies were used.
4 Å relative to the corresponding elements in the 2ioq structure. Solvation of the structures was performed in octahedral boxes with explicit water molecules (TIP3P)  (Jorgensen et al. , 1983)  and neutralized with chloride and sodium ions up to an ion concentration of 0. 1 M using the leap module and employing the parm14SB force field  (Maier et al. , 2015)  of the Amber14 package. All unrestrained simulations were performed using the pmemd. cuda code of the Amber14 package  (Case et al. , 2014). The start structures were energy minimized using steepest descent and conjugated gradient methods (5,000 steps), and slowly heated up to 300 K in 500 ps NVT run using Langevin dynamics, while restraining all heavy atoms with respect to the start structure. During another 150 ps the positional restraints were reduced in a step-wise manner, allowing the system to relax.
ALICE Collaboration Figure  2  shows the product of acceptance and efficiency (Acc × ε) for prompt and feed-down D mesons with rapidity |y lab | < y fid (p T ). The D 0 , D * + , and D + s distributions are overall higher for the feed-down contribution compared to that of the prompt D mesons, while the opposite is true for the D + efficiency because of the topological selection. The correction factor f prompt was calculated per p T interval using a FONLL-based method as described in  [75]. The procedure uses the B-meson production cross section in pp collisions at √ s = 5. 02 TeV estimated utilising FONLL calculations, the B → D + X decay kinematics from the EvtGen package  [76] , the efficiencies for D mesons from beauty-hadron decays and a hypothesis on the nuclear modification factor R feed-down pPb of D mesons from B decays.
The Duke model includes both collisional and radiative energy loss. The POWLANG model considers only collisional processes with two choices for the transport coefficients, based on hard-thermal-loop (HTL) and lattice-QCD (lQCD) calculations. For both the Duke and the HTL based POWLANG estimates, the D-meson nuclear modification D-meson production in p-Pb collisions at √ s NN = 5. 02 TeV ALICE Collaboration factor distribution has a peak structure, with the maximum at p T ≈ 2. 5 GeV/c and p T ≈ 3. 5 GeV/c, respectively, possibly followed by a moderate (< 20-30%) suppression at higher p T , resulting from the interplay of CNM effects and interactions of charm quarks with the radially expanding medium. The trend suggested by these models is not supported by the data. The strong enhancement at p T ∼ 3 -4 GeV/c observed in the model calculations is not consistent with the measured R pPb , and a suppression larger than 10% for p T > 8 GeV/c is excluded by the data with a 98% confidence level.
Acknowledgements The ALICE Collaboration would like to thank all its engineers and technicians for their invaluable contributions to the construction of the experiment and the CERN accelerator teams for the outstanding performance of the LHC complex. The ALICE Collaboration gratefully acknowledges the resources and s NN = 5. 02  TeV ALICE Collaboration National Academy of Sciences of Ukraine, Ukraine ;  Science and Technology Facilities Council (STFC) ,  United Kingdom ;  National Science Foundation  of the  United States of America (NSF)  and  United States Department of Energy, Office of Nuclear Physics (DOE NP) ,  United States of America.
Enzyme directed evolution allows discovering new hotspots for protein engineering otherwise not revealed by rational strategies, while computational design permits to analyze the mutational space of these hotspots much faster than they can be explored in the lab, thus contributing to reduce the screening effort  [16, 17]. In previous works, simulation studies helped us to understand the beneficial effect of the mutations accumulated through directed evolution on laccase activity  [18, 19]. Moreover, they predicted beneficial mutations to enhance laccase activity towards a particular substrate  [20] , or envisaged the oxidation of a target substrate by different laccases, according to differences in their substrate-binding pockets  [21]. These studies mainly consisted of protein-substrate exploration using the Protein Energy Landscape Exploration (PELE) software, in combination with quantum mechanics/molecular mechanics (QM/MM) simulations.
07 Â 0. 07 mm 3. Prior data collection, they were immersed in the precipitant solution containing 20% (v/v) glycerol, followed by rapid flash cooling in liquid nitrogen. A complete X-ray diffraction data set was collected at the beam line I02 at Diamond Light Source (Harwell Campus, UK). Data were indexed and integrated using XDS  [30]  and scaled with SCALA from the CCP4 suite  [31]  Matthews coefficient and self-rotation function indicated the presence of two molecules in the asymmetric unit, with a solvent content of 62. 23%. Molecular replacement was performed with Phaser  [32]  using the Protein Data Bank entry 1GYC as model, and the refinement was carried out with PHENIX  [33]  including rigid body refinement as the first step. Several rounds of iterative refinement and manual building steps were done with Coot  [34].
Coordinates and structure factors have been deposited at the PDB with accession code 6H5Y. Model quality was checked using MolProbity implemented within the PHENIX suite. Figures were prepared with Pymol (Molecular Graphics System, Version 1. 5. 0. 4 Schrödinger, LLC). Details of data collection and processing, refinement statistics and quality indicators of the final model are summarized in Table  S2. 2. 5. Small-angle X-ray scattering SAXS measurements of laccase in solution were performed at Diamond Light Source beam line B21 (Harwell Campus, UK), using a BioSAXS robot for sample loading, from solutions of the glycosylated and deglycosylated forms of 7D5 laccase at different concentrations in 20 mM Tris-HCl pH 7 at 277 K. Samples of 40 ll corresponding to PM1 laccase glycosylated at 17 mg ml À1 and to PM1 deglycosylated at 15 mg ml À1 , were delivered via an in-line Agilent 1200 HPLC system in a Shodex Kw-403 column using the same running buffer.
During the experiment the samples were exposed for 300 s in 10 s acquisition blocks using a sample to detector distance of 3. 9 m and X-ray wavelength of 1 Å. The data were analyzed, buffer-subtracted, scaled, and merged using the Scåtter software package (www. bioisis. net). This software was also used to check possible radiation damage of the samples by visual inspection of the Guinier region as a function of exposure time during data collection. R G and D max values were calculated with PRI-MUS and GNOM, and shape estimation was carried out with DAMMIF/DAMMIN, all these programs included in the ATSAS package  [35]. The radius of gyration (R g ) can be obtained from the P(r) function by integrating the function with r 2 over all values of r. The P(r) distribution function is used to describe the paired-set of distances between all of the electrons within the macromolecular structure and is a useful tool for visibly detecting conformational changes within a macromolecule.
Real-space scattering profiles of atomic models were calculated using FoxS  [36]  and the final ab initio models were superimposed with the high-resolution structure using the program SUPCOMB from the ATSAS package. The proteins molecular mass was estimated with SAXSMoW  [37]. Figures were prepared with Pymol (Molecular Graphics System, Version 1. 5. 0. 4 Schrödinger, LLC). Details of data collection and processing are summarized in Table  S1.
Kinetic constants for the oxidation of HBA were determined using 4-AAP. For that, increasing equimolar concentrations of 4-HBA and 4-AAP were added to the reaction and the increment of absorbance from the coupling of HBA to 4-AAP (e 500 = 12,200 M À1 cm À1 ) was monitored at 500 nm  [39]. Initial oxidation rates were plotted against substrate concentration and fitted to a single rectangular hyperbola function using SigmaPlot 10. 0 software. Parameter a was the k cat and the parameter b was equal to the K m.
Computational analysis Protein-ligand interactions were analyzed using HBT and DMPD as substrates with the PELE software. Ligands were optimized in implicit solvent with the density functional M06 and 6-31G* basis set level of theory using Jaguar from Schrodinger; ESP charges were then extracted for ligand parameterization. The enzymes were prepared with the protein wizard from Schrodinger, at pH 4. PELE is a Monte-Carlo (MC) based software that was developed for mapping protein-ligand interactions, both at the global and local level. Each MC step includes a perturbation and a relaxation phase, before a Metropolis acceptance test accepts or rejects the proposed new pose. Binding energies are then scored using an OPLS-AA proteinligand interaction energy, which includes a generalized surface born implicit solvent.
Enzyme deglycosylation decreases the maximum dimension (Dmax) of both monomeric proteins. Nevertheless, N-glycosylation seems to have a special impact on 7D5 laccase where the glycosylated form adopts a geometrical oblate structure that is converted to a somehow spherical form after deglycosylation. By contrast, PM1 L shows a more spherical structure before and after deglycosylation. Clearly, the size of 7D5_deglyco is higher than that found for PML1_deglyco (Fig. 1 , Table  S1 ), most probably due to the heavier O-glycosylation of 7D5, in line with what we observed by MALDI/ TOF-TOF (Fig. S1C ). To evaluate the influence of the glycan on the intermolecular interactions of 7D5 laccase, SAXS-measurements were done at different concentrations. No indication of strong aggregation was detected during data collection, with data showing linear relationships within the Guinier region (Table  S1 ).
2 ). Mutations V162A, H208Y, S224G, A239P, D281E and S426N accumulated in the protein sequence during the evolution pathway of PM1L for expression in yeast  [24] , while T291S, E457D and I468T come from the shuffling with evolved PcL parent  [25]. The crystal structure of 7D5 laccase (PDB code, 6H5Y) was obtained at 2. 3 Å resolution by molecular replacement, using as search model 1GYC. The real space group I23, led us to a solution with two molecules in the asymmetric unit, a Mathews coefficient of 3. 26 Å 3 /Da and a solvent content of ~63%. The structure confirmed the common three-cupredoxin-like-domain folding of fungal laccases  [44] , quite similar to that of PM1L (PDB code, 5ANH); with a backbone (Ca atoms) rmsd of 0. 46 Å and same topology (Fig. 3 , table  S2 ). Both crystal structures show equal number of b-strands (30) and a-helixes  (7) , although mutation I468T enlarges the sixth a-helix in three residues: from VAAT sequence in PM1L, to TPDVAAT sequence in 7D5 (Fig.
Up to 72 structures of fungal laccases are deposited in Protein Data Bank, including laccases from Ascomycetes and Basidiomycetes. However, the majority of the 54 basidiomycete laccase structures (from 21 different species) correspond to wild enzymes because of the difficulty to obtain recombinant basidiomycete laccases at high yields  [47]. In fact, only two basidiomycete laccases produced heterologously have been crystallized: one from Coprinus cinereus, expressed in A. oryzae (1HFU and 1A65), and other laccase from Trametes hirsuta, expressed in Penicillium canescens (5LDU); both of them correspond to native enzymes (Table  S3 ). Conversely, the structural characterization of new variants engineered in the lab might shed light on the protein determinants responsible for modified catalytic activity or robustness, thus providing highquality information for laccase engineering.
Associated content The Supporting Information includes: Figures, schemes, legends for tables and data sets, materials and methods (PDF). Accession Codes: The structure factors for the 7D5 crystal structure reported herein have been deposited in the ProteinData Bank as entry 6H5Y. Group URL: https://www. cib. csic. es/research/microbial-plantbiotechnology/biotechnology-lignocellulosic-biomass.
Acknowledgements This work has been funded by the  INDOX   EU  project ( KBBE-2013-7-613549 ), the  Spanish  projects  BIO2017-86559-R  and  CTQ2016-79138-R , the H2020-iNEXT grant numbers  1676  and  ISCIII. This work has received funding from the  Bio Based Industries Joint Undertaking (JU)  under grant agreement No  792070. The JU receives support from the  European Union 's  Horizon 2020 research and innovation programme  and the  Bio Based Industries Consortium.
lata and grapevine leaf disc using the millicell infection system (A) Molecular communication between leaf disc and fungal mycelium (E. lata) is enable through the permeable membrane (0. 4 µm pore diameter). Molecules secreted by leaf and fungus can pass through the membrane. This in vitro infection system is adapted from  Veillet et al. (2017). (B) Stilbenes quantification by HPLC analysis in leaf disc and treated or not with E. lata using the millicell infection system. Data represent mean (±SEM) of eight independent experiments. Statistical analysis was performed using GraphPad Prism 7, with a Sidak's multiple comparisons test between control and treated condition of ε-viniferin accumulation ( * * p < 0. 01, * * * p < 0. 0001). No statistical difference has been determined between treated cultivars according to a Tukey's multiple comparison test used to compare cultivars.
Statistical and Computer-Assisted Analysis Statistical and computer-assisted analyses were performed using the GraphPad Prism version 7. 00 (GraphPad Software 1 , La Jolla, CA, United States). Pathogenicity tests were conducted over three consecutive years. Results from each year has been considered as biological replicate. Data presented are the mean of the percentage of each class of foliar symptom (n = 3). Plants inoculated with sterile water have been used to control the absence of cross inoculation during the procedure. Because they were not inoculated with E. lata, they were not integrated in the statistical comparison of the symptom severity between cultivars. For each class of symptoms, percentages of foliar symptom severity of Merlot, Cabernet Sauvignon, and Ugni Blanc cultivars have been compared using a Sidak's multiple comparisons test.
DISCUSSION With the aim to explore biological processes involved in the mechanism of tolerance/susceptibility of V. vinifera against the wood decay fungus E. lata, we chose to undertake an analysis of molecular responses of three grapevine cultivars. To that end, grapevine cultivars with clear contrasting susceptibility to Sauvignon, and Ugni Blanc leaf discs in control and treated (elicited) conditions using the Millicell system. (C) Cell wall invertase activity was studied in control and treated foliar discs using the Millicell system. Data represent mean (±SEM) of six independent experiments for the invertase activity analysis and 10 independent experiments for the gene expression analysis. Statistical analysis was performed using GraphPad Prism 7. 00. Stars represents significant difference between control and treated condition for each cultivar, with a Sidak's multiple comparisons test ( * * p < 0.
ACKNOWLEDGMENTS This work includes content of CC's thesis (Cardot, 2017). We would like to thank  Florian Veillet  for the development of the Millicell culture systems,  Vincent Lebeurre  for his help in growing and monitoring the greenhouse plants,  Adrien Catté  ( BNIC Pre-breeding Center ) and  Vincent Dumot  ( BNIC Viticulture ) for the supply of the plant material and grapevine culture support. We also thank  Claudie Rouland  and  Vincent Dumot (BNIC)  for their scientific and technical help,  Patrice Rey  and  Sébastien Gambier  for the greenhouse availability, their scientific and technical assistance, respectively (INRA, UMR 1065 SAVE),  Jean-Pierre Péros  ( INRA, Montpellier, France ) for providing E. lata strain, as well as undergraduate students who participated in the project ( Kaoutar Ould el Kabla ,  Marie Devers , and Hoang).
Subjects Two groups of a pediatric population from Madeira Island, Portugal: 128 adolescents aged 17-yo (71 females, 57 males) and 195 children aged 9-yo (88 females, 107 males) were studied. Subjects were enrolled from schools that were selected from different areas of the island. All participants were Caucasian. Data on dietary and lifestyle habits were collected and used as a basis for the selection of eligible individuals. All subjects were under a Mediterranean diet and the intake of protein and vegetables/fruit followed the recommended dose/age. Dietary intake was evaluated by application of a semi-quantitative Food Frequency Questionnaire. Acute and chronic illnesses were the exclusion criteria. All selected individuals presented an irrelevant anamnesis and did not take drugs and vitamin supplementation.
Statistical Analysis All statistical analyses were performed using the program IBM SPSS Statistics 22. 0. Normality of data and homogeneity of variances were evaluated, respectively, by Kolmogorov-Smirnov and Levene tests. Data were expressed as the mean ± standard deviation (SD). Continuous variables were compared by independent samples T-test and by one-way analysis of variance (ANOVA). Spearman correlation coefficients were calculated to determine the relationship between all metabolites and vitamins. A p-value lower than <0. 05 was considered statistically significant.
Anthropometric and Biochemical Parameters Anthropometric and routine biochemical parameters (data not shown) of the studied population were stratified according to age and gender. All the analyzed parameters were within the normal range according to age and gender. Between genders, significant differences were observed in the 9-yo group only for the systolic pressure (p < 0. 05), which was higher in females. In the 17-yo group, males presented significantly higher systolic pressure (p < 0. 01), waist circumference (p < 0. 001) and creatinine (p < 0. 001), however lower HDL-cholesterol (p = 0. 001) than females. All the included individuals were eutrophic according to BMI cut-off values of the World Health Organization (WHO) Growth Reference Data 2007.
This study was conducted in a healthy pediatric population of children (aged 9-yo) and adolescents (aged 17-yo). The impact of age on Hcy-related metabolism biomarkers and gender differences were evaluated along with that of common variants in genes (MTHFR, MTR and MTRR) encoding enzymes involved in the folate/Cbl dependent Hcy remethylation cycle, or in the TCN2 gene, which encodes the protein that delivers Cbl to cells. The results showed an increase of tHcy concentration and a decrease of folate and Cbl levels with age (Figure  1  and Table  1 ). Moreover, gender differences were found, however only in the 17-yo group, for tHcy level, with a higher mean value in males. These observations concur with previously published data  [46] [47] [48] [49]. The plasma tHcy values are influenced not only by environmental and genetic factors, however also by nutritional ones, including different fortification policies worldwide  [47, 48].
Study Design and Subjects This retrospective study was a population PK analysis of pooled data collected between 2008 and 2016 from patients treated with mitotane by oral route and total daily dose of 1-7. 25 g/day in 2, 3, or 4 administrations. The two datasets were collected in patients treated for adrenocortical carcinoma in the university hospital of Reims (n = 25) and Montpellier (n = 13). Mitotane plasma concentrations were measured under recommended therapeutic drug monitoring conditions (TDM) as specified in summary of product characteristics. The inclusion criteria were patients with ACC, with therapeutic initiation, with at least four blood samples, and without missing data on covariates. The clinical ethical review committee was consulted and pronounced itself in favor of the analysis and the CNIL ("Commission Nationale de l'Informatique et des Libertés") provided us with the registration number 2049775 v 0 (27 march 2018).
PK Analysis Population PK analysis of mitotane in plasma was conducted using nonlinear mixed effects modelling approach within the Monolix software (version 2019R1; Lixoft, Antony, France, http://lixoft. com/) implementing the stochastic approximation expectation maximization (SAEM) algorithm  [26, 27]. Diagnostic plots were performed by R software (version 3. 3. 0; R Development Core Team, Vienna, Austria, http://www. r-project. org/) using R package ggplot.