dataesr/scientific-paragraphs-categorization huggingface dataset:
0021_2. 87] and [203. 0020_1. 31] in the samples YD2 and YD6. These two compounds correspond to sulfite addition on 4MeC, likely in different C electrophilic sites. The nucleophilic addition of SO2 is known to be minor in comparison with the reduction of the quinone (11% yield against 89%, respectively)  (Nikolantonaki & Waterhouse, 2012). Thus, the abundance of sulfonated 4MeC could provide relative information about the underivatized fraction of the 4MeQ. Besides the GSH and GSH precursor derivatives, few other compounds had been annotated from online databases. Notably two peptides Tyr-Pro-Ala (C24H28N3O10S, m/z = 550. 1502) and Pro-Cys-Gln-Glu (C25H34N5O13S2, m/z = 676. 1594), which were strongly correlated with the abundance of glutamyl-cysteine and GSH derivatives (Figure  3 ). The correlation between two compounds could indicate the co-accumulation of these peptides during the GSH accumulation process, or the degradation product coming from specific macromolecules involved in the GSH accumulation process.
ACKNOWLEDGEMENTS The authors acknowledge the  Regional Council of Bourgogne -Franche-Comté , the  "Fonds Européen de DEveloppement Régional (FEDER) " and  Lallemand SA (31, Blagnac)  for financial support. The authors would like to thank  Lallemand SA  ( 31 ) and Oenobrand (34) for the yeast derivatives supply. They also would like to thank  Dr. Eveline Bartowsky  for a careful reading of the manuscript by a native English speaker.
This trend is clearly evident at 95 KDa bands (phosphorylated band 3). All densitometry analyses performed on membranes scanned on the Odyssey CLx were done using Odyssey 3. 0 software, confirming the large decreases of Tyr phosphorylation levels in band 3 residues caused by Syk protein. Diamide-treated erythrocytes (Figure  2 , lane 2) showed high levels of phosphorylation due to the oxidative stress conditions. All the tested Syk inhibitors efficiently suppressed band 3 phosphorylation (Figure  2A -D, lanes 3-9). Table  1  shows the IC50 values obtained by densitometric analysis; these results were in agreement with those obtained in previous published studies treating RBCs with different concentrations of each drug and quantitating residual parasitemia 24 and 48 h later (Table  2 )  [15, 17].
P505-15 was the most potent Syk inhibitor, with an IC50 of 0. 64 µM, while Syk II was the least efficient, with an IC50 of 1. 72 µM. All densitometry analyses performed on membranes scanned on the Odyssey CLx were done using Odyssey 3. 0 software, confirming the large decreases of Tyr phosphorylation levels in band 3 residues caused by Syk protein. Diamide-treated erythrocytes (Figure  2 , lane 2) showed high levels of phosphorylation due to the oxidative stress conditions. All the tested Syk inhibitors efficiently suppressed band 3 phosphorylation (Figure  2A -D, lanes 3-9). Table  1  shows the IC 50 values obtained by densitometric analysis; these results were in agreement with those obtained in previous published studies treating RBCs with different concentrations of each drug and quantitating residual parasitemia 24 and 48 h later (Table  2 )  [15, 17].
pdb (2. 19 resolution) was available in the RCSB PDB database; this structure was the most complete, although the active site compared to other structures found in the same database was forced by an activation loop. The docking results obtained from the crystal structure of Syk (4FL2) in the complex with ligands showed conserved H-bond interactions (Table  3 ); however, a different disposition of ligands in the pocket was observed compared to the poses of the crystal structure of reference. Although the ligands have a common pattern of interaction with Syk, which is known for all tyrosine kinases  [37] , our molecules presented different rotations and torsions in the site binding, with the exception of P505-15  [38] , which showed an RMSD of 1. 39 Å related to its reference (PDB accession number 4RX9), (Figure  5 ).
R406 Syk II Gleevec P505-15 Leu377 * Leu377 Arg338 Leu377 Gly378 Gly378 Leu377 Val385 Ser379 Val385 Ser379 Ala400 Gly380 Ala400 Gly380 Met448 Val385 Lys402 Asn381 Glu449 ** Ala400 Met448 Phe382 Met450 Lys402 Glu449 ** Val385 Ala451 ** Val433 Met450 Ala400 Glu452 Met448 Ala451 * Lys402 * Gly454 Glu449 Gly454 Met448 Pro455 Met450 Pro455 Met450 Lys458 Ala451 ** Lys458 Ala451 * Leu501 Glu452 Arg498 * Leu453 Gly454 Leu501 Gly454 Pro455 Ser511 * Arg498 * Lys458 Asp512 ** Asn499 Leu501 Leu501 Asp512 Ser511 Asp512 * Tyr525 His531 The different interactions between ligands and proteins observed through their docking and different conformations might be due to the fact that the pocket is capped by an activation loop, causing a steric hindrance. Due to the presence of this buried active site, we considered the 4FL2 crystal's structure in its active conformation compared to the other proteins that we have analyzed in the RCSB database, where their binding pockets were opened.
Western Blot Analysis Proteins separated by SDS-PAGE were transferred to nitrocellulose membranes as previously described with Trans-Blot Turbo Bio-Rad and then probed with antiphosphotyrosine antibody (sc7020, Santa Cruz, CA, USA). This was produced in mice in Santa Cruz, CA, USA, and was diluted to 1:2000. Secondary antibodies conjugated with infrared fluorescent dyes excitable at 680 nm or 800 nm (IRDye, Antimouse 800 CW 926-32210, Li-COR, Lincoln, NE, USA) were then used to visualize the desired antigens with a laser scanner (Odyssey, Licor, Lincoln, NE, USA). Quantitative densitometry analyses of tyrosine phosphorylation levels were carried out by analyzing Western blot images using Image J software. The values were expressed as arbitrary units. The rate of band 3 phosphorylation was expressed as the PTP activity and as a percentage of the maximal activity in RBCs treated with 2 mM diamide.
All graphs precisely show the relative phosphorylation, expressed as a percentage of the maximum observed in each experiment (100%). The results show the average of four experiments, normalized to total beta-actin levels. The error bars represent the standard deviations (SDs) of the data. The IC 50 values of different drugs were calculated using ICEstimator 1. 2 software. The ff10 version of the AMBER force field was used to model the protein, and the General AMBER Force Field (GAFF) was used for the organic ligand using the Austin Model 1-Bond Charge Corrections (AM1-BCC) partial charges derived from the antechamber program of the AMBER suite. In the MD simulation protocol, the SHAKE algorithm was used to constrain all bonds involving hydrogen atoms. A non-bonded cutoff of 8. 0 Å was used.
Langevin dynamics were used to control the temperature (300 K) using a collision frequency of 1. 0 ps-1, along with isotropic position scaling to maintain the pressure (1 atm). Periodic boundary conditions were applied to simulate a continuous system. To include the contributions of long-range interactions, the particle mesh Ewald (PME) method was used with a grid spacing of 1 Å combined with a fourth-order B-spline interpolation to compute the potentials and forces in between grid points. The trajectories were analyzed using the Processing Trajectory program (PTRAJ) module of AMBER. Molecular mechanics and Poisson-Boltzmann (or generalized Born) surface area (MM/PB(GB)SA) calculations and analyses were done with the MM-PBSA program in Amber14 suite. Graphical representation of the hypothetical positions derived from the docking calculations and the trajectory analysis of molecular dynamics calculations was performed using Chimera  [63]  and Visual Molecular Dynamics (VMD)  [64]  software.
Based on the above data and other publications from our labs, we demonstrated that these compounds actually block the phosphorylation of Tyr residues in protein band 3. The in vitro experiments using a proteomic approach allowed us to notice that Syk inhibitors terminate the life cycle during the process of merozoite egress from the infected RBC, leading to a decrease of band 3 phosphorylation and avoiding the destabilization and weakening of the erythrocyte membrane. The biological data obtained by evaluating the IC 50 values using Western blotting for all tested compounds confirmed the results achieved in in silico studies. The development of new drugs that can effectively kill malaria parasites is of increasing importance as the threat of drug resistance continues to grow. However, as highlighted above, the findings of this study require further exploration and testing to elucidate or confirm the role of Syk inhibitors as potential drug targets.
Endothelial Cell Migration in Real Time The potential of metformin and its derivatives to reduce endothelial cell migration was investigated using an in vitro wound healing assay. The assay was performed with the JuLiStage system, which allows to visualize cell growth images and curves in real time. The cells were seeded on 96-well plates for 24 h; a wound was made, and then it was co-treated with various concentrations of synthesized compounds, and metformin as a reference. The ability of compounds to affect HUVEC cell migration was monitored microscopically over 24 h of stimulation. The potential for metformin derivatives 1-10 to attenuate cell migration is presented in Table  S1  (Supplementary Materials). The results are expressed as the width of scratched wound calculated using provided JuLiStage software (NanoEnTek, Waltham, MA, USA).
The experiments showed that all selected compounds (2, 3, 4, 6 and 10) significantly decreased the activity of FX. Importantly, compounds 4 and 6 contributed to a significant decrease in FX activity over the entire concentration range which can explain the effects of these compounds on measured PT and APTT. In conclusion, the results of FX experiments confirm the anti-coagulant properties of synthesized metformin analogs. Thus, these data give evidence on more pronounced anti-coagulant activity of examined compounds in comparison with those of metformin. Compounds 2, 3, 4, 6 and 10 were further studied using a multiparametric CL-test, which allows to measure the overall potential of clot formation and fibrinolysis and to calculate a number of kinetic parameters of this process. Importantly, the incubation of human plasma with examined compounds did not result in significant changes in the overall potential of clot formation and fibrinolysis (CL AUC constant).
The results are presented as mean ± standard deviation (SD), n = 4. The coefficient of variability was calculated: W = 11. 95%, n = 7. The samples for RBCs morphology were prepared according to the same procedure. Microscopy studies were conducted using a phase contrast Opta-Tech inverted microscope, at 400-times magnification, equipped with software (OptaView 7, Warsaw, Poland) for image analysis.
The final volume of sample was 250 µL. The fluorescence was measured by flow cytometry (CytoFlex, blue laser, 480 nm, Beckman-Coulter, Indianapolis, IN, US). The results were analyzed using Kaluza 2. 1 (Beckman-Coulter Inc. , Brea, CA, USA) software. In total, 10,000 cells were analyzed from each sample and the data were presented as the mean ± SD of three independent experiments. The coefficients of variation for the assay was determined (CV = 8. 26%, n = 3).
32) and Kuehneotherium (CV = 4. 89) are significantly lower than previous thin section-based studies (W = 0. 93; minimum extant CV = 14. 2, mean CV = 21. 8, standard deviation = 5. 87; F = 11. 12, p < 0. 01; Supplementary Table  1 ). We estimated body mass ranges of 10. 7-25. 0 g (mean 17. 9 g) for Morganucodon and 14. 9-32. 7 g (mean 23. 8 g) for Kuehneotherium (minimum mass estimates based on skull length  21  and maximum mass estimates on dentary length  48  ; see "Methods"). Maximum lifespan and mean body mass for the mammaliaforms were compared with published data for large Potential maxillary nasal turbinates (MNTs) in derived taxa. 18 sified intraorbital canal suggests sensory vibrissae (whiskers)  17  Brasilitherium endocast reveals gradual increase in EQ through cynodontia to near-mammaliaform levels  28  Most basal taxon found with full fur pelage  65  Earliest morphological and taphonomic evidence for parasaggital posture  23  One of several gliding euharamiyid taxa 3 ** EQ equivalent to extant mammals  21  Mandibular depth measurements suggest determinate growth.
47 docast reveals improved olfaction and tactile sensitivity potentially suggestive of nocturnality. 21 phyodonty (single replacement of milk teeth) may suggest maternal feeding via mammary gland. 31 d blood cell (RBC) size inferred to be similar to extant mammals  samples of terrestrial, non-volant wild extant mammal (n = 278) and non-avian reptile (n = 256) species ("Methods"; Supplementary Data 3). Maximum wild lifespans of extant taxa were chosen for comparison with our fossil taxa, as these values are the closest analogue to our estimated lifespans, relative to captive lifespan values. To ensure robustness of our results, we additionally analysed maximum captive lifespans of extant taxa below 100 g, which show an average increase above maximum wild lifespans of approximately 3. 43 and 4.
Pontalun 3 and Pant 2 fissures have a relatively impoverished fauna, and Pant 4 has a more diverse biota  45  (Supplementary Data 2). Kuehneotherium from Pontalun 3 fissure is Kuehneotherium praecursoris  57  , but those from the Pant fissures are considered to be different species, based on small molar differences  58. All specimens from Pontalun 3 fissure in the NHMUK (Morganucodon and Kuehneotherium) were prepared by immersing dried blocks of clay matrix in hot tap water, with the addition of dilute hydrogen peroxide or sodium hexametaphosphate (Calgon) if required, but those in the UMZC collection were prepared with 10% acetic acid. Kuehneotherium specimens from Pant quarry (Pant 2 and Pant 4) were collected by the Kermack team from University College London, between 1955 and 1978, and are from a harder matrix, which was prepared with 15% acetic acid  58.
The beam energy was set at 21 keV using a double multi-layer monochromator. Samples were scanned using single propagation distance tomography (14 mm sample-to-detector propagation distance), an exposure time of 200 ms and 1601 angular projections over a 180°scan at a voxel size of 330 nm. CT reconstructions of the above tomographic data were generated using a filtered back-projection algorithm coupled with "Paganin-style" single distance phase retrieval  59  algorithms developed in-house at the respective beamlines  60, 61. For data from ID19, β = 8. 1 × 10 -8 , δ = 9. 8 × 10 -9. For data from TOMCAT, β = 3. 7 × 10 -8 , δ = 1. 7 × 10 -10. Of the 71 Morganucodon molar specimens imaged at beamline ID19 in 2014, 4 were additionally imaged at the nano-imaging beamline ID16A of the ESRF synchrotron (project ES 152).
A total of 900 angular projections were collected for a 180°rotation, at an exposure time of 1840 ms and a voxel size of 2 × 2 × 2 μm 3. The raw projection data were reconstructed using filtered back-projection by the reconstruction software datos|x rec, supplied by the system manufacturer. Increment counting and creation of virtual thin sections. Cementum increments were counted in CT data using modifications to the techniques suggested by the Cementochronology Research Program  38  to take into account the 3D nature of the PPC-SRµCT cementum data. First, the cementum was visually inspected throughout the entire volume of each scan, in transverse PPC-SRµCT slices using ImageJ/Fiji 63 to distinguish between specimens that could be confidently interpreted as preserving cementum increments or those that were too badly affected by diagenesis for increment counting.
Between three and five virtual thin sections were created for all specimens with readable cementum increments. For each virtual thin section, increments were counted manually by three different observers: Observer One (E. N. ) had considerable experience in counting cementum increments (>100 specimens studied); Observer Two (K. W. ) had training in counting cementum increments (30 specimens studied under guidance from Observer One) and experience in studying growth patterns in PPC-SRµCT data of long-bones; Observer Three (C. N. ) had no prior experience in counting increments or studying growth patterns. Each observer studied virtual thin sections blind, after collections of virtual thin sections were numbered and randomized between specimens using the RAND function in Microsoft Excel. For each observer, the final increment count for every specimen was determined as the maximum number counted in all of its virtual thin sections.
Once each observer had counted increments in every virtual thin section (Supplementary Fig. 3  and (Supplementary Data 1) and the precision between their increment counts was compared by calculating the CV (Eq. 1; Supplementary Table  1 ): CV ¼ standard deviation mean * 100 ð1Þ 3D modelling of cementum increments. 3D modelling was performed, using the Avizo image analysis software (Avizo 8. 0; Thermo Fisher Scientific), on a subsample of teeth comprising the first tooth imaged using PPC-SRµCT (NHMUK PV M 104131) and the specimens that provided the highest cementum increment counts for each fossil taxon (NHMUK M 104127 for Morganucodon and UMCZ Sy 141 for Kuehneotherium). Original tomographic data were downsampled in each axis by a factor of two to decrease manual processing time while retaining sufficient spatial resolution to preserve the cementum increments.
6 kg, standard deviation = 20 kg; wild lifespan: mean = 12 years, standard deviation = 14 years) (Supplementary Data File 3). Information on maximum captive lifespan was obtained for 644 extant terrestrial mammal species (body mass: mean = 62. 2 kg, standard deviation = 324 kg; captive lifespan: mean = 15. 5 years, standard deviation = 11. 5 years) and 866 extant reptile species (body mass: mean = 2. 4 kg, standard deviation = 15. 9 kg; captive lifespan: mean = 15. 3 years, standard deviation = 11. 6 years). Information for flying or gliding taxa (including birds) was not included as their body masses are known to be secondarily reduced to aid their lifestyle and so may distort observed overall relationships between lifespan and body mass. In particular, birds and bats live on average three-to-four times as long as terrestrial mammals of similar body mass  66.
Similarly, marine mammals were not included as their environment positively affects body mass, allowing significantly higher body masses than terrestrial taxa  67. Mammalian wild and captive lifespan data were obtained from the primary literature. The majority of these data originated from a download from the online databases of the Max Planck Institute (https://www. demogr. mpg. de/longevityrecords/0203. htm) on 10/ 03/2019. The majority of reptile wild and captive lifespans were obtained from the supplementary information of Scharf et al. 68. Body mass estimates were obtained from an online Ecological Archives database 69 (http://www. esapubs. org/archive/ ecol/E084/094/metadata. htm), the AnAge database (https://genomics. senescence. info/species/) and published data  50, 68. Although the Max Planck Institute data are entitled "longevity records", it notes in the introduction that this is equivalent to "highest documented age".
The authors of the database believe that, despite any analytical and conceptual shortcomings, the records are useful in a number of comparative and disciplinary contexts, including demographic, gerontological, ecological and evolutionary. Similarly, the AnAge database states that maximum longevity is synonymous with maximum lifespan. Data on SMR for extant mammals (n = 117; mean = 915; standard deviation = 3018) and reptiles (n = 55; mean = 62. 3; standard deviation = 159) was obtained from a published electronic appendix  50. SMRs for mammals were included in this data set only if measured under basal metabolic conditions  50  and so are synonymous with BMRs. Data on the postnatal growth rate constant K was obtained upon request for extant mammals  32  (n = 115, mean = 0. 03, standard deviation = 0.
Six Morganucodon femur specimens were selected for analysis from the collections of the Cambridge University Museum of Zoology based on their relative completeness. All femora (both fossil and extant) were scanned using a Bruker Skyscan 1272 μCT scanner at 70 kVp source tension and with a 0. 5 mm Al filter. For each scan, 1125-1800 angular projections were collected during a 180°rotation, at an exposure time of 1344 ms. One fossil specimen was scanned at an isotropic voxel size of 4 μm (Fig. 7a ) and five at 5 μm. All femora from extant taxa were scanned at 4 μm voxel sizes. The raw projection data were reconstructed using filtered back-projection with the Feldkamp algorithm by the Bruker reconstruction software "NRecon" (Version 1. 7. 1. 0). Analysis of μCT femora data was conducted using the Avizo image analysis software (Version 9.
Acknowledgements We acknowledge the  European Synchrotron Radiation Facility, Grenoble, France  for provision of synchrotron radiation facilities on beamlines  ID19  and  ID16A  (project  ES152 ) and thank  Peter Cloetens  for assistance in using beamline ID16A. We also acknowledge the  Paul Scherrer Institut, Villigen, Switzerland  for provision of synchrotron radiation beamtime at beamline TOMCAT of the  Swiss Light Source  (project  20141278 ). The research leading to these results has received funding from the  European Community 's  Seventh Framework Programme  ( FP7/2007-2013)  under grant agreement no. 312284  (for CALIPSO). We thank  Keijo Hämäläinen  for his help in the initial stages of the synchrotron imaging. This project was part-funded by a  Natural Environmental Research Council  studentship and an  Engineering and Physical Sciences Research Council  studentship, awarded to E.
Data availability The tomographic data that support the findings of this study are available from the corresponding authors upon reasonable request. Virtual thin sections used for cementum and bone increment counts are available at the University of Southampton's PURE data repository as data number D1506 (https://doi. org/10. 5258/SOTON/D1506). Physiological and phylogenetic data are from online databases of the Max Planck Institute (https://www. demogr. mpg. de/longevityrecords/0203. htm), an online Ecological Archives database (http://www. esapubs. org/archive/ecol/E084/094/metadata. htm), the AnAge database (https://genomics. senescence. info/species/), the VertLife online project (https://vertlife. org) and the literature (references in Supplementary Data file 3) and are provided in Supplementary Tables, as Supplementary Data files, and as a part of the Source data provided with this paper.
Study Design, Setting, and Population This retrospective analysis was approved by our National Ethics committee (Comité d'Ethique en Anesthésie Réanimation, CERAR, Prof. Jean Etienne Bazin; IRB number 00010254). The demographic and surgery characteristics of the patients who received total IV-OFA were analyzed. Data on OFA efficacy, safety, tolerability, and the quality of recovery were extracted from electronic patient data files and then examined and anonymized. The study population inclusion criteria were consecutive, major, or complex open abdominal or urologic surgery (i. e. , lasting more than 90 min) under GA. In our unit, the choice of using the OFA (described in Sect. 3, Results) or the ORA protocol was not performed as a function of the patients' medical conditions but according to the views of each practitioner practicing their procedures under the OFA or the ORA protocol.