dataesr/scientific-paragraphs-categorization huggingface dataset:
This paper is dedicated to the memory of our esteemed colleague Christophe Caron who was instrumental in launching the Cyanorak v2. 1 project. We warmly thank Alexis Dufresne, who designed the first version (v1) of the database as well as Michelle G. Giglio and the Institute of Genome Science (IGS) staff for performing the initial automatic annotation of 32 Synechococcus and Cyanobium genomes using the IGS Manatee pipeline. We also thank Justine Pittera, Théophile Grébert, Garance Monier and Théo Sciandra for participating in the curation of the Cyanorak v2. 1 database, the Roscoff Culture Collection and Sophie Mazard for maintaining and isolating some of the Synechococcus strains used in this study as well as the ABiMS platform for providing computational support for this work. FIGURE LEGENDS.
FUNDING This work was supported by the  French "Agence Nationale de la Recherche "  Programs SAMOSA  ( ANR-13-ADAP-0010 ),  CINNAMON  ( ANR-17-CE2-0014-01 ) and  IFB  ( ANR-11-INBS-0013 ), the  Genoscope  project  METASYN , the  Natural Environment Research Council  grant  NE/I00985X/1  and the  European Union 's  Seventh Framework Programs   FP7 MicroB3 (Grant 287589 ) and MaCuMBA (Grant  311975 ).
For both proteins, the turbidity plateau was a linear function of the initial tubulin concentration, yielding critical concentrations (x-intercept) of 4. 7 + 0. 5 and 0. 19 + 0. 15 µM (mean + s. d. ) for WT and Y222F tubulin, respectively (Extended Data Fig. 1d ). The rate of nucleation was assessed from the inverse of the time required for the turbidity to reach 10% of the plateau value (1/T 10% )  25  , which was log-log plotted as a function of the initial tubulin concentration (Fig. 1k ). For Y222F tubulin, 1/T 10% increased in the lower concentration range and showed higher sensitivity to the tubulin concentration compared to the WT, suggesting that Y222F tubulin nucleates faster than WT tubulin 26. The acceleration of nucleation was also confirmed by using darkfield microscopy. Immediately after the onset of the reaction (at 30 sec), while the Y222F mutant produced many short MTs (initial tubulin concentration: 5 µM; Fig.
Given that the T5 loop in Y222F(GDP) was not anchored in the "in" conformation (Fig. 1g ), it implies a possibility that Y222F(GDP) tubulin nucleates MTs. Indeed, incubating Y222F(GDP) tubulin in the condition of the turbidimetry assay led to a signal that slowly increased over time (Extended Data Fig. 4 ). At 2 h after the onset of the reaction, using darkfield microscopy, we observed the Y222F(GDP) MTs, which were substantially longer and fewer in number than the Y222F(GTP) MTs. Although GTP is required for canonical nucleation under natural conditions, the straight oligomers artificially synthesized by mutation partially complemented the lack of gamma phosphate (γ-Pi).
In all experiments (WT and Y222F, either GTP-or GDP-loaded), after blotting off the excess stain, the grid was dried at room temperature. The sample was observed with a JEM1400Plus electron microscope (JEOL) operated at 80 kV. The images were recorded on an EM-14800RUBY CCD camera (JEOL) at nominal 40,000 magnification (for the analysis of oligomers; Extended Data Fig. 2e-h ) or nominal 2,500 magnification (for examination of MTs; Extended Data Fig. 2a-d ), each corresponding to a pixel size of 0. 413 or 6. 59 nm, respectively.
For quantitation of the length distribution of oligomers (Extended Data Fig. 6a-f ), the length of all oligomers in 10-12 micrographs (with size 843 x 847 nm), each covering ~1,000 oligomers in total, were manually measured using Image J (the exact numbers are indicated in the legend of Extended Data Fig. 6 ). The experiments were performed twice for each condition (10 μM WT(GTP) at 5 min, 5 μM Y222F(GTP) at 15 sec, and 5 μM Y222F(GDP) at 30 min after the onset of the polymerization reaction). For the oligomers with a length above 12 nm, the central trajectory of the oligomer was fit by a circle and the arc length was measured. For the oligomers with a length below 12 nm, the largest distance between two points within the object (Ferret diameter) was measured.
Dynamic parameter measurement. Kymographs were generated from the time-lapse darkfield images of MTs using ImageJ. The MT growth rate was determined from the slope of the growing MT in the kymograph (Extended Data Fig. 5a-e ). The mean and standard deviation of growth rate was calculated from all MTs analysed for each condition (the number of MTs analysed per data point was 4 to 44; a total of 217, 122, and 235 MTs were analysed for WT(GTP), Y222F(GTP), and Y222F(GDP) datasets, respectively). From the tubulin concentration dependence of the MT growth rate,  0 [/s] =  +  0 - -, the rate constants for the association and dissociation of tubulin to the MT plus end (k + and k -) were calculated assuming that a MT with a length of 1 μm corresponds to 1,634 dimers 54 (Extended Data Fig. 5e, g ).
While the introduction of the lag ∆ in Eq. (  2 ) improves the quadratic fit (R improved from 0. 98 to 0. 99 for both WT and Y222F), it affects the value of α by no more than 7%. These results justify our estimation. In estimating the size of critical nucleus, we were concerned about the possible errors due to the nonlinearity of OD 350 to the polymer mass of very short MTs. In the above calculation for Y222F tubulin, the data measured for 4-and 5-µM tubulin were not included, because some of the MTs could be too short to assure the linearity between the turbidity and the mass of MTs  56. When we included the data for 4-and 5-µM tubulin in the fitting (Fig. 3c,  •+○), α was 5. 4 + 0. 2, virtually the same as the calculation excluding these two dataset. The size α calculated by an alternative method also confirms the validity of our method.
5), calculated by the power law dependence of 1/T 10% on tubulin concentration 25 (according to their definition of critical nucleus, α = 6. 0). Assessment of the size of critical nucleus for templated-nucleation. Zheng et al. ,(1995) 14 counted the number of MTs, N MT , formed in the initial 5 min of incubation of brain tubulin at 37°C both in the presence and absence of γTuRC (Fig. 3  of Zheng et al. ). The dependence of this number on the tubulin concentration is fit by the equation 𝑁𝑁 𝑀𝑀𝑀𝑀 ~ 𝐵𝐵(𝐶𝐶 0 ) α. Eq. (  3 ) The size of the critical nucleus, α, for the nucleation templated by γTuRC was then estimated as 6. 7 + 0. 9 (Extended Data Fig. 8b ). Calculation of the molar concentration of 2n-mer,. Based on the dataset for oligomer length, we first plotted a cumulative frequency of length (Extended Data Fig.
Data Fig. 8. Initiation of MTs by the γTuRC template. a, Data from Fig. 3a in Zheng et al. (1995) 14. The number of MTs newly formed within 5 min of incubation at 37°C with and without γTuRC (circle and square, respectively) at variable tubulin concentrations. b, Dataset for γTuRC-dependent nucleation plotted on a log-log scale. The data can be fit by the equation y = 81. 5 + 6. 7x (R = 0. 97), indicating that the nucleation of MTs requires the formation of a critical nucleus composed of ~7 tubulin dimers. We could not estimate the size of the critical nucleus for spontaneous nucleation (without γTuRC) because MTs were barely formed. [Credit: (a) Reprinted from Ref. 14 by permission from Springer Nature, Copyright (2020)].
Acknowledgements This work is supported by the  Grants-in-Aid for Scientific Research  from the  Ministry of Education, Culture, Sports, Science and Technology of Japan ,  17H03668  (EM, SK, HI). A grant from the  Foundation ARC pour la Recherche sur le Cancer (BG)  is also acknowledged. We acknowledge the  Chuo University Electron Microscopy Facility  and the technical assistance by  Ms. Nakahara  ( Chuo University ) for the negative stain EM. Part of the cryo-EM study was conducted at the  Advanced Characterization Nanotechnology Platform of the University of Tokyo , supported by the  Nanotechnology Platform of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. Diffraction data were collected at the SOLEIL synchrotron ( PX1  and  PX2  beam lines, Saint-Aubin, France) and the  European Synchrotron Radiation Facility  (ID23-1 beam line, Grenoble, France).
Drosophila tubulin were obtained as T 2 R complexes and after seeding 22. Such factors have been deposited in the Protein Data Bank under accession codes 6TIS (WT(GDP) tubulin), 6TIY (WT(GMPCPP) tubulin), 6TIZ (Y222F(GDP) tubulin) and 6TIU (Y222F(GTP) tubulin). Figures of the structural models were generated with PyMOL (www. pymol. org). complexes comprise two tubulin heterodimers and one stathmin-like domain of the RB3 protein (RB3 SLD ). Data for WT(GDP) tubulin were collected at the ID23-1 beamline (European Synchrotron Radiation Facility, Grenoble, France), data for WT(GMPCPP) tubulin at the Proxima-1 beamline (SOLEIL Synchrotron, Saint-Aubin, France), and data for both Y222F(GDP) and (GTP) tubulin at Proxima-2 beamline (SOLEIL Synchrotron). They were processed with XDS 48. The sT 2 R structure (PDB ID 3RYC) was used as a starting point for refinement with BUSTER 49 with iterative model building in Coot 50.
Genome Sequencing, Assembly, and Bioinformatic Analyses Genome sequencing of B. bifidum CNCM I-4319 was performed using the Pacific Bioscience SMRT RSII sequencing platform (PacBio, Menlo Park, CA, USA). The obtained raw reads were assembled with the Hierarchical Genome Assembly Process (HGAP) pipeline using the protocol RS_Assembly. 2 implemented in SMRT Smart Analysis portal v. 2. 3 (https://www. pacb. com/support/ software-downloads/). Automatic annotation of predicted open reading frames (ORFs) was performed using a combination of PRODIGAL v. 2. 6. 3 (https://github. com/hyattpd/Prodigal) and BLASTP alignments  [45]  to assign annotation (using an E-value cut-off of 0. 0001 for hits showing at least 50% of similarity across at least 50% of the sequence length) against a non-redundant protein database provided by the National Centre for Biotechnology Information portal (http://www.
ncbi. nlm. nih. gov/). Where appropriate, automatic annotation was refined with information obtained from similarity searches involving alternative databases such as protein family (Pfam)  [46]  and COG  [47]. The generated GenBank file was further inspected in Artemis v. 16  [48]  and, where necessary, manual redefinition of the start codons or removal/addition of predicted coding regions were performed. Ribosomal RNA (rRNA) and transfer RNA (tRNA) genes were detected using RNAMMER v1. 2 (http://www. cbs. dtu. dk/services/RNAmmer/) and tRNA-scanSE v2. 0 (http://lowelab. ucsc. edu/tRNAscan-SE/), respectively. The presence of Restriction/Modification systems was determined through interrogation of the REBASE database (http://rebase. neb. com/rebase/rebase. html), as described previously  [49].
Following assembly and annotation, the genome sequence underwent methylome analysis where modified bases were detected using the "RS_Modification_and_Motif_Analysis. 1" protocol implemented in the SMRT Analysis Portal v. 2. 3 (https://www. pacb. com/support/software-downloads/). Only methylation motifs showing a score higher than 40 (corresponding to a p value of <0. 0001) were considered significant (https://github. com/PacificBiosciences/Bioinformatics-Training/wiki/Methylome-Analysis-Technical-Note). Complete and draft B. bifidum genomes were retrieved from the Genbank ftp repository (ftp://ftp. ncbi. nih. gov/genbank/) available from the National Centre for Biotechnology Information (http://www. ncbi. nlm. nih. gov/). Comparative analysis was performed using a combination of all-against-all, bi-directional BLASTP alignments  [45]  (cut-off: E-value < 0.
Sections were then treated with trihydro-chloride trihydrate (0. 5 mg/mL Hoechst 33342, Invitrogen, ThermoFischer Scientific) in PBS. The slides were mounted using fluorescent mounting medium (Dako, Agilent Technologies). Tissues were visualized using a high capacity digital slide scanner (3DHISTECH Ltd. , Budapest, Hungary) and the Panoramic and Case viewer software (3DHISTECH Ltd. ).
Analyses of Lymphoid Population Mononuclear cells were isolated from spleens and mesenteric lymphoid nodes (MLN) by gentle extrusion of the tissue through a 50 µm-mesh Nylon cell strainer (BD Biosciences, San Jose, CA, USA) and subsequent lysis of erythrocytes in red blood cell lysing buffer (Sigma-Aldrich) as previously described  [52]. For flow cytometry analysis, aliquots of 10 6 -10 7 cells per sample were pre-incubated with purified anti-mouse CD16/CD32 (eBioscience, San Diego, CA, USA) and then labelled with anti-CD3-FITC, anti-CD4-PerCP, anti-Tbet-APC and anti-Gata3-PE (all from eBioscience) according to the manufacturer's instructions. Intracellular staining was performed with the FoxP3 Staining kit (eBioscience). Stained cells were analysed by flow cytometry (Accuri, Ann Arbor, MI, USA) with CFlowSampler software (BD Accuri, Ann Arbor, MI, USA).
Statistical Analysis GraphPad software (GraphPadSofware, La Jolla, CA, USA) was used for statistical analysis. Results were presented as dot plots with median +/interquartile range. Comparisons involved the non-parametric Kruskal-Wallis test followed by a Dunn's multiple comparison test. A p value of less than 0. 05 was considered significant. The results of visceral pain response were analysed by one-way ANOVA followed by Tukey's post hoc test.
B. bifidum CNCM I-4319 Methylome Analysis Methylome analysis of B. bifidum CNCM I-4319 identified seven methylated motifs, all of which are methylated at an adenine base (Table  2 ). Motifs 1 and 2, 3 and 4, and 5 and 6 represent complementary, asymmetric recognition sequences, typical of type I restriction-modification (R/M) systems. Motif 7 shares sequence similarity with motif 6 and is therefore assumed to be a sub-motif recognised by the same R/M system. The annotated genome of B. bifidum CNCM I-4319 was also compared against the REBASE database. Three potential type I R/M systems were identified, corresponding to locus tags CNCMI4319_0147-0151, CNCMI4319_1112-1117 and CNCMI4319_1327-1330, which is in agreement with the methylome analysis data. These predicted type I systems include a methyltransferase, a restriction endonuclease and one or more specificity subunits, characteristic of this type of R/M system  [65].
In addition, a type III R/M system was predicted to be encoded by this genome (corresponding to locus tags CNCMI4319_0898-0891), although apparent frameshift mutations in both the methyltransferase and the restriction endonuclease-encoding genes likely render this system non-functional. Furthermore, three separate type I methyltransferases at locus tags CNCMI4319_0284, CNCMI4319_0408 and CNCMI4319_0825 were identified using REBASE. These genes share high sequence similarity with other methyltransferases in the REBASE databases. However, their accompanying restriction endonucleases could not be identified. Notably, the methyltransferases encoded by the genes at locus tags CNCMI4319_0408 and CNCMI4319_0825 are likely to be pseudogenes because of their small size, thus representing non-functional orphan methyltransferases.
Funding: This work was sponsored by  Danone Nutricia Research, Palaiseau, France. In addition, the authors are supported by  Science Foundation Ireland (SFI)  (Grant No. SFI/12/RC/2273 ) to D. v. S. F. B. is a recipient of a  FEMS Research Grant  ( FEMS-RG-2016-0103 ) and  FEMS/ESCMID  Award.
Acknowledgements The authors are grateful to regional councils of Brittany (France, grant  n°13008651 ) and  Pays de la Loire (France , grant  n°2014-07081 ) for the financial support, and  INRAE for scientific coordination  ( J. Leonil ) through the interregional project  PROFIL , supported by  Bba  industrial association and carried out by the association ' Pôle Agronomique Ouest ".
Experimental Setup and Database The experimental protocol was approved by Directive 2010/63/EU of the European Parliament on the protection of animals used for scientific purposes and the local ethical committee. Hearts were excised from pigs (N = 7, 30-40 kg) and perfused in Langendorff setup as previously reported  (Bear et al. , 2019a,c). The left anterior descending (LAD) artery was cannulated on a separate perfusion. A 108-electrode sock was attached to the free wall epicardial surfaces of the ventricles. After instrumentation, the heart was suspended in a human-shaped 256-electrode torso tank filled with a Tyrode's solution. In 3 hearts, pinacidil (Pin) was injected in increasing concentrations (full dose: 30 µM) into the LAD to locally shorten APD and induce gradients in repolarization with other myocardial regions (Pin Group).
In the other 4 hearts, Pin administration with comparable doses was preceded by progressive perfusion of non-LAD coronaries with dofetilide (Dof, full dose: 250 nM) to further enhance regional repolarization heterogeneities (early repolarization in the Pin-area, late in the Dof-area). This second set was referred to as Dof & Pin Group. Only experiments presenting all mentioned phases were assigned to one of these categories, therefore other phases which were not common to all experiments (e. g. , drug washout) were not included into our analysis. When more recordings were available at baseline, the first recording was included into our analysis. During drug perfusion, the last recording was generally preferred, in order to have enough time for the drug to make effect. R-wave peak time occurrences were identified from tank potentials as signal local maxima above a preset threshold equal to the half of the signal maximum amplitude value, and at a minimum time distance of 330 ms, using the MATLAB function findpeaks.
T-Wave Morphology and Dispersion of Repolarization Overall, abnormal dispersion of electrical recovery strongly affected the morphology of T-wave. In our dataset, a decline in T-wave symmetry was found to be associated with higher dispersion of repolarization. This is in contrast to results from simulations presented by Di  Bernardo and Murray (2000) , who found that T-wave became more symmetrical with increased apico-basal and transmural dispersion. However, other studies presented opposite findings  (Van Huysduynen et al. , 2005; Vicente et al. , 2015) , and this may be due to the use of a non-realistic torso-heart model, with too simple geometries, and the lack of granularity in the modulation of action potential initiation at different sites (Di  Bernardo and Murray, 2000). In contrast, electrocardiographic manifestations reported by our investigation are closer to those presented by  Vicente et al.
Limitations and Perspectives The study was performed on a limited number of hearts, thus the proposed BSPM markers should be tested on a larger dataset to corroborate their descriptive accuracy. However, evolution of BSPM indices was overall consistent across experiments, and deviations from expected trends were linked to experimental conditions (e. g. , delayed drug effect, tissue block etc. ). Paucity of data may also have affected the outcome of the BA analysis of signal features, and in particular with respect to the width of confidence intervals and the impossibility to perform a statistical comparison over such a low number of samples. Nevertheless, most of BSPM indices demonstrated good agreement with all indices of epicardial dispersion of repolarization, thus proving that physiologically relevant information about repolarization alterations can be inferred by body surface T-wave analysis at multiple observation scales.
As a consequence, future works may rather envisage the inclusion of simultaneous endocardial mapping (e. g. , with a basket catheter) to explore additional mechanisms beyond epicardial repolarization heterogeneity more systematically. Future research may include the comparison with other invasive features (e. g. , from intracardiac or optical mapping), to better elucidate the mechanisms underlying body surface manifestations of repolarization dispersion, as well as their direction. For the same purpose, the use of in silico models may help validating BSPM features and possibly link them to specific mechanisms at lower scale. In both datasets, drug injection provoked marked repolarization gradients, both globally at the level of the whole organ and locally between neighboring, smaller sites, and all examined BSPM parameters exhibited a consistent relation with regional and global invasive RT dispersion gradients.
g. , the relative T-wave spatial residuum, T-wave planarity, total cosine R-to-T;  Merri et al. , 1989; Malik et al. , 2000; Korhonen et al. , 2009; Porthan et al. , 2013) , and evaluated their ability to measure repolarization heterogeneity in our database when using between one and three principal components. In line with the findings presented in section "2. 3. 4, " all indices were characterized by an unexpected inverse correlation between T-wave complexity and ventricular recovery dispersion, therefore we considered it appropriate to include a few of them in this report to avoid redundancy. Moreover, as stated above, to clarify whether and how changes in AP downslope and cell-to-cell coupling affect PCA eigenvalues' extraction during drug injection, meaningful insights could be provided by computational models of cardiac repolarization at the single myocyte level, which may help exploring mechanisms at a lower scale than our epicardial sock  (Laguna et al.
, 2016). In this work propensity to ventricular arrhythmias was not systematically explored, as we mainly investigated how substrate-dependent repolarization abnormalities reflected on T-wave properties rather than those trigger-related. Preliminary research from our group on a similar dataset has shown that arrhythmia susceptibility is strongly influenced both by the trigger location and timing, but also by the properties of the underlying substrate  (Bear et al. , 2019b) , and that in vulnerable hearts T-waves are longer, flatter and more asymmetric  (Meo et al. , 2020). However, the potential of electrocardiographic features as a tool for arrhythmogenesis assessment in this model deserves further investigation. Finally, a systematic comparison with T-wave features from an equivalent 12-lead ECG could not be performed, as in most of the experiments electrodes with noisy/low voltage signals were located close to lead III and precordial leads (especially V5-V6) and removed.
Moreover, the human clinical studies available so far have shown controversial results concerning the protective effects of resveratrol against cardiovascular diseases and are extensively detailed in  [69, 88]. Briefly, resveratrol could decrease inflammation  [89] [90] [91]  and endothelial dysfunction  [92, 93]  in several studies, whereas some others have shown no effect  [94] [95] [96] , probably due to the fact that many of these trials use highly variable protocols and doses of resveratrol and suffer from small sample sizes. Finally, numerous randomized studies are currently in progress to evaluate the effects of dietary supplementation with mitoquinone in several conditions, including diastolic dysfunction (NCT03586414), peripheral arterial disease (NCT03506633), or chronic kidney disease (NCT02364648)  [46] , but the impact of mitoquinone supplementation in patients remains to be determined.
These data highlight the ability of the two pentapeptides to inhibit the redox activity of Fe(III), even if less efficient than the positive control DFO (6. 6 mM AscH À consumed, 79% reduction relative to EDTA). To evaluate the impact of this limited Fe(III) redox activity on the production of ROS, two different assays were considered for two different ROS species (i. e. , H 2 O 2 and HO , Fig. 1b ). Firstly, the production of H 2 O 2 was monitored by UV-vis spectroscopy due to its ability to oxidize Amplex Red to the coloured Resorufin (l abs = 570 nm) in the presence of horseradish peroxidase (HRP). 65, 66 As depicted in Fig. 5b , the presence of FD 3 K and FE 3 K induces a strong decrease of H 2 O 2 formation by 88% and 89%, corresponding to 2. 0 mM and 1. 8 mM H 2 O 2 , respectively, compared to the negative control EDTA (16.