dataesr/scientific-paragraphs-categorization huggingface dataset:
Ethics Approval All the animal welfare and experimental procedures were approved by the "Welfare and ethics of laboratory animals" committee of the Guangdong University of Technology (GDUT) (approval no. GDUTXS2022083), and were performed by Guangzhou Huateng Bioscience Co. , Ltd, Guangzhou, China (accreditation no. SYXK-2020-0237), in accordance with relevant guidelines and regulations for the care and use of laboratory animals, including ARRIVE and BJP guidelines. Sprague-Dawley rats are outbred multipurpose laboratory animals, bred especially for physiology and CNS studies, and preclinical assays. In addition, they are docile and easy to handle, a feature that minimizes unsuccessful tests. So, all animals used and all samples collected were included in data analyses. The   a With spiked amounts of TDMQ20 (controls).
Ethics Approval All the animal welfare and experimental procedures were approved by the "Welfare and ethics of laboratory animals" committee of the Guangdong University of Technology (GDUT) (approval no. GDUTXS2022083), and were performed by Guangzhou Huateng Bioscience Co. , Ltd, Guangzhou, China (accreditation no. SYXK-2020-0237), in accordance with relevant guidelines and regulations for the care and use of laboratory animals, including ARRIVE and BJP guidelines. Sprague-Dawley rats are outbred multipurpose laboratory animals, bred especially for physiology and CNS studies, and preclinical assays. In addition, they are docile and easy to handle, a feature that minimizes unsuccessful tests. So, all animals used and all samples collected were included in data analyses. a With spiked amounts of TDMQ20 (controls).
The drug was dosed in blood samples collected from the retro-orbital venous plexus between 2 min and 300 min after treatment, as with groups 3-6. The size of each group (6 animals) was fixed at the minimum necessary to obtain statistically significant data. Each rat was labelled using an ear tag. A single analysis was performed for each sample (blood or brain) collection. Excel software was used to calculate the mean values and SEM (standard error of the mean) of the concentration of TDMQ20 in plasma and in the brain, and to plot this concentration with respect to time after treatment. DAS 2. 0 software (BioGuider Co. , Shanghai, China) was used to calculate pharmacokinetic data (Table  2 ). ± 0. 1 c C max µg/g 1. 1 ± 0. 7 c a n = 6 except otherwise stated, b F (%) = [dose iv × oral AUC((0-∞)]/[dose oral × iv AUC(0-∞)] × 100, c n = 12, male/female ratio = 1/1.
Ethics Approval All the animal welfare and experimental procedures were approved by the "Welfare and ethics of laboratory animals" committee of the Guangdong University of Technology (GDUT) (approval no. GDUTXS2022083), and were performed by Guangzhou Huateng Bioscience Co. , Ltd, Guangzhou, China (accreditation no. SYXK-2020-0237), in accordance with relevant guidelines and regulations for the care and use of laboratory animals, including ARRIVE and BJP guidelines. Sprague-Dawley rats are outbred multipurpose laboratory animals, bred especially for physiology and CNS studies, and preclinical assays. In addition, they are docile and easy to handle, a feature that minimizes unsuccessful tests. So, all animals used and all samples collected were included in data analyses. The staff in charge of the animal experiments received appropriate training, and all efforts were made to minimize animal pain and discomfort.
Concentration of TDMQ20 in brain extracts. Six groups of 6 male rats each were used (groups 4M, 5M, 6M, 7-9). Animals were treated by oral administration of TDMQ20 at a single dose of 25 mg/kg. At 3 h, 5 h, 7 h, 12 h, 24 h and 48 h after administration for groups 4M, 5M, and 6M, 7, 8 and 9, respectively, the brains were collected after cardiac perfusion with 0. 9 wt% aqueous NaCl. Then, the tissues were washed with 0. 9% NaCl, blotted with filter paper, weighed and stored at -20 • C until use. Groups 4F, 5F and 6F, consisting of 6 female rats each, were treated in the same fashion as groups 4M, 5M and 6M, respectively. Data treatment. The plots of the concentrations of TDMQ20 in plasma and brain samples with respect to time after treatment were obtained using Excel software. The standard error of the mean (SEM), which measures how much discrepancy is likely in a sample's mean compared with the population mean, was also calculated using Excel software.
The pharmacokinetics parameters of TDMQ20 were calculated using non-compartmental methods by DAS 2. 0 Software (Drug and Statistics, Shanghai University of Traditional Chinese Medicine, Shanghai, China). Statistical significance (unpaired t-test, Mann-Witney) was determined using GraphPad Prism 7 software (GraphPad Software, San Diego, CA, USA; ** stands for p-value < 0. 01, * stands for 0. 01 < p-value < 0. 05).
Thereafter, the decrease in TDMQ20 concentration was much slower, its concentration being -82-88% at 5 h, compared to the concentration measured at 2 min after administration (divided by 1. 3-1. 9 between 2 h and 5 h) (Table  S7 ). So, the blood collection was stopped at 5 h after collecting eight blood samples per animal. On the basis of these experimental data (0-5 h), pharmacokinetic parameters were extracted using the Drug and Statistics (DAS) version 2. 0 software; the results are summarized in Table  2. samples were 91% and 95%, respectively (Table  S5 ), indicating that the endogenous substances of the plasma and brain tissue do not affect the recovery and quantification of TDMQ20. Stability of TDMQ20 in spiked samples. Quantification of TDMQ20 in plasma and brain homogenate took place at D0 and after storage or treatment in four different conditions: room temperature for 4 h, HPLC auto-sampler for 12 h, -20 °C for 14 d, and three freeze-thaw cycles.
Thereafter, the decrease in TDMQ20 concentration was much slower, its concentration being -82-88% at 5 h, compared to the concentration measured at 2 min after administration (divided by 1. 3-1. 9 between 2 h and 5 h) (Table  S7 ). So, the blood collection was stopped at 5 h after collecting eight blood samples per animal. On the basis of these experimental data (0-5 h), pharmacokinetic parameters were extracted using the Drug and Statistics (DAS) version 2. 0 software; the results are summarized in Table  2.
Quantification of TDMQ20 in Rat Plasma after Oral Administration Twelve healthy adult Sprague-Dawley rats (male/female ratio = 1/1, groups 3M and 3F, respectively) were treated by the oral route with a single dose of TDMQ20 (25 mg/kg, about 5 mg per animal). After treatment, blood was collected from the retro-orbital venous plexus over a 12 h period, and quantification of TDMQ20 in plasma was then carried out from 10 min to 12 h. The plot of the concentration of TDMQ20 detected in rat plasma with respect to time after oral administration of the drug is depicted in Figure  3  (individual rat data are provided Pharmaceutics 2022, 14, 2691 9 of 13 in Table  S8 ). It is noteworthy that the detected concentration of TDMQ20 in plasma after oral administration was significantly higher in female than in male rats, between 1 h and 3 h (p-values 0.
015, 0. 0022 and 0. 0087, respectively). The concentrations before 1 h and after 4-5 h were not statistically different in males and females (p = 0. 24 or 0. 94 at 30 min and 5 h, respectively). Twelve healthy adult Sprague-Dawley rats (male/female ratio = 1/1, groups 3M and 3F, respectively) were treated by the oral route with a single dose of TDMQ20 (25 mg/kg, about 5 mg per animal). After treatment, blood was collected from the retro-orbital venous plexus over a 12 h period, and quantification of TDMQ20 in plasma was then carried out from 10 min to 12 h. The plot of the concentration of TDMQ20 detected in rat plasma with respect to time after oral administration of the drug is depicted in Figure  3  (individual rat data are provided in Table  S8 ). It is noteworthy that the detected concentration of TDMQ20 in plasma after oral administration was significantly higher in female than in male rats, between 1 h and 3 h (p-values 0.
3. 4. Quantification of TDMQ20 in Rat Brain after Oral Administration TDMQ20 was also quantified in brain homogenates between 3 h and 48 h after a single oral treatment at 25 mg/kg. The mean concentration of TDMQ20 detected in the brains of males and females in the range 3-7 h after oral administration of the drug (groups 4-6), is plotted in Figure  4  (individual rat data are reported in Table  S9 ). The differences between males (blue marks) and females (red marks) were not statistically significant (p-values = 0. 093, 0. 937 and 0. 132 at 3 h, 5 h and 7 h, respectively), in contrast to the concentration measured in plasma (Figure  3 ). More importantly, considering the mean value of TDMQ20 concentration for all 12 of the treated animals (male/female ratio = 1/1, black dots), TDMQ20 progressively accumulates in the brain over at least 5-7 h, long after it decreased from plasma (ca.
In addition, this kinetic of brain elimination is consistent with the administration frequency (3 times per week) we have used to evaluate its ability to inhibit AD brain impairment  [20, 21]. The brain-plasma concentration ratio (also referred to as brain-blood ratio) is an important tool to evaluate the brain-targeting efficiency of potential neurotherapeutics, and drugs having a brain-plasma ratio value close to 1 are considered to freely cross the blood-brain barrier (BBB)  [29, 30]. The brain-plasma ratio of TDMQ20 concentration was evaluated to be ca. 2. 6-2. 8 at 3 h after drug administration (see footnote of Table  S9 ). These data confirm the ability of TDMQ20 to cross the BBB and its efficient penetration within brain. This is consistent with its physicochemical properties that meet the criteria for a CNS-pharmaceutical drug  [29, 30]  (MW = 326 g/mol (<450), clogP = 2.
Supplementary Materials: The following supporting information can be downloaded at: https://www. mdpi. com/article/10. 3390/pharmaceutics14122691/s1, Figure  S1  The brain-plasma concentration ratio (also referred to as brain-blood ratio) is an important tool to evaluate the brain-targeting efficiency of potential neurotherapeutics, and drugs having a brain-plasma ratio value close to 1 are considered to freely cross the blood-brain barrier (BBB)  [29, 30]. The brain-plasma ratio of TDMQ20 concentration was evaluated to be ca. 2. 6-2. 8 at 3 h after drug administration (see footnote of Table  S9 ). These data confirm the ability of TDMQ20 to cross the BBB and its efficient penetration within brain. This is consistent with its physicochemical properties that meet the criteria for a CNS-pharmaceutical drug  [29, 30]  (MW = 326 g/mol (<450), clogP = 2.
Collected data 2. 3. 1. Face-to-face questionnaire The data were collected as part of the ARS screening campaign. Ethical approval was given by CNIL n • 341194V42. Written informed consent was obtained from all participants for statistical analysis by Santé publique France. A face-to-face questionnaire was administered by trained social workers and collected information on the socio-demographic characteristics and living conditions of the families. It also included questions to identify potential lead exposure among the occupational activities of families. These activities are listed in France's High Council for Public Health (HCSP) screening guide  [1]  as follows: dismantling cars, recovering batteries, recovering car radiators, storing metals, cutting and handling scrap metal, burning materials to separate metals, stripping ironwork, scraping or sanding old paint, thermal stripping of old paint, and installing or removing lead structures in buildings.
Statistics Santé publique France statistical analyses were performed on anonymous data transmitted to the agency by the ARS. The distribution of blood lead levels was described in terms of percentiles and a geometric mean. The geometric means and their 95% confidence intervals were estimated according to the socio-demographic characteristics of the children and their proximity to at-risk activities. A generalised linear model was used to determine the risk factors associated with higher geometric mean blood lead levels. Variables were selected from bivariate analyses and adjusted for child age and gender. Statistical analyses were performed using R software (R Core Team, 2019).
Acknowledgements Eleonore Clarysse ,  Camille Roingeard ,  Sandrine Brisard ,  Stéphanie Raynaud ,  Stéphanie Balloux ,  Alexandra Bouchard ,  Séverine Chabeauti ,  Amélie Gonthier ,  Damien Pageaud ,  Frédérique Quirino Chaves ,  Gérard Houot ,  Laurent El Ghozi ,  Stéphane Lévêque ,  Erwan Autes ,  Alain Fontaine ,  Jean Claude Desenclos ,  Geneviève Chêne ,  Anne Laporte  and  Jude Sweeney.
The dimer showed no difference in migration in the presence or absence of glycan. In contrast, monomer migration was slightly delayed by 27, 28, and 31% in the gels containing beechwood, birchwood, and oat spelt xylans, respectively. No migration delay was observed with wheat arabinoxylan. The observed smears suggest that the binding of the monomer to xylans could be unstable due to a weak affinity. F5_SusD-like is retained in the gel containing xylans to a much smaller degree than what was observed for all other characterized SusD-like proteins that efficiently bind polysaccharides  (9, 10). These results indicate a weak affinity of F5_SusD-like for xylan, impaired by the presence of side chains on the xylan backbone. Isothermal titration calorimetry (ITC) was attempted using XOS as a ligand, but no binding could be detected (data not shown).
Finally, differential scanning fluorimetry (DSF) was performed, but no significant change in the intrinsic fluorescence of F5_SusD-like was observed in the presence of birchwood, beechwood, or oat spelt xylans or barley b-glucan, carboxymethylcellulose, laminarin, wheat arabinoxylan, or xyloglucan (data not shown). These results indicate that the thermal stability of F5_SusD- like was not affected by significant ligand binding, contrary to what could be observed using DSF for genuine polysaccharide-binding proteins  (33). (ii) Determination of the binding ability by NMR spectroscopy. The value of saturation transfer difference nuclear magnetic resonance (STD-NMR) spectroscopy for the direct analysis of protein-ligand interactions with even weak affinities has been shown previously  (34). However, to our knowledge, this approach has been used only rarely to analyze the binding ability of carbohydrate-binding proteins associated with CAZymes or with carbohydrate transporters  (35, 36).
The most similar sequence listed in the Protein Data Bank (PDB) (https://www. rcsb. org/) (37)  is that of a SusD-like protein from Parabacteroides distasonis ATCC 8503 (PDB accession number 3OTN). The identity is limited, however, with only 34% identity on a short stretch of the sequence (128 amino acids), which made the structure solution by MR (molecular replacement) a challenging task. We therefore solved it using the MR-SAD (single-wavelength anomalous diffraction) technique  (38)  and obtained a refined structure at a 2. 6-Å resolution. Data collection and refinement statistics are shown in Table  1. Despite the very low sequence similarity with structurally characterized SusD-like proteins, the F5_SusD-like protein displays a canonical "RagB/SusD" fold, which includes the conserved tetratricopeptide repeat (TPR) units.
Overall, the structure of F5_SusD-like is similar to those of the 24 other SusD-like proteins that have been listed in the PDB since 2008, when the crystallographic structure of SusD was solved by Koropatkin et al. (7). F5_SusD-like presents a convex surface created by the a-helical bundle and a flat surface on the other side, where the putative sugar binding platform should be located. According to the PDB, no xylan-binding SusD-like protein has been structurally characterized so far. The closest structural homolog identified using the Dali server (http://ekhidna2. biocenter. helsinki. fi/dali/) (39)  is the laminarin-binding protein GM_SusD from Gramella sp. strain MAR_2010_102 (PDB accession number 6GCZ)  (40) , with a root mean square deviation (RMSD) of about 2. 9 Å. The superimposition of both structures highlights the presence of a large region (A328 to I340 and G382 to G444) specific for F5_SusD-like, which is composed of random coils and some b-sheets (Fig.
Nevertheless, a glycerol molecule under crystallization conditions is found on the flat surface where the canonical binding site is located. The glycerol molecule is coordinated by two arginine residues (R339 and R347), and W349 makes a hydrophobic stacking platform (Fig. 3 ). Comparison with GM_SusD shows that two of the three tryptophan residues (W287 and W290) involved in substrate binding are missing in F5_SusD-like (Fig. 3C  and Fig. S7A ). Comparison to the Bacova_02651 SusD-like protein from Bacteroides ovatus (PDB accession number 5E76)  (10) , which displays a high glycan-binding ability toward xyloglucan (Fig. S7B ), shows that an essential aromatic residue involved in substrate binding (W283) is missing in F5_SusD-like. Moreover, W75, which corresponds to W82 in Bacova_02651, displays a radically different side chain orientation.
Attempting to identify the molecular determinants that make F5_SusD-like a nonglycan-binding protein is particularly difficult, especially since no xylan-binding SusDlike protein is available in the PDB. Nevertheless, a striking feature of F5_SusD-like is the long partially disordered loop (D292 to N315) located close to the canonical binding site. It is noteworthy that some of the tryptophan residues involved in substrate binding in the laminarin-binding SusD-like protein GM_SusD from Gramella sp. MAR_2010_102 (PDB accession number 6GCZ) (substrate-binding residues W287 and W290)  (40)  and in the xyloglucan-binding SGBP-A protein from Bacteroides ovatus (PDB accession number 5E76) (substrate-binding residue W283)  (10) , which are missing in F5_SusD-like, are carried by a folded loop located precisely in the area from D292 to N315.
The presence of a disordered loop close to the binding site is reminiscent of the structure of the SGBP-A protein from Bacteroides uniformis (BuSGBP-A) (PDB accession number 7KV1) (RMSD, 3 Å) (41) (Fig. 3D ). This SusD-like protein does not bind to b(1,3)-glucan, while it displays the key binding residues present in the SGBP-A protein from Bacteroides thetaiotaomicron (BtSGBP-A) (PDB accession number 7KV3)  (41) , which were shown to be involved in substrate binding (Fig. 3E ). Finally, the four residues N249, D444, A446, and A516 of F5_SusD-like, corresponding to D, G, P, and V residues in the nearly identical SusD-like protein BVU_0037 from Bacteroides vulgatus ATCC 8482, respectively, are not located in the binding-site area. The oligosaccharide-binding regions of canonical SusD-like proteins are thus strictly identical in F5_SusD-like and BVU_0037, indicating that BVU_0037, like F5_SusD-like, probably does not bind XOSs.
MATERIALS AND METHODS Heterologous protein expression and purification. The gene fragment encoding the F5_SusD-like protein was PCR amplified from the metagenomic DNA of clone F5 (GenBank accession number HE717017), previously isolated from a metagenomic library derived from a human fecal sample  (31). The PCR forward primer F5_SusD_Cloning_F (see Table  S2  in the supplemental material) includes the NdeI restriction site, and the reverse primer F5_SusD_Cloning_R includes the XhoI site. The first 30 amino acids of F5_SusD-like corresponding to the lipoprotein signal peptide predicted by the SignalP 4. 1 and LipoP 1. 0 servers were not included in the PCR amplicon  (51, 52). The gene product was cloned into the NdeI and XhoI restriction sites of the pET-28a(1) vector (Novagen, Darmstadt, Germany) preceding an N-terminal 6ÂHis tag for affinity purification and transformed into E.
26 M sodium citrate, 0. 09 M HEPES-HCl, 10% glycerol [pH 7. 5]). After manual condition optimization, F5_SusD-like crystals were grown using the hanging-drop method by mixing 1 mL of the protein solution with 1 mL of the precipitant solution (1. 7 M Na 3 -citrate, 10% glycerol, 0. 1 M HEPES [pH 7. 5]) and incubating the solution on a 24-well crystallization plate at 12°C. After harvesting, the crystals were soaked in cryoprotectant buffer (1. 7 M Na 3 -citrate, 15% glycerol, 0. 1 M HEPES [pH 7. 5]), with or without the presence of 100 mM xylotriose, and flash-frozen in liquid N 2. Data were collected at the XALOC beamline of the ALBA Synchrotron Light Source (Barcelona, Spain). A long-wavelength data set was also collected at a wavelength of 2. 0 Å, using a special XALOC setup with continuous helium flow around the crystal to reduce absorption from the air (helium cone).
Structure resolution and refinement. Using the native data set only, the structure was solved using the Morda Web server  (55) , which identified a low-homology molecular replacement solution. This starting model was combined with the long-wavelength data set as implemented in the Phaser program  (56)  and used to calculate improved phases. This also enabled the correct positioning of all of the sulfur atoms in the sequence. The structure was determined via several rounds of modeling using the Arp/ Warp Web server (57), alternated with manual rebuilding using Coot  (58) , and passed to Refmac for restrained refinement  (59). The final model was validated with MolProbity (60) and WhatIF  (61).
ACKNOWLEDGMENTS This work was carried out using the equipment at the  PICT-ICEO  facility and at  MetaToul (Metabolomics and Fluxomics Facilities, Toulouse, France  [www. metatoul. fr]). PICT-ICEO is supported by grants from the  Région Midi-Pyrénées , the  European Regional Development Fund , and the  Institut National de la Recherche Agronomique et de l'Environnement (INRAE). MetaToul is part of the  MetaboHUB-ANR-11-INBS-0010 national infrastructure  (www. metabohub. fr). This research was funded by the  European Union 's  Horizon 2020 Framework Programme  ( MSCA-IF-2015_707457  [CaTSYS] and  LEIT-BIO-2015-685474  [Metafluidics]). Z. W. and X. L. are supported by  INSA Toulouse  and the  China Scholarship Council  under the  CSC-UT/INSA Program. We acknowledge  PICT-IPBS (Toulouse, France)  and the  ALBA Synchrotron Light Source (Barcelona, Spain)  for access to crystallization and data collection facilities, respectively.
GOLFIG 3 6 36 FIG 3 F5_SusD-like crystal structure. (A) Overall structure of F5_SusD-like. (B) Secondary-structure-matching (SSM) superimposition of F5_SusD-like (blue) with GM_SusD (PDB accession number 6GCZ) (the closest structural homolog) (yellow) shown to bind to branched laminarin and linear pustulan. The loops specific for F5_SusD-like are shown in red. (C) Zoomed-in view of the superimposition of F5_SusD-like with GM_SusD. (D) Superimposition of F5_SusD-like with the nonbinding SusD-like protein BuSGBP-A (PDB accession number 7KV1) (green) present in a PUL-degrading b(1,3)-glucan and a mixed-linkage b-glucan. (E) Superimposition of F5_SusD-like with BtSGBP-A (PDB accession number 7KV3) (pink) in complex with laminarihexaose. The glycerol (GOL) present in panels C to E belongs to the F5_SusD-like structure.
12 × 10 -8 ). Fourteen MTAs were common to both the TASSEL and FarmCPU models at P � 0. 003. The most significant yield-related MTAs involved seed number and seed length on chromosome 7 (P � 1. 15 × 10-14 and P � 6. 75 × 10-05 , respectively) and seed number on chromosome 1 (P � 2. 38 × 10 -05 ), based on the TASSEL MLM. It was noteworthy that seed length, seed length to width ratio and seed number were associated with markers at different loci, indicating their polygenic nature. Approximately 40 candidate genes that encode embryo and seed development, protein synthesis, carbohydrate transport and lipid biosynthesis and transport were identified in the flanking regions of the significantly associated SNPs and in linkage disequilibrium with them. A significant association of fruit surface anthocyanin intensity co-localised with MYB-related protein 308 on.