dataesr/scientific-paragraphs-categorization huggingface dataset:
Statistical analysis. Statistical analysis was performed with SPSS-17. 0 (SPSS Inc. , Chicago, IL, USA). Descriptive statistics by site was applied for demographic information, summarized by skin site for skin conditions, skin tolerance and aesthetics scores. Selected skin sites were differentiated as normal, dry, and oily by two-step clustering (SPSS 17. 0) based on the best subsets of three skin physiology parameters [moisture, sebum, and trans-epidermal water loss (TEWL), which are considered the most representative parameters of skin micro-environment] 15,25 as described in Fig. 1. In two-step clustering, the pre-clusters were calculated using the hierarchical clustering algorithm. Microbial diversity at different sites was calculated using alpha diversity index (Shannon and Simpson index).
Acknowledgements The authors are indebted to the late  Prof. Xueming Wang  for his valuable contributions during the entire study. The authors express their gratitude to  Yanyan Song  for statistical advice,  Weiming Gu  for supporting with the invitro testing, and  Carlos Galzote  for his involvement in the study design and significant discussions. The authors also thank  Nishi Gupta  and  Dr. Rohit Bhandari  ( SIRO Clinpharm Pvt. Ltd. ) for writing assistance,  Dr. Ellen Baum  ( Janssen Research & Development, LLC ) for additional editorial support and  Kimberly Capone  for helpful discussion in this manuscript. The authors thank the study participants, without whom this study would not have been accomplished.
It would have been important to provide the evolution of this parameter over time rather than providing only the baseline and the maximum value. Also, other parameters such as creatine kinase values and urinary myoglobin, if available, would have been helpful to allow for additional assessment of the potential contribution to rosuvastatin-induced rhabdomyolysis and therefore kidney damage. In addition to rhabdomyolysis-induced acute kidney injury, rosuvastatin has been associated nonrhabdomyolysis causes of acute kidney injury. These nonrhabdomyolysis causes of acute kidney injury with rosuvastatin include renal tubular toxicity and interstitial nephritis. 3, 4, 5 he frequency of acute kidney injury with statin therapy was reported in a large retrospective observational analysis of 7 administrative databases from Canada and 2 databases from the United Kingdom and United States which evaluated the risk of acute kidney injury in patients newly treated with highpotency statins that included rosuvastatin dosages 10 mg.
tHe β-arrestinoMe In order to retrieve β-arrestin protein partners and reconstruct a comprehensive β-arrestin interaction map, we searched for β-arrestin-binding partners in the literature and in publicly available protein interaction databases. First, most of the interactions were extracted from a previously published proteomics analysis of the β-arrestin interactome, following coimmunoprecipitation of FLAG-tagged β-arrestins 1 and 2 in HEK293 cells stimulated by angiotensin II, and peptide identification by mass spectrometry (MS) (MudPIT and LC-MS/MS)  (13). Then, some more β-arrestin partners were sequentially retrieved from queries in NetPath (release 9) (18), BioGRID (3. 4 version)  (19) , Mentha (25-09-2016 release)  (20) , and HIPPIE (v2. 0 24-06-2016) (21) databases. All the relevant experiments were verified in the original publications.
Finally, the analysis was completed by manual curation of the literature. All this information was used to build the β-arrestin interactome. To get all interactions between β-arrestin partners, the interaction networks were inferred in HIPPIE  (21)  that automatically converts protein-protein interactions into a connected network. Upon public database queries and manual curation of the literature, 282 experimentally validated interactions were recovered for β-arrestin 1 and 374 for β-arrestin 2 (Table  1 ). The whole β-arrestinome and interactions among partners, visualized using Cytoscape  (22) , comprises 429 unique nodes and 1,599 unique edges (Figure  1A ). We discriminated direct (yellow diamonds) and indirect interactions. Direct interactions have been revealed by yeast two-hybrid or by in vitro-reconstituted complex of purified recombinant proteins (called "direct" in Table  S1  in Supplementary Material).
strUCtUraL MappinG oF β-arrestin direCt interaCtors It was proposed earlier that extensive conformational flexibility of β-arrestins allows them to adopt many different interfaces, which may provide an explanation for why their relatively small surface can accommodate so many different binding partners. In an attempt to support this view, we used PepX, an algorithm that has been demonstrated earlier to predict docking sites with high precision based on a library of peptide-peptide interactions  (25). Using different β-arrestin protein structures as the input (PDB entries 2WTR, 4JQI, and 3P2D), PepX was used to determine the accessible conformational space for possible bound peptide backbone fragments through interaction constraints using them as anchors. The algorithm is based on the finding that protein-peptide binding occurs for a certain limited number of conformations.
Thus, a heuristic algorithm (CSP) is applied in order to reduce the conformational search space of all overlapping fragments of the PepX database (containing more than 7 × 10 6 interactions from 1,431 PDB structures representing the structural coverage of protein-peptide interactions). This is followed by an unsupervised clustering method to predict possible binding sites and peptide conformations. In the first step, this algorithm predicts all compatible backbone conformations ("fitting"). In the second and more time-consuming step, the interface can be refined by taking side chain modeling into account ("binding"). Using three template structures, namely, dimeric bovine β-arrestin 1 (unpublished), active rat β-arrestin 1 bound to a V2 receptor phosphopeptide (1), and bovine β-arrestin 2 (26), we independently predicted the compatible backbone conformations using different peptide lengths (lengths 5, 6, 7, 8, and 9).
Xor/and interaCtions in tHe β-arrestinoMe in LiGHt oF eXpression LeVeLs and aFFinities Common XOR docking sites on β-arrestins do not necessarily lead to competition for binding among interaction partners. Clearly, the relative abundance of the common hub (here β-arrestin) and the partners are important to consider, because they govern the equilibrium of complex formation within the cell. To analyze how protein expression levels relate between β-arrestin partners, quantitative information for β-arrestins 1 and 2 and 82 direct interactors including receptors was retrieved from RNAseq datasets of gene expression levels in 11 human normal tissues (http://www. medicalgenomics. org/) (Table  S3  in Supplementary Material). The relative expression levels of direct β-arrestin partners were represented with the continuous mapping representation of Cytoscape.
β-arrestin 1 mRNA appeared less abundant than β-arrestin 2 mRNA, although analysis of the respective protein levels shows the opposite  (14, 27) , suggesting posttranscriptional mechanisms to enhance β-arrestin 1 intracellular protein level. Importantly, the cumulated amount of all 80 direct interaction partners greatly over-exceeds the abundance of the two β-arrestins. This suggests that in those cases where interaction partners bind to a common docking site, competition between partners will exist. In this case, the relative abundance of each partner may be decisive (Figure  3 ; Table  S3  in Supplementary Material). As represented with the Cytoscape software  (22) , both NFKBIA and MDM2 interact with the N terminus of β-arrestins (1-60), and their relative expression level in human tissues suggests that the binding equilibrium might be displaced in favor of MDM2 in kidney and testes, whereas NFKBIA is much more abundant in other tissues, except in adipose tissue and heart where both genes are equally expressed.
The volume of a mammalian cell was assumed to be 2. 34 × 10 -15 L (source: HeLa cells in Bionumbers). Endogenous tubulin concentration was estimated as 4 × 10 -4 M (30), and endogenous calmodulin concentration as 8 × 10 -9 M (27). Concentrations of β-arrestin and GPCR were estimated as 8 × 10 -8 M (  27 ). The equilibrium binding model was generated using the Intrinsic Noise Analyzer simulation software     (31) , followed by a time-course analysis until equilibrium. With this model, we found that approximately half of the available β-arrestins was bound to tubulin (Figure  4 ). As tubulin is so highly expressed in cells, an interesting consideration is whether binding of tubulin is specific or just results from the fact that it has a poly-Glu C-terminal tail, which may mimic the phosphorylated GPCR.
FUndinG This work was funded by the Agence Nationale de la Recherche GPCRnet project, by the Centre National de la Recherche Scientifique, by the Institut de la Recherche Agronomique PHASE Department, by the Région Centre, and by the European Commission (EC) Framework programme (FP) 7 project SynSignal (contract nr. 613879). LS is supported by the Spanish Ministerio de Economía y Competitividad, Plan Nacional BIO2012-39754, and the European Fund for Economic and Regional Development. LS and CK are particularly grateful for the support of the Spanish Ministry of Economy and Competitiveness, "Centro de Excelencia Severo Ochoa 2013-2017" (SEV-2012-0208).
Plant material The fruits of Canthium subcordatum DC (syn. Psydrax subcordata DC Bridson) were collected in Foto village (Menoua Division, Western region of Cameroon), in April 2012. Authentication was performed by Victor Nana, a Botanist of the Cameroon National Herbarium, Yaoundé, where a voucher specimen (N°19579/SRF/CAM) has been deposited.
1% Triton X-100 for 2 min (4˚C). They were labeled 1 hour in PBS 1% BSA with a rabbit anti-β-III tubulin antibody (ThermoFisher Scientific, MA1-118) then 45 min with anti-rabbit Cy3 (Jackson ImmunoResearch, 111-165-144) before being submitted to TUNEL labeling following the manufacturer's indications and mounted in Prolong Gold antifade reagent with Dapi (Molecular Probes, P36931). Nuclei, β-III tubulin and TUNEL positive cells were counted manually on images acquired on Olympus microscope (BX53, Olympus) using FiJI and Icy softwares  [26, 27]. TUNEL labeling on fixed rat spinal cord slices was performed following the manufacturer's indications and mounted in Prolong Gold antifade reagent with Dapi. Positives controls were spinal cord slices incubated 10 min with 3000 U/ml DNase I (Sigma) in 50 mM Tris-HCl pH 7.
Acknowledgments We are grateful to  Giuseppina Chece ,  Clotilde Lauro ,  Irene Onorato  and  Myriam Catalano  from the  Department of Physiology and Pharmacology at the Sapienza University of Rome  for their help in primary cells isolation and technical assistance. We also thank the  Center for Human Immunology at Institut Pasteur  for support in conducting the Luminex analysis.
Healthy volunteers For ex vivo experiments, pouches containing 450 ml of blood (for cell purification experiments requiring large numbers of iso-lated cells) or 5 ml-EDTA anticoagulated tubes (for every other experiment) collected from healthy donors were obtained from the blood bank of Lyon (EFS de Lyon). According to EFS standardized procedures for blood donation, informed consent was obtained from healthy volunteers and personal data for blood donors were anonymized at the time of blood donation and before the transfer of blood to our research lab. For transcriptomic studies, peripheral whole blood from 22 healthy volunteers was collected directly in PAXgene Blood RNA tubes (PreAnalytix, Hilden, Germany). Samples were stabilized after collection for at least 4 h at room temperature and stored at -80 °C following manufacturer's instructions.
Microarray hybridization The 73 microarray experiments (51 septic shock patients and 22 healthy donors) were performed as previously described  [12]. Gene expressions were generated using GeneChip Ò Human Genome U133 Plus 2. 0 arrays (Affymetrix, Sta. Clara, CA, USA) according to manufacturer's protocol. Affymetrix GeneChip Operating Software version 1. 4 (GCOS) was used to manage GeneChip array data and to automate the control of GeneChip fluidics stations (FS450) and scanner (GeneChip Scanner 3000). These experimental data have been deposited in the National Centre for Biotechnology Information (NCBI) and are available in the GEO DataSets site under access number GSE95233.
5 lM of primers and 0. 1 lM of probe. qPCR was performed with an initial denaturation step of 10 min at 95 °C, followed by 45 cycles of a touchdown PCR protocol (10 s at 95 °C, 29 s annealing at 68 °C, and 1 s extension at 72 °C). Sequences are for forward primer: CCAGAGCC-CACAGACAGAGG, Reverse primer: TGTCCTTCACGGCAGCATAGA and Probe: TGCAGTGGAGGTCCAGCCCAG. The Second Derivative Maximum Method was used with the LightCycler software (Release 1. 5. 0 SP4) to automatically determine the crossing point for individual samples. Standard curves were generated by using five replicates of cDNA standards and were used to perform efficiency corrected quantification. Relative standard curves describing the PCR efficiency of selected genes were created and used to perform efficiency-corrected quantification with the Light-Cycler Relative Quantification Software (Roche Molecular Biochemicals).
For this assay, AF647labeled probe mix targeting LILRB2 mRNA combined with FITClabeled anti-CD14 and PB-labeled anti-CD45 antibodies were used. As a control for monocyte activation by LPS, similar stainings were performed using AF488-labeled probe mix targeting IL1b mRNA and PB-labeled anti-CD45 antibodies. Figures. Clinical data are presented as number of cases and related percentages for categorical variables and medians, and Q1-Q3 interquartile ranges for continuous variables in the Tables. Nonparametric Mann Whitney U tests and Fisher tests were used to compare data between survivors and non-survivors or between septic shock patients and controls. Correlation between parameters was studied with the Spearman correlation test. Statistical analyses and graphics were developed with the use of R-Studio and GraphPad Prism 5 software.
Acknowledgements The authors gratefully acknowledge the  MIP-REA study group  for their participation in the MIP-REA clinical study. The authors also would like to thank  Hélène Vallin ,  Nathalie Panel , and  Marion Provent  from  Lyon Sud University Hospital , as well as  Fayrouz Mehennaoui  and  Valérie Cerro  from  E. Herriot Hospital , for their valuable help in patient inclusion process of the Immunosepsis study. The authors would also like to thank  Anne Portier  and  Elisabeth Cerrato  for their significant contribution in the flow cytometry and molecular biology experiments. Finally, the authors are grateful to  Alain Johnson  for his great help in English editing of this research paper. This work was sponsored by funds from  Hospices Civils de Lyon  ( FV, GM, AL, AF, TR ), and bioMérieux (MAC, JT).
The level of hyperpolarization induced by mycolactone is dose-dependent. No effect could be observed at submicromolar concentrations. The maximal effect was recorded at 30 min post-addition of mycolactone and remained maximal during one hour. In all subsequent experiments, the dose of mycolactone was set at 3. 5 µM, checked to be non-cytotoxic even after 24 h of exposure (Figure  4A ), with the hyperpolarization effect further validated by patch-clamp experiments (Figure  5B, C ). In addition, monitoring the neurite growth showed that exposure to mycolactone at a concentration of 3. 5 µM for 60 min did not affect neurite lengths (Figure  5D ). Furthermore, expectedly, mycolactone did not induce hyperpolarization in DRG neurons isolated from AT2R-knock-out mice (Figures  5E  and S2 ). Altogether, our data show that mycolactone induces hyperpolarization in DRG neurons targeting specifically angiotensin II type 2 (AT2) receptors.
Image Analysis and Data Management Each image was processed using image analysis software (version 2. 3. 0, Perkin Elmer, Columbus, Waltham, MA, USA). As described in previous studies  [9, 38] , two sets of images that were obtained using the same acquisition position, before and after the addition of neuroactive compounds or DMSO, were analyzed. Each pixel was assigned a threshold value according to DiSBAC 2 (3) intensities. The threshold of DiSBAC 2 (3) intensity from glial cells area was defined as a background signal. The pixels with intensities lower than the background threshold were filtered to "0". Otherwise, the pixels with intensities above the threshold were allowed to define regions of interest concerning DRG neurons. The DiSBAC 2 (3) intensities in the selected regions were measured using the analysis software (Columbus, Perkin Elmer) (Figure  S1 ).
The membrane potential changes in the cells, under the effect of tested compounds, were determined for each well as the ratio (Equation (  1  Neurites were detected on the Tuj-1 positive neuronal cell images based on higher intensity values, compared to the surroundings (Figure  S5 ). The first step of an image's analysis consisted in the segmentation of nuclei in Tuj-1 positive cell populations. Next, the neurite algorithm (CSIRO Neurite Analysis 2 method in the Columbus image analysis software) was used to detect neurites and neurite trees. For each individual cell, the Maximum Neurite Length as well as the length of the longest neurite attached to the Tuj-1 positive nucleus was recorded.
In the plate containing the labeled cells, 50 µL of the compounds to be tested were added prior to the addition of 50 µL of fluorescent angiotensin-II. The plates were incubated for 3 h in the dark at 4 • C before signal detection. HTRF signal detection was performed on a PHERAstar (BMG labtechnologies, Champigny-sur-Marne, France). The signal was collected both at 665 nm and 620 nm. The HTRF ratio was obtained by dividing the acceptor signal at 665 nm by the donor signal at 620 nm and multiplying this value by 1000. The data points were obtained in triplicates, and fitting was performed using GraphPad Prism (version 5. 03, GraphPad Software, Inc. , San Diego, CA, USA). The Kd and Ki values are represented as average values for three independent experiments.
Electrophysiology Whole-cell patch-clamp was performed using an EPC-10USB amplifier (HEKA, Lambrecht, Germany) and the PATCHMASTER software (HEKA, version 2 × 90. 1). The resistances of the patch electrodes were 2-5 MΩ. Cells harvested on a 12 mm coverslip were current-clamped close to their resting potential (-55 to -65 mV in average). The pipette solution was composed of K-gluconate 145 mM, MgCl 2 2 mM, CaCl 2 1 mM, EGTA 10 mM, HEPES 5 mM, and K 2 ATP 5 mM, adjusted to pH 7. 2-7. 3 with KOH; osmolarity was 300 mOsm. The extracellular solution for the current-clamp experiments contained NaCl 2 140 mM, KCl 5 mM, MgCl 2 1 mM, CaCl 2 2 mM, HEPES 10 mM, and glucose 10 mM, adjusted to pH 7. 4 with NaOH; osmolarity was 310 mOsm. The membrane potential was continuously monitored for 20-25 mins after Riluzole or KCl application.
Acknowledgments: Financial support for this work was provided by the  European Community  ( ERC-STG INTRACELLTB Grant  n  • 260901 ,  MM4TB  Grant n • 260872), the  Agence Nationale de Recherche  ( ANR-10-EQPX-04-01 ,  ANR-14-CE14-0024 ,  ANR-14-CE08-0017 ,  ANR-11-LABX-0015-01 ), the  Institut Pasteur of Lille , the  FEDER  ( 12001407  ( D-AL) Equipex Imaginex BioMed ), the  Region Nord-Pas-de-Calais  (convention n • 12000080) and  National Research Foundation (NRF)  grant ( 2012R1A3A2048834  and  2016M3A9B6021209 ) funded by the  Korean government (MEST) , the  Inserm Program ATIP  avenir (granted to L. M. , G. L. and G. S. ), and the  region Pays de la Loire  ( Kalmos  project). We gratefully acknowledge the technical assistance of  Frank Lafont  and  Alain Baulard.
Bodet-Milin et al. studied a new class of bispecific antibodies in a phase I radioimmunotherapy trial (http://ClinicalTrials. gov NCT01221675) to optimize pretargeting parameters. The best dosing parameters were a short pretargeting delay (24 h) and a high bispecific molar dose. A promising avenue for cancer therapy is the use of alphaparticle emitters. Alpha particles have very short tracks (usually less than 100 µm) and a very high cytotoxic potential even against radioresistant tumor cells in hypoxic area. 223 Ra, a bone targeting agent, has been recently approved for symptomatic metastatic prostate cancer therapy. Antibodies may be used to target other alpha-emitting radionuclides. Here,  213  Bi has been targeted to multiple myeloma, in a syngeneic mouse model, by means of an anti-CD138 antibody.
Acknowledgments We gratefully acknowledged the "région  Champagne-Ardenne"  for financial support,  CNRS , the  Conseil Régional de Champagne-Ardenne  and the  EU-program FEDER  for the facilities of the analytical platform (PlAneT  CPER  project). We thank  A. Martinez  (NMR analyses including nOe measurements),  S. Lanthony  (chiral HPLC analyses and HRMS),  Dr S. Chevreux  (X-ray crystallographic structure determination),  Dr D. Harakat  (HRMS),  A. Robert  (NMR analyses) as well as  A. Vallée  and  L. Lepolard  (synthesis of some of the tartrimides 1). We also thank the  French Fluorine Network (GIS CNRS ).
Experimental and Theoretical NMR Features The measurement of the NMR spectra was carried out under carefully controlled anhydrous conditions in dilute chloroform solution (solute concentration between 7-19 mM) at 25 • C. The summary of the chemical shift and coupling constant values is given in Table  1. The data were collected such that the digital resolution was 0. 05 Hz/point. Interestingly, a control experiment in which a 7. 5 mM solution of 4 was spiked with 1 equiv of H 2 O showed no change in the 3 J OH-H and h1 J OH-F values (see supporting information). The theoretical coupling constant and chemical shift values involving the levoglucosan's OH3 and OH4 hydroxyl groups have been computed at the B97-2/pcJ-2 level, on geometries optimized at the B97-D3 BJ /6-311++G(2d,p) level in chloroform at 25 • C (discussed below).
The whole dataset is reported in the Supplementary Materials, and a summary of the most important conformers involving OH4 is given in Table  2 , and of OH3 in Table  3. Figure  3  illustrates typical geometries encountered with the various conformations around the OH4 and OH3 hydroxyl groups. For all structures, the t_t forms are systematically the most stabilized conformers meaning that both hydroxyl moieties are involved in OH•••O intramolecular interactions. 1 Theoretical parameters are calculated at the IEF-PCM/B97-D3 BJ /6-311++G(2d,p) level of theory in CHCl3 at 25 °C. 2 The first descriptor refers to H-C4-O4-H, the second descriptor to H-C3-O3-H, and the last descriptor to the H-C2-O2-CH3 torsion angle. 2 The first descriptor refers to H-C4-O4-H, the second descriptor to H-C3-O3-H, and the last descriptor to H-C2-O2-CH 3 torsion angle.
NMR Data Acquisition NMR data were collected on a Bruker AVIII HD 500 MHz NMR spectrometer (Bruker UK Ltd. , Coventry, UK). Samples were shimmed until the w½ for the residual CDCl3 solvent signal was 0. 5 Hz or better through a combination of sequential iterations of "TopShim" gradient shimming with additional manual intervention, as required. 1 H spectra were collected with TD = 65,536 points and SW = 14 ppm (o1p = 5. 0 ppm); zero-filling afforded digital resolution of 0. 05 Hz/point. 19 F spectra were collected with TD = 262,144 points and SW = 50 ppm (o1p proximal to 19 F signal); zero-filling afforded digital resolution of 0. 09 Hz/point. 19 F{ 1 H} spectra were collected with TD = 262,144 points and SW = 200 ppm (o1p proximal to 19 F signal; inverse-gated decoupling with o2p = 5. 0 ppm); zero-filling afforded digital resolution of 0.