dataesr/scientific-paragraphs-categorization huggingface dataset:
Data analysis was carried out using the equatorial and meridional profi les obtained by integration of the intensity along rectangular thin strips as a function of q. Micro-beam experiments were performed on a total of 9 SC samples from at least 6 different batches/donors of SC (abdominal skin of Caucasian and dark-skinned female donors aged between 30 and 40 years). For clarity, the X-ray data presented in the paper correspond to a single representative batch of SC isolated from a Caucasian female donor between 30 and 40 years old. The main spectral features and the conclusions made here are common to all samples studied. The X-ray data from different measurement campaigns and different donors revealed only small variations in relative intensity of some scattering peaks; for example, the shoulders at q ‫ف‬ 0.
The SAXS and WAXS profi les from all ex vivo sources tested were very similar to those obtained earlier on isolated SC that was used in the present study (with temperature and trypsin treatment). In particular, the SAXS profi les displayed the usual 4. 5, 6. 0, and 11. 5 nm bands, and the WAXS profi les displayed 0. 95 nm and 0. 46 nm bands as well as the sharp 0. 41 nm and 0. 37 nm peaks. The anisotropy and depth-dependent variations were also very similar to isolated SC samples. Therefore, our sample preparation method did not cause any artifacts in the X-ray data and these samples are representative of the real skin surface. Delipidized SC was obtained by immersion in a 1:1 chloroform-methanol mixture for 2 h at ambient temperature. This procedure ensures only partial extraction of SC lipids (see Results); however, using more drastic extraction conditions may further alter other components of the SC and its overall structure.
SAXS patterns The SAXS features are well oriented in the meridional plane ( Fig. 2A  ), which is consistent with periodic lamellar structures predominantly oriented parallel to the SC surface. The intensity profi le I(q) of the untreated SC sample along the meridional plane ( Fig. 2B  , black curve) contains several broad peaks attributed to intercellular lipid lamellae ( 4 ). The major peak contains two components, a main The profi les considered so far represented the bulk scattering of the whole SC sample. We then analyzed the micro-diffraction data obtained at different depths in the SC on a micrometer scale. The series of SAXS meridional profi les collected every 2 µm along a line perpendicular to the SC surface of the control sample did not show any signifi cant differences ( Fig. 3A  , only every other profi le is shown for clarity).
the usefulness of maintenance therapy. ACKNOWLEDGMENTS Editorial assistance in the preparation of this manuscript was provided by Drs. Francoise Nourrit-Poirette and Marielle Romet, from SanteActive Edition (Bois-Colombes, France) Support for this assistance was funded by Pierre Fabre Dermo-Cosmetique (Boulogne Billancourt, France). This study was supported by Pierre Fabre Dermo-Cosmetique. The sponsor provided funding for technical (including products and data analysis), editorial assistance and article processing charges but had no role in the design and conduct of the study, in the collection, analysis, and interpretation of data, or in the preparation of the manuscript, review, or approval of the manuscript. All named authors meet the ICMJE criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.
Furthermore the usefulness of maintenance therapy. ACKNOWLEDGMENTS Editorial assistance in the preparation of this manuscript was provided by Drs. Francoise Nourrit-Poirette and Marielle Romet, from SanteActive Edition (Bois-Colombes, France) Support for this assistance was funded by Pierre Fabre Dermo-Cosmetique (Boulogne Billancourt, France). This study was supported by Pierre Fabre Dermo-Cosmetique. The sponsor provided funding for technical (including products and data analysis), editorial assistance and article processing charges but had no role in the design and conduct of the study, in the collection, analysis, and interpretation of data, or in the preparation of the manuscript, review, or approval of the manuscript. All named authors meet the ICMJE criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.
Statistical analysis Values are representative of the means ± SEM (standard error of the mean) of three independent experiments performed at least in triplicate. Statistical analyses were performed with GraphPad PRISM 5 (GraphPad Software Inc. , San Diego, CA, USA). Comparisons have used one-way or two-way analysis of variance (ANOVA) followed respectively by Dunnett's and Bonferroni multiple comparison posttests. The level of significance was set at p < 0. 05.
Pesticides concentrations ranges were chosen according to their LMR and adapted to the in vitro study as described in material and method. Our results which are summarized in Table  3  clearly showed a cytotoxic effect of DTM, FNT, LCT, and TBZ alone or in combination in human intestinal Caco-2 cells at dose ranging from 1 to 8 M (1 M being equivalent to 0. 7-1. 3 g/well according to the pesticide). These doses could be considered as relevant to human exposure. Indeed based on the LMR values of each compound, pesticides could be present in the digestive tract at dose ranging from 0. 2 to 300 g, when considering a total assimilation of the LMR amount of pesticide in vivo upon a dietary intake of 100 g of vegetables. The most cytotoxic compounds were FPN and FNT that impacted the cell layer integrity, ALP activity, oxidative status, Akt activation, and apoptosis (data summarized in Table  3 ).
In silico analysis All similarity analyses were performed using Basic Local Alignment Search Tool. Amino acid sequences of bacterial topoisomerases type IA were retrieved from UniPro-tKB Protein Knowledgebase (www. uniprot. org). Phylogenetic analysis of bacterial topoisomerases was prepared using MEGA5. 1 software and MUSCLE algorithm for multiple sequence alignment. The guide tree was calculated using the neighbour-joining Method. Secondary structures of ScTopA and EcTopA, respectively, were predicted using GOR, HNN and SOPMA algorithms (www. expasy. org/ tools).
Band intensities and relaxation profiles were analysed on Typhoon 8600 Imager using software provided by the producer. To estimate the kinetic parameters (K m and V max ), 10 ng of ScTopA (5 nM) or 150 ng of ScTopA881 mutant truncated in positively charged C-terminus (75 nM) was incubated with increasing amount of pUC19 plasmid (100-2500 ng) carrying in each DNA molecule 8-10 supercoils that are the substrate for ScTopA. The V max parameters were subsequently linearly extrapolated to the same enzyme concentration allowing their comparison. The reaction was stopped at different stages (30-120 s), plasmid was resolved and visualized as described above. To estimate the initial velocity (V 0 ), the intensity of the band corresponding to the supercoiled form was measured using ImageJ2x Software and compared with non-relaxed plasmid -R value (after time 0 s) according to the protocol described by Xu and Leng  (25).
Subsequently, labelled DNA fragments were attached first to streptavidin-coated magnetic beads (Dynal MyOne, Life Technologies), then to an antidigoxigenin-coated glass flow cell and placed on a home-built magnetic trap running the PicoTwist software suite. Preparation of flow cells for all micromanipulation experiments and measurement of stretching force were performed according to the procedure described in  (26). The flow cell was placed on a magnetic trap instrument based on an inverted microscope. Here the magnetic beads were acted upon by a magnetic field gradient generated by a pair of rare earth magnets located above the sample. The gradient generated a vertical stretching force on the bead. The stretching force could be increased by moving the magnets closer to the sample, and rotation of the magnets caused the bead to rotate in lock-step register (Figure  1A ).
ACKNOWLEDGEMENTS The authors acknowledge financial support from the  Parent Bridge Programme of Foundation for Polish Science , co-financed by  European Union, Regional Development Fund , and from  EURYI. Authors Contributions: M. J. S. contributed substantially to conception and design, acquisition of data, analysis and interpretation of data and drafting the article. T. S. contributed substantially to conception and design, acquisition of data, or analysis and interpretation of data and revising the manuscript critically for important intellectual content. A. S. contributed to acquisition of data. J. Z. C. contributed to revising the manuscript critically for important intellectual content. D. J. contributed substantially to conception and design, drafting the article and final approval of the version to be published.
The metabolites were characterized by highresolution liquid chromatography/tandem mass spectrometry (LC/MS-MS) and by comparison of their retention times on high-performance liquid chromatography (HPLC) and MS spectra with those of reference standards. In addition, by incubation with human liver microsomes, cDNA-expressed CYPs, UGTs, FMOs, and MAOs or human hepatocytes, the products of dronedarone metabolism and the relative contributions of the enzymes involved were determined in the overall cascade of metabolite formation. CYP3A4 was found to be primarily responsible for the formation of N-debutyl-dronedarone, but additional minor pathways were also demonstrated. These data provide a good understanding of dronedarone metabolic pathways and more insight on consequences of DDI involving dronedarone.
Data analysis In human liver microsomes and recombinant isoforms, the percentage of metabolism was determined on the basis of unchanged drug disappearance, using the following equation Metabolismð%Þ ¼ ½1 À ðUD t¼30min =UD t¼0 Þ Â 100 where UD t = 30 min represents the unchanged drug peak area after a 30-min incubation period and UD t = 0 , the unchanged drug peak area at t = 0. In human hepatocytes, the intrinsic in vitro metabolic clearances (Cl int ) were calculated using WinNonLin PK analysis software version 5. 2. All disappearance kinetics data were fitted with a model using the following equation: Cl int ðmL=h=10 6 cellsÞ ¼ k e Á V where k e is the elimination rate constant expressed in h À1 , and V is the incubation volume expressed in mL normalized to 10 6 hepatocytes. The equation was applied to the initial (linear) part of the concentration-time curve.
Dronedarone In the absence of NADPH, dronedarone was not metabolized. In the presence of NADPH, Dronedarone was rapidly metabolized, almost 60% of parent drug being metabolized at the 30 th min of incubation. LC/MS-MS analysis showed that dronedarone was converted primarily to its N-debutyl metabolite (M21). Its chemical structure was confirmed by LC/MS-MS and its retention time matched with the reference standard. In addition to M21, several minor metabolites were also observed and identified as the hydroxyl derivatives (M4 and M7) and phenol-dronedarone (M24). When incubated in the presence of either ketoconazole or ABT, N-debutyl metabolite formation was fully suppressed, suggesting that CYP3A4/5 contributed predominantly to dronedarone oxidation (data not shown).
Data RPTECs culture conditions, CsA concentrations measurements, and TCX, PTX and MTX data collection and analysis were described in detail in Wilmes et al. [1]. Briefly, RPTECs cells were cultured in serum-free medium and matured for two weeks on microporous supports. They were then treated for fourteen days with daily doses of CsA. The assay medium was renewed prior to each dosing. Three groups of assays were performed in triplicate: control, low CsA concentration (5 μM) and high CsA concentration (15 μM). CsA concentration was measured in the medium on the first day at 0. 5h, 1h, 3h, 6h and 24h (just before changing the medium), on the third, fifth, seventh, and tenth day at 24h (before changing the medium), and on day fourteenth at the same times than on the day one. Intracellular (cell lysate) CsA concentration and quantity bound to plastic were measured on the first and last days at the same times.
Second, we performed manual searches to determine marketing status of all drugs for which a DHPC had been issued by one national regulator and not another. As none of the four national regulators maintain a database of medications that have been approved for use along with current marketing status, we may not have accurately determined marketing status of all relevant medications. Similarly, we performed manual searches of all national regulatory agency websites for DHPCs and withdrawals because no downloadable list of these safety communications was available. It is possible that some DHPCs were not identified. In fact, several adverse events communications were found through Google searches within regulatory agency websites, but were not formally issued as DHPCs. Similarly, the United-Kingdom uses a ''Black Triangle List'' to bring attention to currently marketed drugs under safety surveillance.
Similarly, Hb, mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) levels recorded a timedependent gradual decrease at all tested intervals, although this decrease was slightly pronounced after 4 h and significant after seven days for Hb concentration only. Instead, no significant differences were found in MCHC between the control and the ENP-treated groups. In contrast, the mean corpuscular volume (MCV) level showed a time-transit elevation in all groups, either orally administrated or IP injected with ENPs. This increase was markedly pronounced after one week for both treatments with ENPs. At the end of the third week, all blood values were carried up or down, more or less, towards the control values. The data of both functional (O 2 -Hb) and nonfunctional (Met-Hb, S-Hb and Co-Hb) hemoglobin derivatives of different ligands are illustrated in Table  3.
Unfortunately, the nonfunctional met-Hb derivative recorded a time/route gradual elevation, which was significant after three weeks of IP injection with ENPs. Moreover, the data illustrated in Figure  3  revealed that the activity of met-HbR was comparable to the control after four and 48 h, while a significant inhibition was pronounced after the first and third weeks in both routes of treatment, as compared to the control values. It is well documented that in most cells, mitochondria are a major source of ROS  [46]. Despite their lack of mitochondria, ROS are continuously produced in the erythrocytes, due to the high O 2 tension in arterial blood and their abundant heme iron content, inducing Fenton chemistry reactions  [52]. The source of ROS in erythrocytes is the oxygen carrier protein hemoglobin, oxyhemoglobin (Oxy-Hb), which undergoes autoxidation to produce O 2 •-, which yields hydrogen peroxide  [53].
, 1999; Slogoff et al. , 1983). From this sample two were excluded: one subject with pathological modified Allen's test; another withdrew consent for the retest scan. Hence, a total of fifteen healthy subjects (8 females; median age 32 years, range 25 to 65 years), without history of either systemic medical or psychiatric conditions or substance abuse were scanned twice. Demographic data are detailed in Table  1. All subjects underwent a urine drug screen cassette test for 11-nor-Δ 9 -THC, morphine, amphetamine, benzoylecgonine (the main metabolite of cocaine), methamphetamine and oxazepam (Monitect © ; BMC, California, U. S. A. ) prior to PET scanning. All female patients of childbearing age underwent a urine pregnancy test.
PET data acquisition PET scans were acquired on a Siemens/CTI ECAT EXACT HR + 962 camera (Knoxville, TN, USA) in 3D mode. Ten-minute transmission scans for attenuation correction were obtained prior to dynamic emission scans using a rotating 137Cs point source. Each dynamic acquisition was 90 min long and consisted of 35 frames of increasing length (1 × 30″, 6 × 10″, 3 × 20″, 3 × 30″, 3 × 60″, 6 × 120″, 8 × 300″ and 3 × 600″). 30 s after the scan start, [ 11 C]MePPEP was injected as an intravenous bolus injection of ~370 MBq (median 364 MBq, range 316-399 MBq; Table  1 ). Subjects were scanned on two separate days with a median interval of 24 days (range 1 to 309; Table  1 ). The head position was maintained throughout and monitored with the camera's positioning laser. If movement was noticed, subjects were repositioned and underwent a second transmission scan at the end of the dynamic scan.
MRI data acquisition, analysis and generation of ROIs All subjects had 3D T1 weighted MRI scans with approximately millimetric voxel sizes on a Phillips Intera 3 Tesla (3 T) MRI scanner (Best, The Netherlands) at the Robert Steiner MRI Unit, Hammersmith Hospital, for co-registration and ROI definition. There was no visible structural abnormality on any of the T1-weighted images. T1-weighted images were segmented into tissue classes using the statistical parametrical mapping software SPM8 (Statistical Parametric Mapping, Wellcome Trust Centre for Neuroimaging, UCL,  London, www. fil. ion. ucl. ac. uk/spm) under MATLAB© 7. 4 (MathWorks). The T1-weighted images were also anatomically segmented using MAPER (multi-atlas propagation with enhanced registration;  Heckemann et al. , 2010). Using high-dimensional image registration, 30 MRI data sets, each associated with manually determined labels of 83 regions  (Gousias et al.
, 2008; Hammers et al. , 2003) , were propagated to the target brain. Label fusion was used to obtain 83 regions of interest (ROIs) in target space  (Heckemann et al. , 2006). The T1-weighted images and corresponding MAPER-derived individual segmentations as well as individual grey matter (GM) probability images were co-registered with each subject's corresponding processed PET summation image for test and retest scans separately. For the cortical ROIs, the individual atlases in PET space were then multiplied with the grey matter probability maps thresholded at 0. 5 using Analyze© 8. 1 biomedical imaging software  (Mayo Clinic 2002). These regions of interest were then used to sample the dynamic or parametric images.
Regional quantification of distribution/binding/uptake was then performed. In all following analyses, assessment was based on the same ROIs. Binding parameters were calculated directly for the ROI TAC data, except in the "classic" spectral analysis, where the additional aim was the assessment of the quality of parametric maps for use in voxel-by-voxel analyses, and the parametric map itself was sampled using the same ROIs: 1. Compartmental models, requiring arterial IFs (section "Compartmental models, requiring 1 arterial IFs"): with variable blood volume (4kbv) (section "Reversible threecompartment (two tissue compartment) model with four rate constants and a variable blood volume (4kbv)") 2. Model-free analyses, requiring arterial IFs (section "Model-free analyses, requiring arterial IFs"): • "Classic" (non-regularised) spectral analysis (SA), applied to ROI time-activity data (section '"Classic" (non-regularised) SA').
, 2007a) , we changed this to 0. 00063 s -1 (log 10 = -3. 20) in order to reduce noise. Sampling parametric V T images obtained voxel-by-voxel using spectral analysis ("Classic" SA). Parametric images of [ 11 C]MePPEP V T were obtained from the dynamic images and the metabolite-corrected IFs using spectral analysis (SA;  Cunningham and Jones, 1993; Cunningham et al. , 1993)  and receptor parametric mapping software (RPM6;  Aston et al. , 2001; Gunn et al. , 1997)  with the same fast and slow frequency boundaries as above. The resulting parametric maps of V T values were then sampled in the eight selected ROIs. Directly obtaining V T values from ROI data with SA and rank shaping regularisation. V T values were generated directly from dynamic data sampled using ROIs with rank shaping (RS; orthogonalized-functionalbase) regularisation of SA  (Turkheimer et al.
, 2011) : activity Â weight kg ð Þþ70 kg ½ =2 ð Þ =injected dose: ð4Þ Global intensities (GI) Global intensities (GI) were calculated with an in-house script derived from SPM  (Hammers et al. , 2007b) , where the GI is defined as the mean voxel value within a mask defined as all voxels exceeding 1/8 of the mean value of all voxels in the image matrix.
Statistical analyses For statistical testing we used SPSS© for Windows version 16 software (IBM 2008, New York, U. S. A. ). Injectate data were compared between test and retest sessions using the non-parametric Wilcoxon signed-rank test. The percentage test-retest difference of parameters obtained with the various methods was calculated for all subjects in ROIs according to: 2 Á retest value-test value ð Þ test value þ retest value Á 100: ð5Þ Reliability was calculated using intraclass correlation coefficients  (Maclennan, 1993) : ICC ¼ MSBS-MSWS MSBS þ df WS Â MSWS ð Þ ð6Þ where MS = mean sum of squares, BS = between-subjects, WS = within-subjects, and df = degrees of freedom as computed in SPSS, using the "one-way random" model and reporting the "single  measures" ICC. ICC values ≥ 0. 75 were considered indicators of good reliability  (Portney and Watkins, 2009).
Acknowledgments We thank the staff of Hammersmith Imanet Limited and the  Hammersmith Hospital MRI Unit  for their assistance with data acquisition and preparation. This study was supported by the  MRC Clinical Sciences Centre. Authors affiliated with a are grateful for support from the  Department of Health NIHR Biomedical Research Centre 's funding scheme. CJM was supported by an  MRC Doctoral Training Account  (3 + 1) studentship that was awarded by  Imperial College London. JSD and MJK were supported by the  Epilepsy Society ,  UCL ,  UCL Hospitals  and  UCLH/UCL Biomedical Research Centre. AH was supported by an  MRC   Clinician Scientist Fellowship  ( G108/585 ) and the  Neurodis Foundation.
Structural data Crystal structure analyses revealed two structure types for the monocationic, pentacoordinate coordination entities: first, a vacant octahedron (vOC-5) with linear/bent Ru-N-O couples, and, second, a trigonal bipyramid (TBPY-5) with equilibrated Ru-N-O angles. An overview of the compounds, their numbering and the adopted structure type is given in Fig. 4. To illustrate the structural principles, the cations in crystals of 1, 3, 8a/b, 9, 10, and 12a/b are depicted in Fig. 5 -12. Significant bond distances and angles are collected in Table  1. Crystallographic data for all compounds as well as drawings and metrical parameters for 2, 4, 5-7 and 11 are collected in the ESI. † The members of the first group resemble Pierpont and Eisenberg's prototypic dinitrosyl A (Fig. 2 ). They share the structural property of well separated bent/linear 1 NO -/NO + nitrosyl bonding.
Computational details All calculations were performed with the ORCA 3. 0 program package. Structures were optimised with the Becke-Perdew density (BP) method and the Ahlrichs-type basis set tzvp for all atoms except ruthenium and iodine. Found stationary points were confirmed with subsequent frequency analyses on the corresponding level of theory, except that no ECPs were used. Instead, scalar relativistic all-electron calculations were performed for ruthenium and iodine. 31 Continuous shape measures were calculated with the programme SHAPE. 23, 32  spectroscopy at low temperature Measurements of IR spectra at low temperatures were performed using a Nicolet 5700 FTIR spectrometer. The powdered samples were mixed with KBr and pressed into pellets. The KBr pellets were mounted on a copper cold finger using silver paste for good thermal contact.