dataesr/scientific-paragraphs-categorization huggingface dataset:
The seven significant alleles were also reviewed among cases with the most significant liver injury (ALT > 5x ULN, N = 10), and all but HLAs DRB1*03:01 and B*08:01 remained significant at P < 0. 05 (see Supplementary Table  2 ). The population-level carriage frequencies of each of the top HLA alleles according to reference studies in the Allele Frequency Net Database  [22, 23]  (AFND) are reported in Table  4. Wherever possible we used the USA National Marrow Donor Program (NMDP) European Caucasian cohort as a reference population, as the sample size of 1,242,890 subjects is among the largest in AFND and we would expect the USA European Caucasian ethnic makeup to best match the population structure of our study samples. For alleles or haplotypes where the USA NMDP reference was not available, we substituted other "Caucasoid" study populations (e.
Another possible haplotype association was observed among the five HLA alleles B*08:01, C*07:01, DRB1*03:01, DQA1*05:01 and DQB1*02:01, three of which were found to be significantly enriched in infliximab DILI cases on an individual level (see Table  3 ). This 5allele haplotype was observed in 7/16 (44%) cases, but was present in only 7/60 (12%) matched controls. Although this particular haplotype is not reported explicitly in the AFND database, subsets of these alleles consistently appear at a rate of 13-16% (see Supplementary Table  3 ). There are previous reports of HLA haplotypes conferring risk for DILI  [24] [25] [26] , so the haplotypes observed in this study should continue to be considered in future work. While preliminary and limited by a small number of infliximab-induced DILI cases, there appears to be a strong association between carriers of HLA-B*39:01 and developing DILI.
The pH-STAT apparatus was interfaced to SAXS, where samples were aspirated from the digestion vessel using a peristaltic pump to a fixed quartz capillary mounted in the X-ray beam (13 keV, wavelength of 0. 954 Å) and circulated back into the vessel. 20 A sample-to-detector distance of approximately 1. 6 m (0. 01 < q < 0. 40 Å -1 ) and 0. 6 m (0. 04 < q < 2. 00 Å -1 ) was used to detect the liquid crystalline structures of the self-assembled lipids and the crystalline drug signals, respectively. q is the length of the scattering vector defined by 4π/λ sin(2θ/2), 2θ is the scattering angle, and λ is the X-ray wavelength. 2D SAXS patterns were recorded using a Pilatus 1 M detector with a 5 s acquisition time and a 15 s measurement delay. The raw data were reduced to functions of I(q) versus q by radial integration using the in-house software ScatterBrain (Version 2.
During the microscopy observations, sample temperature was kept below 100 K. Specimens were examined with reduced doses ≈1000-2000 e/nm 2 at 200 kV. Zero-loss filtered images (ΔE = 0 eV) have been recorded by a CCD digital camera (Ultrascan 1000, Gatan, Munich, Germany) and analyzed using a GMS 1. 9 software (Gatan, Munich, Germany).
Photon Correlation Spectroscopy (PCS) Vesicle size analysis of ETHO, CA-ETHO, ETHO-pol, and CA-ETHO-pol was conducted using a Zetasizer Nano-S90 (Malvern Instr. , Malvern, UK) with a 5 mW helium neon laser and a wavelength output of 633 nm. Measurements were performed at 25 °C at a 90° angle and a run time of at least 180 s. Samples have been diluted with bi-distilled water in a 1:20 v/v ratio. Data were analyzed using the "CONTIN" method  [32]. Measurements were performed thrice for three months from ETHO production.
X-ray Scattering Small-angle X-ray scattering (SAXS) experiments were performed at the bioSAXS beamline B21 of Diamond Light Source (Harwell, UK). ETHO, CA-ETHO, pol, CA-pol, and CA-ETHO-pol samples were placed into PCR tubes in an automated sample changer and then transferred to a temperaturecontrolled quartz capillary and exposed for 1 s, acquiring 30 frames at 35 °C in order to check equilibrium conditions and to eventually monitor radiation damage. Data collection was performed using a Pilatus Dectris 2 M detector. The X-ray wavelength λ was 0. 10 nm and the explored Q-range (Q is the modulus of the scattering vector, defined as 4π sin θ/λ, where 2θ is the scattering angle) was 0. 1 to 4. 4 nm -1. Two-dimensional data were corrected for background, detector efficiency and sample transmission and then radially averaged to derive I(Q) vs.
Acknowledgments: We acknowledge  Diamond Light Source  for time on Beamline B21 under Proposal  SM21035-182. Authors also acknowledge the kind support provided by  Paola Tedeschi  for antioxidant measurements and  Nikul Khunti  for the work carried out at  Diamond Light Source. Skaidre Jankovskaja  and  Maxim Morin  have prepared pig ear skin for SCOE studies.
The application of metabolomics to nutritional studies has been proposed as a valid approach to assess the high complexity of the interaction between an organism, its microbiome and the wide range of chemical compounds provided by the diet  [14]. Urine is a valuable biofluid for metabolomic analysis since it can be collected in a noninvasive way  [15, 16]  and requires minimal sample pre-treatment, which prevents changes in the metabolome  [17]. Also, urine contains a wide diversity of metabolites (including xenobiotics) that are frequently present at higher concentrations, compared to blood or plasma  [15]. Finally, as a concentrated excretion fluid, urine contains the phenotypical variations of different subjects  [17]. Nuclear Magnetic Resonance (NMR) spectroscopy is considered a very valuable tool for nutritional assessment  [18]  by providing quantitative and reproducible measurements  [19]  using minimal sample pretreatment and generating databases with long term value  [20].
Due to a problem with the water supply into the metabolic cage of one of the animals from the short-term administration experiment, its data was excluded from the analysis. Animals were monitored for symptoms of stress and/or discomfort during social and isolated allocations and their body weights were also measured during the experiments as an indicator of good health. Post-Morten general examination of the organs and tissues was performed by the main author of the study by evaluation of the macroscopic appearance. These organs included skeletal muscle tissue, stomach, intestines, esophagus, heart, liver and kidneys.
Spectral Processing NMR spectra were analyzed using MestreNova 9. 0. 1 (MestreLab Research S. L. , 2014) software. Each spectrum was manually handled using an exponential apodization of 0. 3 Hz with 0. 5 at the first point, which allowed a suitable balance of S/N ratio while retaining resolution and minimizing effects at the first point of the FID. A manual phase correction and an automatic correction of baseline (Whitaker softening) were also applied to each spectrum. After centering to TSP signal (δ = 0. 00 ppm) a local alignment model was applied to all spectra excluding regions from δ = 8. 1; to δ = 8. 3 ppm and δ = 7. 2 to δ = 7. 3 ppm (Imidazole) due to its pH-dependent variation and regions from δ = 4. 5 to δ = 6. 0 ppm (water and urea signals)  [38]. The rest of the spectrum (0. 5 to 10.
0 ppm) was divided into 0. 02 ppm distance regions (bins). A tolerance level of 5% over the baseline and a normalization of the area under the curve using creatinine signal (δ = 4. 05 ppm) as reference  [40] , was applied to the stalked spectrum. The normalization process was performed using the naturally occurring creatinine content of each sample. In situ pH was determined during NMR measurement using imidazole signals as internal standard and calibrated with Chenomx NMR Suite 8. 1 Software (Chemox Inc. Edmonton, Canada). The final pH in the NMR probe was determined by the specific chemical shift of imidazole signals (δ = 7. 2 to δ = 7. 3 ppm) for each sample. Identification of metabolites was performed by comparing suggested chemical structures from Chenomx NMR Suite 8. 1 database with data from HMDB database  [41].
Although individual manual supervision of the alignment was performed on each spectrum, the local alignment model still reflected slight variations in chemical shifts and limited multivariate analysis. However, when comparing the averages of the corresponding bins of controls and treatments, a general trend was observed and each container was associated with specific signals and compounds, which were identified using Chenomx, the Human Metabolome Database and confirmed using 2D-NMR experiments. Since an NMR signal can be distributed in one or more bins, the assessment of significant variations was evaluated by comparing the normalized area under the curve in its respective spectrum. The results of this analysis are summarized in Tables 2, 3 and 4. For acute and short-term administration, no particular conclusion can be obtained from the variation in signals between the δ = 3.
Short-term administration scheme Statistically significant variations in the urinary metabolome after short-term administration of P. friedrichsthalianum juice are shown in Table  3. P. friedrichsthalianum induced a significant reduction in 1 H NMR signals associated with Krebs cycle intermediates (citrate (p <. 001), succinate (p =. 001), and α-ketoglutarate (p =. 001)), together with lactate (p =. 035), allantoin (p =. 002), glycine (p =. 001), benzoate (p =. 004 and 0. 009), and undetermined signals in the characteristic region of carbohydrates (p =. 001). Also, a significant increase in urinary excretion of hippurate (p =. 046) was observed after this intervention. In addition, Table  4  shows the change in ratios (treatment/control) for the creatinine-normalized concentration of urine metabolites by a second targeted approach, calculated using Chenomx Software.
1 > 198. 2 (CV, 56 V; CE, 32 eV). Transition m/z 171. 9 > 136. 8 was used for quantification of gabapentin. MassLynx 4. 1 software was used for quantification. Linearity in blood was observed in blank blood spiked with gabapentin at concentrations ranging from 100 to 100000 µg/L, with a correlation coefficient of 0. 995. QC samples (100 and 10000 µg/L), analyzed in duplicate in six independent experimental assays, were used for determination of a coefficient of variation for precision and accuracy. These CVs were lower than 20 %. The limit of detection and the limit of quantification were established at 1 and 100 µg/L, respectively. Under the chromatographic conditions used, there was no interference with the analytes by chemicals or any various matrices (matrix effect < 20 %). Linearity in hair was observed for gabapentin concentrations ranging from 10 to 1000 pg/mg, with a correlation coefficient of 0.
The authors measured 421 pg/mg in a 2 cm brown hair. Based on an average growth rate at 1 cm/month, this length represents what has been incorporated during the two last months. The toxicological significance of the measured concentration was difficult to establish as limited data are available in the medical literature. Indeed, only 2 laboratories have presented data, although including several subjects. However, daily doses, frequency of consumption are missing data, as well as the minimal detectable dosage in hair. Wang et al  [23]  identified gabapentin at 10 to 56 pg/mg, in 3 subjects treated daily. Musshoff et al  [24] , in their comprehensive database identified gabapentin at 10 to 10400 pg/mg in 140 cases. However, there is no controlled study about pharmacokinetic parameters of gabapentin incorporation in hair that has been published.
Acknowledgements We thank  Veronique Collin-Faure  for her support for flow cytometry experiments and  Daphna Fenel  (ISBG,  Univ. Grenoble Alpes, France)  for the acquisition of TEM images. This work used the EM facilities at the  Grenoble Instruct-ERIC Center (ISBG ;  UMS 3518 CNRS CEA-UGA-EMBL ) with support from the  French Infrastructure for Integrated Structural Biology (FRISBI ;  ANR-10-INSB-05-02 ) and GRAL, a project of the  University Grenoble Alpes graduate school (Ecoles Universitaires de Recherche) CBH-EUR-GS  ( ANR-17-EURE-0003 ) within the  Grenoble Partnership for Structural Biology. The  IBS Electron Microscope facility  is supported by the  Auvergne Rhône-Alpes Region , the  Fonds Feder , the  Fondation pour la Recherche Médicale  and  GIS-IBiSA.
Funding This work was supported by the  Région Auvergne Rhône-Alpes  (Ph D grant for L. G. ) and the  French National Research Agency  in the framework of  LabEx Arcane  and  CBH-EUR-GS  (grant  ANR-17-EURE-0003 ), and  Glyco@Alps  " Investissement d'avenir" program  ( ANR-15-IDEX-02 ).
Western Blot Analysis Equivalent amount of proteins, namely 20 µg for each sample, have been subjected to 12% sodium dodecyl sulfate polyacrylamide electrophoresis gel (SDS-PAGE), electro-transferred onto nitrocellulose membranes, which was then blocked in PBS containing 0. 5% Tween 20 and 5% not-fat milk (BioRad). The membranes have been incubated overnight at 4 • C with the primary antibody HO-1 (Abcam, Cambridge, UK) and finally with horseradish peroxidase conjugated secondary antibody for 90 min at 25 • C. The bound antibodies have been revealed in a chemiluminescent reaction (ECL, BioRad). Chemiluminescence has been ascertained on a ChemiDoc imager (BioRad)  [32]. The blots have been reprobed with β-actin as the loading control. Images of the bands have been digitized and the densitometry of the bands have been measured using ImageJ software  [33].
25 mg of monacolin per capsule or tablet. The H5 resonance (6. 01 ppm) was not used for the quantification of monacolins as it may also contain part of the signal (ddd) of the H23 of DeMK at 5. 97 ppm and can be slightly overlapped with the H1 signal (qd) of monascin at 6. 05 ppm. The H6 (5. 84 ppm) and H4 (  5  The monacolin contents determined by 1 H-NMR are reported in Table  3. For more clarity, the coefficient of variation (CV) and the relative standard deviations (RSD) are given in Table  S2. The RSD of the 1 H-NMR assays ranged between 1. 5% and 13%. The relevance of the 1 H-NMR data will be discussed later when compared to those obtained by UHPLC. Molecules 2020, 25, x FOR PEER REVIEW 16 of 34 The H5 resonance (6. 01 ppm) was not used for the quantification of monacolins as it may also contain part of the signal (ddd) of the H23 of DeMK at 5.
Recording Conditions For the qualitative analysis, the 1D 1 H-NMR experiments were performed on a Bruker Avance 500 spectrometer (Bruker Biospin AG, Fallanden, Switzerland) equipped with a 5 mm 1 H-optimized triple resonance NMR inverse helium-cooled probe (TCI CryoProbe) at 298K (standard 1 H sensitivity for 0. 1% ethylbenzene in CDCl 3 : SNR 4200). Typical acquisition parameters were as follows: spectral width 8000 Hz, 32K data points, pulse width 10. 0 µs (flip angle 90 • ), acquisition time 2. 04 s, relaxation delay 1 s, number of scans 16, corresponding to a recording time of 0. 8 min. For the quantitative 1D 1 H-NMR experiments, analyses were acquired on a Bruker Avance 400 spectrometer equipped with a TBO (Triple resonance Broadband Observe) probe at 298K (standard 1 H sensitivity for 0.
1% ethylbenzene in CDCl 3 : SNR 266). The spectra were recorded with the following parameters: spectral width 8000 Hz, 64K data points, pulse width 3. 7 µs (flip angle ≈ 30 • ), acquisition time 5. 12 s, and relaxation delay 4. 88 s. The number of scans was 64 or 512 for recording times of ≈11 or 85 min respectively. Three different samples of the same DS were analyzed. T 1 relaxation times of the methyl protons of TSP and those of the characteristic monacolin protons used for quantification (ethylenic protons of the hexahydronaphthalene ring (H6 and H4) and of the unsaturated lactone of dehydromonacolin derivatives (H22), and CH-OH proton of the lactone ring (H22)) (see Table  2  for proton numbering) were measured in RYR DS by the inversion-recovery pulse sequence method. Twenty delays from 0.
001 to 30 s were used with an acquisition time of 2. 56 sec and a relaxation delay of 30 s. The T 1 s found were between 1. 6 and 2. 2 s for monacolin derivatives and 4. 5 s for TSP. All the 1 H resonances were thus considered as fully relaxed since more than 98% of the signal intensity of the TSP protons was recovered in the recording conditions used. The concentrations were calculated by comparing the signal areas of convenient protons of targeted compounds with those of TSP, the area of each NMR peak being directly proportional to the number of corresponding nuclei in fully relaxed recording conditions. Data were processed with the Bruker TopSpin software 2. 1 or 3. 1 with one level of zero-filling and Fourier transformation after multiplying FIDs by an exponential line-broadening function of 0.
7 µm) column. The mobile phase consisted of water with 0. 02% formic acid (solvent A) and acetonitrile with 0. 02% formic acid (solvent B) at a flow rate of 0. 6 mL min -1. The temperature of the column oven was set at 40 • C. The chromatographic analysis consisted of an isocratic elution with a 65% A/35% B mixture for 0. 5 min followed by a linear gradient program: from 65% A/35% B to 35% A/65% B between 0. 5 and 15 min and finally to 0% A/100% B over 3 min. After each run, the percentage of solvents ramped to their initial composition in 1 min and then the column was re-equilibrated for 2 min. The UV detection and quantification were performed at 238 nm and UV-Vis spectra were recorded within a range of 200-800 nm. The data acquisition and processing were done with the Empower 2 software.
Data were fitted using the nonlinear dose-response sigmoidal curve, and the IC50 values were estimated by least-square regression fitting. Similarly, therapeutic efficacy evaluations of the developed nanoformulations against L. donovani were performed on the amastigote model in a macrophage cell line, as described above. It should be noted that blank formulations were not introduced in the assay as negative controls because it was expected that PCL and other related polymer-based formulations would have no significant effects or activity when used alone. This hypothesis was also supported by the already published literature discussing PCL-based as well as other polymer-based formulations of Amp B and for other drugs where no negative control of the polymeric nanoparticles was used, as discussed elsewhere  [34] [35] [36].
The encapsulation of Amp B inside the polymer enhanced the oxidative damage activity of Amp B to destroy parasites. The maximum DMSO concentration of 0. 1% was found to have no influence on macrophage/amastigote clearance. After 72 h of incubation (5% CO 2 at 37 • C), slides were fixed with 100% methanol for 1 min and stained for 10 min with 10% Giemsa's solution. The Giemsa-stained intramacrophage amastigote slides were visualized under a light microscope (Zeiss, Pleasanton, CA, USA). The percentage inhibition from the test formulations and the Amp B emulsion were calculated as cells/100 nucleated nontreated control cells. Data were fitted using the nonlinear dose-response sigmoidal curve, and the IC 50 values were estimated by least-square regression fitting. Similarly, therapeutic efficacy evaluations of the developed nanoformulations against L.
Collected Data Preadmission data were collected as usual from the GP's letter referring the patients to the hospital, from interviews with patients, their caregivers, and GPs, as well as the digital patient records compiled during previous hospitalizations. Data for the current hospitalization were collected by the physician responsible for patient management. Six weeks after DGD, data were collected through interviews with patients, their caregivers, and GPs. A standardized questionnaire was completed at DGD then over the phone six weeks later. We analyzed all prescribed medications, including oral nutritional supplements (ONS). Drugs were classified according to the International Anatomical, Therapeutic and Chemical classification of the European Pharmaceutical Market Research Association 5  [12].
At discharge, the following data were collected for each patient: age, gender, residence before and after hospitalization, medical history, cause of hospitalization, where they were referred from (emergency department, directly referred by the GP, referred by another hospital department), stay in the geriatrics department, length of stay, number of medications per prescription at admission and discharge, initiation/discontinuation/adjustment of medication, and whether these changes appeared on the prescription. Six weeks after DGD, the following data were collected for each patient: drug changes during hospitalization notified on the hospital report (HR), number of medications per prescription, the medication that was changed, type of change (initiation/discontinuation/adjustment), and the motive behind the change.
9 Å). A new monoclinic crystal form was obtained with 2 0 -OCF 3 A2670-modied SRL RNA (relative to former SRL RNA crystal forms), containing three molecules per asymmetric unit and diffracting to 2. 4 A resolution (ESI Table 2 ‡). The 2 0 -OCF 3 modication did not affect the overall structure (r. m. s. d. $0. 4 A for 2 0 -OCF 3 -C2667 compared to the unmodied structure; PDB ID 3DVZ), including sugar puckers of modied positions (ESI Fig. 4 ‡ ). As previously observed for the 2 0 -SCF 3 -C2667 modication, 29 a uorine atom of the 2 0 -OCF 3 group closely approached the oxygen atom of its cytosine nucleobase (O2). It is tempting to assume that the short distance observed (2. 9 A) is indicative of a halogen bond, however, uorine (as opposed to chlorine, bromine, or iodine) usually retains a strongly electronegative electrostatic potential in biomolecules.
Acknowledgements We thank  Ulrike Rieder  ( Innsbruck ) for initial 19 F-NMR measurements of the Fn preQ 1 riboswitch,  Martin Tollinger  ( Innsbruck ) for advice in data tting, and  Vincent Olieric  for help during data collection at  SLS, Villigen. This work was supported by the  Austrian Science Fund FWF  ( P27947 ,  P31691 ,  F8011-B  to R. M;  P32773  to C. K. ), the  Austrian Research Promotion Agency FFG [West Austrian BioNMR 858017 ], and the  Wiener Wissenschas-, Forschungs-und Technologiefonds  ( WWTF LS17-003 ).
2. 3-Instrumentation LC-MS/MS analysis was performed with the Agilent 1260 infinity HPLC system (Agilent Technology, Santa Clara, CA, USA) consisting of quaternary pumps, an autosampler and a vacuum degasser. Chromatographic separation was carried out using a Raptor TM biphenyl core-shell column (100 mm x 3 mm, 2. 7 µm) (Restek, Bellefonte, PA, USA) with the corresponding guard column. The HPLC system was coupled to an API 3200 TM triple quadrupole mass spectrometer (Sciex, Framingham, MA, USA) equipped with a turboV TM ion source operating in positive electrospray ionization (ESI + ). Instrument control and data acquisition were performed by Sciex Analyst R 1. 6 software. For qualitative results, compound identification is typically performed by retention time (RT) matching and calculating the ratio of quantifier and qualifier MRM transition for each compound.
BUP-d4 was used as IS for BUP and BUP-GLUC quantification, NorBUP-d3 for NorBUP and NorBUP-GLUC quantification and NLX-d5 for NLX and NLX-GLUC quantification. Data were obtained using the e-noval ® software (Arlenda ® , Liege, Belgium). The acceptance limits were set at +/-40% for all the studied compounds except for NLX-GLUC (+/-50%). The β-expectation tolerance interval was set at +/-10%, selected according to the intended use of the analytical procedure.
Calibration models, LLOQs, ULOQs and LODs Calibration models, limits of detection (LODs), lower limits of quantification (LLOQs) and upper limits of quantification (ULOQs) for each compound were calculated using the e-noval software based on three validation series performed on three independent days. LODs and LLOQs were checked from the concentrations of the two transition qualifier and quantifier compounds giving rise to signal-tonoise (S/N) ratios of 3 for a validation sample near the LOD and 10 for a validation sample near the LLOQ as recommended  [39] [40] [41] 43]. MRM ratios of samples near the LOD and LLOQ were calculated as the ratio of the quantifier and qualifier transition and a 30% generic tolerance permitted according to the SANCO/12571/2013 guidelines  [41]  when compared to mean MRM ratios of the three calibration standards.