dataesr/scientific-paragraphs-categorization huggingface dataset:
Data collection Data were prospectively collected daily by senior physicians in the participating ICUs. For each patient, the data were entered into electronic case report forms using VIGIREA ® and RHEA ® data capture software, and all case report forms were then entered into the OutcomeRea ® data warehouse. All codes and definitions were established prior to study initiation. For each patient, age, sex, and McCabe score were recorded. Severity of illness was evaluated on the first ICU day using the Simplified Acute Physiology Score (SAPS II), Sequential Organ Failure Assessment (SOFA) score, and Glasgow Coma Scale (GCS) score, and Knaus' scale definitions were used to record preexisting chronic organ failures including respiratory, cardiac, hepatic, renal, and immune system failures. Admission category (medical, scheduled surgery, or unscheduled surgery), admission diagnosis (cardiac, respiratory, or neurological failure, infection, and other), invasive procedures (arterial or venous central catheter, Swan-Ganz catheter, or endotracheal intubation), and treatment of organ failures (inotropic support, hemodialysis, and mechanical ventilation) and the use of corticosteroids, gastro-protective drugs, and antibiotics were also recorded.
Daily lymphocyte counts were retrospectively collected from four ICUs participating to OUTCOMEREA database between July 2006 and May 2012. All patients with a lymphocyte count in the first day of admission were included in the study. In order to avoid confusion bias, we excluded patients with chronic lymphocytic leukemia (CLL), infection with the human immunodeficiency virus (HIV) or aplasia at admission. We also excluded patients with limitation of life-sustaining therapy in the four first days after admission. Patients with shock or persistent low blood pressure below 90 mmHg of systolic blood pressure in the first day of admission were included. Study variables were the first lymphocyte count on the first day of admission and its evolution at day 3 after admission. The lymphocyte count at admission was categorized in four predefined classes: normal (>1.
Sources of data All HIV-infected individuals receiving care at LH and MPC were registered in the EMR systems, as described previously (  [23] , https://github. com/openmrs), where detailed patients' records collected were accessible through printed reports or directly via the touchscreen terminals in the reception and clinical consultation rooms. These systems also guided the healthcare workers according to Malawi's clinical HIV guidelines and facilitated medication prescribing and dispensing while performing clinical calculations (e. g. , drug adherences). For this study, socio-demographic, clinical and laboratory data, body weight, ART treatment history and previous trends in antiretroviral drug adherence (through pill counts) for individuals on second line ART were obtained from the EMR systems and patients' medical charts.
Acknowledgements The authors would like to thank the  University of North Carolina Project laboratory staff and Lighthouse Trust clinics  staff for assisting with the data collection for the study. Similarly, we would like to thank  Lighthouse Trust Monitoring  and Evaluation department for their diligence in data extraction from the EMR systems. We would also like to thank all the study participants who were on second line ART at LH and MPC during the study period for their willingness to participate in the study.
No cure is currently available to arrest the disease. Surgical cricopharyngeal myotomy is the only treatment available to improve swallowing in these patients, but the pharyngeal musculature still undergoes progressive degradation leading to severe swallowing impairment, pulmonary infections and choking  2, 22. Molecules potentially ameliorating the OPMD phenotype (for example, trehalose and doxycycline) have been tested in a mouse model of OPMD, where reduction in muscle weakness was observed  23, 24. The use of trehalose is currently in phase II clinical trial (NCT02015481 on clinicaltrials. gov). Other pharmacological strategies currently under pre-clinical investigation include antiprion drugs like 6-aminophenanthridine and guanabenz, and targeting the expPABPN1 with intracellular antibodies  [25] [26] [27].
1c ). The effects of PABPN1 knockdown were also assessed by analysing the amount of insoluble aggregates in the myonuclei, the main pathological hallmark of the disease, which are formed due to expPABPN1 expression. Insoluble nuclear aggregates were readily detected in about 35% of myonuclei in A17 mice, while FvB myonuclei contained virtually no aggregates. While the expression of optPABPN1 did not modify the amount of insoluble aggregates in A17 muscles, the treatment with either shRNA3X alone or the combination of shRNA3X and optPABPN1 greatly decreased the amount of myonuclei containing aggregates to 10 and 5% of myonuclei, respectively (Fig. 2g, h ). These data show that shRNA3X delivered by AAV efficiently downregulates PABPN1 in vivo and significantly decreases the amount of insoluble PABPN1 aggregates.
OPMD is particularly suitable for such a gene therapy approach, as a very restricted number of muscles are clinically affected at the onset of the disease, making local intramuscular injections the most realistic approach in clinical settings. The doses and volume of viral vectors we used in this study are in a standard range for intramuscular purpose in murine models, where a single injection is performed to transduce the whole TA muscle. In the context of potential human OPMD treatment, we envisage that AAV vectors for knockdown and replacement would be distributed in several points of the affected muscles by local intramuscular injection as recently performed for autologous myoblasts (ClinicalTrials. gov NCT00773227). It has previously been demonstrated in cultures of myoblasts that PABPN1 plays an essential role in their proliferation and differentiation  5.
Cell therapy is another appealing strategy to counteract OPMD, as the treatment could be performed locally, thus bypassing the issue of a systemic cell delivery. The local administration of autologous myoblasts in the cricopharyngeal muscle has been shown to improve swallowing function (ref. 28  and NCT00773227). While safe and associated to beneficial effects on a short term, autologous cells still harbour the mutation. An ex vivo gene therapy approach aiming to correct the genetic defect of myoblasts before the injection would be required to guarantee a long-lasting effect. We transduced cells derived from patient's biopsies using a lentiviral vector carrying both the shRNA3X and the optPABPN1 cassettes on the same backbone, and we showed that the combined strategy was replicating at cellular levels the findings observed in vivo by AAV vectors.
A blind analysis was performed by the investigator. The knee and foot were fixed with clamps and the distal tendons of the muscles were attached to an isometric transducer (Harvard Bioscience) using a silk ligature. The sciatic nerves were proximally crushed and distally stimulated by a bipolar silver electrode using supramaximal square wave pulses of 0. 1 ms duration. All data provided by the isometric transducer were recorded and analysed using the PowerLab system (4SP, AD Instruments). All isometric measurements were made at an initial length L0 (length at which maximal tension was obtained during the tetanus). Response to tetanic stimulation (pulse frequency: 75-150 Hz) was recorded and the maximal force was determined. For the measurement of muscle susceptibility to contraction-induced injury, muscles were stimulated at 150 Hz nine times.
Acknowledgements We thank the iVector  ICM Vectorology Core facility  for lentiviral productions ( ICM, Brain and Spine Institute, F-75013, Paris, France ) and MYOBANK-AFM from the  Institute of Myology  (Eurobiobank, code  BB-0033-00012 ) for providing the human OPMD myoblasts. We thank  Karuna Panchapakesan  and  Susan Knoblach  from the  Children's National Medical Center (Washington, USA)  for the array expression profiling. We thank  Ludovic Arandel ,  Fanny Roth  and  Naira Naouar  for technical support. The authors acknowledge the OPMD patients for their collaboration. This work was supported by  Benitec Biopharma LTD , the  Centre National pour la Recherche Scientifique , the  Association Franc¸aise contre les Myopathies  (Research Programs  15123  and  17110 ), the  University Paris VI Pierre et Marie Curie , the  Institut National de la Santeet de la Recherche Medicale , the  Fondation de l'Avenir  (project  ET1-622 ).
Purification and Characterization of the Bioactive Compounds Produced by Oidiodendron griseum UBOCC-A-114129 Antimicrobial activities were only recovered in the F10-90 extract supporting previous data  [9]. The F10-90 extract was afterwards analyzed by Reversed Phase-High-Performance Liquid Chromatography (RP-HPLC) (Figure  1 ). Fractions were collected along the elution, freeze-dried, resolubilized in 20% Acetonitrile (ACN), and assayed for antimicrobial activity. Only, three fractions eluted from 24 to 32 min exhibited antimicrobial activity against Enterococcus faecalis (Figure  1 ). the assayed strains had antimicrobial properties  [9]. Among those 110 fungal isolates, 14 were considered as promising based on their antimicrobial activities, and finally the strain Oidiodendron griseum CB_36 UBOCC-A-114129 (isolated at 765 m below the sea floor) was selected for further investigation since it seemed to be the bioactive strain with the deepest origin known to date.
Purification and Characterization of the Bioactive Compounds Produced by Oidiodendron griseum UBOCC-A-114129 Antimicrobial activities were only recovered in the F10-90 extract supporting previous data  [9]. The F10-90 extract was afterwards analyzed by Reversed Phase-High-Performance Liquid Chromatography (RP-HPLC) (Figure  1 ). Fractions were collected along the elution, freeze-dried, resolubilized in 20% Acetonitrile (ACN), and assayed for antimicrobial activity. Only, three fractions eluted from 24 to 32 min exhibited antimicrobial activity against Enterococcus faecalis (Figure  1 ). Structural elucidations were conducted via NMR. The bioactive compounds isolated from O. griseum UBOCC-A-114129 were identified as fuscin (1), dihydrofuscin (2), dihydrosecofuscin (3), and secofuscin (4) (Figure  2 ).
Fungal Isolation and Identification Isolation and identification of the fungal isolate selected in this study has been described in an earlier report  [3]. Briefly, sediment samples were plated onto five low nutrient media with or without sea salts, at different temperatures and at different hydrostatic pressures. Subcultures of each colony were performed to obtain pure cultures. Purified isolates were then cryo-preserved on beads at -80 • C. The sequence analysis of 18S rDNA and internal transcribed spacer (ITS) genetic markers revealed O. griseum as the nearest relative of our strain with 99% of similarity in GenBank database. The 18S and ITS rDNA sequence were respectively deposited in Genbank under the accession number KM222226 and KM232506, respectively. The O. griseum isolate studied here has been deposited in the Université de Bretagne Occidentale Culture Collection under the UBOCC-A-114129 number (www.
Purification of Bioactive Compounds Cell-free culture supernatant resulting (25 mL) from a 14-day-long incubation culture of O. griseum UBOCC-A-114129 was used and subjected to the extraction procedure previously described (i. e. , C-18-SPE). A 10× concentrate of Fractions 10-90 was fractionated (each 2 min) on a semi-preparative column C-18-reverse-phase HPLC (Uptisphere strategy; 5 µm; 250 × 10 mm; 4 mL/min, Interchim, Montluçon, France). A gradient from 20% to 90% acetonitrile +0. 07% TFA in water +0. 1% TFA over 35 min was used and allowed the isolation of 19 fractions. Antimicrobial activity of those fractions was assessed. The antimicrobial compounds in the F10-90 were then purified using a gradient from 36% to 45% acetonitrile +0. 07% TFA in water +0. 1% TFA over 18 min (data not shown).
Characterization/Spectral Data The pure compounds were further characterized using liquid chromatography-mass spectrometer (LC-MS) and NMR. The LC-MS analyses were conducted using an ultra Performance Liquid Chromatography (UPLC) system (Acquity H Class Bio, Waters, Milford, MA, USA) coupled with detection by spectrophotometry (PDA eλ detector, Waters) and mass spectrometry (QuattroMicro). Elutions were performed on a C-18 column (BEH, 2. 1 × 50 mm, 1. 7 µm) using a linear gradient of acetonitrile (0. 1% Formic Acid). All the LC-MS instruments and column come from Waters Corporation. 1 H NMR measurements were carried out on a Bruker AVANCE 500 spectrometer (Bruker, Wissembourg, France) with a TCI cryoprobe. The spectra were recorded at 298 K. Homo-nuclear (Correlation Spectroscopy COSY), Total Correlation Spectroscopy (TOCSY), and hetero-nuclear (Heteronuclear Single Quantum Coherence (HSQC), Heteronuclear Multiple Bond Correlation (HMBC), and HSQC-TOCSY) standard pulse sequences of the Bruker database were used.
Acknowledgments: This research project is part of the European project  MaCuMBA (Marine Microorganisms: Cultivation Methods for Improving Their Biotechnological Applications ) and was founded by the  European Union 's  Seventh Framework Program  ( FP7/2007-2013)  under grant agreement No. 311975  and  Brittany region  under grant agreement  8433. The authors thank PRISM for NMR analysis. The authors also thank the  Cancéropôle Grand-Ouest  (axis: Nature sea products in cancer treatment),  GIS IBiSA  ( Infrastructures en Biologie Santé et Agronomie, France ), and  Biogenouest  ( Western France  life science and environment core facilty network) for supporting the  KISSf screening facility (Roscoff, France)  and  PRISM (Rennes, France). Thanks to  Amélie Weill  who cultivated strains after preservation, and  Denis Rousseaux  for expert technical advice.
Two-photon calcium imaging Fluorescence was imaged using a 40×water-immersion objective (Olympus) with a custom-built two-photon laserscanning microscope. Broken line scan acquisition (~100Hz, 0. 8 s, repeated 4 times with an interval 15 s) with a custommade software (LabVIEW, National Instruments) was performed every 5 mins after establishing the whole-cell configuration to measure calcium signals in the soma and the dendrites of the recorded neurons. During calcium imaging acquisition, we triggered 10 action potentials (10 pulses of 2 ms duration at 50Hz) by injecting currents of appropriate amplitude through the patch pipette to induce calcium signals in soma and dendrites. Alexa-488 and Rhod-2/Rhod-PEG fluorophores were excited at 830 nm, the two emission signals were separated by a dichroic (560 nm) and collected by two different photomultiplier tubes (PMT).
This low replication rate was confirmed by our own infection data analysis that allowed us to calculate a generation time of amastigotes in vivo of 10. 4 days. Genomic sequencing. All sequencing analysis were performed using Illumina short-read technology. The sequences for BPK282/0 promastigotes and amastigotes shown in Figure  2a  were generated using the Nextera XT library preparation kit (Illumina), the KAPA Library Quantification Kits (KAPA Biosystems), and paired-end sequencing on a HTSeq 1500 sequencer (Illumina). The sequences of LD1S liver and spleen amastigotes (Figure  5c , Supplementary Figure  8  and 9 ) were carried out as a service by the Centro Nacional de Análisis Genómico (CNAG, Barcelona) using the following protocol: 0. 3-0. 6 micrograms of sheared genomic DNA (Covaris E201) was end-repaired, adenylated and ligated to Illumina specific indexed paired-end adapters (adapter:insert molar ratio 40:1).
In order to estimate chromosome polysomy level in each sample, chromosome 34 -which showed a stable disomic level across samples -was used to normalize other chromosomes read depth. This measure was calibrated to determine polysomy levels, under the assumption that the most frequent polysomy levels correspond to disomy. Intermediate polysomy levels were classified as trisomic or tetrasomic events by using cutoffs on the normalized chromosome read depth values. Chromosomes with values ranging between 2. 6 and 3. 4 were classified as trisomic, and values between 3. 6 and 4. 4 as tetrasomic. These calibrated values were used to select subsets of chromosomes having comparable aneuploidy levels. (Accession number: PRJEA61817) Aneuploidy co-occurrence. Aneuploidy co-occurrence analysis was carried out by measuring the Pearson correlations between pairs of chromosomes, with each chromosome being represented as vector of normalized depth values, each value being drawn from an isolate.
Plasma half-lives of these compounds are in the range of minutes to a few hours, and the poor solubility in aqueous solutions precludes the continuous dosing using pumps; hence, we rely on once-daily oral dosing in rats. In contrast, for malaria patients, a typical treatment cycle with artemisinins lasts only 4 days, but dosing occurs at relatively high concentrations every 8 hr. Currently, clinical studies are ongoing for the long-term effects of artemisinins in cancer patients  (Ericsson et al. , 2014 ) (NCT02263950). Therefore, investigation of the effects of longterm artemether treatment for the induction of endogenous insulin expression in C-peptide-negative type 1 diabetes patients appears clinically feasible. Regardless of the direct clinical use of artemether in diabetes, our findings open up completely new avenues for transdifferentiating a cells by structurally different gephyrin stabilizers, GABAreceptor transcriptional activators, and additional targets in the GABA-receptor signaling pathway, toward a treatment for type 1 diabetes.
Images were exposed for 10 ms in the Hoechst channel and for 500 ms in the Alexa Fluor 546 channel. Images were analyzed using the Harmony software (Perkin Elmer). Nuclei were identified (Harmony Method C) and cytoplasm was defined based on the nuclei (Harmony Method C). In total 1152 wells were screened containing 280 compounds from the CeMM Library of Unique Drugs (CLOUD) (M. Licciardello, P. Markt, F. Klepsch, and S. K. , unpublished data) in triplicates with control wells. Hits were selected based on the intensity of insulin in the Alexa Fluor 546 channel and cell numbers in the Hoechst channel. Immunofluorescence staining for all other antibodies was performed as described above, images were acquired on an automated microscope (Perkin Elmer Operetta) or a Leica DMI6000 B inverted confocal system with a 63x 1.
Libraries were pooled and sequenced on the Illumina HiSeq platform using the 50 bp single-read configuration. Reads were aligned with tophat (v2. 0. 4) with the-no-noveljuncs-no-novel-indels options  (Kim et al. , 2013). Gene expression was calculated as Reads Per Kb per Millions of reads (RPKMs) using RPKM_count. py from the RSeQC package  (Wang et al. , 2012)  and the NCBI RNA reference sequences collection (RefSeq) downloaded from UCSC. Sample preparation and data analysis for single cell RNA-seq was conducted as previously described  (Li et al. , 2016).
RT-qPCR After the RNA was isolated with the RNeasy Mini Kit (QIAGEN), it was reverse transcribed with random primers using the High Capacity cDNA Reverse Transcription Kit (Applied Biosystems). Quantitative PCR was performed with Power SYBR Green PCR Master Mix (Applied Biosystems) on a Lightcycler 480 (Roche). Primer sequences used were published previously  (Fomina-Yadlin et al. , 2010) , novel sequences are indicated in Table  S2. Ca 2+ imaging Ca 2+ responses were measured using Fura-2AM (Invitrogen). Ratiometric imaging was performed using a VisiChrome monochromator (Visitron Systems) on a CoolSnap HQ2 camera (Photometrics) and recorded in VisiView software (Visitron Systems). Data were statistically analyzed and plotted using SigmaPlot 13. 0 (Systat Software). Krebs-Ringer solution was used as basic external solution and contained: 119 mM NaCl, 2.
Chloride imaging To assess muscimol induced Cl À changes, aTC1 cells were preincubated with MQAE for 0. 5 hr (Thermo Fisher Scientific). The fluorescence was recorded with CoolSnap HQ2 camera (Photometrics) and VisiView software (Visitron Systems) using 350 nm excitation with VisiChrome monochromator (Visitron Systems) and the emission filter (445 ± 50 nm). Experiments were done at 25 C in Krebs-Ringer solution. Basal levels were measured after 1 hr incubation with MQAE and washing with PBS by live cell imaging on an automated microscope (Perkin Elmer Operetta) using a 20x objective and analyzed using the Harmony software (Perkin Elmer). Moco synthase assay aTC1 cells were pretreated with artemether for three days and lysed with NP-40 buffer. The measurement of Moco synthase was performed with Xanthine Oxidase Assay Kit (Abcam ab102522).
After elution, enriched proteins were reduced with dithiothreitol, cysteine residues alkylated by incubation with iodoacetamide and the samples digested with modified porcine trypsin (Promega, Madison, WI). Three percent (and multiples thereof) of the digested eluates were purified and concentrated by C18 reversed-phase material. Samples were analyzed at pH 2. 4 on an Agilent 1200 nano-HPLC system (Agilent Biotechnologies, Palo Alto, CA) coupled to a hybrid linear trap quadrupole (LTQ) Orbitrap Velos mass spectrometer (ThermoFisher Scientific, Waltham, MA) utilizing the Xcalibur software version 2. 1. The analysis was performed in a data-dependent acquisition mode. The 15 most intense ions were isolated and fragmented by collision-induced dissociation (CID). Dynamic exclusion for selected ions was 60 s and a single lock mass at m/z 445.
120024 (Si(CH 3 ) 2 O) 6 ) was used for internal mass calibration  (Olsen et al. , 2005)  with the target loss mass abundance of 0%. Maximal ion accumulation time allowed was 500 ms and overfilling of the C-trap was prevented by automatic gain control set to 10 6 ions for a full FTMS scan and 5 3 10 3 ions for MSn. Intact peptides were detected in the Orbitrap mass analyzer at a resolution of 60,000 with a signal threshold of 2,000 counts for triggering an MS event. Further details of the LCMS methodology are as previously described  (Maurer et al. , 2013). Peak extraction and conversion of raw MS files into the mgf format was performed with msconvert (ProteoWizard Library v2. 1. 2708) and the peak lists searched against the mouse SwissProt database v2013. 01_20130110 (24,615 sequences including isoforms obtained from varsplic.
pl (Kersey et al. , 2000)  and appended known contaminants) with the search engines Mascot (v2. 2. 03, MatrixScience, London, UK) and Phenyx (v2. 5. 14, GeneBio, Geneva, Switzerland)  (Colinge et al. , 2003). Submission to the search engines was via a Perl script that performs an initial search with relatively broad mass tolerances (Mascot only) on both the precursor and fragment ions (±10 ppm and ± 0. 6 Da, respectively). High-confidence peptide identifications are used to recalibrate all precursors and fragment ion masses prior to a second search with narrower mass tolerances (±4 ppm and ± 0. 3 Da for CID). One missed tryptic cleavage site was allowed. Carbamidomethyl cysteine and oxidised methionine were set as fixed and variable modifications, respectively. To validate the proteins, Mascot and Phenyx output files were processed by internally developed parsers.