dataesr/scientific-paragraphs-categorization huggingface dataset:
Statistical analysis Data are representative of at least three independent experiments. Results are reported as both individual data points, mean ± standard deviation (SD). To determine statistical significance, the 2-tailed unpaired Student's t test was used for normally distributed data. Survival rates were compared using the log-rank (Mantel-Cox) test. GraphPad Prism 5. 0 software was used for all statistical analyses. P values <0. 05 were considered statistically significant.
Targeting NETs was effective at clearing the pulmonary NETs component, with a subsequent reduction in histopathological lung injury. Moreover, the clinical status of the mice improved, with a remarkable increase in arterial oxygen saturation and reduced mortality. Rh-DNase-1 is a well-known mucolytic therapy widely used in cystic fibrosis. Rh-DNase acts via disruption of extracellular DNA which interferes with mucociliary clearance, thereby reducing the rate of infectious respiratory exacerbations  [36]. Interestingly, as mentioned by the Food and Drug Administration, side effects are rare, moderate and transient. A recent Cochrane database review reported an increased risk of rash (RR=2. 40 [95%CI: 1. 16-4. 99]), voice alteration (RR=1. 34 [95%CI: 0. 64-2. 78) and, to a lesser extent, cough and conjunctivitis.
Experimental approach Experimental approaches are one of the commonly used methods to investigate the ballistic impact performances of different materials, and to characterize and obtain relevant data to optimise applications of the ballistic material  [103]  The experimental approach while ballistic impact test could also help to determine the energy absorbed by the target and transmitted beyond the target based on different parameters while using in body armours  [22]. The different phenomenon including backface signature (BFS), damaged targets, residual velocity and caught bullets will be thoroughly examined using various techniques and equipment including optical microscope, SEM and high speed camera etc. for further analysis and interpretations. After the test, the impacted projectile could be either perforated the material or trapped inside the target.
Besides, similar results were also recorded for the contact time between projectile and plate. Regardless of nondimensional ratio, the fibre failure, cone formation and fibre elastic deformation were the principal energy absorbing mechanisms at no plate perforation, impact velocities over the ballistic limit and impact velocities close to the ballistic limit respectively. The formulations were also verified by experimental data for plates up to 7. 5 mm in thickness  [260]. Similar to the nondimensional ratio, the areal densities were also exhibited an influence on residual velocity, the minimum energy and energy absorption and contact time between the plate and the projectile during the impact event. Study on the highvelocity impact behaviours of monolithic laminates involving various areal densities varies show that the perforation energy, perforation velocity and size of the damaged area varies based on the thickness of the composites  [262].
1 × 10 -3 ). Next, we tested if the 2 common PRKN missense variants were    S3 ). To confirm that the V380L variant contributed to the genewise association we conditioned the genewise model with all nonsynonymous variants of PRKN on the V380L mutation. We observed the same drop in the P value as in the genewise analysis with only rare variants (P SKAT-O = 7. 4 × 10 -5 to P SKAT-O = 5. 7 × 10 -3 ). This observation indicated that although the rare variants were the main driver of the PRKN association with T1R the common V380L variant also contributed to T1R risk. The PRKN rare variants were dispersed across the primary structure of Parkin, with 3 mutations in the central RING1 domain, 1 in the Ubl domain, 1 in the IBR domain, and 2 in the REP linker between the IBR and RING2 (Fig. 1B ). Alterations in 3 Parkin residues (D243N, R275Q, and R366W) were pre-dicted to be damaging in all 5 databases curated (Dataset S1).
Two other substitutions (R42C and K299R) were predicted to impair Parkin function in more than 1 database while the remaining 2 rare variants located toward the terminal end of Parkin (R396G and K408R) were predicted to be tolerable (Dataset S1). Structural analyses of the 5 amino acid changes shared by PD and T1R cases predict impairment in either phosphorylation by PINK1 (R42C), ubiquitination activity (D243N), or stability (R275Q, R366W, and R396G) (SI Appendix, Fig. S2 ). To assess the functional impact of Parkin mutations, we tested these 5 amino acid changes for protein stability, ubiquitination, phosphorylation, and mitophagy (Fig. 4  and SI Appendix, Fig. S3 ). Using a thermal shift assay, all mutations except D243N showed a significant lower protein melting point compared with wild-type Parkin (Fig.
4H ). Of note, different Parkin mutants displayed variable impact in the different assays used to probe Parkin function. Pleiotropic Effect of LRRK2 and PRKN Amino Acid Changes on T1R and PD. Since mutations in LRRK2 and PRKN are main causes of PD we assessed if the amino acid substitutions identified in our study were curated in 2 PD mutation databases  (20, 21). The main evidence for association between LRRK2 and T1R was provided by variants P755L and R1628P and, while not causally linked with PD, both variants are risk factors for PD (Table  2 ). Interestingly, antagonistic pleiotropy of the 1628P variant was also observed for PD and Alzheimer's disease  (22). For the PRKN gene, 5 of the 7 amino acid mutations identified as risk factors for T1R had previously been implicated in PD (Fig.
0 and InbreedingCoeff < -0. 8). Additional thresholds were used to ensure the quality of the variant calling by 1) setting as missing genotypes with GQ < 30 and/or with depth of coverage per individual <10× and 2) excluding variants with a population mean depth of coverage < 30× and call rates < 90%. The function of the variants that passed quality control were annotated with ANNOVAR  (46). Transcribed variants (untranslated regions, splice sites, and synonymous and nonsynonymous variants) and the subset focusing only on coding nonsynonymous variants (missense, stop gain/loss, and frameshifts) were selected for further evaluation. Statistical Analyses. The enrichment of protein altering variants per gene was evaluated using 2 different statistical tests: the variable threshold (VT)  (47)  method and the optimal unified burden and SNP-set Kernel Association Test (SKAT-O)  (48)  both implemented in the software EPACTS  (49).
As not all amino acids of a protein have the same probability of being mutated in the general population, 2 databases, dbSNP (51) and gnomAD  (52) , were accessed to catalog both LRRK2 and Parkin mutated residuals. In the enrichment analysis, only protein mutated residuals with frequency lower than 1% in the curated databases were considered as baseline since common mutations are likely to be present in both T1R and PD samples merely due to their frequency. For instance, in the curated databases Parkin presented 287 out of its 465 amino acids residuals mutated at least once in the general population. The number of Parkin residues associated with PD in the PDmutDB  (20)  and LOVD (21) databases was 72. The hypergeometric test calculated the statistical significance of randomly selecting 5 PD-associated residues in the T1R samples when 6 out of the 287 known mutated positions were observed in our population (SI Appendix, Table  S5 ).
After incubation cells were washed twice with PBS/0. 2% BSA and once with 1× binding buffer followed by incubating with Annexin V in 1× binding buffer for 15 min at room temperature in dark conditions. Finally, cells were washed once with 1× binding buffer and resuspended in 200 μL of 1× binding buffer for flow cytometry with BD FACSCanto II (BD Biosciences). The data were analyzed on FlowJo v10. 4. 2 (FlowJo, LLC) with viability and Annexin V single stains as fluorescence minus one (FMO) controls. Thermal Shift Assay. Parkin at 10 μM (0. 5 mg/mL) was mixed with 2× Sypro Orange (5,000× stock, S6650; ThermoFisher). The mix was distributed in a 96well black-coated plate and analyzed with a QuantStudio 7 Flex analyzer (Life Technologies). The temperature was ramped from 15 °C to 70 °C with continuous fluorescence readout at excitation/emission 488/570 nm.
The melting temperature was derived from the peak of the first derivative from the temperature-fluorescence profile. Measurements were performed in quadruplicates and analyzed using one-way ANOVA with the Dunnet's test to calculate significance of difference to the wild-type group. Intact Mass Spectrometry. Protein samples were diluted at 0. 5 mg/mL in 1% formic acid and 2 μL (1 μg) was injected on a Waters C4 BEH 1. 0/10-mm column and washed 5 min with 4% acetonitrile, followed by a 10-min 4 to 90% gradient of acetonitrile in 0. 1% formic acid, with a flow rate of 40 μL/min. The eluate was analyzed on a Bruker Impact II Q-TOF mass spectrometer equipped with an Apollo II ion funnel electrospray ionization source. Data were acquired in positive-ion profile mode, with a capillary voltage of 4,500 V and dry nitrogen heated at 200 °C.
Spectra were analyzed using the software DataAnalysis (Bruker). The total ion chromatogram was used to determine where the protein eluted, and spectra were summed over the entire elution peak. The multiply charged ion species were deconvoluted at 5,000 resolution using the maximum entropy method. Mitophagy Assay. Mitophagy was examined using a fluorescence-activated cell sorting (FACS)-based analysis of mitochondrially targeted Keima (mt-Keima) as previously described  (36, 53). Briefly, U2OS cells stably expressing an ecdysoneinducible mt-Keima were induced with 10 μM ponasterone A, transfected with GFP-Parkin for 24 h, and treated with 20 μM carbonyl cyanide m-chlorophenyl hydrazone (CCCP) for 4 h. For FACS analysis, cells were trypsinized, washed, and resuspended in PBS before their analysis on an LSR Fortessa (BD Bioscience) equipped with 405-and 561-nm lasers and 610/20 filters (Department of Microbiology and Immunology Flow Cytometry Facility, McGill University).
Measurement of lysosomal mt-Keima was made using a dual excitation ratiometric pH measurement where pH 7 was detected through the excitation at 405 nm and pH 4 at 561 nm. For each sample, 50,000 events were collected, and single, GFP-Parkin-positive cells were subsequently gated for mt-Keima and the percentage of cells with an increase in the 405 nm:561 nm ratio of mt-Keima was quantified. Untreated, single GFP-Parkin-positive cells were gated for quantification of the geometric mean of the GFP signal as a measure of steady-state Parkin protein levels. Data were analyzed using FlowJo v10. 1 (Tree Star). For statistical analysis, the data represent the average percentage of mitophagy from at least 3 independent experiments, and P values were determined by one-way ANOVA with Dunnett's post hoc tests.
ACKNOWLEDGMENTS. We thank all leprosy patients who participated in this study and members of the  E. S. laboratory  for many helpful discussions. We thank  Kai Sheng  for technical support. We thank the  McGill Pharmacology  surface plasmon resonance-mass spectrometry facility and the  Canadian Fund for Innovation  for infrastructure support. This work was supported by  Foundation  grants from the  Canadian Institutes of Health Research (CIHR)  to E. S. ( FDN-143332 ) and to E. A. F. ( FDN-154301 ); a  Canada Research Chair  ( 229792 ) and a Project grant from the  CIHR  to J. -F. T. (154301); the  Van Berkom-Saucier Foundation , a  Basic Research Fellowship  from  Parkinson Canada  to M. A. E. ; and a  Graduate Student Award  from  Healthy Brains  for Healthy Lives to E. J. M. The provision of M.
Results In this section, the topology optimization is applied to a 2D cantilever beam (dimensions: 200 × 50 mm) to find the best distribution of material. The material in this beam is steel, which has a Young's modulus E = 200 000 MPa and a Poisson's ratio equal to: v = 0. 3. The density of the material is ρ = 7. 190 × 10 Kg/mm. The behavior of the material is linear elastic isotropic. The objective is to perform topology optimization to obtain the best distribution of the materials. The topology optimization problem is to minimize the compliance of the structure, subject to the volume fraction 50 %. To carry out topology optimization, the meshing model is constructed using the nonlinear element (PLANE82 -8-node) and the used method is the Optimality Criteria (OC) implemented in ANSYS Software.
Results Data. We used the seismic station RER of the GEOSCOPE seismological network installed in a 4. 7 km-long tunnel, 8. 2 km north of the summit (Fig. 1 ). In 2007, this permanent station was the only broadband seismological station installed on La Réunion Island able to record the caldera collapse. The station was equipped with three 1-component STS-1 seismometers  29  and a Quanterra Q330 digitiser. The three seismometers recorded the three seismic components (vertical, north-south and east-west) of ground velocity. The corresponding instrumental responses of the broadband (BH) raw seismic channels (sampling rate of 20 Hz) are flat in velocity in the 1/360-5 Hz frequency range. Data from teleseismic stations of the global seismic network were also used to determine the moment tensor solution for the main collapse event (CE1) and for surface-wave magnitude estimates.
In this study, the moment magnitude Mw together with the seismic moment M 0 were determined only from the moment tensor inversion for the CE1 event. For the other 47 events, we determined the M S values, based on the amplitude of surface waves, which does not suffer from saturation at these magnitudes and which allowed us to quantify and compare most of the individual collapse events on a uniform basis. We computed the M S values (see Methods) from data recorded at teleseismic stations SUR (Sutherland, South Africa), BOSA (Boshof, South Africa), LBTB (Lobatse, Botswana), LSZ (Lusaka, Zambia), KMBO (Kilima Mbogo, Kenya), FURI (Mt. Furi, Ethiopia), LSA (Lhasa, Tibet, China), CRZF (Ile de la Possession-Crozet Islands, France), DBIC (Dimbokro, Cote d'Ivoire), KMI (Kunming, Yunnan Province, China), MBAR (Mbarara, Uganda) and TSUM (Tsumeb, Namibia) for 42 collapse events occurring between April 5 at 20:48 and April 14 as six other collapse events records were contaminated with interference from teleseisms.
Methods Surface-wave magnitude and scalar seismic moment. M S was determined from the following classic equation  37  : We estimated the scalar seismic moment of each collapse event (CE1 to CE48) and of the events occurring prior to the caldera formation (E2 to E5) from the calculated M S values using the following formula  38, 39   Moment tensor inversion. To better constrain the seismic source associated with the main collapse event, we analysed three-component broadband data from permanent stations retrieved from the Incorporated Research Institutions for Seismology Data Management Center (IRIS DMC). Seismic stations with epicentral distances up to 60 degrees from the Dolomieu Caldera were selected. From an initial set of 50 stations only ones with signal-to-noise ratio (from the power spectrum) greater than 2 were considered.
A linear combination of these mechanisms can create any arbitrary moment tensor. We ran a grid search  61, 62  over trial points beneath the caldera to find the optimum depth. These points start at depth 5 km and end at depth 15 km with steps of 2 km. The optimum time is searched by shifting the seismograms around the hypocenter time. We did not search for the lateral location of the event because we know the location of the caldera. We used the PREM  63  velocity model and the Mineos package  64  to generate synthetics data. The optimum depth is at 5 km, the shallowest grid point. The shallower depths were not searched since the vertical dip-slip components of the moment tensor cannot be resolved at long periods. The combination of the grid-point and time-shift that provides the highest correlation between real and synthetic data is considered as optimum centroid depth and time.
Acknowledgements Data from the following sources were used:  Observatoire Volcanologique du Piton de la Fournaise  (OVPF), GEOSCOPE: https://doi. org/10. 18715/GEOSCOPE. G, IRIS/IDA: https://doi. org/10. 7914/SN/II, the  Global Seismograph Network : https://doi. org/10. 7914/SN/IU, the  New China Digital Seismograph Network : https:// doi. org/10. 7914/SN/ICand the Global Telemetered Seismograph Network: https://doi. org/10. 7914/SN/GT. The constructive comments of three anonymous reviewers have been appreciated. We thank  M. Gudmundsson ,  B. L. N. Kennett ,  T. Ohminato  and  M. N. Vitry  for fruitful discussions. This work was supported by the  Institut de Physique du Globe de Paris (IPGP). This is IPGP contribution number  4041.
Data Availability The seismological data used are available from GEOSCOPE: https://doi. org/10. 18715/GEOSCOPE. G, IRIS/IDA: https://doi. org/10. 7914/SN/II, the Global Seismograph Network: https://doi. org/10. 7914/SN/IU, the New China Digital Seismograph Network: https://doi. org/10. 7914/SN/IC and the Global Telemetered Seismograph Network: https://doi. org/10. 7914/SN/GT. The GPS data is available from the volcanological observatory of Piton de la Fournaise (http://volobsis. ipgp. fr).
Patients We analyzed clinical and radiological data of the pediatric patients seen in consultation at Gustave Roussy (Villejuif) with diagnosis of NF1-like OPG seen followed at Gustave Roussy (Villejuif, France) between January and December 2017. All patients had an ophthalmological and dermatological screening and a genetic consultation. The written informed consents were obtained during the genetic consultation. The diagnosis of NF1-like OPGs was based on (i) histological diagnosis of low-grade glioma, (ii) the presence of radiologic features of NF1-associated OPGs.
NF1 sequencing Amplicon sequencing libraries were prepared from 10 ng of DNA per sample according to the TruSeq Custom Amplicon Library Preparation Guide (Illumina Inc, San Diego, CA). The custom primer panel targets the entire NF1-coding exons, intron boundaries (25 bp), and the 5′ and 3′ untranslated regions (UTRs) with amplicons with an average size of 150 bp. The pooled libraries were paired-end (2 × 150) and sequenced with NextSeq 500 Mid Output Kit v2 on a NextSeq500 instrument (Illumina). After demultiplexing and generation of FASTQ files, the sequence analysis was performed according to the Genome Analysis Tool Kit (GATK) guidelines using Polyquery (Paris Descartes University, Paris, France). Assessment of variants implication was performed based on population databases (dbSNP and GnomAD), mutation databases (HGMD and COSMIC), and predictions software (Alamut and mutation taster).
RAS-MAPK panel sequencing We performed an NGS analysis of the RAS-MAPK pathway in the tumor samples. The Ion AmpliSeq custom panel was designed using the Ampliseq designer software (ThermoFisher). The panel targeted the coding sequences and IVS boundaries of the following genes encoding major RAS-MAPK pathway components and regulators: BRAF, RAF1, RRAS, HRAS, KRAS, NRAS, MAP2K1, MAP2K2, SOS1, CBL, ETV5, PTPN11, RASA1, RASA2, SPRED1, SPRED2, SPRED3, SPRY1, SPRY2, and SPRY4. NGS library preparation used the Ion AmpliSeq Library Kit 2. 0 according to the manufacturer's instructions. We used the Ion Personal Genome Machine System (ThermoFisher). Ion Reporter 5. 6 (ThermoFisher) was used to perform the calling of the variants from the BAM files. Variants annotation and filtering was performed according to the Genome Analysis Tool Kit (GATK) guidelines using Polyquery (Paris Descartes University).
Neuro-Oncology Advances patients. 31 NF1-associated OPGs have more frequently an indolent course; thus, "wait and see" can be considered as an option for nonprogressive patients more often than in sporadic cases. On the contrary, surgery may be indicated more frequently in sporadic OPGs as first option, since they are often presented as large, cystic, exophytic, or hypothalamic life-threatening tumors. Therapy targeting the MAPK-and mTOR-pathways could be a valuable alternative to the standard treatment of pediatric OPGs. Recently, Fangusaro et al. have shown that the different genomic alterations of this pathway have implications in therapeutic responses. 32 Single or combination therapy with FGFR, NTRK2, and/or MEK inhibitors represents rational treatment options. 33, 34 Moreover, a phase 1-2 trial assessing Selumetinib in childhood OPGs is currently opened (NCT01089101, Pediatric Brain Tumor Consortium-Memphis).
Our data support that, in front of an atypical presentation of the OPG, molecular information on the tumor and constitutional NF1 status may provide crucial indications for proper management. In addition, we identified a complex mutation of the KRAS gene in a patient presenting an OPG with greater extra-optical component and no signs and symptoms of neurodevelopment disorder (patient P11: Table  3 ; Figure  2  and 3). No other mutation was found in the tumor. The KRAS complex inframe indel mutation would be a gain-offunction mutation as it affects codons 66-68 (next to the KRAS hotspot codon 61) and it is predicted to be probably damaging in prediction softwares. Although other alterations of the RAS-MAPK pathway such as mutations in RAF1, KRAS, FGFR1, PTPN11, and NTRK2 have been described in OPGs, the KRAS complex mutation identified in patient P11 has been never reported.
Acknowledgments We thank the  Genetic Laboratory at Gustave Roussy (Natacha Castor) , the  Necker Imagine DNA biobank  ( BB-033-00065 ), the  Tumor Bank of Necker-Enfants malades Hospital (Gisèle Le Gal) , the  Tumor Bank of Gabriel Montpied-Clermont Ferrand Hospital  ( Prof. Kemeny ), the  Paris-Descartes Bioinformatics Platform , and the  CAP NF FOUNDATION  (https://www. anrfrance. fr/).
The 96-well filter plate was moistened with 100 µL of assay buffer. Then, the samples were diluted to 750 µg of prot/mL for cytokines and 250 µg of prot/mL for MMPs with sample diluent HB + 0. 5% BSA. The bead solutions were made, and 50 µL of bead solution was added to each well. Washing using wash buffer was performed twice, and 50 µL of each sample was deposited per well. The plate was sealed using an adhesive and incubated at room temperature for 1 h while shaking (850 ± 50 rpm) followed by washing three times. Image analysis was performed by the imaging platform located at Biopôle. All the results obtained are in arbitrary units and have been normalized with respect to the size of the image, thanks to the Java-based Image J software (National Institutes of Health, Bethesda, MD, USA).
3% Triton X-100 (Sigma-Aldrich) in PBS at RT for 30 min. The primary antibodies were added to the cells diluted in 1% FCS in 0. 3% Triton-X-100-PBS: anti-vimentin (monoclonal mouse anti-human #V6630, Sigma-Aldrich) 1 : 200 for 1 h at RT; anti-E-cadherin 1 : 100 (monoclonal rabbit anti-human #3195, Cell Signaling, Denver, MA, USA) for overnight at 4 °C; and anti-fibronectin 1 : 20 (polyclonal sheep anti-human #AF1918, R&D Systems, Minneapolis, MN, USA), again overnight at 4 °C. The incubation with secondary Alexa-488-conjugated antibodies (Invitrogen, Carlsbad, CA, USA) was performed for 1 h at room temperature. The cells were mounted with propidium iodide containing antifading media Vectashield (Vector Laboratories, Burlingame, CA, USA). Imaging was performed with a Zeiss AxioImager Z1 fluorescence microscope using AxioVision image analysis software (Carl Zeiss, Göttingen, Germany).