dataesr/scientific-paragraphs-categorization huggingface dataset:
93 and an RMSE of 0. 15 (Table 1). A min = 0. 56 • Dd -1. There is a similarity in the equations between A min as a function of Dd obs at different scales and in different countries with r 2 performances between 0. 82 and 0. 86 (Table  2 ). Likely, this relationship does not depend on the scale of the hydrographic database. Calibration of the hydrographic database at different scales in other countries would help to confirm this hypothesis.
Conclusions This study proposes a method to develop a model of minimum contributing areas (A min ) as a function of environmental variables (lithology, precipitation, evapotranspiration, runoff, slope, vegetation cover). The first step presented here leads to a very performant relationship between A min and Dd obs in Burkina Faso. This relationship may even be independent from the scale of the hydrographic database. However, this quality needs confirmation by additional calibration tests in other countries with different scales of hydrographic databases. If validated in other countries with different climates, lithology, and drainage density, this first relationship should allow us to locally estimate the best A min from the observed drainage densities without having to extract 400 different hydrographic networks for example.
However, the final goal is to characterize A min in areas lacking hydrographic information, where observed drainage densities are therefore not available. To this end, we plan to establish a second empirical relationship, linking observed drainage densities and environmental variables. Once calibrated in Burkina Faso, this relationship between Dd obs and environmental variables can be combined to the first one between A min and Dd obs , such as to directly infer A min from environmental variables. For validation, we plan to apply this spatial model of A min to extract the rivers of Benin, Kenya, South Africa, and Madagascar, where hydrographic networks have been collected from national institutes. These countries were chosen because of the ease of access to the data and the different types of climate they cover.
Data availability. DEM data are freely available at https://doi. org/10. 1029/2008EO100001 (Lehner et al. , 2008). The hydrographic reference networks of Burkina Faso and Bénin are available on request from the agencies (Institut géographique du Burkina Faso -IGB, Institut géographique national du Bénin -IGN Bénin). The hydrographic network of France is freely available on the website: https://www. data. gouv. fr/fr/datasets/ cours-deau-metropole-2016-bd-carthage/ (BD Carthage, 2016). Author contributions. APB did the conceptualization, methodology, formal analysis, writing -original draft. The co-authors contributed as follows: AD participated in Conceptualization, Methodology, writing -review and editing, supervision; HK participated in conceptualization, methodology, writing -review and editing, supervision.
The height of the lapse-rate tropopause and the equivalent latitude Meteorological data were also taken from ERA-Interim reanalyses by the European Centre of Medium-Range Weather Forecasts (ECMWF)  (Dee et al. , 2011). Hybrid reanalysis levels in the TTL are located at various pressure heights  (i. e. around 177, 154, 133, 113, 96, 80, 67, and 55 hPa, respectively)  representing a vertical resolution of about 1 km in this region. The aircraft data are analysed in coordinates relative to the tropopause height and to the monsoon anticyclone centre, respectively. The height of the lapse-rate-based thermal tropopause was determined based on ERA-Interim data and following the WMO criterion  (WMO, 1957). The potential temperature θ at tropopause level was interpolated to the 1 Hz resolved position along the flight track of the M-55 Geophysica, and the measurement data were sorted as a function of θ distance ( θ ) to the local tropopause as a vertical coordinate.
Analyses of trajectories and the air mass transport history Backward trajectories of 50 d were calculated for each sampling position along Geophysica's flight track in 1 Hz resolution during the StratoClim 2017 mission using the trajectory module of the Chemical Lagrangian Model of the Stratosphere (CLaMS;  McKenna et al. , 2002; Konopka et al. , 2012; Pommrich et al. , 2014)  driven by horizontal winds from ERA5 reanalysis  (Hersbach and Dee, 2016). With the vertical resolution of the ERA5 data, a much better representation of convective updraught and tropical cyclones is realised  (Hoffmann et al. , 2019)  compared to earlier reanalyses  (Dee et al. , 2011) , in particular in the region of the Asian summer monsoon  (Li et al. , 2020). Further detailed validation of the very new ERA5 products is required, so ERA interim reanalyses still represent the state of the art until ERA5 becomes the new standard.
Mixing ratio of sub-micrometre particles, abundance, and fraction of refractory particles from StratoClim 2017 observations The entire StratoClim 2017 data set of measured (1 Hz resolved) particle mixing ratios n 6 and n 10 is summarised in Fig. 3a  as a function of potential temperature. The resulting median profile n 6 of the StratoClim 2017 measurements is shown with the 25th and 75th percentile (blue profile). This allows for a direct comparison with the corresponding median profiles from earlier COPAS measurements at tropical regions (in red: TROCCINOX, Brazil, 2005; in dark green: SCOUT-AMMA, West  Africa, 2006; cf. Borrmann et al. , 2010 and Weigel et al. , 2011). Figure  3a  also includes the median vertical profile of the mixing ratios of fine-mode particles (bright-green line), which was obtained from measurements over the central Pacific, at tropical latitudes  (Brock et al.
e. 355-365 K). Further aloft, the particle mixing ratios obtained from different locations decrease with altitude on a similar gradient. In the altitude range between 360 and 400 K, the tropical data obtained over South America (red) constitute the lowest particle mixing ratios (by median values), whereas all other profiles are almost in line with each other up to 400 K. ratios at each height level up to ∼ 415 K. Additionally, the AMA profile features a substantial increase in the median mixing ratio at altitudes of ∼ 410-415 K, where the values exceed those from the tropical regions by about 35 %. Above 415 K, the continuation of the tropical profiles from West Africa and Central America (coloured green) with altitude is largely consistent with the particle mixing ratios measured throughout StratoClim 2017, while at these altitudes the measurements from South America (red) show comparatively increased values.
Above 440 K, the particle mixing ratio over West Africa (dark green) significantly deviates from those of all other vertical profiles, as is visible from the gradual increase in the particle mixing ratio with altitude. This deviation was attributed to the influence of the high-reaching volcanic injections of the Soufrière Hills  (Borrmann et al. , 2010). The 1 Hz resolved StratoClim 2017 data (grey dots in Fig. 3a ) are added to the graph to illustrate how the scatter of measured particle mixing ratios relates to corresponding median profiles. Figure  3b  shows the vertical distribution of the mixing ratio of the nucleation-mode particles n nm (see Sect. 2. 2. 1). The flight-by-flight colouration of the data points indicates that increased n nm values were observed during each of the eight StratoClim 2017 mission flights.
Determining whether this pronounced frequency of NPF occurrence at a particular time of day is due to bias effects would require a larger database. Beyond this, preferred times of day when NPF was observed with particular frequency were not identified in the Strato-Clim observations, while instead, within the same region, a diurnal dependence of NPF was previously concluded based on a larger data set  (Hermann et al. , 2003). The diurnal dependence of NPF would be expected if H 2 SO 4 is assumed to be the main nucleating compound whose production maximum (from the reaction SO 2 + OH) at the local noon time correlates with the solar zenith (cf. Weigel et al. , 2011). Throughout StratoClim 2017, NPF was predominantly observed before local noontime during the mission flights KTM 2, KTM 3, KTM 5, and KTM 7, while all other observations were made mainly during the afternoon.
, 2010; Weigel et al. , 2011). Only a few events which lasted more than 100 s were observed during StratoClim 2017, but it cannot be excluded that they were actually composed of individual events of smaller extent. Very short events (< 10 s) make up almost 40 % of all NPF events observed. Consequently, hereafter, all events shorter than 5 s (i. e. 25 out of 130 events) are discarded from further analyses. In this way, individual 1-2 s features are filtered from the data. In addition, for the evaluation of individual NPF events, the reliability of the results increases if the arithmetic averaging occurs over more than five data points. Finally, the accuracy of the specified event duration improves as the raw signal processing (Sect. 2. 1. 3) smooths the temporal salience of short events. 4.
In Fig. 10  (Fig. 10a  and b ; see also respective close-up view), the contour of the Himalayas is clearly reproduced by the distribution of the data points (transport times of less than ∼ 5 d and fastest vertical updraught). Hence, for the duration of the StratoClim 2017 mission, the convective uplift mainly occurred within the AMA. This more compact regional distribution of vertical uplift (Fig. 10b ) is possibly related to the occurrence of a vertical conduit for upward transport in the monsoon, as conjectured by  Bergman et al. (2013). Figure  10  also indicates air masses of elevated n nm , which have experienced convective uplift over Tajikistan and northern Afghanistan as well as over regions around the Yellow Sea, the Korean Peninsula, or Japan, hence far away from the AMA system. Figures 9 and 10 both finally show that the region of the air's last BL contact and the location of the fastest vertical uplift do not necessarily coincide.
Similarly, the locations of the fastest updraught do not always match the shortest transport times, but for most cases in the immediate vicinity of the Himalayas this correlation is clearly visible from the StratClim 2017 data set. Ultimately, it cannot be excluded that, within the free troposphere, the air is subject to loading from various source regions (not exclusively from the location of the last BL contact) prior to its convective uplift. Of course, this finding complicates an unambiguous apportioning of NPF to specific source regions of precursors in the BL. The vertical distribution of the n nm mixing ratios as a function of the air mass transport time from the BL is shown in Fig. 11   Values of n nm that were several times higher (with 10 3 -10 4 mg -1 ) were detected below 380 K in air masses, which had experienced more than 25 d of transport time from the BL.
From the StratoClim 2017 database emerges that NPF occurs at the lower TTL (i. e. below the tropopause) of the AMA in air masses that have been lifted by convection in time intervals ranging from 5 d to about 2 weeks. However, it remains unclear whether in some of the observed events the air samples were taken at a very advanced stage of NPF. Therefore, it can only be surmised whether or how often the short time period was missed during which NPF is detectable by aircraft-based measurements. Potential uncertainties remain to be considered in connection with the uncertainty in the reanalysis data and the representation of the transport history of the air masses.
The release of the precursor material in the outflow region of the convective top had occurred up to 6 d before the NPF observation. Occasionally, however, air mass residence times of more than 6 d and up to 14 d were found at TTL levels prior to the NPF detection, while the entire data set covers residence times from ∼ 3 h to about 26 d. For the period of the StratoClim 2017 mission, the observed NPF rates are not unambiguously attributable to (a) a specific source region in the BL, (b) the effectiveness of the convective vertical transport, or (c) the recent release of NPFcapable material from the convective outflow. Nevertheless, it is the convective uplift which intermittently supplies the lower TTL with NPF precursor material. At altitudes well above tropopause levels, such an immediate supply by convection is lacking and could alternatively only proceed by the slow uplift superimposed on the anticyclonic ascent of the AMA (∼ 1 K d -;  Vogel et al.
The observations made during StratoClim 2017 demonstrate that frequent NPF with high production of nucleationmode particles is capable of directly affecting the extent and persistence of the Asian tropopause aerosol layer (ATAL). The continuous supply of freshly formed aerosol material, which coagulates both internally and with the background aerosol and which itself provides a surface for the condensation of supersaturated gaseous substances, contributes significantly to the available aerosol material that composes the ATAL. In this case, the chemical composition of the ATAL aerosol includes significant fractions of the material which was previously involved in the NPF process and the particles' condensational growth, which is subject to further investigation using the StratoClim 2017 data set.
Stolzenburg et al. , 2020)  under variable conditions and various admixtures. Data availability. The data shown in this study will be available from the HALO database at https://halo-db. pa. op. dlr. de/mission/ 101 (last access: 30 July 2021) (German Aerospace Center, 2021), or they may be provided by respective PI upon request. Author contributions. RW evaluated and analysed the data, created the figures, and drafted the manuscript with contributions by CM, MB, and AD. SB participated in the data analyses and the manuscript drafting. The code of the coagulation simulation was provided by BPL, and the code was adapted by MB, while the calculations were performed by CM. BV and FP contributed with meteorological reanalyses; BV, SiB, and BL performed the air mass trajectory analyses. SV and FD took care of the CO data.
UCSE data were delivered by GB. The manuscript was reviewed by CM, MB, AD, BV, FP, SV, FD, SiB, BL, BPL, and SB. Competing interests. The authors declare that they have no conflict of interest. Disclaimer. Publisher's note: Copernicus Publications remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Special issue statement. This article is part of the special issue "StratoClim stratospheric and upper tropospheric processes for better climate predictions (ACP/AMT inter-journal SI)". It is not associated with a conference. Acknowledgements. The contributions from the technical staff at the workshops of the MPI for Chemistry and the Institute for Physics of the Atmosphere (Johannes Gutenberg University Mainz) as well as the Myasishchev Design Bureau (MDB) were essential.
Financial support. Some of our research leading to the presented results received funding from the European Research Council under the European Union's Seventh Framework Programme  (FP/2007 (FP/ -2013) )  ERC grant agreement no. 321040 (EXCATRO). The Stra-toClim project was funded by the EU (FP7/2007-2018 grant no. 603557) and also supported by the German "Bundesministerium für Bildung und Forschung" (BMBF) under the joint ROMIC project SPITFIRE (01LG1205A). The work presented includes contributions to the NSFC-DFG 2020 project ATALtrack (BO 1829/12-1 and VO 1276/6-1). Review statement. This paper was edited by Martina Krämer and reviewed by two anonymous referees.
Characterization of EVs. The characterization of EVs in terms of size and concentration was performed by nanoparticle tracking analysis using a NanoSight NS300 (Malvern Panalytical), equipped with a sCMOS camera, Blue488 laser, and NTA 3. 3 Dev Build 3. 3. 104 software. The experiments were conducted at 25°C, with a camera level of 15 and a syringe pump speed of 50. Concentration, focus, and other parameters were adjusted accordingly for each experimental group. A detection threshold of 3 was employed to determine valid particles. EV homogeneity and integrity were also confirmed by negative staining electron microscopy (data not shown). Evaluation of EV activity in vitro. Two HT-29 human colon adenocarcinoma cell lines were employed to characterize the activity of EVs in vitro, as previously reported  (30).
Identification and quantification of proteins using mass spectrometry. One microgram of EV was dissolved in SDS and subjected to SDS-PAGE for a short period, allowing the entry of the protein into 2 to 3 mm of separating gel. The gel pieces were subjected to in-gel trypsinolysis followed by peptide extraction, as described previously  (30, 72, 78). After digestion, the peptides were stored at 220°C until further analysis. Nano-liquid chromatography tandem mass spectrometry (LC-MS/MS) experiments were performed as previously described  (30, 79). The peptides were identified from MS/MS spectra using X! TandemPipeline software  (80) , and searches were performed against the genome sequence of P. freudenreichii CIRM-BIA129 (GenBank accession no. NZ_HG975455). The database search parameters were specified as the following: trypsin cleavage was used, and peptide mass tolerance was set at 10 ppm for MS and 0.
05 Da for MS/MS. Methionine oxidation was selected as a variable modification. For each peptide identified, an E value lower than 0. 05 was considered a prerequisite for validation. A minimum of two peptides per protein was imposed, resulting in a false discovery rate (FDR) of ,0. 15% for protein identification. Each peptide identified by tandem mass spectrometry was quantified using the free MassChroQ software (81) before data treatment and statistical analysis with R software (R 3. 4; Project for Statistical Computing). A specific R package, called MassChroqR (v0. 4. 3), was used to automatically filter dubious peptides and group the peptide quantification data into proteins. Two different and complementary analytical methods were used, based on peak counting or XIC (extracted ion current).
The Venn diagram, heatmaps, and volcano plot were conceived using Python's Matplotlib-venn 0. 11. 5, Seaborn 0. 10. 0, and Bioinfokit 0. 7 packages, respectively. Functional enrichment analysis. For functional enrichment analysis, the lists of up-and downregulated proteins were submitted to the g:Profiler web server  (86, 87) , together with an ortholog-based Gene Matrix Transposed (GMT) file (see Files S1 and S2 in the supplemental material) constructed from KEGG pathways and COG whole-proteome annotation categories obtained from eggNOG-mapper v2  (84, 85). Protein lists were ordered by decreasing relative level of abundance, and a significance threshold (adjusted P value) of 0. 05 was adopted. For visualization, adjusted P values of 1 Â 10 26 or lower were capped to this value. Prediction of protein-protein interactions.
Human and bacterial protein sequences were retrieved from the UniProt and NCBI databases, respectively. Bacterial sequences identified in EVs derived from at least one of the growth conditions, as well as the human sequences corresponding to KEGG's NF-κB pathway, were submitted to the InterSPPI web server for the prediction of interactions  (88). Only interactions with a score of 0. 9765 or higher were considered valid, with a specificity of 0. 99. These interactions were gradually filtered so that human counterparts corresponded to, or were specific to, the LPSinduced portion of the NF-κB pathway, and/or bacterial proteins displayed a significant fold change in their expression according to quantitative proteomics. The lists of human proteins used for filtering are available in Tables  S1 to S3.
Predicted interactions and protein annotations were processed using the Pandas Python package  (89). Visualization of the interaction network was achieved using Cytoscape software  (90). Statistical analysis. All experiments were performed independently and at least in triplicate. The results are presented as means 6 standard deviations. Absorbance measurements were normalized to the control conditions. The differences between experimental groups were analyzed using the Mann-Whitney test or two-way analysis of variance (ANOVA) followed by Tukey's multiple-comparison test. Statistical analysis was performed using GraphPad Prism (GraphPad Software, San Diego, California, USA).
ACKNOWLEDGMENTS We are grateful to  Ludovica Marinelli  and  Nicolas Lapaque  ( INRAE, AgroParisTech, University Paris-Saclay, Micalis Institute, Jouy-en-Josas, France ) for their technical advice on the NF-κB reporter cell line. We also thank  Victoria Hawken  for English language editing of the manuscript. We thank the  CNIEL (Centre National Interprofessionnel de l'Economie Laitière)  for providing the ITG P20 strain (alias  CIRM-BIA129 ) of P. freudenreichii. V. R. R. , G. J. , Y. L. L. , V. A. C. A. , and E. G. conceived and designed the experiments. V. R. R. , V. B. -B. , J. J. , and B. S. R. L. performed the experiments. V. R. R. , A. N. , J. J. , and E. G. analyzed the data. F. L. R. C. , A. N. , J. J. , V. B. -B. , G. J. , and E. G. gave practical suggestions regarding performance of the experiments.
V. A. C. A. , Y. L. L. , and E. G. contributed to funding acquisition. V. R. R. and E. G. wrote the original draft. All authors contributed to data interpretation, drafting the manuscript, critically revising the manuscript, and approving its final version. This work received financial support from  INRAE (Rennes, France)  and  Institut Agro (Rennes, France). V. R. R. and B. S. R. L. were supported by the  International Cooperation Program CAPES/COFECUB  at the  Federal University of Minas Gerais  funded by  CAPESthe Brazilian Federal Agency for the Support and Evaluation of Graduate Education of the Brazilian Ministry of Education  (number  99999. 000058/2017-03and 88887. 179897/2018-00 , respectively).
Treatment of NPM1c AML cells with BETi I-BET151 resulted in downregulation of this specific core transcriptional program and subsequent cell cycle arrest, induction of apoptosis, decreased proliferation, and I-BET151 prolonged survival in a NPM1c mouse model  [16]. OTX015 (MK-8628) was the first in class inhibitor to be tested in a phase I dose-escalating multicenter trial in hematologic diseases (NCT01713582). Response rates in acute leukemias were modest including 5 responses among 36 patients (13. 9%) enrolled with 1 responder having AML with NPM1c  [22, 23]. It was recently demonstrated that BETi-resistant cells yield a leukemic stem cell (LSC)-like signature including upregulation of the Wnt/Beta-catenin pathway  [24, 25]. Based on those data, we investigated BETi compared to ATO + ATRA in NPM1c cell lines and patient samples to investigate their potential for further clinical development.
Primary cells were maintained in IMDM (Life Technologies, Courtaboeuf, France) supplemented with 10% heat-inactivated fetal bovine serum, 2 mM L-glutamine, 100 IU/mL penicillin, and 100 µg/mL streptomycin without growth factors, at 37 • C with 5% CO 2 as reported formerly  [15]. Patients provided informed consent prior to BM aspiration at diagnosis, according to the Declaration of Helsinki. Approval for this study was obtained from the local institutional review board of the CHU Saint Louis, Paris (France). One patient with relapsed NPM1c AML was treated in a phase I dose escalating multicenter trial in hematologic diseases (NCT01713582) and patient BM cells were obtained at day 1 and 22 during the first treatment cycle. The patient provided informed consent prior to BM aspiration at diagnosis, according to the Declaration of Helsinki and the study was approved by the local institutional review boards of CHU Lille (France), CHU Saint Louis, Paris (France), CHU Lyon Sud (France), Institut Paoli Calmettes, Marseille (France), CHU Toulouse (France), Princess Margaret Cancer Center, Toronto (Canada) and Royal Marsden Hospital, London (UK) for all patients included in the trial NCT01713582, approved date: 24 October 2012  [22].