dataesr/scientific-paragraphs-categorization huggingface dataset:
In this respect we understand that the relatively coarse (with respect to HiRes) resolution of ERA-Interim SST may have an effect on the atmospheric surface layer and PBL. Currently, several high-resolution SST datasets, while limited in time coverage, are available  (Chelton and Wentz 2005; Chao et al. 2009; Ricchi et al. 2016). Nevertheless, for the 40-yrlong NAAD experiments we used ERA-Interim SST, which is considered to be homogeneous and adequate for multidecadal scales. To reduce unrealistic atmospheric dynamics in the regional domain in both LoRes and HiRes experiments, we applied throughout the 40-yr period the procedure of spectral interior nudging  (Jeuken et al. 1996; Miguez-Macho et al. 2004 ). The spectral nudging technique optimizes the adjustment of the large-scale dynamics inside the domain to that implied by the boundary conditions.
The NAAD grid is based on a cylindrical equidistant projection (lat-lon in the namelist; http://www. naad. ocean. ru) with the rotated pole in order to locate the equator at the middle of the domain ( pole_lat 5 45; pole_lon 5 180; stand_lon 5 245). For this projection, the maximum map-scale factor amounts to 1. 2 in the northernmost and southernmost regions of the domain (Fig. 1 ). This allowed for keeping a constant third-order Runge-Kutta time step of 30 s in HiRes and 240 s in LoRes. In NAAD we used the USGS topography data with 10 min spatial resolution.
NAAD products and data availability NAAD products (see http://www. naad. ocean. ru for the parameter identification and namelist) include surface and upper-troposphere variables provided at the native NAAD grid for HiRes and LoRes products with resolutions of 14 and 77 km, respectively, for the period of 1979-2018. Since the NAAD core model (WRF-ARW) uses a staggered Arakawa C grid, all 3D fields are preinterpolated from the C grid on the mass points (unstaggered grid). No interpolation was applied for surface variables and fluxes, provided at the mass points. The entire archive of the NAAD data amounts to 150 terrabytes (TB) with individual annual files ranging from approximately 140 MB in LoRes to 3. 3 GB in HiRes for surface variables on to 165 GB for HiRes 3D fields. The whole NAAD data output is organized as annual NetCDF files by variable and is available online (http://www.
In this respect it is of interest to consider the representation of polar lows in NAAD. Polar lows represent highly localized maritime atmospheric phenomena associated with extreme winds and advection of very dry cold air, playing an important role in high-latitude atmospheric dynamics and air-sea interaction processes  (Zahn and von Storch 2008; Condron et al. 2008; Condron and Renfrew 2013, among others). They are hardly detectable in global reanalyses primarily due to their small size  (Zappa et al. 2014; Stoll et al. 2018). Many publications, however, report the capability of the WRF Model even without data assimilation to effectively simulate polar lows  (Wagner et al. 2011; Wu et al. 2011; Føre et al. 2012; Kolstad et al. 2016). Kolstad (2011)  developed a unique database of 63 polar lows  (1999) (2000) (2001) (2002) (2003) (2004) (2005) (2006) (2007) (2008) (2009)  in the subpolar and subarctic North Atlantic and Arctic using AVHRR and QuikSCAT winds.
Summary and outlook We presented NAAD-a new 3D multidecadal atmospheric dataset for the North Atlantic produced with a WRF nonhydrostatic model at mesoscale resolution (NAAD HiRes). In parallel, a coarser-resolution dataset (NAAD LoRes) was produced with a spatial resolution close to ERA-Interim used in both experiments as a lateral boundary condition. Our evaluation demonstrates reasonably realistic representations of most climatological characteristics in both NAAD HiRes and NAAD LoRes datasets. The main differences are identified in the ice-covered subarctic regions, especially for surface air temperature and partly for surface humidity. At the same time, atmospheric dynamics was quite adequately represented. The major purpose of the NAAD at this stage was not to provide extremely close comparability of NAAD LoRes with, for example, ERA-Interim.
This is hardly achievable because ERA-Interim (as well as the other reanalyses) is largely constrained by data assimilation. The major NAAD focus was rather to develop a highresolution atmospheric dataset that allows a better analysis of subsynoptic and mesoscale features-the task still not resolved by global reanalyses over the North Atlantic. In this respect, the objectives for NAAD are similar to those posed for the other regional reanalyses (e. g. , ASR;  Bromwich et al. 2018 ). The NAAD model configuration was quite close to the one used in ASR, the lateral conditions are the same (ERA-Interim) and the resolutions of the two products are similar. At the same time ASR (both ASRv1 and ASRv2) used extensive data assimilation input that exceeds data assimilation in the global reanalysis (e.
Acknowledgments. We acknowledge the support by the  Russian Academy of Sciences  ( ST-ASS-0149-2018-0001 ) and the  Ministry of Science and Higher Education of Russian Federation  under the Agreement  14. W0331. 0006. Authors Tilinina and Markina were also supported by Grant  17-77-20112  from the  Russian Science Foundation. The analysis of the hydrological cycle (authors Zolina, Dufour, and Krinitskiy) benefited from  Helmholtz-RSF  Grant  18-47-06202. We greatly appreciate critically important comments of the two anonymous reviewers and FIG. 17. (a) Mean SWH in NAAD-WHR and (b) difference in the mean SWH between NAAD-WHR and NAAD-WLR over the period of 1979-2018, as well as (c) mean 95th percentile of SWH in NAAD-WHR and (d) difference in 95th percentile of SWH between NAAD-WHR and NAAD-WLR.
A review of trans-Neptunian binaries (TNB) is given by  Noll et al. (2020). These authors outline the current understanding and progress in the study of TNBs from the identification of binaries, determination of their mutual orbits, measurements of the system's mass, density, rotational state, component colours, mutual events, and the shapes. They reported 86 known TNBs at the time of writing. Today, 107 binary and multiple systems are known in the TNO population (including Pluto and Charon) that have one or more companions 2. This paper is organised as follows. Section 2 provides an overview of the Varda-Ilmarë system. Section 3 describes our occultation prediction approach. Section 4 presents the data and the derived timings for each of the positive chords. In Sect. 5, we obtain the projected size and geometric albedo of Varda and constrain its 3D shape and density, and discuss the physical implications.
Varda's satellite, Ilmarë The Hubble Space Telescope (HST) Snapshot programme 11113 (conducted between July 2007 and April 2009) allowed the observation of 142 TNOs with the Wide Field and Planetary Camera 2 (WFPC2). HST images obtained on April 26, 2009, revealed the Varda satellite, Ilmarë, at a separation of about 0. 12 arcsec (corresponding to ∼4000 km, i. e. about 12 Varda radii). Its size is about half that of Varda (Table  1 ). Additional (visible and near-IR) data acquired between April 2009 and July 2013 with the HST, the Keck II Telescope, and the Gemini North Telescope provided the relative offsets of Ilmarë with respect to Varda at twelve different epochs  (Grundy et al. 2015 and references therein). The derived orbit of Ilmarë has a mirror-ambiguity: two solutions are possible (cf.
Data analysis Observations were performed at thirteen different stations in the USA (see the acronyms in Table  3 ). The observers were   2. Dark grey, light grey, and clear areas are in the night, twilight, and daytime, respectively. The Varda shadow is delimited by the continuous blue lines. It moves from north to south, and each bullet corresponds to one-minute intervals. The largest bullet corresponds to the geocentric closest approach. The red dashed lines show the 1σ path uncertainty, which is largely dominated by the uncertainties of the NIMAv6 ephemeris (Fig. 1 ) when compared to the position of the star (Table  2 ). organised into eight RECON teams and five IOTA 6  (non-RECON) teams. The BDR team used a QHY174M-GPS, while all the other stations used the IOTA-VTI time stamp. All other relevant information regarding the observing circumstances is summarised in Table  3.
Occultation light-curves Thirteen stations recorded data during the occultation, five of which (TWF, MHV, YMA, CAR, and FLO) reported positive detections. Differential aperture photometry was used to obtain the occultation light-curves, using the Platform for Reduction of Astronomical Images Automatically (PRAIA,  Assafin et al. 2011 ). The light-curves from the five stations listed above are shown in Fig. 3 ; their photometric measurements are provided as supplementary material to this paper. Figure  3  presents these light-curves, to which we applied a manual offset in flux and centred at their respective mid-occultation times for the sake of legibility.
(2000)  formulae 7. Given the geocentric shadow velocity of 10. 86 km s -1 and exposure times >1 s at all stations (see Tables  2  and 3 ), the main cause of light-curve smoothing is the finite integration time and not Fresnel diffraction or stellar diameter. However, the CAR station required further analysis, as an instrumental effect caused a smoothing of the light-curves over several data points (see Sect. 4. 3), resulting in gradual ingress and egress, see discussion below. The occultation timings are obtained by minimising the classical χ 2 function, using the same procedures as described in  Sicardy et al. (2011). The best-fitting functions are displayed in Fig. 4 , and the resulting chord details are listed in Table  4.
The CAR station The CAR station light-curve (Fig. 5 ) shows a gradual ingress and egress of the star; the ingress and egress extend over more than 5 data points, i. e. over five seconds. Two scenarii were considered to explain this behaviour, (i) a Varda atmosphere, or (ii) an instrumental effect. In case (i), a ray-tracing code was considered. It uses a nitrogen atmosphere with a temperature profile comparable to that of Pluto, with a rapid increase in temperature just above the surface that connects to an upper isothermal branch at ∼100 K. Then a surface pressure and temperature of ∼1 µbar and 38 K reproduce the profile of Fig. 5. Meanwhile, the signal-to-noise ratio (S/N) of the four other stations (TWF, MHV, YMA, and FLO) is insufficient and/or the time resolution is too low to test this model.
Acknowledgment. This campaign was carried out within the  "Lucky Star " umbrella that agglomerates the efforts of the Paris, Granada and Rio teams. It is funded by the  European Research Council  under the European Community's  H2020  ( 2014-2020/ERC Grant  Agreement No. 669416 ). The following authors acknowledge the respective CNPq grants:  F. B. -R. 309578/2017-5; R. V. -M. 304544/2017-5, 401903/2016-8; J. I. B. C. 308150/2016-3  and  305917/2019-6; M. A. 427700/2018 M. A. 427700/ -3 ,  310683/2017 M. A. 427700/ -3 ,  473002/2013-2. This -2. This study was financed in part by the  Coordenação de Aperfeiçoamento de Pessoal de Nível Superior -Brasil (CAPES) -Finance Code 001  and the  National Institute of Science and Technology of the e-Universe project (INCT do e-Universo ,  CNPq  grant  465376/2014-2 ).
Methods The present updated guidelines on the use of ECP were developed based on best medical practices, web review of relevant medical databases and literature, and collected expert opinions on the appropriate use of ECP. In general, ECP is employed for the therapy of severe refractory disease courses or in situations in which other treatments have failed. However, ECP availability is limited, and evidence for its efficacy is derived from retrospective data, and small cohort or case-controlled studies. There is a lack of randomized, controlled clinical trials in the literature. Double-blind trials are challenging to perform and using sham photopheresis may be unethical for patients with severe diseases. The present guidelines were drawn up to display the indications for which ECP is currently considered useful, as well as other indications where studies have shown promising results.
82 uidance on the monitoring of treatment success is also provided. Assessments at 3-month intervals will allow non-responders to be offered a combinatory or alternative therapy to ensure that ECP treatment is not unnecessarily prolonged. In 2006, the British Photodermatology Group and the UK Skin Lymphoma Group reported on the use of ECP in a variety of clinical conditions based on data that were derived between 1987 and 2001. 83. These groups concluded that there is (i) 'fair' evidence of the clinical benefit of ECP in patients with erythrodermic MF/SS (stage III/IVA/B1/0), with a strength of recommendation B (on a scale from A to E) based on a level of evidence of II1 (i. e. derived from well-designed, non-randomized, controlled trials); (ii) 'fair' evidence that supports the use of TSEB plus ECP for erythrodermic MF/SS patients, with a strength of recommendation B, level of evidence II2 (i.
Also, local radiotherapy can be performed either before or during ECP to treat localized infiltrated skin lesions. While the combination of ECP with histone deacetylase inhibitors appears potentially useful, there are no published data available which support this approach at present. HDAC inhibitors may also blunt the immune response and might likely inhibit the generation of an optimal response to ECP. Systemic concurrent therapies can be initiated at any time point. However, the consensus is that ECP monotherapy should be continued for at least 3 months before another drug or therapy is added. If patients are already on other therapies (bexarotene and/or IFN), ECP can be added without the withdrawal of the previous treatment. Response assessment Response assessments should be performed every 3 months according to the ISCL/EORTC/USCLC consensus statements.
115  The CR rates were 76% for skin symptoms, 75% for gastrointestinal manifestations, and 60% for liver involvement. The 5-year OS rate was significantly better for responders than for non-responders (69% vs. 12%; P = 0. 001). Due to ECP therapy, immunosuppressive treatment was discontinued in eight out of nineteen survivors (42%) and reduced in another seven patients (36%). The med an Karnofsky performance score improved significantly from 60% before ECP therapy to 100% (range 80-100%) after the completion of ECP therapy. Supportive data were derived from subsequent small studies using a twice-weekly ECP treatment regimen. 117, 137 In fifteen paediatric patients with steroid-refractory aGvHD, the strongest predictor of response to ECP treatment was the stage of the disease itself: there was a 100% response rate for stage II, 75% for stage III, and 0% for stage IV.
The authors recommended that ECP therapy be started at three times a week until a maximum response has been achieved, followed by individual progressive tapering of immunosuppressive treatment. Recommendations on vascular access and ECP technique in children were also provided. Martin et al. 110  published the recommendations of the American Society of Blood and Marrow Transplantation (ASBMT) for the treatment of aGvHD based on a comprehensive and critical review of published reports. In total, data from 67 reports on 6month survival, CR and PR of aGvHD have been reviewed. Among the five studies with outliers in the 6-month survival rate, the clinical trial by Messina et al. was particularly prominent. Since only children were treated (median age of 9. 6 years), Martin et al. 148  concluded that these outliers could be the result of age differences between patient cohorts, as the benchmark study had used horse ATG and included patients with a median age of 27 years.
Whole exome sequencing DNA was extracted from fresh-frozen tissue from patients (n=18; with a tumor content >90%) and matched peripheral blood from four patients using the QIAgen DNAeasy Blood and Tissue Kit (Qiagen, Hilden, Germany), following the manufacturer's instructions. Library preparation was conducted using the Nextera Rapid Capture Exome Kit before samples were sequenced, at either the Washington State University Core (Illumina HiSeq2500) or the Molecular Diagnostics and Personalized Therapeutics Unit, University of Ha'il (Illumina MiSeq) (Online Supplementary Table  S4 ). Sequencing data are available at the Sequence Read Archive (https://www. ncbi. nlm. nih. gov/sra) under accession number PRJNA491296. The bioinformatic processing is detailed in the Online Supplementary Methods.
The genomic profile of anaplastic large cell lymphoma Eighteen ALK + ALCL exomes sequenced in this study in addition to seven previously sequenced samples  9  (Online Supplementary Table  S1 ) were analyzed. The samples comprised 17 pediatric cases (≤18 years) and eight adult cases (Online Supplementary Table  S4 ); a flowchart illustrating the cohorts of patients is shown in Online Supplementary Figure  S1. All patient samples were collected at diagnosis. Data regarding variants found in at least a quarter of the patients are summarized in Figure  1 , which shows that the most commonly mutated genes in both adult and pediatric cases were TYW1B, DEFB132 and KCNJ18 (the full list of variants can be found in Online Supplementary Table  S6 ). None of the variants in these genes has been reported previously in hematologic malignancies and were not studied further here.
4%), in keeping with a previous publication reporting that the ALK + ALCL genome is largely stable. 4 Single nucleotide variants were followed in frequency by frameshift and non-frameshift deletions and splice variants (24. 1%, 10. 8% and 10. 6%, respectively), while the germline genome of ALCL patients points to an overwhelming presence of single nucleotide polymorphisms (89. 3%) (Online Supplementary Figure  S2B ). The proportion of each type of variant detected differed between patient tumors (Figure  2B ), although in general, pediatric patients known to have relapsed (n=9) had a significantly higher proportion of non-synonymous single nucleotide variants than patients who did not (n=9; P<0. 0001) (Figure  2B ), suggesting that a high percentage of non-synonymous single nucleotide variants at diagnosis may be indicative of relapse, although this requires validation in a larger dataset of patients treated with comparable treatment protocols.
20 The etiology of signature 12 has not yet been identified, although signature 26 is associated with a breakdown in DNA mismatch repair. The combination of signatures 3 and 26 may indicate, from an evolutionary perspective, how ALCL tumors accumulate mutations. Comparable patterns were found when comparing signatures to the COSMIC signature database 22 (data not shown). There was no detectable difference between the mutational signature of pediatric (n=4) or adult (n=7) ALK + ALCL patients (data not shown).
Gene set enrichment analysis confirms the importance of T-cell receptor signaling, but also of the Notch pathway in ALK + anaplastic large cell lymphoma pathobiology Gene set enrichment analysis (GSEA) of mutated genes showed that TCR signaling and Notch pathways are enriched across all five databases used (Figure  2D ; Online Supplementary Table  S8 ). Further analysis of the domains frequently found in the mutated genes revealed an enrichment in proteins with epidermal growth factor (EGF)-like or calcium-ion binding domains (Figure  2E ), two features of the NOTCH1 protein, and indeed the locus of both of the NOTCH1 mutations identified in this study (see below). Twenty of the 25 patient tumors carry mutations in proteins of the Notch pathway with a range of one to four and a median of two mutations per patient (Online Supplementary Table  S8 ).
However, if adult patients were considered in isolation, there was a significant reduction in overall survival for those with NOTCH1 mutations (P<0. 05) but these data are based on just three patients and so should be interpreted with caution. Variant T349P, at position 1045, is within the sixth of 34 exons of NOTCH1, which encodes one of the numerous EGF-like domains that make up the extracellular domain of NOTCH1 (EGF-like domain 9 of 36, which is a calcium-binding domain). NOTCH1 T349P was predicted to be a function-altering mutation by variant effect prediction software including SIFT (score=0. 01) and PolyPhen (score=0. 999), 7] [28] [29] [30]  Furthermore, the COSMIC database shows that T311 and T349 are the two most frequently reported mutated amino acids at the presumed NOTCH1/JAG1 interface across a range of cancers (including chronic myelomonocytic leukemia, 31 chronic lymphocytic leukemia,  32  T-cell acute lymphoblastic leukemia,  33  rhabdomyoscaroma  34  and squamous cell carcinoma  35  ) (Figure  3A ).
7, 8, 58 Intriguingly, NPM-ALK has previously been shown to be sufficient to induce NOTCH1 expression. 25 Not only did we confirm this by silencing NPM-ALK in ALCL, but we also showed that NPM-ALK acts through STAT3, which binds to the NOTCH1 promoter. This could explain why we observed synergistic effects between crizotinib and GSI in inducing cell death despite our evidence that NPM-ALK promotes NOTCH1 expression. Indeed, studies have shown that crizotinib synergizes with brentuximab vedotin, which targets CD30-expressing cells, despite NPM-ALK having been shown to drive CD30 expression. 59 ALK inhibitors are now being added to frontline therapy 60 (e. g. , in trial NCT01979536) although this combination has led to some unexpected toxicity. 11 NOTCH1 inhibition may therefore serve as a second-line treatment.
Indeed, although GSI have suffered from gastrointestinal-related toxicity, isoform-specific GSI or antibody-based treatments that target NOTCH1 directly (NCT03422679) have shown more promise. 61 ] [64]  Ultimately, our data show that GSI and ALK inhibitors act additively/synergistically and induce apoptosis of ALCL cell lines, and furthermore that ALK inhibitor-resis-tant cell lines remain sensitive to NOTCH1 inhibition. Hence, inhibition of NOTCH1 via GSI might represent a therapeutic option for both treatment-naïve and ALK inhibitor-resistant ALCL -while NOTCH1 expression may be a viable biomarker predictive of relapse.
Acknowledgments The authors would like to thank  Professor Christopher Aster  and  Dr Johnson  ( Harvard Medical School ) for providing the fulllength NOTCH1 cDNA. We also thank: the  Cambridge NIHR BRC Cell Phenotyping Hub ;  Medical Research Laboratories Core for Sanger sequencing; Washington State University Genomic Sequencing  for library preparation, quality control and sequencing; the  CCLG Tissue Bank , the  CCLG  centers and the  ECMC Pediatric Network  for the collection and provision of tissue samples. We especially thank the patients and families who voluntarily donated the samples.
Funding This work was supported by grants from the  Ministry of Science, Kingdom of Saudi Arabia to SDT, AI  and  SM  (grant number  74497 ) and  Bloodwise  to SDT (grant number  12065 ). HL is supported by a  Department of Pathology, University of Cambridge Pathology Centenary Fund  PhD studentship. SDT, LK, OM, SK, NP, SPD, CGP, WW, CDW and CL are recipients of funds from a  European Union Horizon   2020 Marie Sklodowska-Curie Innovative Training Network (ITN-ETN) grant , award n. 675712. CL is supported by a  Czech Science Foundation  research grant n. 19-23424Y  and by research infrastructures EATRIS-CZ ( LM2015064 ) and the  NCMG  ( LM2015091 ) funded by  MEYS CR. WK is supported by the  KinderkrebsInitiative Buchholz, Holm-Seppensen. The  CCLG Tissue Bank  is funded by  Cancer Research UK  and  CCLG.