dataesr/scientific-paragraphs-categorization huggingface dataset:
The analysis also highlighted the potential role of multiple degradative enzymes, 11 chitinases (GH18; PHI:144; 6/6 OG5_126929, 2/2 OG5_142806, 2/2 OG5_210539, 1/1 OG5_152762), known to be important for the virulence of nematophagous fungi  [7, 66] , and subtilisin-like and extracellular metalloproteases (PHI:2117 and 479, with 9 and 5 members, respectively). These are often found in expanded gene families in pathogenic fungi (e. g. [67] ). There were also 11 Pth11-like receptors (PHI:404), which can be involved in host sensing and have established roles in virulence in other species  [68]. Three of them contain a CFEM domain (PF05730), found in proteins with proposed roles in fungal pathogenesis  [69]. As expected from the OrthoMCL analysis, there were also multiple hits to enterotoxin A proteins (PHI:698, with the PF01375 domain), scattered throughout the genome (g496.
coniospora and H. minnesotensis or P. chlamydosporia were restricted to nematopathogenic species (3/38 and 4/44, respectively). Indeed, there were only 9 clusters present in D. coniospora and another nematopathogenic fungus but not any of the 7 non-nematopathogenic species. Only one of these clusters corresponded to proteins with a conserved domain, namely fungal hydrophobin (PF01185), also found in rodlet proteins, a major component the hydrophobic sheath, or rodlet layer, that covers the surface of fungal spores, required in Aspergillus nidulans for efficient spore dispersal  [70]. To gain a more synthetic and rigorous overview of these results, we used correspondence analysis of the clusters of the secreted proteins from the 5 nematopathogenic fungi. Correspondence analysis is conceptually similar to principal component analysis, but can be used with  ), 5 other clusters include at least one member with a PFAM domain.
Consistent with our previous domain-centric analyses, among them we found the M35 (PF02102) and heat-labile enterotoxin alpha chain (PF01375) domains, reinforcing the notion that these domains potentially characterize the pathogenic capacity of D. coniospora. The remaining 3 were a domain of unknown function (PF11999), and 2 expected to be involved in fungal adhesion, the GLEYA (PF10528) domain,  [71] , and the hydrophobic surface binding protein A (PF12296) domain discussed in the next section. It is noteworthy that GLEYA domain proteins are highly expressed by nematode-trapping fungi during infection of C. briggsae  [5].
t1 and g2509. t1 (group 6 and Cluster01087), g4179. t1 (group 2), and g2083. t1 (group 34). The functional role in spores of the members these different paralogous groups merits further investigation in the future. Two genes g3607. t1 and g6474. t1 encode proteins that contain the hydrophobic surface binding protein A domain (PF12296) mentioned above. By analogy with the eponymous protein from Aspergillus oryzae  [72] , we hypothesize that this protein is important for spore attachment to the cuticle of C. elegans and that further, they may act together with g5675. t1 that contains a CFEM domain (PF05730  [69] ), that is structurally related to fungal adhesins and is highly preferentially expressed in spores. The differential expression of such genes will depend on stage-specific expression of transcription factors, such as g5153.
t1 that is predicted to be a transcription factor with Zn 2 Cys 6 (PF00172) and fungal-specific (PF11951) domains, and is also preferentially expressed in spores (S12 Table ). Genes that are more highly expressed in mycelia than spores would be predicted to be important for vegetative growth but also potentially for virulence. The list of these genes included candidates in both categories (S12 Table ). Thus, on the basis of the domains found in the corresponding predicted proteins, 5 genes are associated with carbohydrate metabolism (GO:0005975; g1835. t1, g1896. t1, g3555. t1, g7200. t1, g7950. t1), while g7950. t1 corresponds to a pyruvate/2-oxoglutarate dehydrogenase, a key metabolic enzyme, and fg7260. t1 to a sulfide: quinone oxidoreductase that catalyzes the first step in the mitochondrial metabolism of H 2 S.
These are expected to fulfil metabolic needs that are not present during the early growth of spores. Otherwise, there is g3889. t1 that encodes a highly conserved protein, annotated as a putative NRPS-like enzyme in multiple fungal species; it was not identified as such by SMURF analysis. g3999. t1 encodes a subtilisin and was also preferentially expressed in mycelia. Subtilisin-type proteases are associated with virulence, including nematicidal activity  [73] , in many species  [6]. As in other nematophagous fungi  [8] , as detailed above, D. coniospora has a large family of subtilisin-type proteases (PF00082; S7 Table  and Table 5 ). These different genes are all potentially linked to growth in the nematode host. Strikingly, 46 of the 86 (53. 5%) proteins corresponding to genes preferentially expressed in mycelia currently have no identifiable domains nor homologs in the UniProtKB database, compared to 30.
8% for the full set of 8733 predicted proteins (S5 and S12 Tables), and among them 41/46 are shorter than the median length. Manual searches suggest that many may have homologues in other fungal species. As a single example, fg6211. t1 is expressed at almost 10-fold higher levels in mycelia than spores, encodes a predicted 70 amino acid protein and matches a predicted 64 amino acid protein of unknown function from Trichoderma reesei (Genbank XP_006962079). Determining the role of these different genes will require extensive functional analyses in the future.
The first, g2153. t1 (PHI:184), potentially encodes a cysteine-rich secretory protein family  (PF00188) member, similar to the pathogen-related protein Pry1. Members of this family have different roles in various pathogenic fungal species, including the neutralization of host defenses, and antimicrobial activity to inhibit the growth of competing microorganisms  [75]. The second, g2390. t1 (PHI:257), encodes a widely conserved cell surface protein of unknown function, and the third, g6908. t1 (PHI:2117), an alkaline serine protease, homologous to the peptidase S8 of Beauveria bassiana. Interestingly, among the 17 genes, there were 3 groups of neighbours, suggesting a coordination of gene expression at the genome level. These included a group of 3 genes, g4815. t1-g4817. t1, that encode proteins that are completely unrelated in sequence: g4815.
Initial characterisation of a potential fungal counter-defensive strategy Our in silico analysis highlighted the atypical presence of 2 proteins with saposin A (PF02199) domains, one of which (g3895. t1) was predicted to be secreted (S11 Table ). Mammalian saposins are synthesized as precursor proteins (prosaposin) that contain four Saposin-B domains (PF05184; PF03489) and two Saposin-A domains that are removed during the process of activation. Saposin-B domains also occur in proteins without Saposin-A domains across many species including nematodes. In C. elegans, they are represented by a large family of 23 proteins, also called caenopores  [82, 83]. They are structurally similar to the innate defense proteins of the SAPLIP family, including vertebrate NK-lysin and granulysin  [84]. Several of them are upregulated upon infection, some by multiple pathogens  ([85]  reviewed in  [22] ), including spp-2, spp-6, spp-13, spp-14 and spp-15 that are induced upon infection by D.
coniospora  [74]. A number of the SPP caenopores/saposins have been demonstrated to play a role in host innate immunity  [86, 87]  suggesting that certain SPP proteins could be also be direct effectors of antifungal defense. The D. coniospora protein g3895. t1 is characterized by the presence of 3 Saposin-A domains, but no Saposin-B domain. There are currently no clear orthologs in any species in publically available databases. Given its unusual structure, we hypothesised that this protein, which we call here SapA, might act as an inhibitor of one or more nematode Saposin-B domain-containing caenopores/saposins and thereby interfere with host defense. As a first step in the analysis of sapA, we chose to assay directly its expression during the infection of C. elegans. Using the D. coniospora actin gene as a control, by RT-PCR we observed a clear increase in the relative level of expression of sapA across the time-course of infection (S4A Fig).
anisopliae  [106]. Thus D. coniospora does not show the pattern of gene family expansions observed in characterized nematode-trapping fungi, which are more similar to those seen in plant pathogens than to insect and animal pathogens  [5]. An atypical loss from the D. coniospora genome is of genes encoding NACHT-domain proteins, which as mentioned above are present in multiple copies in all the 11 other fungal species analysed. The NACHT domain is a constituent domain in one of the two main classes of NOD domain proteins. The second class has the NB-ARC (PF00931) domain, a signalling motif shared by plant resistance gene products and regulators of cell death in animals  [107]. These too are absent from the predicted set of D. coniospora proteins. Again this is highly unusual, since they are found often in all the other species, (8, 9, 10 and 15 times in M.
Optical mapping A whole genome map of D. coniospora was generated using the Argus Whole-Genome Mapping System (www. opgen. com). To obtain size-optimized restriction fragments (6-12 kb on average and no fragment larger than 80 kb across the genome) we used Enzyme Chooser (OpGen Inc. , Gaithersburg, MD) that led to the selection of Xba I. We sorted out 42,622 molecules longer than 200 kb (average 310 kb) used for the assembly, performed with MapSolver software (www. opgen. com). The resulting map contigs were manually validated leading to 9 maps (ranging from 0. 58 to 11. 3 Mb) with a cumulative size of 31. 8 Mb. These were used for comparisons with the in silico Xba I digestion profile of the scaffolds obtained after sequencing.
Functional annotation Genome annotation was performed using standard open source software. Repetitive elements were mined using RepeatScout version 1. 0. 5  [42]. A specific repeat library was generated in order to mask the genome with RepeatMasker version 4-0-5 (Smit, Hubley, & Green, Repeat-Masker Open-4. 0; www. repeatmasker. org). TransposonPSI v08222010 (transposonpsi. sourceforge. net) was used to characterize different types of transposable elements. Non-coding RNA were identified using Rfam scan perl script v1. 0  [117]  and tRNAscan-SE v1. 3. 1  [43]  for transfer RNAs.
The set of Augustus-predicted protein-coding genes were annotated using Interproscan The same protocol of InterProScan annotation was performed to annotate the predicted set of proteins from eleven additional fungi. The names indicated are from the NCBI Taxonomy Database; commonly used synonyms and/or NCBI genome assembly accession numbers are in brackets: Arthrobotrys oligospora (ADOT00000000. 1) [8] , Fusarium graminearum (Gibberella zeae; AACM00000000. 2)  [119] , Fusarium oxysporum (AAXH00000000. 1) [120] , Hirsutella minnesotensis (JPUM00000000. 1) [9] , Metarhizium acridum (ADNI00000000. 1) [40] , Metarhizium anisopliae (AZNF00000000. 1) [40] , Monacrosporium haptotylum (Dactylellina haptotyla; AQGS00000000. 1) [5] , Ophiocordyceps sinensis (ANOV00000000. 1) [41] , Pochonia chlamydosporia (Metacordyceps chlamydospora; AOSW00000000.
CAZy analysis Each D. coniospora protein model was compared using BLASTP  [127]  to proteins listed in the CAZy database (www. cazy. org; [128] ). Because the e-value depends on the length of the aligned segment (for instance a 30% sequence identity results in widely different e-values, from non-significant to highly significant, if the two aligned proteins are 40, 100, 250 or 500 residues in length), CAZy family assignments rather included examination of sequence conservation (percentage identity over CAZy domain length). Proteins that gave more than 50% identity over the entire domain length of an entry in CAZy were directly assigned to the same family. Proteins with less than 50% identify to a protein in CAZy were all manually inspected and conserved features such as catalytic residues were searched.
Secretome and comparative PFAM analysis Secretome analysis was carried out as previously described  [130]  by combining predictions from SignalP v4. 1  [122] , WolfPSORT  [131, 132]  and NucPred  [133]. A WolfPSORT search using mature secreted proteins and model 'ANIMAL' was used to determine probable target protein localization in host. For sequence-based clustering, a database consisting of predicted proteomes of D. coniospora, H. minnesotensis, P. chlamidosporia, M. haptotylum, A. oligospora and PHIbase v3. 6  [65]  entries was built. The result of a BLASTP search of this database against itself with an e-value cutoff of 10 -30 was used as input for clustering with the MCL program in Biolayout Express 3D  [134]. Some of these clusters (S11 Table ) were projected onto the Circos plot (Fig  1 , in red, purple and green, respectively): OG5_126718 as putative nonribosomal peptide synthetases; OG5_127207 (serine carboxypeptidase S28), OG5_138644 (deuterolysin metalloprotease (M35) family), OG5_137388 (PA domain; subtilase family), OG5_128249 (subtilase family), OG5_149879 (serine carboxypeptidase), together with orthoMCL-defined paralogGroup 11 (subtilisin-like serine protease; S6 Table) as diverse proteases; paralogGroups 1, 4, 9 and 17 as enterotoxin-like proteins.
Clusters that did not contain predicted secreted proteins from any of the 5 fungal species were discarded. Correspondence analysis was performed using the FactomineR package in R. TargetP v1. 1  [123]  was used to determine probable protein localization, using mature proteins for secreted proteins or full-length sequences otherwise. A consensus predicted localization was derived using the following rules: TargetP predictions with reliability < = 3 only were considered; NLS were considered if predicted by NLStradamus and with a NucPred score <0. 6; PredGPI predictions were considered if probability > = 90. PFAM domains were identified through a search against PFAM 28. 0 database using gathering thresholds.
Nucleotide sequence accession numbers MIseq reads used for de novo genome assembly and Hiseq reads used for RNAseq de novo have been deposited at SRA under accession numbers SRX883538 and SRX969055, respectively. The Whole Genome Shotgun project has been deposited at DDBJ/ENA/GenBank under the accession JYHR00000000. The version described in this paper is version JYHR01000000.
Acknowledgments We thank  Jérôme Gouzy  for his input on an initial round of genome annotation and  Aude Barani ,  Jérôme Belougne ,  Carole Couillault ,  Stéphane Coulon ,  Jan Dijksterhuis ,  Laurent Hannouche ,  LaDeana Hillier ,  Matthias Leippe ,  Luis Lopez-Llorca ,  Hans-Börge Jansson ,  Martijn Rep  and particularly  Nathalie Pujol  for their contributions, advice and/or the generous gift of reagents. We also thank the anonymous reviewers for their constructive criticisms.
The version described in this paper is version JYHR01000000. Funding: This work was supported by a program grant from the  ANR  ( ANR-12-BSV3-0001-01 ) and institutional funding from  INSERM ,  CNRS  and  AMU. The  Functional Genomics Platforms of Nice Sophia Antipolis  and Toulouse are supported by the  Program "Investissements d'Avenir " managed by the  National Research Agency  ( ANR-10-09-INBS ) with support from the  National Infrastructure France Génomique  ( ANR-10-INBS-09-03  and  ANR-10-INBS-09-02 ), the  Cancéropôle PACA , the  Fondation pour la Recherche Médicale  ( DEQ20130326464  to PB) and the  Labex Signalife  ( ANR-11-LABX-0028-01 ); microscopy used the  France-BioImaging infrastructure  supported by  ANR-10-INSB-04-01 ; worm sorting infrastructure supported by  ANR-11-LABX-0054  ( Investissements d'Avenir-Labex INFORM)  and  ANR-11-IDEX-0001-02  ( Investissements d'Avenir-A Ã MIDEX ).
SR is supported by a  Marie Curie grant  ( MC-CIG 334036  project  SEPAraTE ), a starting grant of the  European Research Council  ( ERC-StG 336808  project  VariWhim ) and the  French Laboratory of Excellence  project  TULIP  ( ANR-10-LABX-41 ;  ANR-11-IDEX-0002-02 ). LDH received a  China Scholarship Council fellowship , and  NT  supported by an  AMU doctoral fellowship and Labex INFORM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
5% (51) 0. 7% (11) Metan1/Metan1. home. html Tolypocladiumophioglossoides 95% (1374) 10% (157) 1. 6% (24) 2. 7% (40) PRJNA91059 Metarhizium acridum 95% (1370) 10% (152) 4% (58) 0. 6% (10) Metac1/Metac1. home. html Pochonia chlamydosporia 88% (1270) 11% (168) 9% (130) 2. 6% (38) www. fungalinteractions. org/index. php/en/ genome Ophiocordyceps sinensis 71% (1026) 7. 3% (105) 10% (152) 18% PRJNA59569 (260) The table shows the percentage of the different categories of USCOs, with the corresponding number of proteins in brackets, as calculated by BUSCO. Orthologs are classified as 'complete' when their lengths are within two standard deviations of the BUSCO group mean length, otherwise they are classified as 'fragmented' (length not within the threshold) or 'missing'. 'Complete' orthologs found with more than one copy are classified as 'duplicated'.
33 (0. 8) 0. 14 (0. 3) 0. 17 (0. 4) 0. 32 (0. 8) 0. 04 (0. 1) 3. 176 (5. 2) 0. 11 (0. 3) 0. 07 (0. 2) elements in Mb (%) NCBI PRJNA269584 ADNI00000000. 1 PRJNA156697 AOSW00000000 ADOT00000000. 1 AQGS00000000. 1 AACM00000000. 2 AAXH01000000 PRJNA118357 PRJNA91059 accession a See S1 Text doi:10. 1371/journal. pgen. 1006017. t004.
Patients PPBL was diagnosed from the persistence during three months of binucleated lymphocytes on a peripheral blood film. Patients were included after written informed consent, in accordance with the Declaration of Helsinki and with institutional guidelines and after approval of the French relevant competent authorities and ethics committees (Committee of Protection of Individuals (CPP), Advisory Committee on the Processing of Information for Medical Research (CCTIRS) and the French National Commission for Data Protection (CNIL)). Using multiparameter flow cytometry (MFC), B-cells were polyclonal in all cases, based on the expression of CD19 and the absence of a restriction of expression of light chain of immunoglobulin. Blood smears were reviewed in the same laboratory.
Chips were analyzed using Affymetrix ™ Chromosome Analysis Suite ® (ChASver 1. 0. 1). Database of annotations was NetAffx Build 30. Quality controls of the chips were set up according Affymetrix ™ recommendations (SNP-QC ≥ 1. 1 and MAPD (CN-QC) ≤ 0. 27). Copy Number Aberrations (CNA) were called according user-defined thresholds (Copy Number (CN) markers >50 and size >25 kb). The Database of Genomic Variants (DGV, http://projects. tcag. ca/ variation/) was consulted to determine whether CNA corresponded to genomic variants. Number and size of Copy Number Aberrations (CNAs) were analyzed and compared between patients and between CD19 + and CD19 -cells. CNA are called recurrent when at least two patients present the same CNA. Mosaicism phenomenon was detected in case of allele frequencies between disomic and trisomic states.
Six cases of MGUS (IgM) (4 %) and NHL (4 %) occurred with a mean time of 75 months (0-264) and 58 months (0-120), respectively. Four patients developed a diffuse large B-cell lymphoma and 2 patients a splenic marginal zone lymphoma (Table  2  for details). Among these 18 cases, 17 patients were chronic smokers. These data strongly lead us to consider PPBL as a premalignant state requiring a longterm follow-up. At diagnosis, CCA and FISH were performed in 140 and 128 patients, respectively. During the follow-up, CCA was performed in 32 patients (21 %). CCA and FISH detected no cytogenetic abnormality in 52/140 patients (37 %). Recurrent supernumerary isochromosome +i(3)(q10) was identified in 82/140 patients (59 %). PCC, arising from asynchronous mitotic activity in multinucleated cells, was observed concomitantly with +i(3)(q10) in 30/140 patients (21 %).
, 1998) , and the peptide binding stability was presented as the time required for 50% decay of the HLA molecules (DT 50 ), as calculated by linear regression analysis  (Dong et al. , 2004). The 51 Cr release assay was conducted as described earlier; briefly, after 0, 1, 2, 4, or 6 hr, labeled cells were harvested and washed and then used as target cells in killing assays, with an E:T ratio of 1:1. The specific lysis activity was calculated as described earlier  (Fujiwara and Takiguchi, 2007). Crystallization, Data Collection, and Processing Soluble peptide-HLA-A*24:02 complexes were prepared as previously described  (Shi et al. , 2011; Sun et al. , 2014). The individual proteins were then purified by SuperdexTM 200 10/300 GL gel-filtration chromatography (GE Healthcare). All crystallization attempts were performed by the hanging drop vapor diffusion method at 18 C with a protein/reservoir drop ratio of 1:1.
Diffraction data were collected by using beamline NE3A in the KEK synchrotron facility (Tsukuba, Japan) and an ADSC Q270 imaging-plate detector at a wavelength of 1. 0 A ˚. Data were indexed, integrated, and scaled by using HKL2000  (Minor, 1997). Data were analyzed by molecular replacement using MolRep in CCP4  (Collaborative Computational Project, Number 4, 1994). We used the A24VYG molecule (PDB: 2BCK) as the search model. All of the structures were further refined by several rounds of refinement using the PHENIX program  (Adams et al. , 2002). The data collection and refinement statistics are given in Table  S2. The detailed interactions between HLA-A*24:02 and peptide were analyzed by using Contact in the CCP4 package  (Collaborative Computational Project, Number 4, 1994). The PyMOL Molecular Graphics System (Schro ¨dinger; http://www.
ACCESSION NUMBERS The accession numbers for the structures of pMHCs of HLA-A*24:02-RF10, HLA-A*24:02-RF10-2F, HLA-A*24:02-RW8, and the HLA-A*24:02-RW8-2F reported in this paper are PDB: 5HGH, 5HGD, 5HGB, and 5HGA, respectively.
ACKNOWLEDGMENTS We thank  Dr. Masaya Baba  for critical reading of the manuscript and  Sachiko Sakai  for her secretarial assistance. This research was supported by a  JSPS KAKENHI   grant-in-aid for scientific research (B)  (grant no. 26293240 ), the  Ministry of Health, Labor, and Welfare of Japan: Research on HIV/AIDS  (grant no. H24-AIDS-007 ), the  Japan Agency for Medical Research and Development  (grant no. 15Afk0410019 ), the  International Research Center Aiming at the Control of AIDS Group for Globally Advanced Research at Kumamoto University , and the  China Ministry of Science and Technology National 973  Project (grant nos. 2013CB531502  and  2014CB542503 ).
Patients A total of 224 patients with RA for at least 6 months and fulfilling the American College of Rheumatology (ACR) 1987 criteria were included in the SMART study (NCT01126541). This study is a 2-year, national, multicenter, randomized open-label study evaluating the efficacy and tolerability of two doses of RTX for retreatment after one initial course of RTX at a usual dose (1000 mg on days 1 and 15) described previously  [21]. All patients had active disease, defined by a Disease Activity Score in 28 joints (DAS28) using C-reactive protein (CRP) (DAS28-CRP) >3. 2, with ≥6/66 swollen and ≥6/68 tender joints, or a CRP ≥10 mg/L, or an erythrocyte sedimentation rate (ESR) ≥28 mm/h. Erosive status was based on the reading of hand and feet X-rays by the investigators in each center. Each patient received a stable dose of methotrexate (MTX) (≥10 mg/week for at least 4 weeks) and had experienced an inadequate response or intolerance to TNF inhibitors, or had contraindications to TNF inhibitors.