dataesr/scientific-paragraphs-categorization huggingface dataset:
Funding This work was supported by funding from  Institut National de la Santé et de la Recherche Médicale  under Grants  BIO2012-02 ,  BIO2014-08 , and  HTE2016 ,  Fondation pour la Recherche Médicale ,  Association de la Recherche Contre le Cancer  ( PJA 20131200436 ),  Institut National du Cancer  under Grant  INCA 2011-1-PL BIO-12-IC-1  and  2012-1-GYN-04-IC-1 ,  Agence Nationale de la Recherche  under Grants  ANR-13-BSV1-0024-02 ,  ANR-10-IDEX-0001-02 PSL*  and  ANR-11-LABX-0043 ,  CIC IGR-Curie 1428 , the  European Research Council  ( ERC IT-DC 281987 ),  European Research Council  under Grant  IT-DC 281987 ,  Institut Curie PIC program  ( PIC-TME ), Ligue nationale contre le cancer under grants: labellisation  EL2016. LNCC/VaS , and postdoctoral fellowship for M. G-D. LF was supported by a fellowship from the  French Ministry of Research.
Availability of data and materials The data generated or analyzed during this study are available in Table  S6. The dataset supporting our conclusions is included within the article as a supplementary excel table (Table  S6 ). It contains several sheets: the dataset with imputation of data according to limit of detection (LOD) as explained in material and methods, the raw dataset (with ND for values below detection limit), Table  S2 , and a summary of used abbreviations in the dataset.
We report here a novel HLA-B*08 allele, now named B*08:302 that carries one nucleotide substitution in exon 3 when compared to the B*08:01:01:01 allele, identified in a volunteer bone marrow donor. The HLA typing was performed using Next-Generation Sequencing (AllType NGS, One Lambda, Canoga Park, CA) on the Ion S5 system platform (ThermoFisher Scientific, Waltham, MA),  1   1 ). This nucleotide change was confirmed using other NGS reagents provided by Immucor (Mia Fora NGS Flex, Norcross, GA) run on the Illumina MiSeq system (San Diego, CA) and analyzed with the Mia Fora Flex software (Immucor, version 5. 1). We were very confident in the phasing as the sample displayed a mean read length of 324 base pairs over all the loci, the mismatched C base was attributed 179 times to the new HLA-B*08 allele and can be only attributed to this allele because it was possible to discriminate from the associated HLA-B*35:08:01:01 allele by virtue of 11 variant positions each distant by less than 100 base pairs.
HLA typing by Luminex reverse sequence-specific oligonucleotide (SSO) was performed (One Lambda Labtype XR, Canoga Park, CA). 3 With this assay (lot 006, catalog RSSOX1B_007_02), the pattern of positive beads did not result in an acceptable HLA typing. We had to modify the bead #600 and bead #706 from negative to positive to obtain a HLA-B*08:01 result. Indeed beads #600 and #706 displayed oligonucleotides targeting the sequence surrounding codon 116. The analysis of the localization of this amino-acid and its antibody accessibility with the pHLA3D database  4  indicated that this amino-acid is located into the peptide binding groove. As such this could have an importance in both allogeneic hematopoietic stem cell transplantation and solid organ transplantation. The coding nucleotide sequence of the new allele has been submitted to the GenBank database (Accession No.
ON933816) and to the IPD-IMGT/HLA Database (Submission No. HWS10062188). The name B*08:302 has been officially assigned by the WHO Nomenclature Committee for Factors of the HLA System in August 2022. This follows the agreed policy that, subject to the conditions stated in the most recent Nomenclature Report, 5 names will be assigned to new sequences as they are identified. Lists of such new names will be published in the following WHO Nomenclature Report. 1 ). This nucleotide replacement in the splicing region might impact the protein's cell surface expression. This nucleotide change was confirmed by NGS typing on the Ion S5 system platform (ThermoFisher Scientific, Waltham, Massachusetts), using TypeStream Visual software (v. 2. 0. 1). 2  We were very confident in the phasing as the sample displayed a mean read length of 135 base pairs over all the loci, the mismatched T base was attributed 554 times to the new HLA-B*15 allele and can be only attributed to this allele because it was possible to discriminate from the associated HLA-44:02:01:01 allele by virtue of 5 variant positions each distant by less than 100 base pairs.
from exons 1 to 7. The reads were analyzed using the TypeStream Visual Software version 2. 1 (One Lambda). This donor was found to have a new B*08 allele and was consequently typed A*01:01, 11:01; B*08:302, 35:08; C*03:03, 07:01; DRB1*03:01, 13:03; DRB3*01:01, 01:01; DQA1*05:01, 05:05; DQB1*02:01, 03:01P; DPA1*01:03, 02:01; DPB1*02:01, 11:01. Using the IPD-IMGT/HLA Database, 2 nucleotide sequence alignment with HLA-B alleles shows that this new allele has one nucleotide change from B*08:01:01:01 in codon 116 in exon 3 where T ! C, resulting in a coding change (TAC ! CAC, Tyrosine ! Histidine, Figure.
FUNDING SI was funded by a  French doctoral research grant  from  Ecole Doctorale des Sciences de la Mer  (EDSM) and  Region Bretagne. AR and EG were funded by  MINECO  Grant COPAS "Understanding top-down control in coastal bloomforming protists". SM is supported by the  Région Bretagne fellowship  ( SAD 2019 'PlastPerk' N • 1537 ) ( CTM2017-86121-R ) and acknowledge the institutional support of the  "Severo Ochoa Centre of Excellence " accreditation ( CEX2019-000928-S ). This review was funded by the  ANR  project  ACHN 2016   PARASED  ( ANR-16_ACHN_0003 ), the  ANR  project  JCJC PANIC (2022-2026 ) ( ANR-21-CE02-0025 ), and by the  French National program EC2CO (Ecosphère Continentale et côtière)  project  THRAUSTO  ( N • 13046 ).
Samples were run using a minimum of two technical replicates and all standard curves had an R 2 greater than 0. 95. The protocol was as follows: 95°C for 15 minutes, 95°C for 15s, 60°C for 1 min, repeated 50 times. Quantification of copy number was done using the CFX manager software. The ratio of virus genome copy number to mouse genome copy number was obtained using the following equation: #copies of ORF50 #copies of PTGER Â 2 copies PTGER2=genome 1copyORF50=genome (simplified to #copies of ORF50 #copies of PTGER Â 2).
Fluorescently conjugated antibodies directed against CD4 (clone RM4-5), CD8 (clone 53-6. 7), CD3 (clone eBio500A2), IFN-g (clone XMG1. 2), Foxp3 (clone FJK-16s), and IL-17 (eBio17B7) were all purchased from eBiosciences. Samples were acquired using a FACS LSR II (BD Biosciences) and analyzed with FlowJo software (Tree Star, Inc. ).
Study population We disposed of two cohorts of patients with NSCLC receiving treatment with anti-programmed death 1 (PD-1/PD-L1) checkpoint inhibitors between 2014 and 2020. Cohort 1 was composed of 89 patients treated in the Georges François Leclerc Cancer center or the University Hospital of Dijon or the Hospital of Montréal and cohort 2 was composed of 70 patients treated in the Georges François Leclerc Cancer center. For all patients, abundance of transcripts from RNA-seq data was available, sequenced on different platforms using different technology for mRNA isolation (ribosome depletion for cohort 1 and polyA purification for cohort 2). Only patients from whom informed consent was obtained and recorded in the medical chart were included in this retrospective study. For RNAseq analysis, this study falls within the scope of the biological collection authorization registered under the number AC-2014-2260.
LIPI score calculation Blood cell counts and lactate dehygrogenase (LDH) levels at baseline before ICI treatment (within 30 days prior to the first treatment) were obtained from the electronic medical records. Demographic, clinical, pathological, and molecular data were also collected. The LIPI (Lung Immune Prognostic Index) was developed on the basis of the derived neutrophil/lymphocyte ratio (dNLR = leukocytes/(leukocytes -neutrophils)>3)  14  or LDH>230 U/L (considered as the upper limit of normal in our center). We considered two distinct groups: negative if neither of these two conditions was met, and positive if one or both conditions were met.
RNAseq data For cohort 1, total RNA was extracted from formalinfixed paraffin-embedded (FFPE) tumor slices (5 × 5 µm) using the Maxwell 16 LEV RNA FFPE Purification kit (Promega) following the manufacturer's instructions. Libraries were prepared from 12 µL of total RNA with the TruSeq Stranded Total RNA using Ribo-Zero (Illumina) following the manufacturer's instructions. Once qualified, paired-end libraries were sequenced using 2 × 75 bp output on a NextSeq 500 device (Illumina). For cohort 2, 10 ng of total RNA or 40 ng from FFPE were fragmented and 3'-end of mRNA were captured using an RT primer poly(T) containing a unique molecular identifier. Illumina adapters were added during this step by template switching. Fragments were then amplified with two PCR to complete Illumina adapters and add indexing sequences.
Libraries were sequenced on NovaSeq 6000 platform. Abundance of transcripts was quantified using the Kallisto program. 15 This program is based on pseudoalignment for rapidly determining the compatibility of reads with targets, without the need for alignment. The Kallisto transcript index used as reference was built from merged human cDNA and ncDNA files from the GRCh37 assembly ENSEMBL. Gene-level count matrices were then created with the DESeq2 library. Low-count genes were prefiltered by removing genes with too few reads. 16 enes differentially expressed according to MER4 expression were selected using the DESeq2 R package;  16  cohorts were pooled and batch effect was accounted for by adding cohort as a covariate in the regression model. Gene set enrichment analysis (GSEA)  17  was performed on resulting differential genes using Hallmarks of cancer gene sets from the Broad Institute and the R package 'clusterProfiler'.
Transcriptomic signatures Six transcriptomic signatures were computed as a metagene by taking the mean expression of corresponding genes. Expression was based on variance-stabilized RNAseq data and batch effect due to different platforms was removed as described above. Three signatures are related to IFN pathways or checkpoint inhibitors: IFNy, extended immune gene signature (EIG), and T cell-inflamed gene expression profile (GEP) and four are related to T cell immune infiltrate: cytotoxicity (CYTOX), TH1 orientation (TH1), cytotoxic lymphocytes (CTL), and CD274 gene expression (online supplemental table 1). 23 24 atistical analysis Patient characteristics were compared by group of origin (cohort 1 or cohort 2) using the χ² or Fisher's exact test for qualitative variables, and the Wilcoxon test for continuous variables, as appropriate.
Size selection of the corresponding library was performed by two consecutive AMPure XP bead (Beckman) steps. Sequencing was performed on a NextSeq 500 system (Illumina), and reads were mapped on the available C. albicans genome sequence assembly 22 (candiagenome. org) using Hisat2  (Kim et al. , 2019). Transcription factor binding sites were identified using bPeaks  (Merhej et al. , 2014)  and visually inspected with IGV  (Thorvaldsdottir et al. , 2013). The Irf1 binding dataset is available in Table  S2.
Libraries were prepared with the TruSeq stranded mRNA library kit (Illumina) followed by sequencing on a Hiseq2500 system (Illumina). After quality control assessment and adapter trimming, corresponding reads were mapped on the assembly 22 C. albicans genome sequence (candiagenome. org) using Hisat2  (Kim et al. , 2019). DEseq2  (Love et al. , 2014)  was used for differential expression analysis assuming a fold-change of 1. 5 with P-adj< 0. 05 as significant. The Irf1 transcript profiles are available in Table  S2.
, 2012) , overexpression of IRF1 induced the formation of filamentous growth in the control strain. The elongated cell shape and the distinct constrictions at the septal sites are indicative of pseudohyphae. In contrast, the irf1-mutant formed long cell chains, indicating a change in cell surface properties. As the cell chains could be resolved by gentle vortexing, a cell separation defect can therefore be excluded. The morphology of the cells essentially corresponded to that of yeast cells. Similar to the overexpression in the control strain, the overexpression of IRF1 in the mutant induced the formation of pseudohyphae (Figure  1A ). Next, we looked at hyphal inducing conditions by examining the morphology of the colonies. Unexpectedly, the irf1-mutant showed no hyphae defect on several media conducive to hyphal growth, namely SPIDER medium (Figure  1B ), Lee's medium, Serum-containing medium or RPMI (data not shown).
In addition, to distinguish between Irf1 direct and indirect target genes, genome-wide binding of Irf1 was investigated by chromatin immunoprecipitation followed by next generation sequencing (ChIP-Seq) in strains expressing either HA-tagged or unmodified IRF1, both under the control of the TETpromoter in ATc-containing YPD medium for 4 hours at 30°C. Using the bPeaks program  (Merhej et al. , 2014) , we identified 242 binding sites of Irf1 localised mainly upstream of ORFs on all 8 chromosomes (Table  S2 ). Overall, the 242 binding sites matched 215 target genes, assuming that two ORFs sharing the same bound promoter are both direct targets of Irf1 (Figure  2A ). Many promoter regions had more than one binding site of Irf1; for instance, 6 binding sites were identified for the 10kb promoter region of EFG1 (Figure  2B ).
In conclusion, of the 215 direct target genes identified, 64 genes showed stimulation of their expression mediated by IRF1 overexpression and 18 genes were inhibited, indicating that Irf1 acts as both an activator and a repressor of gene expression. The identified binding sequences of Irf1 were used for motif enrichment analysis with the program MEME-ChIP  (Ma et al. , 2014). The analysis revealed that Irf1 binding regions are enriched in the sequence (T/C)GNN(A/G)ATC. Comparison with the S. cerevisiae binding motif database (Yeastract) revealed that the identified binding motif is identical to that of Cmr3 (YPR013C), the Irf1 closest homolog in S. cerevisiae. However, protein sequence analysis revealed that the two proteins share only 19. 2% identity, which is mainly conserved in the zinc finger coding sequences (Figure  S1 ).
Macrophotographs were taken after 2 days of incubation at 30°C. (B) Similarly, growth of hap5 mutant strains harbouring either the empty plasmid CIp10 or the overexpression plasmid P TET -IRF1 were investigated by spot dilution assay under the same conditions. strain, in YPD medium or in YPD medium supplemented with BPS. While the transcript level of IRF1 itself was increased more than 40-fold by TET-promoter induced overexpression (Figure  6A , left panel), iron deficiency resulted in a 16-fold increased transcript level, indicating that expression of IRF1 is modulated by iron. The expression of the identified Irf1 target genes CFL4, CFL5 and FTR1 (Figure  2B ), which are involved in the acquisition of iron by the reductive pathway, were also upregulated by iron deficiency and by the overexpression of IRF1, which agrees with our RNA-Seq data and the published data of the iron deficiency transcriptome  (Lan et al.
Acknowledgments We thank all members of the  UnitéBiologie et PathogeńiciteF ongiques , particularly  Laxmi Rai  and  Thierry Mourer , for their support and numerous insights during the course of this project. We are also thankful to  Juliana Pipoli Da Fonseca  for supporting our ChIP-Seq and RNA-Seq experiments at the  Biomics platform at Institut Pasteur  and to  Gaëlle Lelandais  for sharing her insights into NGS derived data analysis.
Funding The work was supported by the  Agence Nationale de la Recherche  grant ( CANDIHUB ,  ANR-14-CE-0018 ). SZ is a  Pasteur Network Affiliate Program Fellow. Work in the laboratory of Cd 'E is supported by the  French Government 's  Investissement d'Avenir program  ( Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases ,  ANR-10-LABX-62-IBEID ). AHC was the recipient of a post-doctoral fellowship from the  European Commission  ( ERA-Net Infect-ERA, FUNCOMPATH ,  ANR-14-IFEC-0004 ), from the  French Government 's  Investissement d'Avenir program  ( Institut de Recherche Technologique BIOASTER , and from the  National Council of Science and Technology, Mexico. VB was supported by a grant from the  Pasteur-Paris University (PPU)   International PhD program  and the " Fondation Daniel et Nina Carasso ".
87, 102 s real-world evidence suggests that caplacizumab may be discontinued when ADAMTS13 activity reaches 20% or even 10% activity,  88, 103  trials are ongoing to personalize caplacizumab treatment on the basis of ADAMTS13 activity (NCT04720261). Taken together, these new regimens associating systematically PEX, immunosuppression with corticosteroids and rituximab, and caplacizumab frontline allow achieving impressive survival rates of >95%, far surpassing the historical survival rate of 80%-85% provided by PEX and steroids for 30 years, while alleviating substantially the burden of care. 87, 88, 99 In line with these statements, intensive salvage regimens including twicedaily PEX, boluses of cyclophosphamide and splenectomy at the acute phase for highly resistant patients should become rare indications while front-line rituximab and caplacizumab are increasingly used.
109 The incidence of strokes in iTTP survivors is fivefold higher than in the general population, and is associated with lower ADAMTS13 activity during remission. 110 In this setting, it becomes important to evaluate and control these added risk factors during follow-up to improve life expectancy and quality of life (QoL) of TTP survivors (Figure  2 ). 8] [69]  Data from the Japanese TTP registry shows that patients diagnosed with cTTP before pregnancy had prior planning consisting of ADAMTS13 activity monitoring and prophylactic plasma infusions throughout pregnancy, allowing for significantly higher live birth rates. 111 The authors suggest initiating prophylactic treatment immediately after conception because patients experience subclinical symptoms that are preventable by prophylactic treatment and the risk of foetal complications and death increases after 20 weeks of gestation.
A new hope: The recombinant human ADAMTS13 (rhADAMTS13) ADAMTS13 activity deficiency is a direct cause of TTP. This sets a rationale for using treatments based on direct enzyme replacement of ADAMTS13. In Adamts13 -/-mice where clinical features of TTP are reproduced through overload of VWF as an additional trigger, administration of rhADAMTS13 allowed for clinical and haematological features to be reverted. 114  first-in-human clinical trial to assess the safety of a single dose of rhADAMTS13 in cTTP patients has been performed and key findings included: (a) a similar pharmacokinetic profile to the wild-type enzyme found in plasma of healthy donors; (b) tolerability in the doses tested (5, 20 or 40 U/kg); and (c) no signs of immunogenicity after 28 days of exposure. 57  The efficacy of rhADAMTS13 for cTTP is now being tested in several phase 3 studies (NCT04683003 and NCT03393975), both as prophylactic and on-demand treatment, and their outcomes are eagerly anticipated.
121, 122 n iTTP, the scenario for applying rhADAMTS13 is different. The already-ongoing immune response of the patient, the different titres of autoantibodies, and the different ADAMTS13 domains targeted in each individual case will pose challenges. 4] [125]  Because of these encouraging preclinical results, a clinical trial is currently ongoing to assess the efficacy and safety of wildtype rhADAMTS13 in addition to SOC in aTTP patients (SOAR-HI Trial, NCT03922308). Hurdles regarding standardization of treatment are expectable: dosing schedules and regimens may need to be tailored to each patient. This can likely be improved upon with rhADAMTS13 mutant variants resistant to a large fraction of the patients' autoantibody mixtures,  126  as long as rhADAMTS13 intrinsic activity is not lost. 49 A full-length ADAMTS13 variant with an artificially introduced N-glycan and with these characteristics was recently reported by us.
TH E I M PORTA NCE OF PATIE N T E M POW ER M E N T Specific strategies for further patient empowerment need to be set. A recent questionnaire study submitted to 120 TTP patients revealed that two-thirds had a low to intermediate F I G U R E 3 The nature of polyclonal autoantibody mixtures in Immune-mediated Thrombotic Thrombocytopenic Purpura (iTTP) patients and ideal characteristics of a 'bio-better' ADAMTS13. The domain structure of ADAMTS13 in letter and number codes is shown. From left to right: M, metalloprotease; D, disintegrin; T1, thrombospondin (TSP) repeat 1; C, Cys-rich; S, spacer; T2-T8, TSP repeats 2-8; CUB-1 and CUB-2, complement subcomponent C1r/C1s, embryonic sea urchin protein Uegf, bone morphogenetic protein 1 domain. The general characteristics of patients' autoantibody mixtures are shown, based on compiled data shown in the supplementary data of reference  49.
2. Raising the bar in the elderly is a current goal, since age does widen the risk for premature death of iTTP patients. 108 Caplacizumab may not prevent thromboembolic events as efficiently in this subpopulation, for which the use of adequate anti-platelet agents may further improve outcomes. 87. It is necessary to gain more knowledge on the general cognitive deficits TTP patients develop, their mechanisms and how to prevent them. In this regard, caplacizumab and rhADAMTS13 hold a rationale; however there is yet lack of data in this field. 122 The cardiovascular risk factors these patients display must be aggressively controlled to prevent further damage, reduce comorbidities and improve outcomes in light of ADAMTS13 activity. 108, 121  iTTP, ELISA-based detection of open-conformation ADAMTS13 may become helpful for a differential diagnosis, because it is a hallmark in acute-stage iTTP patients and reverts upon remission or rituximab treatment.
| Raw RNA-seq data Raw RNA-seq data files were accessed from the NCBI Gene Expression Omnibus (GEO) portal, under the accession numbers GSE74246 for the sorted hematopoietic normal and AML cells from Corces et al. ,  32  GSE49642, GSE52656, GSE62190, GSE66917, GSE67039 and GSE106272 for the LEUCEGENE data sets. TCGA LAML  33  and BEAT-AML  34  data were accessed from the NCI Genomic Data Commons (GDC) data portal (https://portal. gdc. cancer. gov/). Raw data for the AMLCG cohort  18  were directly provided by the AMLCG group. HLA genotyping of TCGA, BEAT, and AMLCG cohorts was assessed using archasHLA v0. 2. 0. 35 THP-1 cell line data were accessed from the Broad Institute Cancer Cell Line Encyclopedia (CCLE) portal (https:// portals. broadinstitute. org/ccle).
| ATACseq data Significant peaks called from ATACseq data analysis were retrieved from the original paper. 32 Briefly, peaks were called using MACS2 and filtered using a custom blacklist. A final set of 590 650 significant peaks were defined among a list of non-overlapping maximally significant 500 bp peaks ranked by their summit significance value. These significant peaks were re-annotated using HOMER with the command "annotatePeaks. pl" and two different references: Gencode v33 only and Gencode v33 with the previously used HERV annotation. Regions containing significant peaks around +/À 1000 or 3000 bp of a HERV TSS were considered to be active HERV regions.