dataesr/scientific-paragraphs-categorization huggingface dataset:
Statistics A descriptive analysis of the study population was performed. Categorical data were compared using the chi-square test. Quantitative data was tested for normality with the ShapiroeWilk test. Data were compared between the 2 groups using the Student t test for normal distributions and the ManneWhitney U test for nonnormal distributions. All P values were 2-sided, and P values 0. 05 were considered statistically significant. Statistical analyzes were performed using XLstat software (version 2020; Addinsoft).
The study was sponsored by St. George's University of London (Joint research office (JRO) reference 14. 0195). Demographic and clinical information were collected using the patients' clinical notes. Baseline data were collected, including age, weight, height, comorbidities and indications for antimicrobial therapy, and admission to critical care. Evidence of organ dysfunction was gathered from routine observations, blood tests, and acute illness severity scoring. Microbiology results were recorded, including any positive cultures and MIC data. Antibiotic doses and timing were recorded from electronic prescriptions and drug delivery devices (infusion pumps) to ensure the accuracy of the drug administration data. Patients receiving benzylpenicillin were given either 1. 2 g intravenously at 4-hourly or 6-hourly intervals or 2.
4 g intravenously at 4-hourly intervals, with the dose determined by the treating clinicians. Pharmacokinetic samples were taken from radial arterial lines. An opportunistic sampling strategy was utilized to time with routine clinical samples, with an aim to obtain samples at specified time points within the dosing frame (Table  3 ). These were immediately placed upon ice and plasma separated by centrifugation. The plasma sample was then frozen for subsequent analysis. The measurements were performed by Analytical Services International Ltd. , using tandem ultra-high-performance liquid chromatography-mass spectrometry. This method has previously been described  [23]. The data for adults receiving benzylpenicillin during the ABDose study were analyzed for this work. Population pharmacokinetic analysis was performed using the nonlinear mixed effects modelling software NONMEM ® (version 7.
Model evaluation and selection was based on minimization of the NONMEM objective function value (OFV) (with nested models requiring a minimum reduction of 3. 84 for a significant improvement in model fit at the level of p < 0. 05  [24, 29]  for one additional parameter), review of parameter estimates for biological plausibility, goodness-of-fit plots, and assessment of model simulation properties. Non-parametric bootstrap analysis (n = 2000) was performed to calculate median and 95% confidence interval values using Perl-speaks Nonmem (PsN version 5. 3. 0) [27]. Elimination half-life was calculated using the final model parameter estimates. Simulations of 10,000 patients based on the final pharmacokinetic model were undertaken using the linpk package in R  [30]. The following standard and alternative doses were simulated: (a) standard dosing of 1.
Acknowledgments: We would like to thank the participants and their families for taking part in this study. We are grateful to the following members of the research team and students at  St. George's, University of London and St. George's University Hospitals NHS Foundation Trust  for their help in enrolling patients and sample collection:  Michael Tumilty ,  Helen Farrah ,  Veronica Barnes ,  Johannes Mellinghoff ,  Christine Ryan ,  Joao Macedo ,  Naomi Hayward ,  Vana Wardley ,  Grace Li , and  Joanna Ashby.
Funding: The study was supported by the  National Institute for Health Research (NIHR) Clinical Research Network  ( UKCRN ID 18318 ). C. I. S. B. received salary support from the  National Institute for Health Research  ( NIHR ACF-2016-18-016 ) and from the  European Union 's  Seventh Framework Programme  for research, technological development, and demonstration under grant agreement No. 261060  ( Global Research in Paediatrics-GRiP Network of Excellence ) as a Clinical Research Fellow. J. F. S. and C. I. S. B. were supported by the  NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London ; the views expressed are those of the authors and not necessarily those of the  NHS , the  NIHR , or the Department of Health. J. F.
S. was supported by a  UK Medical Research Council fellowship  ( MR/M008665/1 ). K. K. received funding from the  People Programme  ( Marie Curie Actions ) of the European Union's  Seventh Framework Programme  ( FP7/2007-2013)  under  REA  grant agreement No. 608765  and from  Estonian Research Council  grant agreement  PUTJD22. Laboratory work carried out by K. K. was supported by  Analytical Services International. R. V. S. received salary support from the  National Institute for Health Research  ( NIHR ACL-2019-16-001 ). R. V. S. and D. O. L. were supported by the  Wellcome Trust (Institutional Strategic Support Fund -204809/Z/16/Z ). No other support was received for this work outside of the authors' affiliated institutions. The study was sponsored by  St. George's University of London  (Joint research office (JRO) reference  14.
Microscopy, imaging, and quantification Images were acquired with the Axio Observer Z1 inverted wide-field epifluorescence microscope (100X or 63X objectives/N. A. 1. 46 or 1. 4) (Zeiss) and a CoolSnap HQ2 camera from Photometrics. Identical settings and contrast were applied for all images of the same experiment to allow data comparison. Raw images were treated with Fiji software or with Photoshop (Adobe). HIRA complex accumulation in PML NBs was attested by manual counting of a minimum of 100 cells for each condition and per replicate. PML-NBs and genes loci proximity was measured using the Fiji RenyiEntropy mask on PML and FISH staining. X and Y coordinates for the center of the spots were recovered and all distances between each PML NBs and gene loci were calculated using the formula ! = #(%1 -%2) * + (,1 -,2) * to find the minimal distance in each nucleus.
ChIP-Seq analysis After ChIP, libraries were made in BGI and sequenced on a BGISEQ-500 sequencing platform (https://www. bgi. com). An average of 34 Million single-end 50bp reads was obtained for each library. Reads were trimmed using Trimmomatic and quality assessed with FastQC. Reads were aligned to the human genome hg38 using the BWA alignment software. Duplicate reads were identified using the picard tools script and only nonduplicate reads were retained. Broad peaks calling was performed with MACS2  (Zhang et al. 2008 ) ("--extsize 250 -q 0. 01 --broad --broad-cutoff 0. 05"), using input DNA as control. We defined all possible locations of H3. 3 by merging broad peaks identified in our four conditions (n=190295), and annotated them with Homer (http://homer. ucsd. edu/homer/download. html ).
CPMs were obtained similarly, and input DNA CPMs, used as background, was substracted from ChIP CPMs. Genes with the log2 of differential TES enrichment between IFNb treated and not treated conditions being higher than 5 (log2(Fold Change)>5) were retained for GO analysis, as described above. PlotProfile were generated using the DeepTools suite, starting from the MACS2 fold enrichment bigwig files, which take into account the read extension, the input DNA background and the library size normalization. The list of 48 core ISGs and 48 non-ISGs equal in size to the core ISGs was taken from  (McFarlane et al. 2019). In order to reduce the noise on the profiles, we selected for each gene the transcript with the highest H3. 3 enrichment at the TES in the IFNb treated condition. Genome browser snapshots of H3.
Acknowledgments We thank  Dr. Valérie Lallemand-Breitenbach  for the Pml WT and Pml-/-MEFs. We thank  Dr. Chris Boutell  for the pLVX-His-SUMO1/2/3 plasmids. We thank  Dr. Roger Everett  for the PML-containing plasmids. We thank  Dr. David J. Hughes  for the SUMO-specific Affimers plasmids. We thank  Lars Jansen  for the pBABE-H3. 3-SNAP-HA3plasmid. We thank  Dr. Caroline Schluth-Bolard  for her kind help with the FISH on ISGs and for the GHRL BAC.
Funding P. L. laboratory is funded by grants from the  Centre National de la Recherche Scientifique (CNRS) ,  Institut National de la Santé et de la Recherche Médicale  (INSERM),  University Claude Bernard Lyon 1 ,  French National Agency for Research-ANR  [ EPIPRO ANR-18-CE15-0014-01 , CHROMACoV  ANR-20-COV9-0004 ;  IFN-Epi-IM   ANR-21-CE17-0018 ];  LabEX DEVweCAN  and  DEV2CAN  [ ANR-10-LABX-61 ];  AFM-Téléthon Plans stratégiques MyoNeurALP & MyoNeurALP2 , the  Comité départemental du Rhône de La Ligue contre le Cancer  and the  Fondation pour la Recherche Médicale (FRM)  (grant number  FDT202001010820  to C. K. ). P. L. is a CNRS Research Director and A. C. is assistant professor in the University Claude Bernard Lyon 1.
sonrai ticks were found in 100% (17/17) of the villages surveyed in the Niakhar area and in 66% (10/15) of the villages in the Sine-Saloum area. A total of 1275 soft tick specimens were collected from small mammal burrows. The ticks collected were morphologically identified as O. sonrai. About 20% (259/1275) of the specimens were also submitted to MALDI-TOF MS for identification. Among the resulting MS profiles, 87% (139/159) and 95% (95/100) were considered good quality specimens, preserved in alcohol and silica gel, respectively. All spectra of good quality were tested against our MALDI-TOF MS arthropod spectra database and identified as O. sonrai species, corroborating the morphological classification. The carriage of four micro-organisms was detected in the ticks with a high prevalence of Bartonella spp.
DNA Extraction and Molecular Identification of Ticks Each half of the legless ticks was transferred to a 1. 5 mL tube containing 180 µL of G2 lysis buffer and 20 µL of proteinase K (Qiagen, Hilden, Germany). It was then tissueground with metal beads and incubated at 56 • C overnight. DNA extraction was performed using an EZ1 DNA tissue kit (Qiagen) according to the manufacturer's recommendations. DNA from each sample was eluted with 200 µL of Tris-EDTA (TE) buffer (Qiagen) and stored at -20 • C until use. Only specimens for which leg MS spectra were added to our reference spectra database were subjected to molecular identification. Their DNA was then subjected to standard PCR and sequencing in an automated DNA thermal cycler (Applied Biosystems, Foster City, CA, USA) using the 16S rDNA gene amplifying 420 base pair (bp) fragments (Table  1 )  [23, 27, 31].
DNA from laboratory-reared uninfected Rhipicephalus sanguineus s. l. ticks was extracted simultaneously with field-collected samples, and used as a negative control for standard PCR. PCR-positive amplicons were sequenced using the Big Dye Terminator Cycle Sequencing Kit (Perkin Elmer Applied Biosystems, Foster City, CA) and the resulting sequences were assembled using ChromasPro software (ChromasPro 1. 7, Technelysium Pty Ltd. , Tewantin, Australia). All assembled sequences obtained from standard PCR-amplified genes were compared to the NCBI GenBank (https://blast. ncbi. nlm. nih. gov/Blast. cgi accessed on 20 August 2023) by BLAST search to identify the closest genetically related genotypes.
MALDI-TOF Mass Spectrometry Parameters Protein mass profiles were obtained using a MicroFlex LT MALDI-TOF Mass Spectrometer (Bruker Daltonics, Germany), with detection in the linear positive-ion mode at a laser frequency of 50 Hz within a mass range of 2-20 kDa. The setting parameters of the MALDI-TOF MS apparatus were identical to those previously used  [34]. MS spectra were acquired automatically using the AutoXecute of the flexControl v. 2. 4 software (Bruker Daltonics).
MALDI-TOF Spectral Analysis, Database Creation The MALDI-TOF MS profiles obtained from the four legs of the ticks preserved in silica gel or alcohol were evaluated by visually assessing the quality, intensity and reproducibility of all MS spectra obtained using flexAnalysis v. 3. 3 and ClinProTools 2. 2 software (Bruker Daltonics). MS profiles judged to be of good quality are presented with high-intensity protein peaks (>3000 au), no background noise and a smooth baseline  [27, 38]. MS spectra which passed quality control criteria were selected for further analysis. MS profiles of samples preserved in alcohol and silica gel were compared with the MALDI-TOF MS dendrogram and principal component analysis (PCA) tools using MALDI Biotyper v3. 0 and ClinProTools 2. 2 software. To evaluate the ability of the MALDI-TOF MS tool to distinguish between male, female, and nymph ticks, MS spectra from randomly selected specimens were used for PCA, blind test and cluster analysis (dendrogram) using ClinPro-Tools 2.
2 and MALDI Biotyper v3. 0, respectively. The performance of MALDI-TOF MS to distinguish ticks infected and not infected by Borrelia was also tested. Leg MS spectra from specimens whose infection status was confirmed by molecular biology were used to assess whether it is possible to separate these groups using PCA, comparison of discriminating peaks, and cluster analysis (dendrogram) using ClinProTools 2. 2 and MALDI Biotyper v3. 0, respectively. The MS reference database (DB) was created using four and ten spectra of ticks preserved in silica gel and alcohol, respectively, using MALDI Biotyper (Bruker Daltonics). MS spectra were created with an unbiased algorithm using information on peak position, intensity and frequency. The reference spectra of 14 molecularly identified tick specimens used to create the database are available at the following link (https://doi.
MALDI-TOF Blind Test Identification Blind tests were performed against the MS reference spectra DB update with the spectra of 220 remaining specimens, including 129 spectra from ticks preserved in alcohol and 91 from ticks preserved in silica gel. The reliability of species identification was estimated using log-score values (LSV) obtained from the MALDI Biotyper v. 3. 0 software, which ranged from 0 to 3  [27].
The primers and probes used in this study are listed in Table  1. The obtained sequences were assembled, corrected by Chromas Pro (Technelysium Pty. Ltd. , Tewantin, Australia), and then compared with the sequences available in GenBank by BLAST search. The sequences of the ftsz and gltA Bartonella genes and the 23S and 16S genes of bacteria of the Anaplasmataceae family were used for phylogenetic analyses  [27, [34] [35] [36]. MEGA software version 7. 0. 21 was used to perform sequence alignments and construction of phylogenetic trees with 1000 bootstrap replications for the different genes.
Molecular Identification of Ticks Twenty-two ticks were randomly selected for molecular identification. From them, the PCR products for the 16S-tick gene were obtained for 14 samples. The BLAST of the 16S gene sequences of the tick species revealed a strong and consistent identification of the species according to morphological identification, with coverage of between 99 and 100% and identity between 99. 53 and 100% with O. sonrai sequences deposited in GenBank (GenBank accession numbers: OP947085 to OP947088).
MALDI-TOF MS Identification of O. sonrai Ticks A total of 259 specimens of O. sonrai, comprising 72 males, 94 females and 93 nymphs, and randomly chosen from the specimens collected in all rodent burrows were subjected to MALDI-TOF MS for identification. A total of 100 specimens had been preserved in silica gel and 159 in alcohol (Table  3 ). Visualisation of the MS profiles using flexAnalysis v. 3. 3 software showed that 87. 4% (139/159) and 95% (95/100) of the spectra obtained from the samples stored in alcohol and silica gel, respectively, met the criteria of sufficient quality for future analyses. The MS profiles obtained from the two preservation methods appeared to be different for all samples, as illustrated by the six representative specimens selected for each method, dendrogram and PCA analyses, which confirmed this difference between the MS protein peaks of O.
sonrai tick specimens preserved in alcohol and silica gel (Supplementary Figure  S1 ). The MS spectra from the 14 specimens identified molecularly, including ten specimens preserved in alcohol and four in silica gel were added to our database. The blind test against the updated MALDI-TOF MS database revealed that all remaining spectra (n = 220) preserved in silica gel and alcohol matched with the O. sonrai species. The LSVs for specimens preserved in alcohol ranged from 1. 6 to 2. 4 (mean ± SD: 2. 03 ± 0. 17), while spectra preserved in silica gel had higher LSVs ranging from 1. 8 to 2. 6 (mean ± SD: 2. 25 ± 0. 17) (Table  3 ). The first identification hit corresponded to a specimen with the same preservation methods. Visual comparison of MS spectra from ticks preserved in alcohol indicated that they seemed to be different, notably between stages of development (Figure  2B ).
Comparison of our 36 gltA gene sequences with the GenBank database indicated that 27/36 (75%) were similar to a Bartonella sp. (JX428749) detected in a rodent, Cricetomys gambianus, with genetic identities ranging from 98. 49 to 100%. The closest known species to these 27 sequences was B. elizabethae (GenBank accession number: GQ225710), with genetic similarities ranging from 98. 45 to 98. 98%. In addition, 4/36 (11%) were 100% similar to a Bartonella sp. (GenBank accession number: KM233490) detected in the shrew Crocidura olivieri. The closest known species to these four sequences was B. florencae (GenBank accession number: HM622142) with a genetic similarity of 97. 46%. Meanwhile, 3/36 (8%) were 99. 50 and 100% identical to an uncultured Bartonella sp. (GenBank accession number: MF443365) detected in Xenopsylla cheopis.
The closest known species to these three sequences was B. taylorii (GenBank accession number: AY584853) with a genetic similarity of 94. 47%. Finally, 2/36 (6%) sequences were 100% identical to an uncultured Bartonella sp. (GenBank accession number: MK892986) and close to B. elizabethae (GenBank accession number: MK660539), with a genetic identity of 98. 49% (Supplementary Table  S3 ). Of the 13 reliable sequences obtained from ftsZ amplicons, 9/13 (69%) were close to B. tribocorum (identity ranging from 97. 25 to 97. 60%) isolated from Rattus norvegicus rats in France (GenBank accession number: AF467759) and 3/13 (23%) were identified as 100% identical to B. massiliensis (GenBank accession number: HM636443) isolated from the O. sonrai tick in Senegal. In addition, 1/13 (8%) sequences were 100% identical to an uncultured Bartonella sp.
(GenBank accession number: MK902922) detected in Mastomys erythroleucus rodents in Mali, and close to B. Mastomydis (GenBank accession number: KY555065), with a genetic identity of 98. 97% (Supplementary Table  S3 ). The phylogenetic position of Bartonella detected in our study with the ftsZ and gltA genes are shown in the phylogenetic trees in Figure  3A  and Figure  3B , respectively. Our Bartonella ftsZ and gltA genes sequences have been deposited in GenBank under accession numbers OP947080 to OP947084 and OP948207 to OP948216, respectively. For the qPCR-positive samples from bacteria of the Anaplasmataceae family, 38/69 (55. 07%) sequences were obtained with the 23S rRNA gene. The BLAST of these sequences showed that they belonged to three different genera, including Ehrlichia, Wolbachia and Anaplasma (Figure  4A ).
Thirty-six sequences were close to the Ehrlichia genus and had 98. 76 to 99. 36% identity with the corresponding sequence of Candidatus Ehrlichia sp. isolated from the spleen of a rodent in Senegal (GenBank accession number: MK484069). Our Ehrlichia, Wolbachia and Anaplasma 23S gene sequences were deposited in GenBank under accession numbers OP935908 to OP935910, OP935907 and OP935906 respectively. Sequencing these 38 samples with the 16S Ehrlichia gene yielded 36 sequences. BLAST of these sequences showed that 28 had 97-100% identity with the Occidentia massiliensis sequence (with GenBank accession number: NR149220), while 5/36 had 95-100% identity with an uncultured Ehrlichia sp. (GenBank accession number: MH250197), and three had 99% identity with Candidatus Ehrlichia khabarensis (with GenBank accession number: KR063138).
Our Occidentia 16S gene sequences were deposited in GenBank under accession numbers OP947012 to OP947019. The phylogenetic position of the sequences obtained with the 16S Ehrlichia gene are represented on the phylogenetic tree in Figure  4B. Only one 23S rRNA presented 99. 13% similarity with the corresponding sequence of Wolbachia endosymbiont detected from Ctenocephalides felis in California (GenBank accession number: CP051156). BLAST of the sequence obtained for this sample with the Wolbachiaspecific ftsZ gene showed 93% identity with Wolbachia sp. detected on Cimex japonicus in Japan (GenBank accession number: AB508953). The last 23S rRNA sequence had 94% identity with uncultured Anaplasma sp. detected in the spleen of Mastomys natalensis in Tanzania (GenBank accession number: OL982744).
Funding: This study was supported by the Institut Hospitalo-Universitaire (IHU) Méditerranée Infection, the French National Research Agency under the "Investissements d'avenir" programme, reference ANR-10-IAHU-03, the Région Provence Alpes Côte d'Azur and ERDF PRIMMI funding. Ndiaye E. H. I. , received a PhD thesis grant from the IHU Méditerranée Infection. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Institutional Review Board Statement: The Senegal National Ethics Committee for Health Research (CNERS) approved this study in the context of the "pathogens responsible for fevers (IDEPATH) protocol" SN21/09 SN37/09 in 2012, under number 00081MSAS/DGS/DS/CNERS. Informed Consent Statement: Ornithodoros ticks were collected inside homes after the owners had been informed about the aim of the study and had given their consent.
coli culture (2 litres) (Figure  S3B-C ), indicating that the mutant is less stable than the WT. Furthermore, the MAGEA4 L121/122A mutant eluted in the void volume upon size-exclusion chromatography, indicating that the protein is aggregated (Figure  S3C ). This suggests that the dileucine motif is important for the correct folding of the MAGEA4 MHD and likely only plays an indirect role in the RAD18 interaction. In fact, the crystal structures of MAGEA3, MAGEA11 and MAGEB1 also show that the dileucine motif exists within the hydrophobic core of WH-A, with one of the leucine residues exchanged for isoleucine in MAGEB1  (25, 26)  (PDB: 6R7T) (Figure  S3D ), further supporting the notion that the dileucine motif is not a general feature utilized by MAGEs for binding to partner RING ligases. Instead, in many MAGE proteins, the conservation of the dileucine motif is likely to be necessary for the correct folding of the MHD.
MAGEA4 alters RAD18/RAD6 complex architecture The E3/E2 complex of RAD18/RAD6 was shown, through the use of multiple RAD18 deletion constructs and cross-linking mass spectrometry experiments (XL-MS), to adopt an intricate architecture where the catalytic N-terminal RING domain and the C-terminally located R6BD both bind non-exclusively to RAD6 (Figure  1A )  (5, 27). The superposition of the crystal structure of RAD6/RAD18 R6BD (PDB:2YBF)  (15)  with the AF model of MAGEA4/RAD18 R6BD reveals that the simultaneous binding of both RAD6 and MAGEA4 to the RAD18 R6BD would result in steric clashes between RAD6 and MAGEA4 (Figure  2A ). Therefore, we postulate that MAGEA4 displaces RAD6 from the RAD18 R6BD, whilst still allowing RAD6 to bind to the RING domain of RAD18. To test this, we performed ITC experiments between RAD6 and the RAD18 R6BD peptide and obtained a Kd of 25.