dataesr/scientific-paragraphs-categorization huggingface dataset:
1 using CGViewServer software  (Stothard et al. , 2017). Variant calling on the snippy tool version 4. 6. 0 was used to detect single nucleotides variants (SNV), both between bla OXA-48 plasmids and between strains of the same species. Pangenome analysis was performed with Roary  (Page et al. , 2015)  and visualized using Phandango software  (Hadfield et al. , 2018). The percent similarity of the C. freundii strains and Enterobacter sp. strains was calculated by pairwise comparison of their average nucleotide identity based on Blast (ANIb) and using JSpecies  (Richter et al. , 2016). Genomes of P7535, P7536, P7537, P7538, P7697, P7698, P7699, P7700 and P7702 strains have been submitted to GenBank under accession numbers JAGDEG000000000, CP071788-CP071792, JAGDEH000000000, CP071830-CP071833, CP071834-CP071838, JAGDEI000000000, CP071907-CP071913, JAGDEJ000000000, and JAGDEK000000000, respectively (Table  2 ).
Data availability statement The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: https://www. ncbi. nlm. nih. gov/genbank/, JAGDEG000000000, https://www. ncbi. nlm. nih. gov/genbank/, CP071788-CP071792, https://www. ncbi. nlm. nih. gov/genbank/, JAGDEH000000000, https:// www. ncbi. nlm. nih. gov/genbank/, CP071830-CP071833, https://www. ncbi. nlm. nih. gov/genbank/, CP071834-CP071838, https://www. ncbi. nlm. nih. gov/genbank/, JAGDEI000000000, https://www. ncbi. nlm. nih. gov/genbank/, CP071907-CP071913, https://www. ncbi. nlm. nih. gov/ genbank/, JAGDEJ000000000, https://www. ncbi. nlm. nih. gov/ genbank/, JAGDEK000000000.
e. tambons). The land area of the administrative divisions in the central region are relatively smaller and highly populated compared to other areas of the country. The shapefiles used to map and conduct the analysis which contains administrative divisions of Thailand were downloaded from the database called "The Humanitarian Data Exchange" version v1. 34. 2 (https ://data. humdata. org); the metadata of the shapefile listed the Royal Thai Survey Department (https://www. rtsd. mi. th/main) as the original source of data. Given the variation of granularity (Table  1 ), a decision was made to aggregate all variables at the administrative districts for the analysis (Table  1 ), hence the unit of analysis in both spatial and nonspatial models was the districts.
Data on human and animal rabies cases Rabies is a notifiable disease in Thailand. Human rabies cases are documented and monitored by the Division of Epidemiology) (www. boe. moph. go. th) and the Department of Disease Control of the Ministry of Public Health of Thailand  [32]  (Table  1 ). A total of 35 human cases (during 2013-2016) were reported. While it is possible that they acquired the disease from elsewhere, the human cases were assigned to the districts where those were reported. Human cases are reported based on hospitals and healthcare systems, whereas, animal cases are tested and confirmed based on suspected carcass submissions and supplemented by a limited active surveillance effort. Animal rabies case data were captured from both active and passive surveillance and were obtained from the Department of Livestock Development (DLD).
The active surveillance conducted by veterinary services entails sampling animal died due to inconclusive symptoms and through a minimum active sampling of animals by collecting at least one sample from each subdistrict every year  [29]. Further details on current animal rabies status in Thailand is found elsewhere  [29]. Animal rabies data included cases from the 2012-2017 period and; 1706 (90. 8%), 117 (6. 2%), and 54 (2. 8%) of those cases were associated with dogs, cattle, and cats, respectively. All reported animal rabies cases were included in the analysis regardless of the type of animal affected, considering the limited reporting of animal rabies. Therefore, a total of 1912 human and animal rabies cases were used in the analysis (Fig. 2 ). Among the districts, 621 (67%) reported no cases of human or animal rabies.
Human rabies cases, animal rabies cases, and dog bites/attack counts were compared across districts and months regardless of the year of reporting (Fig. 3 ). (Table  1 ). A total of 2,764,254 dog bites/attacks were reported during 2013-2017 (Table  1 ). The data indicated a yearly average of 453,086 dog bites/attacks and nearly 7 dog bites/attacks per 1000 people (assuming the total human population of Thailand is susceptible)  [33]. The dog bites/attacks were defined according to the WHO guidelines of the possible human exposure to rabies  [2]. 2. Human population data were obtained from the Worldpop database (www. worldpop. org). The UN-adjusted population count grids consist of estimates of the number of persons per 30 arc-second (~1 km) grid cell, adjusted to match the 2015 revision of the UN World Population Prospects national population estimates, and the population estimates for 2015 were used in the analysis  [34].
Dog and cat populations and vaccines: To estimate the dog and cat populations of Thailand, a survey was conducted in 2016 by the DLD  [45]. The collected data included the number of households surveyed, the number of owned and un-owned dogs and cats and their sex. The estimates of animal rabies vaccine distribution by province for 2016 was available from DLD (Table  1 ). As per the survey, the total dog population in districts ranged between 3367 and 98,689 with an average of 8052. 7. The monthly PEP data during January 2014 through March were summarized into yearly averages per province and disaggregated based on the ratio of human population across the districts for the analysis. 8. Household income and poverty: Another key factor influencing the decision to vaccinate pet animals against rabies and maintain responsible pet ownership is the household income  [10] , therefore, poverty index in the units poverty index data available from through 2015  [45]  were collected and summarized by averaging across the years as well as calculating the median of the poverty index for each province.
The variables dog bites and total dog counts were invariably included in the final models given these were considered in the current rabies control programs when disseminating resources  [54]. The relative importance and the goodness-of-fit of models for each variable were assessed by comparing the Akaike information criterion (AIC) values for the alternative models including different sets of covariates (Supplementary Table  2 );  [55, 56]. The "pscl" package  [57, 58]  was used to fit the frequentist ZIP models in R statistical software  [59]. A simple inflation model in which all zero counts were assumed to have the same probability of belonging to the zero component was specified. The residuals of the finalized multivariable ZIP model at the district level were subjected to Moran's I global spatial autocorrelation test to test for spatial dependence between model results at the district level using the 'spatialreg' R-statistical package  [60, 61].
While the transmission pathways are peculiar for animal-to-animal transmission and the zoonotic risk of rabies, here we assumed that having animal cases predicted would indicate a risk for the human population alike. Temporal cross-validation of the model fits was done by using data from 2015 to predict cases in 2016 and 2017. Both multivariable ZIP and Bayesian ZIP CAR models were fitted to the human and animal rabies cases reported between 2012 and 2015 (training data), and fitted value were tested based risk assigned to districts with cases reported between 2016 and 2017 (testing data). Given the data availability for both human and animal rabies varied across the years (Fig. 3 : Panel A), 2015 was chosen as the cut off year; which resulted in 701 (37%) cases in the training dataset and 1211 (63%) cases in the testing data.
Acknowledgements This project was funded by the  Center for Global Health and Social Responsibility of the University of Minnesota. We would like to acknowledge  Thailand's Department of Livestock Development, Ministry of Agriculture and Cooperatives and Department of Disease Control, Ministry of Public Health, and Food and Agriculture Organization of the United Nations (FAO)  for their support providing information and technical consultation to the project. We extend the acknowledgement to the  Centers for Disease Control and Prevention  for their feedback on the manuscript.
To this end, cells (10 5 ) were incubated with 10 nM TMRM in PBS for 15 min at 37 °C, washed and then stimulated with the IgCD95L (100 ng/ml) for the indicated times. TMRM fluorescence was detected in the FL-2 channel (560 nm) of the flow cytometer and data analyzed by Cell Quest software (BD bioscience, San Jose, CA, USA).
Surface Plasmon resonance experiments Experiments were performed at 25 °C with a Biacore ™ T200 apparatus (Biacore ™ , GE Healthcare Life Sciences, Uppsala, Sweden). The experiments were performed on CM5 sensor chips (Biacore ™ ) coated with 140 resonance units (RU) of FasL (Peprotech). A flow cell left blank was used for double-referencing of the sensorgrams. Soluble full-length extracellular domain of CD95 (sCD95) or Δ58 truncated constructs (sCD95-Δ58) were prepared in the running buffer, 10 mM Na 2 HPO 4 , 150 mM NaCl, 3 mM EDTA and 0. 05% Tween-20 at pH 7. 4 and injected in triplicate at 25 µl/min. The regeneration of the functionalized surface was achieved with a 1-min pulse of 0. 5% SDS. The sensorgrams were processed using Biacore T200 Evaluation Software 2. 0 (Biacore ™ ). The association and dissociation rate constants, k a and k d , were determined by direct curve fitting of the sensorgrams to a Langmuir 1:1 model of interaction.
Flow cytometry CD95 surface expression was determined by cell staining with anti-CD95 or isotype control antibodies. Briefly, cells (2. 10 5 ) were washed in PBS and blocked for 30 min with PBS containing 1% bovine serum albumin (BSA). Cells were then incubated for 20 min on ice with an anti-CD95 or isotype antibody in PBS-BSA buffer. Then, cells were washed in PBS supplemented with 2% BSA and resuspended in 150 μL of same solution. Staining was analysed immediately by flow cytometry using a BD FACSCalibur TM and the Cell Quest software (BD Bioscience, San Jose, USA). To decrease antibody internalization and background all steps were performed at 4 °C.
Confocal fluorescence microscopy Cells were fixed with 4% PFA and stained with the indicated antibodies. Fluorescence microphotographs were taken using a laser scanning confocal system (TCS SP8 model mounted on a DMI 6000 CS inverted microscope, Leica, Heidelberg, Germany). Images were taken using a 63x oil-immersion objective (1. 4 N. A. ), collected in a format of 1,024 ×1,024 pixels and analyzed using the ImageJ software (NIH, Bethesda, Maryland, USA).
Proximity ligation assay (Duolink) Proximity ligation assays (PLAs) were performed on fixed cells in 96 multiwells plates. PLA was carried out using the DUOLink TM kit (OLINK, Uppsala Sweeden) according to the manufacturer's instructions. After blocking, antibodies were used at the following concentrations: anti-CD95 (DX2) 1:100 and anti-CD95 (N18) 1:100. The number of in situ PLA signals per cell was counted by using the ImageJ software (NIH, Bethesda, Maryland, USA).
Computer modeling The building of a complete CD95 extracellular protomer started from the most complete crystal structure of the receptor (D55 to E167, PDB:3TJE  [14] ). The lacking Ct loop (connecting to the TM) in the crystal structure (K148 to E156) was built ab initio using Prime, with a VSGB solvation model and OPLS3e force field, as implemented in Maestro 12. 4 (Schrödinger LLC, NY). The lacking Nt part (R17 to Q47) was built by a threading approach, as described previously  [15]. After splicing of each additional fragment to the crystal structure, the completed protomer was embedded in a solvent box of water molecules and Cl -ions for periodic boundary conditions. 16376 H 2 O and 4 Cl -were used for the wild type protomer, 16683 H 2 O and 3 Cl - for the K33G mutant, 16807 H 2 O and 2 Cl -for the Δ36truncated protomer.
Mass spectrometry Plasma membrane CD95 was immunoprecipitated from CEM or H9 cell with the anti-CD95 mAb APO1-3. After several washes to clean unbounded antibodies, cells were lyzed for 30 min in a HEPES-Triton X-100 based lysis buffer on ice. CD95 immunoprecipitation was resolved by a 10% SDS gel and coomassie blue staining was used for protein identification. A band around 40-50 kDa corresponding to CD95 present in parental CEM and H9 cells but absent in CD95-KO counterparts was cut. Mass spectrometry and data analysis were done by Alphalyse as described by the company. Briefly, protein samples were reduced, alkylated, and subsequently digested with trypsin. Resulting peptides were concentrated by Speed Vac lyophilization and re-dissolved for injection on a Dionex nano-LC system and MS/MS analysis on a Bruker Maxis Impact QTOF instrument.
3B ), MMP3 treatment did not (Fig. 3B ). Similar data were obtained by analyzing this staining by western blot confirming that only MMP7 was able to cleave the amino-terminal region of CD95 encompassing the N18 epitope (Fig. 3C  & supplementary raw data). To next identify where the CD95 was cleaved within its amino terminal extremity, we immunoprecipitated plasma membrane CD95 endogenously expressed in leukemic T-cells and sequenced the amino terminal region. To do so, cells were pre-incubated with the agonist anti-CD95 mAb APO1-3, washed to eliminate the excess of antibody and then lyzed before performing the immunoprecipitation. Membrane CD95 was next analyzed through LC-MS/MS. Using LC-MS/MS, we found that the first peptide corresponded to residues 71-100 (RDCTVNGDEPDCVPC-QEGKEYTDKAHFSSK) (Fig.
N-terminal CD95 cleavage reduces the magnitude of CD95 aggregation To gain insight on the possible impact of MMP7 cleavage on CD95 function, we first performed a structural approach. Although two different X-ray structures of CD95 exist, its amino terminal region has not been yet elucidated: the solved amino terminal sequence starts with aspartic acid at position 55 (PDB:3TJE) or leucine at position 52 (PDB:3THM)  [14]. The lack of electron density for the most amino terminal region of CD95 (residues 17 to 58) suggests that it is a flexible and disordered domain. This was confirmed by molecular dynamics experiments (Fig. S3A-B ) with a mean RMSD of 6. 6 Å for residues R17-G56 during the simulation, as compared to 4. 7 Å for Q57-T147. Therefore, we reconstituted the full-length CD95 protein by combining available X-ray data and computer modeling (Fig.
4B, C ). The trimer interface involved more amino acids, among which N31, E36, R38, K39, T40, P64, P65 and E67. In agreement with the presence of many interacting residues in the amino-terminal extremity of trimeric CD95, the full-length Fig. 4  The N-terminal region of CD95 contributes to receptor aggregation. A Superimposition of the two incomplete crystal structures (PDB:3THM in orange and PDB:3TJE in red). Using these structures, the complete amino-terminal region from R17 to G51 in PLAD was reconstituted by ab initio modeling and fused to the X-ray CD95 structures (in blue). Long molecular dynamics experiments (2µs) were finally performed to equilibrate the model. B The 3D organization of the CD95 dimeric model was generated by protein-protein docking of the protomer using SymmDock, with an imposed 2-fold symmetry.
FUNDING This work was supported by  INCa PLBIO, Ligue Contre le Cancer ,  Fondation de France  ( Price Jean Valade), Fondation Ruban Rose, ANR   PRCE ,  ANR-12-JSV2-0004-001  and  Rennes Métropole AIS  grants. With also financial support from  ITMO Cancer of Aviesan  within the framework of the 2021-2030 Cancer Control Strategy, on funds administered by  Inserm. We thank  Avril T. ( Centre Eugène Marquis, Rennes ) for technical assistance with cytometry analysis of peripheral blood cells. The Biacore T200 instrument used in the work was acquired with the support of the  Conseil Régional d'Aquitaine , the  GIS-IBiSA , and the  Cellule Hôtels à Projets  of the CNRS.
Mice received i. p. injections of either olaparib or vehicle every other day and were evaluated when moribund. A majority (90. 9%) of vehicle-treated Mx1-Cre;Brca1 fl/fl ;Trp53 +/-mice developed the expected elevated WBC counts (average 68. 4 K/μL) indicative of disease (Figure  5, B  and D ). In contrast, of the olaparib-treated Mx1-Cre;Brca1 fl/fl ;Trp53 +/-mice, only 2 (13. 3%) developed elevated WBC counts (Figure  5 , C and D), and these elevations were modest (16. 6 K/μL and 28. 8 K/μL). Olaparib was also able to abrogate the hepatosplenomegaly associated with Brca1/Trp53 deficiency (Figure  5E ). Olaparib was nontoxic, as control mice showed no changes in WBC reads, spleen and liver weights, or viability. These data show that treatment with olaparib prior to disease development significantly prevented the highly penetrant neoplastic phenotypes observed in untreated Mx1-Cre;Brca1 fl/fl ;Trp53 +/-mice.
WES data from each spleen were compared with respective paired brain tissue. DNA was extracted using the Qiagen DNeasy kit. Quantity of DNA was measured by picogreen method using Victor X2 fluorometry. Integrity of DNA were checked by Agilent genomic DNA screentape, offering a numeric measurement DNA integrity number (DIN). Sequencing libraries were generated using Agilent SureSelectXT Kit (Agilent Technologies) following manufacturer's recommendations, and index codes were added to attribute sequences to each sample. Read length for paired-end reads was 151 bp. Barcoded WES libraries were sequenced on Illumina-based platform. Average depth was 136×. Paired-end clean reads were aligned to mouse reference genome GRCm38. p6 using Burrows-Wheeler Aligner (BWA) software  (65). Picard was used to mark duplicates.
GATK Best Practices were followed for preprocessing BAM files  (66). GATK and SAMtools were used for variant calling. SnpEff program was used to examine structural changes. Sequences were aligned and graphically visualized using the Integrative Genomic Viewer (IGV) (http://software. broadinstitute. org/software/igv/). WES data were deposited in the Sequence Read Archive (SRA) database (accession no. PRJNA887455). Drug treatment. Olaparib (AZD2281, LC Laboratories) was dissolved in DMSO (Thermo Fisher Scientific) and stored as a 50 mg/mL stock. Prior to use, the olaparib stock was diluted with 10% 2-hydroxyl-propyl-β-cyclodextrine/PBS (Fisher Scientific) in a 1:10 ratio (v/v). Vehicle preparation was the same minus olaparib. All mice began treatment 2. 5 weeks after the final pIpC injection.
Mice received vehicle or olaparib (50 mg/kg) i. p. injections every other day. BM transplantation. BM transplantations were done as previously described  (17). Adult recipient mice (CD45. 1) were administered a minimum lethal dose of radiation using an XRAD 320 x-ray irradiator (Precision X-Ray) to deliver 2 doses of approximately 540 rad (1,080 rad in total) at least 3 hours apart. Cells were injected into the retro-orbital venous sinus of anesthetized recipients. Blood was obtained from the submandibular plexus of recipient mice at the indicated time points after transplantation. RBCs were lysed with ammonium chloride potassium buffer. Statistics. Data are displayed as mean ± SEM. Statistical significance between 2 groups was assessed using the 2-tailed Student's t test. Statistical significance between multiple groups was determined by 1-way ANOVA followed by Bonferroni corrected post hoc comparisons.
Acknowledgments We thank members of the  Ross lab  and  Stephen Chung  for their intellectual contributions to this work. We would also like to thank  Jonathan Rios  for his assistance in analyzing WES data and  Karine Pozo  for her critical input. This work was supported by  NIH   R01 HL132251-02 , the  Nancy Tartaglino Richards Cancer Genetics Research Fund , the  Lucy and Henry Billingsley Fund , the  Cancer Prevention Initiative (CPI) , and a  Burroughs Wellcome Fund   Clinical Scientist Award in Translational Research  (TSR). Address correspondence to:  Theodora Ross ,  University of Texas Southwestern Medical Center , NB2. 102, 5323  Harry Hines  Blvd. , Dallas, Texas 75390, USA. Phone: 214. 648. 1220; Email: Theo. Ross@utsouthwestern. edu.
Data collection Data from eligible patients were extracted and collected from the computerized order entry (CPOE) software for anticancer chemotherapy (CHIMIO v5. 7, Computer Engineering, Paris, France). The following clinical, pathological and therapeutic variables were collected: age, sex, primary cancer location, cetuximab-based regimen type (monotherapy or chemotherapy-based combination, concomitant radiotherapy) and use of premedication with corticosteroids and/or H1A. Finally, the occurrence and symptoms of CI-IRs (any grades) on the rst infusion of cetuximab and outcome (potential cetuximab rechallenge, desensitization procedure, and switch to panitumumab) were recorded. CI-IRs were graded retrospectively based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTC-AE) version 5.
Statistical analysis Quantitative data were described with their median and inter-quartile ranges (Q1-Q3) and compared with the non-parametric Kruskall-Wallis test. Qualitative data were described by frequencies and percentages and compared with the Chi-square test or Fisher's exact test when appropriate. Subgroup analyses of CI-IR risk factors by area were carried out. Multivariate analyses were conditioned to a minimal number of events at the statistician's discretion. All analyses were performed using SAS version 9. 4 (SAS Institute Inc. , Cary, NC, USA). Statistical signi cance was de ned as a P-value < 0. 05 for all tests.
Discussion The CETUXIR study is the rst one to investigate CI-IR distribution in a large cohort of 1392 consecutive patients treated in real life in four different French areas. Our study shows a higher incidence of CI-IRs in the area with the highest risk of Lyme disease in a European country, in line with previous non-European ndings. The present study found an overall incidence of 8. 4% of any grades CI-IRs, consistent with previous data provided by the cetuximab SCP  [1]  (Fig. 2 ). CI-IR rates were signi cantly higher in the high-risk area of Lyme disease compared with others (13. 2% versus 7. 1%, 8. 1%, 6. 4%; P = 0. 016) and compared with the literature  [1, 2, 4, 5, 7, [43] [44] [45]. Severe CI-IR rates also seemed to be higher in the high-risk area (8. 3% versus 3. 4%, 5. 4% and 3.
Among the 374 CI-IRs reported during a 15-year period in The French Pharmacovigilance database, the indication of cetuximab was more likely HNSCC than colorectal cancer (P < 0. 001)  [23]. In a French monocentric study, combined tobacco and alcohol history (P = 0. 009) and prior allergy history (P = 0. 003) were associated with CI-IRs in 428 patients treated for HNSCC  [25]. The pathophysiological mechanisms of the relation between CI-IR risk and HNSCC with alcohol and tobacco history remain unclear. Tobacco and alcohol exposure could mediate local chronic in ammation and favour an IgE-mediated reaction  [25]. In the present study, tobacco-alcohol consumption was not collected and the risk of CI-IRs in HNSCC patients was higher only in the Limoges high-risk area. This result suggests the existence of a still unknown confusion bias between HNSCC and Lyme disease.