dataesr/scientific-paragraphs-categorization huggingface dataset:
Acknowledgements. The authors wish to thank the staff of the  "Centres Científics i Tecnològics" of the University of Barcelona (CCiTUB)  for their assistance in the preparation of samples. JM is a member of the 2017-SGR-1008 research group. EBG was granted an  FPI predoctoral scholarship by "Gobierno de Canarias " co-funded by " Fondo Social Europeo " ( 85% ) and " Consejería de Economía, Industria ,  Comercio y Conocimiento". Funding from the University of La Laguna  and the  Canary Council of Economy ,  Knowledge and Employment (CEI program ) is acknowledged.
Psoriatic arthritis SPIRIT-P3 (NCT02584855) and SPIRIT-H2H (NCT03151551). 5] [16] [17]  Briefly, patients were required to have active PsA that met the classification criteria for PsA with at least 3 of 68 tender and at least 3 of 66 swollen joints, and active psoriatic skin lesions or a documented history of psoriasis. Patients were excluded if they had active Crohn's disease or active ulcerative colitis or if they had any condition that would pose an unacceptable risk to the patient or otherwise confound the results of the respective studies. Detailed study designs have been previously published.
Statistical analysis Safety analyses were based on all randomised patients who received at least one dose of the study drug (pooled data from patients at 80 mg every 4 weeks and every 2 weeks); a post-hoc safety analysis of the two ixekizumab regimens (every 2 weeks and every 4 weeks) was also conducted. Total exposure was calculated by summarising the duration of ixekizumab exposure (in days) for all patients divided by 365. 25 and expressed in total patient-years (PY). All safety events were reported by number and percentage of patients with AEs and EAIRs per 100 PY (95% CI). All EAIRs were calculated as divided total number of patients who experienced the TEAE for each preferred term by the sum of all patients' time (in 100 years) of exposure during the treatment period. The entire time on study during the treatment period was used.
5) of patients reported an event of allergic reaction or hypersensitivity (table  4 ). The most frequently reported events were rash (1. 4%, EAIR=0. 8), eczema (1. 1%, EAIR=0. 7), drug hypersensitivity (0. 7%, EAIR=0. 4) and allergic rhinitis (0. 7%, EAIR=0. 4). TEAEs of allergic reaction or hypersensitivity were more frequently reported after 1 day of injection and before the next injection. All reported events were mild (4. 1%) to moderate (3. 1%) in severity except for one severe case. Most cases were non-serious; two serious cases were identified (one case of angio-oedema and one case of bronchospasm) and both have recovered or resolved (table 2). No cases of anaphylaxis were confirmed after medical reviews. Also, available data do not support any association between immunogenicity and TEAEs.
Psoriatic arthritis exposure to onset of the first IBD events was 351 days, with four subsequent events. Another patient was a 28-year-old white woman who had one event categorised as moderate IBD (adjudicated as Crohn's disease) and did not recover and led to discontinuation of the study drug. This patient reported IBD at 183 days after exposure to ixekizumab. The last patient, a 64-year-old white woman, experienced a moderate IBD event (adjudicated as Crohn's disease) that was resolving or recovering at the time of the data lock. This IBD event was reported at 113 days after ixekizumab exposure. Among the three confirmed cases, two were serious (0. 1%, EAIR=0. 1) (table  2 ). As assessed in exposure period analyses, the incidence of IBD was low (EAIR ≤0. 6) and stable over time (figure  2D ).
DISCUSSION In this analysis we reported the updated safety profile of ixekizumab in 1401 patients with PsA across four clinical trials for up to 3 years of ixekizumab. Because of the chronic nature of the disease, long-term pharmaceutical management of PsA is required to maintain adequate disease control. In the current analysis, the long-term ixekizumab exposure did not increase the exposure-adjusted rates of TEAEs and SAEs reported in previous safety reports. 10 11 20 As assessed, EAIRs were decreasing or constant over time. The data reported in this analysis of patients with PsA are consistent with the known safety profile in the entire ixekizumab clinical development programme. 20.
Polymorphisms and CNV in the GSTe2 gene A total of 57 mosquitoes were PCR positive for presence of the GSTe2 gene. 47 confirmed positive samples were chosen for purification and sequencing, and 21 mosquitoes were successfully sequenced in the whole GSTe2 gene (Five susceptible and 16 resistant). Seven non-synonymous SNPs resulting in the following changes: L111S, C115F, P117S, E132A, I150V, E178A and A198E. These substitutions were consistently distributed across two distinct haplotypes. Thirteen of the 21 sequenced haplotypes belonged to haplotype 1 (4 susceptible and 7 resistant) and 8 belonged to haplotype 2 (1 susceptible and 7 resistant) (S2 Fig). Haplotype 2 showed low similarity (~90% homology) to available sequences in Genbank, whereas haplotype 1 showed ~96% homology. However, no statistically significant association between haplotype variant and insecticide resistance was found (p = 0.
Sequence data analysis Sequencing was made on a HIseq 4000 sequencer (Illumina, 2x125nt) using the v4 chemistry/HBS Hiseq kit. One line was used for each sample to produce up to 300x10 6 reads per sample. Image analysis and base calling were performed using Illumina Real-Time Analysis software version 2. 7. 3 with default parameters. Raw sequence data produced by the Genotoul platform and Integragen were sent to the laboratory on oppy disks for processing and analysis. The two sequence extremities were rst trimmed to remove the remaining primer sequences and any bases with poor quality base calling often present at the extremities of the reads with Cutadapt  (25). The trimmed sequences were then aligned with STAR. v2 through Galaxy (Sigenae)  (25). The resulting BAM les were analyzed with Samtool, Bedtool, Cu ink and Stringtie  (26)  on the Toulouse Genocluster and with the Geneious suite  (27).
Given this, we therefore believe the two gures 0. 27 and 0. 31, representing the percent of mismatches between the sequence reads aligned onto the reference genome (CanFam3. 1), are indicative and representative of any slight polymorphism differences Analysis of the sequence data with the Geneious suite (  27 ) allowed us to identify many genes and to calculate their respective FPKM values, i. e. the number of reads corresponding to each transcript, a metrics de ning the abundance of all transcripts (Additional data les 1a, b) and OR transcripts (Additional data le 2). For these two samples, despite the very deep sequencing strategy only 14% and 16% only of the OR gene transcripts were detected with an FPKM > 0. 1, corresponding to 112 Bichon and 104 Golden Retriever OR genes respectively, percentages to be compared to 90% for the OR murine and human repertoires and the 70% for canine repertoire  (10, 13).
Reliability and reproducibility of the approach In this series of experiments, we analyzed 14 samples from four dogs only, i. e. two to six per dog, to appreciate the reproducibility of the samplings, as well as the difference that could exist between the right and left nostrils. As shown in Additional data le 3, a strong correlation does exist between the different FPKM values obtained for the same dog, either if one compares the right and left nostril samples or the different samples from the same nostril. In the heat map presented in Fig. 2  hierarchical clustering is seen for the four Labrador Retriever samples, for the two West Highland White Terrier samples and for four out of the ve Whippet samples. A discrepancy was seen for the two Belgian Shepherd samples which are not grouped, suggesting a sampling or a sequencing problem.
Using the same set of oligonucleotides, we captured the OR gene nucleotide sequences and sequenced them. As each gene is present in two copies, we anticipated that (a) the FPKM values of each gene should be similar or identical in the two libraries and (b) the comparison of the FPKM of the different OR genes within each library will reveal the e ciency of the capture method itself. In Additional Data le 4, we plotted the calculated FPKM values, in blue for the Cane Corso sample and in red for the Golden Retriever. As shown in this le, most of the blue and red dots are confounded or very close, indicating a good reproducibility of the capture itself, as supported by the Pearson correlation test. However as seen in Additional Data le 4, comparison of the FPKM of the different OR gene within each of the two sample indicates a large difference, con rming the previous observation that the e ciency of hybridization capture is in part sequence dependent (32).
Study design and data curation The study was carried out using data on Charolais young bulls collected between 2016 and 2018 by AZoVe, a cooperative of beef producers located in the North-East of Italy (Cittadella, Italy). Specifically, information on animal ID, date of birth, fattening farm, start and end of the fattening cycle, entry BW (available as mean BW of the batch, in kg), carcase weight at slaughter (CW, kg), number of parenteral treatments administered to the animals, date of treatment, reasons of administration (respiratory diseases, locomotor disorders, gastrointestinal diseases and others), amount of antibiotic administered per each parenteral treatment (mL) and number/type of vaccines were available. Animals with incomplete information on AMU and performance traits were discarded from the dataset.
Other variables such as age at the beginning of the fattening period, slaughter age (SA, days), duration of the fattening cycle (days) and average daily carcase gain [ADCG ¼ CW (kg)/duration of the fattening cycle (days)] were calculated. The Animal ID allowed to retrieve the French department of origin of the animals and the number of French farms that provided animals to each batch. The map of the French departments which originated the animals is depicted in Figure  1. To avoid potential biases, batches with less than 10 animals were removed from the dataset because they were considered not representative of the French procedure of commingling. Indeed, most of those batches contained only 1 animal. Similarly, we retained only batches with animals from 3 to 8 French departments since 90% of the data fell within this range.
Quantification of antibiotic use A total of 57 veterinary medicinal products (VMP) that contained antibiotics were used in the 3-year period of the study. A defined daily dose animal for Italy (DDDAit) was assigned to each medical active ingredient (MAI) with the antibiotic activity of those VMP. A DDDAit is the dose (mg) of the MAI administered per kg of BW per day. In particular, the DDDAit was established during the development of the ClassyFarm integrated monitoring system (www. classyfarm. it) of the Italian Ministry of Health and was based on Italian summaries of VMP characteristics. Six out of 57 VMP were removed from the final dataset because the DDDAit of their MAI was not available. Then, an index called treatment incidence 100 for Italy (TI100it) was calculated for each VMP at the animal level using the DDDAit as a metric.
Indeed, although the actual measures would provide a more accurate estimate, the former would reduce the opportunity of comparing AMU data beyond the national level. The TI100it of all VMP were summed up to obtain a total TI100it per animal. If a VMP had two MAI, both were considered in the calculation of the DDDAit as two different treatments. A TI100it of zero was attributed to animals that did not receive any treatments. The number of animals that received at least one treatment during the fattening cycle, the percentage of parenteral treatments according to the reason of administration, the percentage of parenteral treatments per class of antibiotics and the prevalence of the most used vaccines were calculated.
4 (SAS Institute Inc. , Cary, NC, USA). The model accounted for the fixed effects of class of commingling, month of arrival, year of arrival, age of bull at arrival to the fattening farm (3 classes, according to mean age ± 0. 5 standard deviations; young: age at arrival <291 days; medium: age at arrival between 291 and 355 days; old: age at arrival >355 days) and the interaction between the class of commingling and age at arrival to the fattening farm. Fattening farm and the residual were the random effects. The TI100it was not normally distributed and thus a generalised linear mixed model with gamma distribution and log link function in GLIMMIX procedure of SAS was used for the analysis. Since the TI100it was always positive and skewed near the ordinate axis, the gamma distribution was assumed for TI100it in statistical analysis.
▸ Figure  6. MM primary tumors are highly susceptible to mycolactone toxicity and synergy with BZ. Mononuclear cells from bone marrow aspirates of newly diagnosed (#2, #5, #9, and #13) or relapsed (#7 and #12) MM patients were treated with mycolactone and/or BZ at the indicated concentrations, or vehicle as control, for 18 h. Then, MM cells were identified by staining with anti-CD38 and anti-CD138 antibodies using the gating strategy depicted in Appendix Fig  S2. A Following treatment, induction of apoptosis/necrosis was measured by exposure of annexin V and PI incorporation. Data are Mean % of live cells from technical duplicates, relative to controls. B Synergy between mycolactone and BZ in treated tumors. Data are Mean Loewe scores from technical duplicates, shown as heatmaps. Serum levels of paraproteins, the antibody fragments produced by MM, are used clinically to diagnose MM and monitor its progression  (Tate, 2019).
Patients Patients were seen at Saint-Louis hospital, Paris, France, for a new or known diagnosis of MM. Characteristics of the patients are shown in Table  1. Bone marrow aspirates were performed in the Department of Immuno-Hematology of the Saint-Louis Hospital using standard procedures, as part of routine diagnostic work-up. Written informed consent was obtained from all patients, and experiments conformed to the principles set out in the WMA Declaration of Helsinki and the Department of Health and Human Services Belmont Report. All samples containing measurable numbers of viable mononuclear cells were processed and included in data analysis. The protocol received approval of the ethical committee "Groupements hospitaliers universitaires" GHU Nord; No. 23798-2020012709469025 # 121.
Data were analyzed with the FlowJo software  (Tree Star, Ashland, OR). Mean fluorescence intensities (MFI) of isotype controls recommended by the Ab supplier were systematically subtracted to that of each stained sample. Cell viability was assessed by Annexin V exposure and PI incorporation using the FITC-Annexin V/PI kit from Miltenyi Biotec (#130-092-052) following the manufacturer's protocol. Live cells were characterized as Annexin V -PI -, apoptotic cells as Annexin V + PI À , and dead cells as Annexin V + PI + and Annexin V À PI + as shown in Appendix Fig S1. Detection of secreted immunoglobulin light chain by ELISA Supernatants from MM cells cultures treated with mycolactone and/ or BZ alone were collected after 24 h, and the concentration of free light chain was assessed using the SEBIA FLC lambda ELISA kit (SEBIA, 5101) according to the manufacturer's recommendations.
Flow cytometric analysis of MM patient-derived samples and PBMCs Patient-derived mononuclear cells were isolated from bone marrow aspirate by density gradient centrifugation with Pancoll separating solution (PAN-Biotech, DE). 2 × 10 5 cells were then plated in 96 wells plates in culture medium in the absence or the presence of mycolactone or BZ alone or in combination as described in the text for 18 h. Cells were then washed and stained with fluorescentconjugated anti-CD38 and anti-CD138 antibodies to gate plasma cells, in the presence of Annexin V-FITC and PI for 15 min at room temperature. Cells were then acquired using a flow cytometer (Attune NXT, ThermoFisher) immediately after the staining and cell viability was assessed by analysis using FlowJo software (Tree Star, Ashland, OR). PBMCs were isolated from blood samples of healthy donors collected by the French Blood Establishment (EFS), by Pancoll density gradient centrifugation.
Mouse experiments In vivo toxicity assays were performed on 8-week-old C57BL/6J (B6) mice purchased from Charles River laboratories as follows. Mycolactone (0. 3 mg/kg) and BZ (0. 3 mg/kg) alone or in combination were diluted in NaCl solution (0. 9% w/v) administrated every 3. 5 days via the intraperitoneal route. The toxicity of the treatments was assessed by measuring the percentage of T and B cells in the blood sample collected in tubes containing EDTA (0. 05 M) from the tail vein 5, 15, 20, and 25 days after the first injection. Red blood cells were lysed using red blood cells lysing buffer (SIGMA R7757). Leukocytes were stained with anti-mouse CD3/PerCPcy5. 5 (#45003182 eBioscience, diluted 1/100) and CD19/APC (#550992 BD Pharmingen, diluted 1/800) antibodies and fluorescence data were acquired by Cytoflex flow cytometer (Beckman Coulter).
The percentages of T (CD3 + ) and B (CD19 + ) cells were determined using FlowJo software. Experiments assessing the effect of the treatments on the development of xenografted MM tumors were performed in 8-to 12-week-old NSG mice. 3 × 10 6 human MM-1S cells were subcutaneously injected in the right flank of the animals in 200 µl of PBS. After 24 h, mice were randomly assigned to four groups and 6 days later, each group was randomly assigned a treatment. Mice were injected by intraperitoneal route with mycolactone (0. 3 mg/kg and/or BZ (0. 3 mg/kg), in 200 µl NaCL (0. 9% w/v), or vehicle as control, every 3. 5 days. Tumor growth was assessed daily by unblinded measurement of tumor size with a digital caliper. Data are presented as the average of two perpendicular diameters (millimeters). Mice were sacrificed when the tumor diameter reached 20 mm or whenever animals showed clinical signs of pain according to ethical guidelines.
Acknowledgements We would like to thank  Jean-David Morel  (now at  EPFL, Lausanne ) for advice regarding the experiments using v-abl cells, and the staff of Animal facility of  Institut Pasteur  for supervising mouse housing. This work was supported by the  Canc eropôle Ile de France  (CD and J-CB; Emergence 2019), the  Fondation Française pour la Recherche contre le My elome et les Gammapathies (CD, FFRMG) , and the  Sanofi iAwards program  (CD, 2020). CD also acknowledges core support from  Institut Pasteur  and  INSERM  ( U1221 ). LB was recipient of a  Roux-Cantarini post-doctoral fellowship  ( Institut Pasteur ). AD is a  BioSPC-Universit e de Paris  PhD student, recipient of a doctoral fellowship from the  Minist ere français de l'Enseignement Sup erieur, de la Recherche et de l'Innovation.
Such feature revealed that chromosome 1 has a metacentric centromere, whereas chromosomes 2 and 3 have a telocentric centromere, and chromosomes 4 and 5 have an acrocentric centromere (as illustrated in the diagram below Figure  2B ). A similar organization was observed in three of the four chromosomes of Babesia bovis (22). Using BUSCO v5  (23) , a software tool that measures completeness and redundancy of a genome in terms of expected gene content, we found that the B. duncani WA1 nuclear genome has 95. 1% of the gene models derived from the apicomplexa_odb10 database (85. 2% single-copy, and 9. 9% duplicated) with another 1. 8% fragmented gene models, and only 3. 1% of the gene models missing. The chromosomal organization of the B. duncani nuclear genome was further validated using PFGE analysis.
Transcript analysis using BUSCO v5  (23)  showed the transcripts' annotations matching with 88. 6% of the transcripts in the apicomplexa_odb10 database (80. 5% single-copy, and 8. 1% duplicated), whereas 5. 8% are fragmented and 5. 6% are missing. BUSCO analysis further showed that the B. duncani protein annotations match 87. 7% of the proteins in the apicomplexa_odb10 database (79. 6% single-copy, and 8. 1% duplicated), whereas 5. 6% are fragmented and 6. 7% are missing. Only 1. 2% of the genome is considered repetitive by RepeatMasker. Repeats were detected in the following categories: simple repeats (0. 79%), low complexity repeats (0. 09%), small RNA (0. 29%) and other interspersed repeats (0. 03%).
These families can be divided into two classes: BdUMGF (unique to B. duncani) and BdOMGFs (with orthologs in other Apicomplexa). The BdUMGF class includes 327 genes grouped into 52 gene families. The largest family in this group (BdUMGF1) consists of 51 members (Fig. 5A  and 5B ). The BdOMGFs comprises 420 genes grouped into 105 genes families each belonging to an orthologous group among Apicomplexa. The largest family, BdOMGF1, belongs to orthology group OG6_101304 that includes 288 orthologs in Theileria spp, majority of which are hypothetical proteins, 5 Tpr-related proteins in B. microti, 5 hypothetical proteins in B. bovis and 3 members of the bir1, PIR and YIR in P. yoelii. The components of each of the gene families and their properties are available in the supplemental datasets. The chromosomal location of the genes in the three largest BdUMGF and BdOMGF families, as well as the GPI and AP families, is illustrated in Figure  5C.
Regulation of gene expression in B. duncani. Our RNA-seq analysis, which was used to refine the genome annotation, helped determine the expression levels of encoded gene to gain insights into their importance during the parasite life cycle in mammalian blood or the tick vector families as well as to provide evidence for function metabolic pathways that could be targeted for the development of novel therapeutic strategies. Using transcript abundance values based on the mean depth of coverage (see Experimental procedures), we found that the total range of transcriptional activity captured using the continuous in vitro growth conditions varied by more than four orders of magnitude (Fig. 6  and supplemental datasets). Overall, RNA-Seq data captured close to 90% of the predicted annotated genes in the assembled B.
We then exploited this dataset further to mine and identify additional molecular components that could be critical to the survival of the parasite. Of the reads that mapped uniquely against the babesia genome, ~83. 91% mapped to predicted protein-coding genes and 23. 6% mapped within 300-bp up-or downstream of genes as well as within intergenic regions, demarcating possible UTRs and lncRNAs respectively. Long non-coding RNAs (lncRNAs) are non-protein coding transcripts that are generally regulated and processed similarly to mRNAs and have been shown to play a critical role in biology including cell differentiation throughout changes in epigenetics and chromatin structures. Their roles have also been implicated in the regulation of genes involved in antigenic variation in human malaria parasites  (36).
This sub-group of proteins includes one DNA binding proteins of the AP2 class, one RAD51-like protein, and a putative RNA-binding RAP protein associated with Pfam domain PF08373 that could be targeted to the mitochondria as was shown in P. falciparum  (41). The Babesidiae cluster is composed of 554 OrthoMCL IDs (Fig. S3 ), 259 of which are B. duncani proteins. 33 proteins were associated with OrthoMCL ID that were unique to true-Babesia species. Most functions in this group are related to the regulation of gene or protein expression. BdWA1_000742 was the only surface protein which was part of this group of Babesia specific protein. It is a one transmembrane domain protein with four EGF-like domains (hEGF, PF12661) with more divergent homologs in Plasmodium and Theileria. Another unique property of B.