dataesr/scientific-paragraphs-categorization huggingface dataset:
The European Vaccine Initiative (EVI)  [20]  and its partners have been instrumental in mobilizing funds for the development of a vaccine against placental malaria, through the PRIMALVAC (Institut National de la Santé et de la Recherche Médicale, Inserm, France) and PAMCPH (University of Copenhagen, UCPH, Denmark) projects funded by the German Federal Ministry of Education and Research through Kreditanstalt für Wiederaufbau, the Irish Aid and the Danish National Advanced Technology Foundation as well as the PlacMalVac (University of Copenhagen, Denmark) project funded under European Commission Seventh Framework Programme (FP7). Both, the PRIMALVAC and PAMCPH/PlacMalVac projects currently have VAR2CSAbased vaccine candidates in Phase Ia/b clinical trials. Although the two vaccine candidates are based on the same protein VAR2CSA, the selected antigens encompass different VAR2CSA regions and sequences with potentially distinct antigenic properties that might complement each other in terms of immunogenic potency and protective efficacy.
Decision criteria In terms of the safety requirements for transition from the Phase I stage in non-endemic region (Phase Ia) to the Phase I stage in endemic region (Phase Ib) of the first clinical trial, there should be no serious adverse events definitely related to the vaccine candidate, and serious adverse events possibly related to the vaccine candidate or grade 3 adverse events lasting for more than 48 h should be reviewed by the independent safety monitoring board appointed for the clinical trial with recommendation made to the sponsor. The phase Ib data will be evaluated for both safety and immunogenicity, and the threshold criterion for further clinical development requires at least 60 % seroconversion against the vaccine candidate antigen in the target population. The major outcomes on the clinical development plan are depicted in Table  1.
However, HPV vaccine offered to all subjects enrolled in the Phase Ib after completion of the clinical trial would be an appropriate benefit to participants. Potential inclusion/non-inclusion criteria were defined. The main inclusion criteria for Phase Ia stage in Europe will be healthy adult females willing to practice contraception and adult males. The main inclusion criteria in Africa will be healthy nulligravid female adults living in malaria endemic areas willing to practice contraception for the duration of the vaccinations and a defined follow-up period. The main non-inclusion criteria include pregnancy, concurrent infection with malaria, known HIV-positive status and known carriers of Hepatitis B (HBV) or Hepatitis C (HCV). The subjects will be followed for six months after the last dose to assess vaccine safety as per regulatory guidelines and to gather the appropriate immunological and (if possible based on assay development standards) functional data on the performance of the vaccine candidate.
Even if RTS,S/AS01 were developed for pregnant women, it only confers partial protection in children and perhaps less in adults, so its potential activity against placental malaria is uncertain. Additional tools are required to combat placental malaria. Vaccines designed specifically for placental malaria are attractive because they could lead to reductions both in disease incidence and severity. The two placental malaria vaccine candidates, PAM-VAC and PRIMVAC adjuvanted with Alhydrogel (Brenntag, Denmark), GLA-SE or GLA-LSQ (IDRI, USA) entered Phase Ia/b clinical trials in May 2016 (NCT02647489, NCT02658253). To allow comparison of the clinical trial results and to enable informed decision making for further development, two workshops were conducted by EVI with the aim of standardizing and harmonizing the clinical development plans and the immunoassays for assessing responses to the two placental malaria vaccine candidates.
Acknowledgements Scientific Oversight Committee Clinical development WS:  Adrian J. F. Luty ,  Institut de recherche pour le développement (IRD), France ;  Alister Craig ,  Liverpool School of Tropical Medicine, UK ;  Odile Launay ,  Centre d'Investigation Clinique (CIC) Cochin-Pasteur, France ;  Patrick Duffy ,  National Institute of Allergy and Infectious Diseases/National Institutes of Health, USA.
2a ). These data are in line with a higher frequency of IL-17A + and RORγt + expressing CD4 + Th17 cells detected by flow cytometry analysis in N1N2 ΔCD4Cre compared to control mLN cells (Fig. 2b, c ). Mice lacking Notch expression in their T cells had an overall larger number of total and CD4 + T cells in their mLNs, resulting in an overall higher number of Th17 cells expressing IL-17A and RORγt (Fig. 2d ). Of note, cell number of other peripheral lymph nodes such as inguinal lymph node (iLNs) did not differ between N1N2 ΔCD4Cre and control mice (Fig. 2e ). To analyze cytokine secretion by mLN Th17 cells, N1N2 ΔCD4Cre and control mLN cells were isolated and their TCR activated ex vivo. 72 hours later, cytokine levels were analyzed in cell-free supernatant. In agreement with the higher frequency of Th17 cells detected by flow cytometry, higher levels of IL-17A were observed in mLN total cells, or CD4 + T cells of Notch-deficient mice, compared to those observed in control mLN cells.
4b  and Fig. S2 b, c ), or TCR stimulation (Fig. S2a ). These data indicate that, as observed in the gut, N1 and N2 receptors control T h 17 cell differentiation following immunization. To further analyze Th17 effector function the levels of Th17-associated cytokines secreted following OVA/ CFA immunization, dLN CD4 + T cells were isolated from control and N1N2 ΔCD4Cre mice 9 days after immunization and restimulated, or not, ex vivo, with αCD3 or OVA in the presence of irradiated splenic cells. Th17-secreted cytokines were then assessed in cell-free supernatant. Surprisingly, and in contrast to the elevated levels of intracellular IL-17 observed in N1N2 ΔCD4Cre CD4 + T dLN cells, a marked decrease in the levels of Th17 cytokines IL-17A, IL-22 and GM-CSF were observed in the supernatant of TCR, or antigen-specific-restimulated N1N2 ΔCD4Cre CD4 + T cells, compared to that observed in control dLN T cells.
A selective decrease in IL-17A, IL-22 and GM-CSF cytokine secretion was observed with no impact on IL-13 and TNF-α secretion (Fig. 4g ). These data suggest that proteolytic activation of the Notch receptors is necessary for modulating Th17 cytokine secretion. Furthermore, kinetics of cell viability was analyzed following ex vivo stimulation with OVA. The latter revealed no differences between control and N1N2 ΔCD4Cre CD4 + T cells (data not shown). Taken together, our results show that Notch regulates Th17 differentiation and that depending on the context, Notch receptor signaling regulates secretion of IL-17A and other Th17-related cytokines.
mTORC1 activity was measured by phosphorylation of ribosomal protein 6 (p-S6) and mTORC2 activity by that of Akt phosphorylation at serine 473, two canonical mTOR substrates. In agreement with the data obtained for STAT3 and HIF-1, no difference in p-S6 activity was observed in dLN cells of N1N2 lox/lox and N1N2 ΔCD4Cre Th17 cells (Fig. 6d  left panels) suggesting that Notch is not regulating Th17 differentiation and effector function through mTORC1. In contrast, we observed decreased Akt S473 phosphorylation in N1N2 ΔCD4Cre compared to N1N2 lox/lox Th17 cells (Fig. 6d  right panels) which links Notch signaling with mTORC2 activity in immunized Th17 cells. Downregulation of the mTORc2-Akt pathway in CD8 + T cells has been shown to promote mitochondrial biogenesis through a FOXO1-dependent manner  40, 41.
Permeabilized CD4 + T cells were stained with anti-mouse CD71-PeCy5 (Transferrin receptor) (R17217) (eBioscience), IL-17A-PE (eBioscience), anti-mouse GM-130-Alexa647 (35) (BD Biosciences) and DAPI. Cells were acquired using Inspire software (Amnis) on a 4-laser 12-channel imaging flow cytometer (Image Stream X Mark II) using 40x and 60x magnifications. Prior to each experiment the machine was fully calibrated using ASSIST (Amnis). Per file 20000-100000 single cells were acquired using the 40x objective. In addition a file with 200-300 IL-17A + cells using the 60x magnification was acquired for each sample. Debris and doublets were excluded based on their area and aspect ratio. Single stain controls were acquired as required (all channels on, no brightfield and no side scatter image) and a compensation matrix was calculated and applied to the files using IDEAS (v6.
Acknowledgements We thank  Yazmin Hauyon-La Torre  for technical assistance and  Dr. Marc Descatoire  for discussion together with  Dr. Anne Wilson  and the flow cytometry facililty of the  University of Lausanne. This work was financed by a  SNF grant  ( 310030. 166651/1  to FTC). MC is supported by an  Institut Suisse de Recherche Expérimentale sur le Cancer foundation (ISREC)  Ph. D. fellowship. P. -C. H. is supported by a  SNF grant  ( 31003A_163204 ) and  Melanoma Research Alliance Young Investigator Award.
Modeling studies of the P64T and R134M amino acid changes Models of the human UMP/CMPK1 were built using as template the three-dimensional structure of the Dictyostelium discoideum UMP/CMPK in the closed conformation complexed with ADP and CMP (pdb code: 2UKD). The cytosine base interacts via water-mediated hydrogen bonds and hydrophobic interactions with residues Ile-62, Val-63 and Asn-97 (Figure  5A ). Pro-64 is located next to Ile-62 and Val-63 and allows the positioning of these residues close to the cytosine moiety for the establishment of efficient interactions. The P64T substitution may modify the distance between Ile-62, Val-63 and CMP, and therefore reduce the intensity or abolish the interactions observed in the wild-type UMP/CMPK1 at this position (Figure  5B ). The Arg-134 is located in the LID domain, a mobile domain that contains positively charged residues able to stabilize the phosphate of the ATP with the magnesium ion in the active site (Figure  5C ).
In HaCaT CDV , no changes in UMP/CMPK1 protein content were detected. These results are in line with impairment of CDV metabolism in SiHa CDV and HeLa CDV but not in HaCaT CDV. These data highlight a different pattern of CDV metabolism in each CDV R cell lines and that reduction of UMP/CMPK1 protein level is not enough to explain CDV R , since HaCaT CDV cells exhibited CDV R despite no impairment of UMP/CMPK1. Reduced levels of UMP/CMPK1 in SiHa CDV resulted in poor CDV activation as shown by a significant decrease in CDVp but not in CDVpp or CDVp-choline. The enzymatic UMP/CMPK1 assay demonstrated that both amino acid changes (i. e. P64T and R134M) abolished the capacity of the enzyme to efficiently phosphorylate CDV. However, we did detect intracellular CDVp and the subsequent metabolites CDVpp and CDVp-choline in SiHa CDV , suggesting that both wild-type and double mutant UMP/CMPK1s are expressed in these cells.
Microarray experiments Parental and CDV R cells were allowed to grow for 72 h in medium without CDV. Total RNA of 1 × 10 6 cells was isolated with TRIzol reagent (Invitrogen) and further purified by RNeasy Mini Kit (Qiagen). RNA quality and quantity were assessed with a Bioanalyzer system (Agilent). www. impactjournals. com/oncotarget Microarray data were generated as previously reported  [12]  and is deposited in the Gene Expression Omnibus (GEO, http://www. ncbi. nlm. nih. gov/projects/ geo) according to MIAME standards under accession number GSE39293: http://www. ncbi. nlm. nih. gov/geo/ query/acc. cgi?acc = GSE39293. Bioinformatics analysis of differentially expressed (DE) genes was carried out with Ingenuity Pathways Analysis (IPA, Ingenuity ® Systems) version 9 as previously reported  [12].
Genotyping of UMP/CMPK1, UMP/CMPK2, HPV E6 and E7 Total mRNA from parental and CDV R cells was isolated with the Quickprep mRNA purification kit (Amersham Biosciences) and converted to cDNA with the first-strand cDNA synthesis kit (GE Healthcare). The entire cDNA from each selected gene was amplified by PCR using specific primers. The PCR products were purified using PCR product purification kit (Roche) and directly sequenced using a cycle-sequencing kit (Dyenamic dye terminator kit; Amersham Biosciences), specific primers targeting both strands of the specific gene, and a capillary DNA sequencing system (MegaBACE 500; Amersham Biosciences). The data were assembled and compared to the DNA sequences obtained from reference sequences using Vector NTI software (Invitrogen). The primers used for the genotyping of UMP/CMPK1 and 2, and HPV oncogenes E6 and E7 are listed in Table  S2.
Structural model for the amino acid changes in human UMP-CMPK1 The role of the amino acid changes identified in the human UMP-CMPK1 in SiHa CDV cells was investigated by building a model of the enzyme complexed to ADP and CMP based on the published three-dimensional structure of the Dictyostelium discoideum UMP-CMPK (pdb code: 2UKD). Pymol Delano software was used to introduce the identified mutations and to visualize the generated models. A comparison of the open conformation of the human enzyme free of substrate (pdb code: 1TEV) and the closed conformation obtained by modeling was performed to predict the impact of the P64T mutation. All figures were generated using PyMol software.
Statistical analysis Plotting and statistical analysis were performed using GraphPad software. The unpaired t-test was used to analyze several parameters between parental and CDV R cells (i. e. intracellular CDV metabolites, drug transporter protein levels, UMP/CMPK protein levels and drug-sensitivity). Comparison of CTP and UTP biosynthesis in parental and CDV R cells was carried out using the two-way analysis of variance test (two-way ANOVA). No correction for multiple testing was used due to the large number of statistical analyses performed. Data are presented as mean ± standard deviation (SD) and p < 0. 05 was considered significant.
Therefore, the aim of the present work was to analyse the presence of T. gondii in intensive pig farms and to investigate: (i) the farm-level and within farm proportion of seropositives, and (ii) factors associated with seropositivity. For this purpose, sera and data related to herd characteristics, biosecurity, management and housing conditions (obtained by questionnaire) were collected from 60 confined farrow-to-finish farms. All studied farms were located in western France, the region were almost 60 % of total country's pork production is located  [14, 15].
Database and serum bank Sera samples and epidemiological data were obtained from a previous study, conducted from November 2006 to February 2008 in 125 farrow-to-finish pig productions from western France with more than 100 sows per farm  [14]. In each of these 125 farms, blood samples were collected from pigs. A face-to-face interview, which included 610 questions, was conducted with the farmer, as well as herd investigations (using a standardized protocol with 257 measurements and observations, see Additional file 1 for the part of the questionnaire used for the present study), by the Swine epidemiology and welfare unit (ANSES), as described in  [14]. The resulting dataset included a general description of the herd and of its neighbourhood, and data about biosecurity and hygiene practices, as well as management and animal husbandry.
Herd selection and risk factors A written consent from farmers (represented by their organisations of producers) was asked for the use of pig sera and data in the present study. A farm was considered as T. gondii-positive if specific antibodies were found in at least one pig. The a priori estimate of the proportion of positive farms was set at 20 %. For a relative precision of 5 %, the sample size was calculated to be 60 farms, which were randomly chosen among 125 available from the database. Assuming a withinherd prevalence of 5 %, the number of samples per farm necessary to detect T. gondii presence (i. e. to obtain at least one positive serum) at a 95 % confidence level was 60 sera. These 60 sera were equally distributed in the 4 age classes. Thus, for each of the 60 chosen farms, 60 pig sera were randomly selected in the serum bank: 15 sera from <1 month suckling piglets, 15 sera from 1 to 2 months weaned piglets, 15 sera from 2 to 3 months fattening pigs, and 15 sera from >3 months fattening pigs.
On all farms pigs were kept in completely confined conditions, without any outside access neither for piglets or sows. Farm buildings were separated according to each of the 4 age classes: farrowing rooms for suckling piglets (and sows) from birth to one month of age, weaning rooms for one to two months old piglets, fattening rooms for animals of 2-3 months of age, and rooms for >3 months old animals. The dataset associated to farm-and age-class specific serological results (number of tested and number of positive animals) included both room-level and farm-level variables. Room-level variables were the type of floor (slatted floor, straw, combination of slated and concrete floor) and the feed distribution method (automatic feeders or manual). Farm-level variables included hygiene practices: the use of specialized boots (yes/no) and clothes (yes/no), the compliance with all-in, all-out management (time in days during which pens/rooms/buildings were left empty in post-weaning and post-fattening processes), and the presence of a Danish entry facility (yes/no): a closed facility with at least two doors that open successively, upon entering the breeding rooms.
Analysis of Plasmodium falciparum isolates Parasite DNA was extracted from filter paper using the Chelex method  [26]. The propeller domain of the K13 gene was amplified by nested PCR using the following primers: for the primary PCR (K13_PCR_F 5 0 -G GGAATCTGGTGG-TAACAGC-3 0 and K13_PCR_R 5 0 -C GGAGTGAC-CAAATCTGGGA-3 0 ) and for the nested PCR (K13_N1_F 5 0 -GCCTTGTTGAAAGAAGCAGA-3 0 and K13_N1_R 5 0 -GCCAAGCTGCCATTCATTTG-3 0 ). The reaction volume and amplification programme used were reported previously  [1]. Amplified products were bi-directionally sequenced by Sanger sequencing using BigDye Ò v3. 1 from ThermoFisher Scientific by Beckman Coulter Genomics. The sequence reactions were then run on an ABI3730xl following the manufacturer's protocols. The propeller domain of the K13 sequence data for single nucleotide polymorphisms (SNPs) was analysed using Geneious software (www.
PATIENTS AND METHODS Patients. For this analysis, the data collected during the first 2 years of follow-up in the DESIR cohort were used. The DESIR cohort has been described extensively  (16). Briefly, consecutive patients ages 18-50 from 25 centers in France were included. Patients had inflammatory back pain in the thoracic spine, lumbar spine, and/or buttocks area based on either the Calin  (17)  or Berlin  (18)  criteria with a duration of $3 months but ,3 years. They were included in the study if the treating rheumatologist considered the symptoms to be suggestive of axial SpA, with a score of $5 on a scale of 0-10, where 0 was not suggestive of axial SpA and 10 was very suggestive of axial SpA. Between December 2007 and April 2010, 708 patients were included. The study was conducted according to good clinical practice guidelines and was approved by the appropriate medical ethics committee.
A detailed description of the study protocol is available online at http://www. lacohortedesir. fr/desir-inenglish/. The research proposal for this particular analysis was approved by the scientific committee of the DESIR cohort. Data collection. A database was built using a standardized case report form that included data from questionnaires, findings of physical examinations, ongoing treatments, comorbidities, and laboratory test results according to the DESIR protocol. The database used for this analysis was locked in October 2014. Demographic and disease characteristics. At baseline, the following information was collected: age, sex, smoking status, HLA-B27 status, and duration of axial symptoms. At baseline and at the 6-month intermediate visits during the first 2 years of follow-up, the following parameters were also collected: Bath AS Disease Activity Index (BASDAI)  (19) , Bath AS Functional Index (BASFI)  (20) , CRP level, TNF therapy intake, and nonsteroidal antiinflammatory drug (NSAID) intake according to the ASAS NSAID score  (21).
g. , complete ankylosis of the SI joint). The 2 radiographs for each individual patient were evaluated at the same time. Readers were aware that the 2 radiographs were of the same patient but were unaware of the chronology of the radiographs. The readers were blinded with regard to all clinical and laboratory data and the other imaging modality (i. e. , MRI). Agreement between the 2 readers with regard to fulfillment of the modified New York criteria for sacroiliitis at the patient level (i. e. , at least unilateral grade 3 or bilateral grade 2 and/or a progression of at least 1 grade for each SI joint) was calculated. In cases in which the readers disagreed, a radiologist (MR) or a rheumatologist (PC) experienced in the field of SpA served as adjudicator. The adjudicator scored the pelvic radiograph as yes or no according to the modified New York criteria by assigning a grade for each SI joint based on the scale described above, and was blinded with regard to the assessment of the primary readers.
An image was marked as positive if 2 of the 3 readers agreed. MRI of the pelvis. The MRIs collected at baseline were stored centrally after anonymization. The images were evaluated by 2 central readers (RvdB and FT). A detailed description of the central reading has been published previously  (23). Briefly, findings of MRI of the SI joint were considered positive according to the ASAS definition if bone marrow edema lesions highly suggestive of SpA were present (either $1 bone marrow edema lesion on $2 consecutive slices or severe bone marrow edema lesions on a single slice)  (24). All available baseline MRIs of the SI joint were read independently by the 2 readers, who were blinded with regard to all clinical and laboratory data and the other imaging modality (i. e. , pelvic radiographs).
e. , at least minimal abnormality). The third definition was the percentage of patients with a change other than 0 in the total score of the 2 SI joints (mean of the 2 readers); for this analysis, we defined a "progressor" as a patient with a change in the total score of. 0 and "regressor" as a patient with a change in the total score of ,0. These analyses were performed on the whole set of patients for whom pelvic radiographs were available but by presenting the data with regard to the presence or absence of baseline radiographic structural damage according to the modified New York criteria. Possible predisposing factors for structural progression were evaluated according to different definitions of the dependent variable and to a similar list of potential independent variables. The potential independent variables included selected variables collected at baseline (i.
e. , 10% of patients with non-radiographic structural damage will switch to radiographic structural damage after 2 years of follow-up) that is frequently mentioned in reviews  (35). The low rate of progression observed in the present study has recently been confirmed in a population-based cohort study, with 6. 4%, 17. 3%, and 26. 4% of patients switching from nonradiographic to radiographic disease after 5, 10, and 15 years of follow-up, respectively  (36). The relatively high number of missing values could also be considered a limitation. In our study, only 449 of the 708 patients enrolled were evaluated, mainly due to missing images. However, the similarity in the baseline clinical presentation between the 2 groups (the ones for whom we had a complete data image set and the ones for whom images were missing) is evidence that our results are valid and interpretable.