dataesr/scientific-paragraphs-categorization huggingface dataset:
However, manipulation of this major metabolic pathway can also be detrimental for the host. For instance, Lovastatin treatment, an inhibitor of cholesterol synthesis, appears to delay infection and increases survival rates in AG129 mice infected with Dengue Virus Serotype 2 while it also tends to increase viremia which could affect disease progression  [65]. A better understanding of the interactions of pathogens with the host cell lipid metabolism and other metabolic pathways could provide new therapeutic targets to control infections by tickborne pathogens. Furthermore, as recently proposed the application of machine learning and big data analysis to the tick-host-pathogen interactions datasets may also lead to the high throughput identification of candidate vaccine protective antigens  [66].
Thus, defining specific immunophenotypic and functional markers that will allow researchers to unequivocally discriminate the features of circulating and tissue infiltrated immunosuppressive PMN-MDSC from their normal counterpart is of key importance. The importance of standardization experiments has been recognized by colleagues in the field and first data sets have been obtained  [43, 52, 53]. In this same context, the COST consortium has recently agreed on a minimal number of immunophenotypic markers required as a first step to identify circulating PMN-MDSC in blood (Fig. 1 ). In addition, a number of published procedures to collect and manipulate blood for PMN-MDSC and M-MDSC recovery has been evaluated as part of the activities of the Mye-EUNITER COST consortium. The conclusions reached from this comparison have resulted in a number of experimental guidelines and a minimal marker panel summarized in Table  1  and Fig.
Conclusions and future perspectives Myeloid cells show high plasticity and readily adapt to changing conditions such as those present in cancer, infection and inflammation. As a consequence many myeloid cells can acquire (immune) regulatory activity. A prototypic example among those "myeloid regulatory cells" are MDSC, which are characterized by their profound immunosuppressive activity and key pathophysiological importance. One of the aims of the Mye-EUNITER COST consortium is to standardize markers and protocols to study these different MDSC to provide the scientific community with better tools to analyze these cells, distinguish functional subsets and ultimately decipher their important role in health and disease. Recent data using high-end approaches such as mass cytometry have confirmed the crucial role of MDSC and other myeloid cells with regulatory activity in disease and their potential as targets for therapy as well as biomarkers for therapy response prediction.
Inclusion criteria comprise clinical diagnosis of TTP, severe deficiency of ADAMTS13 activity (<10%), hemoglobin level <10 g/dL and/or platelet count <150 x10 9 /L, while exclusion criteria include cancer, HIV and organ graft. Clinical and biological data were collected after extensive analysis of medical records, including 8 to 14 years of follow-up (relapse and/or death). Neurological symptoms were particularly looked into: symptoms such as headaches or confusion were considered mild neurological symptoms, while seizures, coma, focal deficiency or two (or more) neurological symptoms were labelled severe. Cerebral ischemia was assessed by clinical presentation and magnetic resonance imaging. Written informed consent was obtained from all patients according to the Declaration of Helsinki. The study was approved by the Ethics Committee of Hospital Pitié-Salpêtrière (Paris.
France). The study is registered at www. clinicaltrials. gov as number NCT00426686, at the Health Authority and by the French Ministry of Health as number P051064/PHRC AOM05012. Venous blood was collected at the time of enrollment (acute phase) before any treatment, into 1:10 final volume of 3. 8% sodium citrate. A normal pooled plasma (14 healthy volunteers) was used as normal control for all biologic assays.
Statistical analysis. Categorical variables were compared with χ2 or Fisher's exact tests as appropriate. Continuous variables were compared with the non-parametric Mann-Whitney U test. Linear regression was performed using Pearson's formula. All tests were two-sided and statistical significance was set at p <0. 05. Statistical analysis was performed using GraphPad Prism® version 7. 00 (GraphPad Software. La Jolla. California. United States).
Discussion This study focusing on acquired TTP shows that VWF-HMWM could partially explain the clinical variability exhibited by TTP patients, and that VWF-HMWM can satisfactorily be assessed by VWF:CB, much easier to carry out than electrophoresis. Demographic, biological and clinical data are consistent with previous descriptions of large TTP cohorts  [14, 15, 16, 17] , with however an apparent over-representation of idiopathic TTP, probably related to the exclusion criteria of our study. USS patients exhibited as expected high levels of VWF-HMWM and higher than normal VWF:CB, consistent with the constant excess of HMW due to the genetic deficiency of ADAMTS13. These profiles were used as internal control to evaluate the performances of both electrophoresis and ELISA to detect and quantify VWF-HMWM excess.
The tumor microenvironment is an important determinant of glioblastoma (GBM) progression and response to treatment. How oncogenic signaling in GBM cells modulates the composition of the tumor microenvironment and its activation is unclear. We aimed to explore the potential local immunoregulatory function of ERK1/2 signaling in GBM. Using proteomic and transcriptomic data (RNA seq) available for GBM tumors from The Cancer Genome Atlas (TCGA), we show that GBM with high levels of phosphorylated ERK1/2 have increased infiltration of tumor-associated macrophages (TAM) with a non-inflammatory M2 polarization. Using three human GBM cell lines in culture, we confirmed the existence of ERK1/2-dependent regulation of the production of the macrophage chemoattractant CCL2/MCP1. In contrast with this positive regulation of TAM recruitment, we found no evidence of a direct effect of ERK1/2 signaling on two other important aspects of TAM regulation by GBM cells: (1) the expression of the immune checkpoint ligands PD-L1 and PD-L2, expressed at high mRNA levels in GBM compared with other solid tumors; (2) the production of the tumor metabolite lactate recently reported to dampen tumor immunity by interacting with the receptor GPR65 present on the surface of TAM.
Acknowledgments We would like to thank  Dr Aur élien de Reynies  ( Paris, France ) and  Dr V ésteinnThorsson  ( Institute for Systems Biology, Seattle, WA, U. S. A. ) for their help with data accessibility. The authors also acknowledge the contribution of the patients and researchers involved in TCGA. Work in our laboratory is supported by the  CHU Amiens Picardie and Ligue contre le Cancer, comit é de la Somme.
CMML MSC their TF to HSCs We then investigated whether peritumor MSC sEVs could, in turn, interact with CD34 1 cells (hereafter HSCs) to impact their PCA and proliferation ability. First, coculture of CD34-FITC-labeled HD HSCs and DiD-labeled CMML MSC sEVs was performed. Confocal microscopy imaging showed that sEVs were able to interact with HSCs and were integrated into their cytoplasm (Figure  6A ). HSCs) and sEVs were performed for 48 hours. HSC PCA was then studied by TGA (Figure  6B ). We explored 6 different conditions: CMML and HD HSCs were cultured alone, with HD MSC sEVs, or with CMML MSC sEVs For both HD and CMML HSCs, there was no significant difference in terms of thrombin peak values when HSCs were cultured alone or with CMML or HD sEVs (data not shown). Regarding HD HSCs, the coagulation lag time of HD HSCs (fold change: 3.
Acknowledgments The authors thank the  R émy Sadoul's research group , especially  Karine Laulagnier  of the  Grenoble Institute of Neuroscience, University Grenoble Alpes , for access to Nanosight, advice on particle analysis, and helpful discussions on EVs, as well as  Anne Bertrand  for technical assistance with electron microscopy. They also thank  Fr éd éric Garban  for providing patient samples.
Genome Sequencing The genome of the E. minasensis strain Cuiabá was recently sequenced, annotated, and announced  [21]. Briefly, DNA was extracted from DH82 cells infected with E. minasensis, and a Nextera XT library was prepared (Illumina, San Diego, CA, United States). Sequencing was performed using the sequencer NextSeq 550 System (Illumina, San Diego, United States). A total of 37 million reads passed the quality filter and were merged and assembled. Genome annotation was run with Prokka 1. 14  [22]. The raw sequence reads were submitted to NCBI SRA and are available under the accession number PRJNA478569. The whole-genome shotgun project of the E. minasensis strain Cuiabá was deposited in DDBJ/EMBL/GenBank and is available under the accession number QOHL00000000. Genome assembly data are available under the accession number GCA_004181775.
Core-Genome-Based Phylogenetic Tree Genome assemblies of E. canis (2 strains), E. chaffeensis (9 strains), E. muris (2 strains), E. ruminantium (10 strains), and E. minasensis (2 strains) available in the refseq database of NCBI were downloaded in fasta format. Genome accession numbers of the strains used are available in Supplementary Table  S1. Three Anaplasma genomes (i. e. , A. marginale-SAMN02603338, A. centrale-SAMN02604279 and A. phagocytophilum-SAMN02585077) were used as outgroups in the core-genome-based phylogenetic tree. The coding sequences of the genomes were used for ortholog genes identification, using the OrthoMCL pipeline  [23]. The nucleotide sequences of all the ortholog genes identified in the 28 bacterial genomes were aligned using MACSE  [24]. The final alignment included 97,908 nucleotide positions of 125 protein-coding genes present in the core-genome of the selected bacteria.
Bacterial Pan-Genome Profiles Gene clusters of Anaplasma and Ehrlichia genomes (see Section 2. 6) were predicted with OrthoMCL  [23] , using best-matching gene similarities with an E-value ≤ 1 ×10 -5. The number of gene clusters was plotted against the number of genomes, and the resulting rarefaction curves were used to visualize the pan-genome and core-genome of Anaplasma and Ehrlichia. Rarefaction curves were built by using the settings recommended for datasets larger than 15 genomes. Pan-genome and core-genome profiles were calculated with the software PanGP  [27].
Genome Comparative Analysis The functional annotation of E. minasensis Cuiabá genome (SAMN09519635) was compared to that of other 9 genomes of the Order Rickettsiales: A. central Israel (SAMN02604279), A. marginale Florida-1 (SAMN02469629), A. phagocytophilum HZ2 (SAMN02604172), E. canis Jake (SAMN02598261), E. chaffeensis Arkansas (SAMN02604010), E. muris AS145 (SAMN02641637), E. ruminantium Welgevonden (SAMEA1705918), Rickettsia conorii Malish (SAMN02603141), and Rickettsia prowazekii Rp22 (SAMN02604077). All genomes were functionally annotated, using PATRIC  [28] , a web-based tool that uses RAST  [29] , which assigns gene functions and groups them according to different categories: superclass, class, subclass, and subsystems. The two-proportion test, implemented in R (prop. test function), was used to detect differences between the functional categories of E.
Previous studies have implicated Tlr2 in immune response to infection, stress and injury  [57]. However, our laboratory has recently shown that the expression of Tlr2 in the developing brain is highly sensitive to manipulations of the indigenous gut microbiota  [32 ]. Taken together, these observations support the hypothesis that Tlr2 and other PGN-  Protein Atlas; (https://www. proteinatlas. org/)] [58]. Containing transcriptomic datasets from different human tissues, we investigated whether PGN-sensing molecules are expressed in the human placenta. We have ascertained that NOD1, NOD2, TLR2, as well as the putative transporters PepT2 and PAFr are abundantly expressed in the placenta (Figure  3 ). Collectively, these observations raise the possibility that PGN fragments from the maternal indigenous microbiota may also be capable of influencing the developing fetal brain, and that disruption of components of this signaling pathway could lead to abnormal motor, social, and cognitive development.
sensing molecules may have a dual role in immunity and in neural development. However, little is known about the expression of PRRs and putative PGN transporters in the developing human brain and placenta. Such information is essential to better understand signaling pathways through which the maternal gut microbiota can influence human fetal brain development. Taking advantage of an existing public database [i. e. the Human PGN from gut microbiota to brain Tosoni, Conti and Diaz Heijtz 111.
In contrast, CD3E mRNA was mostly observed at the perinuclear area in CD3E-transfected HeLa cells (Figure  S4B ). In humans, the kinesin superfamily encompasses several kinesins with different binding specificities and transport functions  (Hirokawa et al. , 2010). To identify the kinesins involved in mRNA transport in T lymphocytes, we interrogated public databases of transcriptomes from purified T cells by screening for high expression levels and mRNA cargo functions. This bioinformatics approach pinpointed the KIF1B, KIF3A, KIF5B, and KLC1 candidate genes. The individual knock down of either KIF5B or KLC1 but not of KIF1B, KIF3A, or DYNEIN significantly decreased the PD-1 protein level in PDCD1-transfected HeLa cells (Figures  4B  and 4C ). In contrast, in CD3E HeLa transfectant controls, neither KIF5B nor KLC1 knockdown impaired the expression of CD3ε protein (Figures  4B  and 4C ).
, 2016). To size the immune reinvigoration by MTDs at a population level, we identified in VigiBase (World Health Organization) 202,693 individual case safety reports (ICSRs) related to the drugs of interest-nivolumab, pembrolizumab, and ipilimumab (collectively referred to as ICB), MTDs, and control drugs from this pharmacovigilance database. Among them, 1,958 ICSRs ($1%) concerned the classes of IrAEs reported for ICB (Tables  S1  and S2 ). The case/noncase analysis revealed a significantly high disproportionality of IrAEs for colchicine and mitopodoside, with reporting odds ratios (IrAE-RORs) of 4. 05 and 3. 61, respectively, while the IrAE-ROR was just above 1 for vinca alkaloids and taxanes. The IrAE-RORs were 10. 67, 8. 97, and 7. 14 for nivolumab, pembroluzimab, and ipilimumab, respectively, and $0.
Immunoblotting Cells were lysed on ice for 30 min with lysis buffer containing 10 mM HEPES, 100 mM KCl, 150 mM NaCl, 0. 5% NP40, 1 mM DTT and a cocktail of protease inhibitors (Complete, Roche). Whole cell lysate was centrifuged at 10. 000 3 g for 15 min at 4 C. Supernatants were collected and cell extract was quantified using the BCA assay. Samples were heated at 95 C for 5 min in SDS-buffer, separated by SDS-PAGE, and transferred to nitrocellulose membranes. Membranes were blocked in 5% BSA in 1x PBS + 0. 1% tween-20, probed with the specified antibodies, and detected with HRP based enhanced chemiluminescence (ECL prime western blotting detection reagent, GE Healthcare). Semi quantification of immunoblots was performed with the ImageJ software. Protein expression level was normalized to GFP for transfection experiments, and to GAPDH when studying protein from endogenously expressed gene.
Immunolabeling were visualized the next day with fluorescent secondary antibodies (all from ThermoFisher Scientific): Alexa Fluor 568 goat anti-rabbit (tubulin in Figures  2A  and S5D ; DCP1A in Figures  5F  and S5A ; EIF4G in Figure  5G ), Alexa Fluor 488 goat anti-rabbit (tubulin in Figures  4A  and S3B ), Alexa Fluor 633 goat anti-mouse (PD-1 protein in Figure  2A ), Alexa Fluor 555 goat anti-mouse (PD-1 protein in Figure  S3B ), Alexa Fluor 488 goat anti-mouse (G3BP1 in Figures 5F, 5G, S5A, S5C, and S5E). Coverslips were mounted with Dako fluorescent mounting medium (Dako, Agilent). Images of the stained cells were taken using a Zeiss LSM 780 Axio Observer Z1 confocal microscope and processed using Icy software (France-BioImaging, Institut Pasteur, France)  (de Chaumont et al. , 2012).
High resolution fluorescence microscopy image (Figure  4A ) was taken with a Zeiss LSM 880 FAST Airyscan using a 63X Plan-Apochromat objective with 1. 4 aperture under immersion oil. Quantification of SG and Tubulin staining were obtained using the Operetta CLSTM system from Perkin Elmer at 40x air objective and processed using Harmonyâ 4. 6 high content imaging and analysis software (Perkin Elmer). Profile plot for co-localization analysis was performed with RGB profiler in ImageJ. Overlap correlation coefficient was calculated with Zen Blue (Zeiss Microscopy GmbH).
Disproportionality analysis The pharmacovigilance data were obtained from Vigibase (sourced on July 2017), the World Health Organization's (WHO) safety reports database (https://www. who-umc. org/vigibase/vigibase/) which currently holds > 15 million anonymized individual case safety reports (ICSR) collected from 121 countries. This database uses medical and drug classifications by terminologies from WHO-Adverse Drug Reaction terminology (WHO-ART), Medical Dictionary for Regulatory Activities (MedDRA) and the medicinal products dictionary, WHO Drug, to allow structured data entry, retrieval and analysis at different levels of precision and aggregation. Reactions to drugs are encoded with MedDRA and WHO-ART, and hierarchized in five levels from very specific to very general. The immunerelated adverse events (IrAE) were first selected from the MedDRA Preferred Term (PT) reported in clinical trials of nivolumab, pembrolizumab and ipilimumab (referred as ICB).
, 2017)   An IrAE-ROR > 1 for drug X means that IrAE are more likely than other events for this drug, in comparison with all other drugs in the database, whereas IrAE-ROR < 1 for drug X means that IrAE are less likely than other reactions with this drug. Statistical significance of IrAE-ROR (significantly different of 1) were estimated through 95% confidence interval (95% IC) for each ROR (i. e. , at least p < 0. 05), calculated as: 95%IC ROR = e lnðRORÞ ± 1:96 ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi 1 a + 1 b + 1 c + 1 d q The correlation of IrAE-ROR and in vitro IC 50 for PD-1 expression by the same drugs (without tamsulosin, irinotecan and ipilimumab), was calculated by Spearman coefficient since normality of IrAE-ROR distribution could not be assumed (Shapiro-Wilks p > 0.
DATA AND SOFTWARE AVAILABILITY Analysis of 3 0 -UTR length: The 194,503 FASTA sequences for 3 0 -UTR of human genes were downloaded from UTRdb (http://utrdb. ba. itb. cnr. it; Grillo et al. , 2010) , in which each FASTA sequence is identified by a 3 0 -UTR code. The correspondence file of 3 0 -UTR codes with each gene symbol was downloaded from UTRdb such as to attribute each FASTA sequence to a gene symbol. The length of each sequence was then measured for each gene symbol, and its longest 3 0 -UTR was selected for each gene using the ''Find Fasta max length'' software (code available at: https://sites. google. com/site/fredsoftwares/products/ find-fasta-max-length). Kinesin gene expression in immune cells: Public raw data of (n = 265) transcriptomes from purified lymphoid cell types obtained using Affymetrix HGU133 Plus 2.
0 microarrays were downloaded from NCBI GEO dataset repository (https://www. ncbi. nlm. nih. gov/ gds, series GSE12195, GSE13738, GSE14879, GSE27291,GSE28490, GSE28491, GSE28726, GSE43769, GSE45535, GSE56314, GSE56464, GSE61697, GSE65010, GSE66384, GSE71566, GSE72642, GSE8059). These transcriptomes were RMA normalized together, collapsed to HUGO gene symbols and the expression levels for the genes KIF1A, KIF1B, KIF1C, KIF2A, KIF2B, KIF2C, KIF3A, KIF3B, KIF3C, KIF4A, KIF5A, KIF5B, KIF5C, KIF6, KIF7, KIF9, KIF11, KIF12, KIF13A, KIF13B, KIF14, KIF15, KIF17, KIF18A, KIF19, KIF20A, KIF21A, KIF21B, KIF22, KIF23, KIF24, KIF25, KIF26A, KIF26B, KIF27, KIFAP3, KIFC1, KIFC2, KIFC3, KLC1, KLC2, KLC3, and KLC4 were compared.
ACKNOWLEDGMENTS We acknowledge  A. Galy ,  E. Vivier , and  M. Cogne  ´for critical comments, and  M. Bonneville ,  S. Pyronnet ,  C. Touriol ,  F. Lopez , and the other members of the Fournielaboratory for discussions. D. -M. F. and M. T. were funded by the  CAPTOR  and TOUCAN programs; O. L. , A. C. , L. L. , C. -M. S. , F. P. , and S. M. are employees of  Institut National de la Santeet de la Recherche Medicale (INSERM ); P. B. A. and J. -J. F. are employees of  Centre National de la Recherche Scientifique (CNRS ); C. L. , F. D. , M. A. , and M. L. -M. are employees of  Toulouse University Hospital. This work was supported in part by institutional grants from  INSERM , the  UniversiteToulouse III -Paul Sabatier , the  CNRS , the  Programme Hospitalo-Universitaire en Cancerologie CAPTOR  ( ANR11-PHUC0001 ), the  Laboratoire d'Excellence TOUCAN  ( ANR11-LABX ), the  Institut Universitaire du Cancer de Toulouse-Oncopole  (CIEL), and the  Institut Carnot Lymphome (CALYM).
Two major USUV outbreaks affecting wild birds were identified with extensive circulation in Northern Europe in 2016 (Belgium, Germany, the Netherlands and France)  [9] , and in Western and Central Europe in 2018 (France, Austria)  [2, 10]. Given that USUV and WNV are genetically, antigenically and epidemiologically closely related, in Europe the question emerged of the influence of one virus on the spatiotemporal dynamics of the other. This highlights the need to obtain more epidemiological data on the spatiotemporal dynamics of USUV in endemic and nonendemic areas of WNV. A better understanding of the spatiotemporal distribution of flaviviruses is needed to define risk areas of virus circulation, and to gain knowledge on the dynamics of virus transmission cycles. Although global changes (climatic, environmental or anthropogenic factors) may impact the geographical distribution of tick-borne flaviviruses, these viruses generally exhibit more epidemiological stability over time than mosquito-borne flaviviruses, which evolve by epizootic waves  [6].
Data and Study Area In 2009, the French National Hunter's Federation launched a voluntary program for departmental (French administrative unit) hunting associations aimed at serum banking of wild ungulate samples. Blood samples were taken from the thoracic cavity of freshly killed hunted animals and centrifuged. Serum samples were then stored at -20 • C by local hunter's associations. Animals were killed during the hunting season, which is from September to February. Animals were classified by gender and by age according to dentition patterns (juveniles: <1 year old and adults: >1 year old). Among the 31 departments in which local hunter's associations participated in this program, we selected 18 departments to represent different bioregions of France (Figure  1C ). For the sampling scheme and analysis, given their smaller size, the departments from the "Ile-de-France" region (departments 78, 91, and 95 in Figure  1C ) were considered one department.
In cases of positive reactions with several rEDIIIs for viruses belonging to the Japanese (i. e. , USUV and WNV) or tick-borne encephalitis serocomplexes (i. e. , TBEV and LIV), an animal was considered infected with a specific flavivirus if the corresponding bead coupled to rEDIII generated an MFI at least double that generated with the other beads. MNTs were performed for the detection of specific neutralizing antibodies against WNV (strain Is98, Genbank ID AF481864. 1, provided by Philippe Desprès, IPP, Paris), USUV (strain Italy 2012, 206795-3/2012, Genbank ID KX816653. 1, provided by Davide Lelli, IZSLER, Brescia), TBEV (strain Hypr, Genbank ID U39292. 1), LIV (strain Li 3/1, Genbank ID KP144331. 1, provided by Nicholas Johnson, APHA, Weybridge), and BAGV (strain Spain 2010, Genbank KR108244) as described in  Beck et al.