dataesr/scientific-paragraphs-categorization huggingface dataset:
This work was funded partly by a  Wellcome Trust-Massachusetts Institute of Technology  (http://www. wellcome. ac. uk)Postdoctoral Fellowship and Recruitment Enhancement awarded to MAH, a  Cancer Research Institute  (http://www. cancerresearch. org)postdoctoral fellowship awarded to KDJ and a  New England Regional Center of Excellence for Biodefense nerce. med. harvard. edu/)grant ( AIO57159 ) awarded to JPJS. JPJS was also funded by grants from the  National Institutes of Health  (www. nih. gov) ( RO1-AI080621 ) and  PEW Charitable Trusts  (http://www. pewtrusts. org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Acknowledgments We acknowledge financial support of the  ANR international program , Project  ANR-CONICYT 39  (No. ANR-2010-INTB-402-02 ) COLORS, M. G. C. and M. A. G. N, thank for the financial support of  FONDECYT  projects  1150507 , and  11130450 , respectively. Y. Z. acknowledges the support of  CONICYT  by  BCH721300436/2013 , and S. C. acknowledges the financial support of  Ministry of Higher Education and Research, Nord-Pas de Calais Regional Council  and  ERDF  through the CPER 2007-2013, as well as by the  ANR LABEX   CEMPI  project ( ANR-11-LABX-0007 ).
In our clinical practice, we perform array comparative genomic hybridization (aCGH) as an adjunct to histopathologic diagnosis for difficult to classify melanocytic tumors. In our database of copy number profiles (n=1202), we noticed cases with copy number transitions within the MET locus on chromosome 7q31. 2, resulting in amplification or gain of the 3' end of the gene that encodes the kinase domain in 7 of 1202 cases, suggesting the presence of a MET fusion kinase in these cases. MET is the high-affinity tyrosine kinase receptor for hepatocyte growth factor (HGF). It functions in angiogenesis, cellular motility, growth and invasion  13, 14. In addition, MET plays a role in melanocyte development and homeostasis  [15] [16] [17]. In 1984, it was identified as a proto-oncogene when TPR-MET, a constitutively active MET fusion kinase, was isolated from a human cell line chemically transformed in vitro  18  ; however initial reports of TPR-MET expression in human cancer were not replicated  [19] [20] [21].
In case 4, no 5' partner was identified, as the DNA sequencing data indicated that the 3' portion of MET starting from within intron 14 of MET was fused to an intergenic region on 7q22. 3. Kinome transcriptome sequencing of this case identified in-frame TRIM4-MET fusion transcripts joining exon 6 of TRIM4 to exon 15 of MET and we verified this fusion by RT-PCR. Reexamination of the aCGH profile revealed copy number gains with similar amplitudes of the 5' end of TRIM4, the intergenic region on 7q22. 3 fused to MET, and the 3' end of MET (Supplementary Fig. 2 ). Altogether, this indicates a complex rearrangement joining intron 6 of TRIM4 to a small intergenic region on 7q22. 3 and then on to intron 14 of MET with subsequent copy number increase of the MET fusion kinase. In case six, two separate breakpoints were identified within MET resulting in four detectable fusion junctions between chromosomes 1 and 7 (with only one fusion junction resulting in a predicted in-frame transcript).
Study Population We analyzed a database of 1202 melanocytic neoplasms, for which array comparative genomic hybridization (aCGH) was performed as part of the diagnostic assessment at the Dermatopathology Section of the Departments of Dermatology and Pathology at the University of California, San Francisco over a thirty-six month period from 2010 through 2013. The majority of these cases are borderline lesions with histopathological features that overlap those of benign nevus and melanoma, for which aCGH was performed as an ancillary diagnostic test. The final diagnosis was determined by review of the final pathology report for each patient. The morphologic classification of the tumor types into Spitz, conventional, deep penetrating nevus-like, or blue was determined by review of the final pathology reports and the microscopic descriptions.
Array comparative genomic hybridization aCGH was carried out with 500-1000 ng of genomic DNA on Agilent 4x180k microarrays (Agilent, Santa Clara, CA). The raw microarray images were processed with Agilent Feature Extraction software, and analyzed using Nexus Copy Number Software version 7. 0 (Biodiscovery, El Segundo, CA). Cases demonstrating copy number transitions with copy number increase of the 3' portion of MET and with sufficient residual DNA or tissue were selected for sequencing. A total of 74 cases were identified with gain of the distal portion of the long arm of chromosome 7 (including the 6 cases with MET copy number transitions). Of the 68 cases without copy number transitions in MET, 41 with sufficient residual DNA or tissue were selected for sequencing.
DNA sequencing and analysis Multiplex library preparation was performed using the Ovation Ultralow Library System (NuGEN, San Carlos, CA, p/n 0331-32) or Nextflex (Bioo Scientific, Austin, TX, p/n No. 5140-53) according to the manufacturer's specifications with 200 ng of sample DNA. Hybridization-capture of pooled libraries was performed using custom-designed bait libraries (Nimblegen SeqCap EZ Choice, p/n 06588786001) spanning ~1. 8 Mb of the genome including the exons of BRAF, NRAS, HRAS, KIT, GNAQ and introns 13-16 of MET (Supplementary Data 1). The target intervals cover mostly exonic but also some intronic and untranslated regions of 293 (version 1) or 365 target genes (version 2). The target genes were curated to comprise common cancer genes with particular relevance to melanoma. Captured libraries were sequenced as paired-end 100bp reads on a HiSeq-2000 or HiSeq2500 instrument (Illumina).
Sequence reads were mapped to the reference human genome (hg19) using the Burrows-Wheeler aligner (BWA)  43. Recalibration of reads and variant calling were performed using the Genome Analysis Toolkit (GATK)  44. Coverage and sequencing statistics were determined using Picard CalculateHsMetrics and Picard CollectInsertSizeMetrics. Variant annotation was performed with Annovar  45. For fusion detection, read pairs with one or more reads unaligned, insert sizes greater than 1000 bp, or with soft clipping of at least one read were extracted and re-aligned using BWA-SW  46  and used as input to CREST  47. Structural variants predicted by CREST were reviewed by visual inspection in the Integrative Genomics Viewer  48. We predicted the resulting fusion transcripts by joining the exon directly upstream from the genomic breakpoint with the exon directly downstream.
Acknowledgments This work was funded by grants from the  National Institutes of Health   P01 CA025874  (to B. C. B, I. Y. and T. B. ), the  Dermatology Foundation  (to I. Y. ) and the  Melanoma Research Alliance  (to I. Y. ) and the  Melanoma Research Foundation  (to I. Y. ). We thank  Sonia Mirza  and  Jingly Weier  for assistance with DNA extraction and aCGH and  Arthur Delance  for assistance with DNA and cDNA sequencing library preparation.
An additional separate group of flaviviruses that do not appear to infect vertebrate cells currently consists of nine viruses: Lammi virus (LAMV)  (23) , Ilomantsi virus (ILOV)  (24) , Marisma mosquito virus (MMV)  (19) , Donggang virus (DONV) (unpublished data; GenBank accession number NC_016997), Chaoyang virus (CHAOV)  (25, 26) , Nounane virus (NOUV)  (27) , Barkedji virus (BJV)  (28) , Nhumirim virus (NHUV)  (29) , and Nanay virus (NANV)  (30). These nine viruses form a distinct clade that sits within the MBFV group of viruses. Moreover, flavivirus-like genomic sequences integrated within the genomes of Aedes mosquitoes  (21, 31)  have also been identified. Finally, three viruses with very highly divergent genetic lineages, viz. , Tamana bat virus (TABV), Ngoye virus (NGOV), and Mogiana tick virus (MGTV), are also considered to be flaviviruses because they share similar genome organizations with the recognized flaviviruses  (1, 32).
The only representative of a sand fly-borne flavivirus, Saboya virus (SABV), sits in the group of mosquito-borne flaviviruses primarily associated with Aedes mosquitoes in Africa  (5, 33). Flavivirus RNA has also been discovered in phlebotomine sand flies from Algeria  (34)  and Portugal (unpublished data; GenBank accession number HM563684). However, these sequences align closely with those of the clSFs. We report here on the detection, isolation, complete genome sequence, and phylogenetic assignment of a novel sand fly-borne flavivirus in Psathyromyia abonnenci (Pa. abonnenci) sand flies. We propose the name Ecuador Paraiso Escondido virus (EPEV), based on the village where the sand flies were collected. We also discuss the possible significance of the discovery of a New World (NW) sand fly-associated virus that shares a common ancestral lineage with nonvectored Old World (OW) flaviviruses.
Briefly, 140 l of each sample was incubated at 37°C for 7 h in 30 U of Benzonase endonuclease (catalog number 70664-3; Novagen) to eliminate cellular DNA and RNA and preserve encapsidated viral particles. The encapsidated viral particles were then processed for RNA extraction using a BioRobot EZ1-XL Advanced viral RNA minikit (Qiagen) without an RNA carrier. Random amplification was performed using a tagged random primer for RT and using tagspecific and random primers for PCR amplification (Applied Biosystems). The PCR products were purified (Amicon Ultra centrifugal filters; Millipore), and quantification was done using a Qubit fluorometer. Two hundred nanograms of the sample was processed for sequencing using an Ion PGM sequencer (Life Technologies SAS, Saint Aubin, France)  (39). Analyses of the sequencing data were performed using the CLC Genomics Workbench program (v6.
Specific primers were designed to perform RT-PCR and to amplify the extremities using an Access RT-PCR one-step kit (Promega). The positive samples were gel purified using a QIAquick gel extraction kit (Qiagen), and both strands were sequenced. Phylogenetic analysis. Flavivirus sequences available in the GenBank database were collected to obtain a data set including a representative of at least one sequence for each species of the genus Flavivirus available as an amino acid sequence of the complete ORF. Alignments of the amino acid sequences of the complete ORF were generated using both the Clustal W2  (40, 41)  and MUSCLE  (42)  programs, available at the EMBL server (http: //www. ebi. ac. uk/Tools/), and refined manually for comparison. The effect of mass removal of regions of ambiguous alignment by use of the GBlocks algorithm (43) was also investigated.
Phylogenetic trees were reconstructed using Markov chain Monte Carlo (MCMC) analysis implemented in the MrBayes software program (v3. 1. 2)  (44). The analysis was performed using the WAG substitution model with a gamma-distributed rate variation among sites and default priors. Five independent Markov chains were run for 10 million generations, with the first 10% of samples being discarded as burn-in. Stationarity was confirmed on the basis of effective sample sizes of Ͼ400 using the Tracer program (v1. 4. 1)  (45). A maximum clade credibility tree was summarized using the Tree-Annotator program, which annotates all nodes with posterior probability support values. Genetic distances. The amino acid distances among the representatives of the flaviviruses were calculated for the complete ORF and NS5 protein by use of the p-distance method in MEGA software (v5)  (46).
EPEV genome strategy. (i) Complete genome sequencing and cyclization. Initially, an almost complete sequence of C6/36 cell-derived virus was obtained by NGS. Unfortunately, the sand fly homogenate-derived virus gave very poor sequence readouts after NGS. Reads with minimum lengths of 30 nucleotides and with a minimum quality of 99% per base were trimmed using the CLC Genomic Workbench program (v6. 5) and mapped to reference sequences previously obtained by Sanger sequencing. Parameters were set to ensure that each accepted read mapped to the reference sequence for at least 50% of its length and had a minimum of 80% identity to the reference sequence. Thus, the reported sequence was derived from NGS of the C6/36 cell-derived virus and Sanger sequencing of the gaps. Missing regions, including segments of the capsid protein, the Pr protein, and the 5= and 3= noncoding regions, were successfully amplified after cyclization of the genome and sequencing of the concatenated 3= and 5= termini.
This resulted in determination of the complete genomic sequence of EPEV (GenBank accession number KJ152564), which was 10,761 nucleotides (nt) in length and which had an ORF of 10,323 nt (positions 120 to 10,442). The single complete ORF was predicted to encode a polyprotein of 3,441 amino acids (aa). The lengths and positions of the genes or genomic regions are shown in Table  1. (ii) Terminal dinucleotides. At each terminus of the genome, 2 nucleotides which are conserved among members of the entire Flavivirus genus (51-53), i. e. , 5=-AG and CT-3=, were detected. Mutagenesis studies have previously shown that CT-3= is probably a recognition site for the replication complex to initiate RNA synthesis  (54, 55). (iii) 5= NCR and 3= NCR. The 5= and 3= NCRs are thought to function as recognition sites for virus translation, replication, and possibly, assembly  (56).
It was also isolated from Anopheles mosquitoes and ticks  (77). In addition, two flavivirus sequences were detected in Phlebotomus perniciosus sand flies in Algeria. These formed a monophyletic group more closely related to Culex-associated insectonly flaviviruses  (34). Flavivirus RNA has also been discovered in phlebotomine sand flies from Portugal (unpublished data; GenBank accession number HM563684). The phylogenetic analysis showed that EPEV diverges from the common ancestral lineage of Aedes-associated mosquito-borne flaviviruses that include YFV and also the NKV-like flaviviruses (YOKV, ENTV, SOKV). EPEV is more distantly related to the other group of Aedes-borne flaviviruses that include dengue viruses and the Culex-associated group that includes WNV, SLEV, and Zika virus. Interestingly, EPEV is also only distantly related to the clSFs (CFAV, Kamiti River virus, Hanko virus, and CxFV) and dual-host-affiliated ISFs (dISFs) (NOUV, LAMV, CHAOV, Donggang virus (DGV) and ILOV) and the NKVs that include bat-and rodent-associated flaviviruses, such as Modoc virus and Montana myotis leukoencephalitis virus.
Strains The wild-type prototroph strains of the Yarrowia clade investigated in this study were the following (abbreviations of strains are within brackets): Y. lipolytica W29 = CBS 7504 (YALI), Y. Competing Interests: The authors have the following interests: The study was performed, in partnership with the SAS PIVERT. The SAS PIVERT was created on May 29th, 2012 within the frame of the "Programme Investissement d'Avenir". It is a private company based on a public-private partnership, in charge of the Institute for Energy Transition P. I. V. E. R. T. (Picardy Plant Innovations, Teaching and Technological Research). There are no patents, products in development or marketed products to declare in relation with this study. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.
Strain number Reference Yarrowia lipolytica CBS 7504 = W29  [41]  Candida galli CBS 9722  [53]  Yarrowia yakushimensis CBS 10253  [54]  Candida phangngensis CBS 10407  [55]  Candida alimentaria CBS 10151  [56]  Candida hispaniensis CBS 9996  [57]  CBS: Centraalbureau voor Schimmelcultures, Utrecht, The Netherlands doi:10. 1371/journal. pone. 0143096. t001 with a minimum length of 40 bp, which corresponded to about 98% of the raw data, were further analysed. Tophat2 v2. 0. 10 with Bowtie2 v2. 1. 0 were used to map the reads on the nuclear genome of the three strains  [22]. The options used were the following: -micro-exon-searchmin-intron-length 30 -min-coverage-intron 30 -min-segment-intron 30 -max-intronlength 4000 -max-multihits 1 with the transcriptome being provided. Reads were counted using a custom BioPerl script based on samtools utilities v0.
1. 18 [23]. In a preliminary step, low expression features were filtered as they generally cause serious biases in differential expression studies. To this end, we followed the procedure described in the egdeR user guide  [24]. Thus, only features with at least one count per million (cpm) in at least two conditions/replicates were kept. Differential expression was performed with DEseq2 v1. 2. 8  [25]. The default normalization proposed by the DEseq2 package was used and the "parametric" estimation of data dispersion was chosen. All the pairwise comparisons of the three different conditions for the three species were investigated. The resulting p-values were corrected using the Benjamini-Hochberg procedure  [26]. Assuming that the variability between replicates was lower in YALI than in YAGA and YAPH (data not shown), the adjusted P-value cut-off for the differential expression was fixed at 1.
Selection and dN/dS ratio Pairwise nucleotide alignment was deduced from MAFFT protein alignment using tranalign in the EMBOSS package  [28]. The dN/dS ratios were calculated from this alignment using Codeml model from PAML4 package version 4. 4b with a run mode equal to -2  [36]. Saturated dS values were removed from the analysis, which notably excluded all pairwise comparisons involving CAHI. Box plots were constructed with R  [37].
Expression patterns are conserved only in the LIP2 family Transcriptomic analysis through a RNA-Seq strategy was conducted on YALI, YAGA and YAPH. These species have at least 9 different genes, however only half of them (19 out of 39) were transcribed in the culture conditions of our study, i. e. minimal medium plus oleic acid, tributyrin or glucose. No reads were obtained in the RNA-Seq data for 7 lipases of YALI and 7 of YAGA. In YAPH, none of the LIP2-like lipases except LIP2a which is the syntenic ortholog of YlLIP2 and thus the ancestral copy, were transcribed, neither the YpLIP18 lipase. Thus, only 9 lipases in YALI, 7 in YAGA and 3 in YAPH were considered to be transcriptionally active (S2 Table ). Their relative expression differed with the growth media. In the three strains, YlLIP2, YgLIP2 and YpLIP2 were the lipases most frequently expressed in oleic acid with more than 95% of the lipase transcripts in YALI and YAGA, and about 80% in YAPH (Fig  3A ).
Institute for the Energy Transition (Institut pour la Transition Energétique -ITE) P. I. V. E. R. T. (www. institutpivert. com) selected as an Investment for the Future ("Investissements d'Avenir"). This work was supported as part of the Investments for the Future, by the French Government under the reference ANR-001-01 and by INRA through the AIP-Bioressources YALIP project. Muchalin Meunchan acknowledges the Thailand Research Fund (TRF) together with Khon Kaen University for financial support through Royal Golden Jubilee PhD program (grant number PHD/0282/2549) and French Embassy. Stéphanie Michely has a PhD fellowship funded by the French Minister of Research via the ABIES doctoral school. The funders had no role in study design, data collection and analysis, or preparation of the manuscript.
Fastq files of the RNA-Seq reads have been deposited at the European Nucleotide Archive (ENA-EMBL) under the project number PRJEB6632 (http://www. ebi. ac. uk/ena/data/ view/ERP006181). The sequence of all LIP genes have been deposited at the European Nucleotide Archive ENA-EMBL under accession numbers LM652719-LM652763. The strains.
8 Diabetic polyneuropathy is overall the mosttrialed NP condition. Advantages for trials include high and increasing prevalence, global relevance, and widespread availability of inexpensive blood tests for hyperglycemia. Cancer chemotherapy, another common cause of painful polyneuropathy, has unique advantages because it is preplanned and temporal precise. Pretreatment data can be obtained. Research tools for diabetic polyneuropathy are well developed, less so for other causes. A potential disadvantage is that the motor cortex representation of the feet is not easily accessible transcranially (Fig. 2 ), although evidence from patients with central causes of foot pain (see section 3. 1) supports efficacy of off-site stimulation. The cooled, Hesed (H)-coil, that reportedly allows deeper penetration of TMS is reported as efficacious for painful diabetic polyneuropathy.
Generic instruments facilitate comparison with data from other healthy or ill cohorts and facilitate collaboration (see section 4. 4; Resources for multicenter networks and trials), whereas condition-specific instruments may better capture disease-specific concerns. 118 For example, the 36-item Medical Outcomes Study Short-Form Questionnaire (SF-36) was designed to assess overall health of populations in which no one disease is excessively prevalent. Unless supplemented by questions targeting mental health, physical function, and other domains important for assessing HRQOL, the SF-36 lacks the sensitivity necessary for decisions about whether a specific treatment is working at the N-of-1 level. 102 The voluminous array of generic and specific HRQOL assessment instruments is summarized in monographs and Web-based repositories of open-access questionnaires and other instruments.
Some collaborations originate from within communities of researchers focusing on specific conditions, others are organized by governmental agencies. An example of a disease-based consortium is the United States' Northeast amyotrophic lateral sclerosis (NEALS) consortium (http://www. alsconsortium. org/) created in 1995 to coordinate collaborative clinical research on amyotrophic lateral sclerosis. Membership grew to more than 100 centers comprising more than 500 personnel with varying roles. Clinical data and biosamples are banked and shared, and clinical research training is offered. An example of a governmentfunded organization is the NIH-funded consortium of Clinical and Translational Science Award Centers at more than 60 US academic medical institutions (https://www. ctsacentral. org/).
Mapping transcranial magnetic stimulation electric fields on cortical surfaces Current TMS navigators localize the TMS coil, but not its predicted cortical activations, yet this refinement is within reach. Each person's individual cortical surface can be automatically extracted from their MRI, eg, with FreeSurfer software. 34 This also permits parsing of possible cortex orientation-specific influences. Individual cortical surfaces can also be nonlinearly morphed to other brain surfaces (eg, group averages), to facilitate group-level studies and meta-analyses, as recently published. 6 Estimating the primary electric fields induced in the brain by specific TMS parameters requires volume conductor models. Present-day commercial navigation devices either omit these or use simplified less-accurate spherical models.
Acknowledgements Supported in part by the  Radcliffe Institute for Advanced Study  and the  Samuels Family Foundation , the  Public Health Service  ( K24NS059892 ,  K23NS083741 ,  NS38493 ,  R01HD069776 ,  R01NS073601 ,  R21 MH099196 ,  R21 NS082870 ,  R21 NS085491 ,  R21 HD07616 , and  U01NS077179 ) and  NINDS  intramural support to  M. Hallett , the  UK National Institute of Health Research  ( PB-PG-0110-20321 ) to  T. Nurmikko , the  Hopkins Neurosurgery Pain Research Institute , the  American Academy of Neurology/American Brain Foundation , the  Sidney R. Baer Foundation , the  Harvard Catalyst-Clinical and Translational Science Center  ( UL1 RR025758 ). Article history: Received 22 August 2014 Received in revised form 30 March 2015 Accepted 17 April 2015 Available online 25 April 2015.