dataesr/scientific-paragraphs-categorization huggingface dataset:
w ij is the probability of patient i belonging to cluster j and can be expressed as: w ij = 1 c k=1 xi-cj xi-c k 2 Note that, for a given patient i, the following holds: where c is the average of the centroids. The number of clusters were chosen between 2 and n-1 inclusively such that the VFS was minimised. Plotting the clustering results was done using a multidimensional scaling (MDS) algorithm which projects multidimensional data onto a 2D plane while keeping distance metric scaled relatively to original data (Python library sklearn. manifold [42] ). Correlation coefficients between original Euclidean distance and 2D-Euclidean distance were calculated were high for all models (¿ 0. 98) which showed that the MDS projections were accurate  [43]. S1 Fig.
1 Patient data best-fit of irinotecan PK model with original delivery profile and not PDE delivery profile. Each subplot represent an individual patient dataset, fit to the model independently. The top figure shows the fit of irinotecan plasma concentration, the bottom figure shows that of SN38, the active metabolite of irinotecan. SN38 data and model simulations include both bound and free SN38. S1 Eq 2. The equations for oxaliplatin PK model. S1 Table 5. Individual Parameter Estimates of oxaliplatin PK model, including mean and CV of each parameter. S1 Table 6. Sum of Square Residuals (SSR) for oxaliplatin PK model, with either the original delivery profile, or that simulated throught the PDE pump-to-patient model. The table also shows improvement in percentages for each patient and average improvement for all patients.
The margins of this radiolucent defect were shown well-defined by a cortical bone outline (data not shown). The main differential diagnoses include focal fibrous hyperplasia, benign soft-tissue neoplasms, peripheral odontogenic tumors and minor salivary gland tumors. Surgical excision of the whole lesion was performed under local anesthesia. Gross examination showed a multinodular and un-encapsulated tumor (Figure  1(b) ). Microscopic examination revealed well-circumscribed nodules predominantly composed of compact spindle cells (Antoni A pattern). Scarce hypocellular and myxoid areas compatible with an Antoni B pattern were also identified. Higher magnification highlighted the presence of Verocay bodies in areas with Antoni A pattern. In areas with Antoni B pattern, hyalinization of the walls of blood vessels was noticed (Figure  2(a)-(d) ).
Neoplastic cells exhibited diffuse and strong staining for S100 and SOX-10 (Figure  3 (a) and (b)). Focal staining for CD34, neurofilament (NFP) and CD117 (c-kit) was also noted (Figure  3(c)-(e) ). Immunostaining was negative for desmin, vimentin, epithelial membrane antigen (EMA) and bcl-2 (data not shown). Mitotic activity was low (less than four mitoses per 10 high-power fields) and tumor cells had a low Ki-67/MIB-1 labeling index (Figure  3 (f)). Moreover, these tumor cells strongly expressed INI1/SMARCB1 (Figure  3(g) ). Full physical examination and magnetic resonance imaging (MRI) of the head and neck region were performed in order to investigate signs or symptoms in favor of neurofibromatosis and were normal (data not shown). Furthermore, no family history of skin or oral mucosa nodules was reported.
ChIP-exo and ChIP-seq data analysis Single-end 36 bp reads were generated on the Illumina Hi-Seq2500 and mapped to hg19 genome using bowtie2 2. 2. 6  [31]. Aligned reads with the mapping quality less than 5 were filtered out. Peaks were called with MACS2 version 2. 0. 10. 20131216 [19]  for HER2 data and Sicer version 1. 1  [32]  for the histone mark data. using sequences from the SKBR3 and BT474 chromatin extracts as a background input control. A further filtration was carried out by removing reads falling into the 'blacklist' regions identified by ENCODE  [33]  or in regions found to have high signals in cell-line-specific input samples as determined by the Bioconductor package GreyListChIP (http://www. bioconductor. org/packages/release/bioc/html/ GreyListChIP. html). The peaks yielded with MACS2 q value < = 1e-3 were selected for downstream analysis.
RIME analysis Raw MS data files were processed using Proteome Discoverer v. 1. 4 (Thermo Scientific). Processed files were searched against the SwissProt human database using the Sequest HT. The Nodes for SequestHT included the following parameters: Precursor Mass Tolerance 20ppm, Fragment Mass Tolerance 0. 5 Da, Dynamic Modifications were Oxidation of M (+15. 995 Da) and Deamidation of N, Q (+0. 984 Da). Protein quantification was based on the relative precursor intensity of the light and heavy R(10), K(8) SILAC labelled versions of their matching peptides. The level of confidence for peptide identifications was estimated using the Percolator node with decoy database search. FDR<1% was applied in all the runs.
Proximity ligation assay (PLA) Cells were fixed and permeabilised by treating 5 minutes with methanol (-20˚C) and washing thrice with cold phosphate buffered saline. PLA was carried out according to the supplier's protocol (Olink Bioscience). Primary antibodies used for the PLA reaction were anti-methyl Histone H3 Lysine 4 at a 1/50 dilution (Abcam ab8895) and anti HER2 at a 1/75 dilution (Abcam ab16901). Cells were observed with a Nikon Eclipse Ni-E microscope at magnification x630 and images were captured with Nikon's NIS Elements Imaging software. DAPI and PLA fluorescence were captured at high resolution with automated 0. 5μm z-sections for a total of 8 separate z-sections per observation field. All Z-sections were then stacked. Cell numeration and PLA labeling were carried out using Image J software.
RNAseq data analysis Single-end 40BP reads generated on the Illumina HiSeq were aligned to the human genome version GRCh37. 64 using TopHat version 2. 0. 4  [35]. Read counts were then obtained using HTSeq-count version 0. 5. 3p9 (http://www-huber. embl. de/users/anders/HTSeq/doc/overview. html). Read counts were then normalised and tested for differential gene expression using the Bioconductor package DESeq2  [36]  version 1. 8. 1. Multiple testing correction was applied using the Benjamini-Hochberg method. Genes were selected as differentially expressed such that FDR <0. 01.
Integration of RNAseq and ChIP-seq data Chip-seq/exo binding sites were annotated using genomic features of the Human Genome Assembly [GRCh37]. Genes whose body coordinates were in the proximity to chip-seq peak summits within region of +/-10kbp were selected as potential target genes for regulation by HER2. P-values derived from DESeq2 analyses of the RNA-Seq data for all selected genes were-log10 transformed. These values were subsequently used for ranking and weighting of genes. GSEAPreranked analysis tool from Gene Set Enrichment Analysis (GSEA) software, version 2. 2. 3 (http://software. broadinstitute. org/gsea/index. jsp) has been used for establishing potential functional relation between Chip-seq/exo site location and gene expression. For hierarchical clustering, RNA-seq read counts were normalised using library size and standard deviation coefficients and then log2 transformed.
Acknowledgments The authors thank  Aurelien Serandour  for help with the ChIPexo method, the  Genomics, Bioinformatics (Tom Carroll & Suraj Menon ) and Proteomics core facilities at  CRUK Cambridge Institute. We would like to acknowledge the support of the  University of Cambridge, Cancer Research UK  and  Hutchison Whampoa Limited. J. S. C. is supported by an  ERC   Consolidator grant. M. L. R is supported by a grant from  Fondation ARC Cancer.
Auriculariopsis and Schizophyllum have unusual wood-decay strategies The substrate-wise phylogenetic PCA portrays a separation of these two species from the other 29 species used in this dataset. In the case of cellulases, these two species cluster together with WRs and S/L/O, suggesting a similar arsenal of CAZymes acting on the cellulose degradation (Figure  1b ). Enzyme families acting on crystalline cellulose (cellobiohydrolases -GH6, GH7) were present in lower numbers than in WRs and S/L/O species, but similar to ectomycorrhizal ones. The pattern was mostly identical for hemicellulases and pectinases (Figure  1b ) where CAZyme copy numbers were similar to that of white rotters and litter decomposers. However, some CAZymes related to xylanase and pectinase activities including xylosidases, pectate lyases, pectin acetylesterases, and acetyl xylan esterases (AA8, GH30, GH43, GH95, CE12, PL1, PL3, PL4) have higher copy numbers in the two species than in most WRs.
We built on previous datasets to obtain putative suberinase  38, 39  and tannase 40 copy numbers for 31 species in our dataset. In general, suberin comprises aromatic compounds cross linked by poly-aliphatic and fatty-acid like components which requires extracellular esterases and lipases for their breakdown  38. Based on. CC-BY-ND 4. 0 International license under a not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available The copyright holder for this preprint (which was this version posted February 14, 2019. ; https://doi. org/10. 1101/550103 doi: bioRxiv preprint phylogenetic PCA of putative suberinases A. ampla and S. commune were transitional between typical WR and ECM, BR (Fistulina), uncertain (Cylindrobasidium, Pluteus) or tentative WR (Fibulorhizoctonia) species.
It is the largest family of basidiomycete lectins  3  and was shown to be toxic to nematodes  29, 74  , although their diverse carbohydrate-binding abilities (mannose and N-acetylgalactosamine) could confer additional or other functions as well. F-box and BTB/POZ domain containing proteins have recently been reported as an interesting family with probable functions in fruiting body development and a significant expansion in the Agaricomycetes  3. Auriculariopsis has 246 F-box protein encoding genes, of which 12 were developmentally regulated in our dataset. Of the 96 BTB/POZ domain-containing proteins 26 were developmentally regulated, including some genes with remarkable expression dynamics during development (e. g. fold change 526x, Auramp1_515369). This is similar to figures reported for S.
The quantified library was then multiplexed with other libraries, and the pool of libraries prepared for sequencing on the Illumina HiSeq sequencing platform utilizing a TruSeq paired-end cluster kit, v4, and Illumina's cBot instrument to generate a clustered flow cell for sequencing. Sequencing of the flow cell was performed on the Illumina HiSeq2500 sequencer using HiSeq TruSeq SBS sequencing kits, v4, following a 2x150 indexed run recipe. Illumina fastq files were QC filtered for artifact/process contamination and de novo assembled with Trinity v2. 1. 1  88  and used for genome annotation The genome was annotated using the JGI Annotation pipeline  89  and made available via JGI fungal genome portal MycoCosm (jgi. doe. gov/fungi;  89 ). The data also deposited at DDBJ/EMBL/GenBank under the accession (TO BE PROVIDED UPON PUBLICATION).
Bioinformatic analyses of RNA-Seq data RNA-Seq analyses were carried out as reported earlier  3, 4. Paired-end Illumina (HiSeq) reads were quality trimmed using CLC Genomics Workbench 9. 5. 2 (CLC Bio/Qiagen), removing ambiguous nucleotides as well as any low quality read ends. Quality cutoff value (error probability) was set to 0. 05, corresponding to a Phred score of 13. Trimmed reads containing at least 40 bases were mapped using the RNA-Seq Analysis 2. 1 package in CLC requiring at least 80% sequence identity over at least 80% of the read lengths; strand specificity was omitted. Reads with less than 30 equally scoring mapping positions were mapped to all possible locations while reads with more than 30 potential mapping positions were considered as uninformative repeat reads and were removed from the analysis.
"Total gene read" RNA-Seq count data was imported from CLC into R 3. 0. 2. Genes were filtered based on their expression levels keeping only those features that were detected by at least five mapped reads in at least 25% of the samples included in the study. Subsequently, "calcNormFactors" from "edgeR" 3. 4. 2  90 was used to perform data scaling based on the "trimmed mean of M-values" (TMM) method73. Log transformation was carried out by the "voom" function of the "limma" package 3. 18. 13  91. Linear modeling, empirical Bayes moderation as well as the calculation of differentially expressed genes were carried out using "limma". Genes showing at least four-fold gene expression change with an FDR value below 0. 05 were considered as significantly differentially expressed. Multi-dimensional scaling ("plotMDS" function in edgeR) was applied to visually summarize gene expression profiles revealing similarities between samples.
Analyses of Carbohydrate Active Enzymes (CAZymes) The CAZymes in the 31 species used in this study were annotated using the CAZy annotation pipeline  94. Copy numbers for most species were extracted from JGI Mycocosm, whereas those of Flammulina velutipes, Coprinopsis marcescibilis, and Galerina marginata were annotated for this study. Of all the families found in the dataset, we took into account the CAZyme families reported having a putative role in plant cell wall degradation  6, 8, 9, 22  (Supplementary Table  5 ) and analyzed their copy numbers across the 31 species. We used 45 CAZy families in our dataset (Supplementary Table  5 ) and divided them based on the degradation of celluloses, hemicelluloses, lignin, pectin. In addition to these substrates, we also assessed genes encoding proteins with putative roles in suberin and tannin degradation.
The prepared SMRTbell template libraries were then sequenced on a Pacific Biosciences RSII sequencer using Version C4 chemistry and 4-hour sequencing movie run times. Filtered subread data was assembled together with Falcon version 0. 4. 2 (https://github. com/PacificBiosciences/FALCON) and subsequently polished with Quiver version smrtanalysis_2. 3. 0. 140936. p5 (https://github. com/PacificBiosciences/GenomicConsensus).
Acknowledgements This work was supported by the  'Momentum' program  of the  Hungarian Academy of Sciences  (Contract No. LP2014/12  to L. G. N. ) and the  European Research Council  (Grant No. 758161  to L. G. N. ). The work conducted by the  U. S. Department of Energy Joint Genome Institute (JGI) , a  DOE Office of Science User Facility , was supported by the  Office of Science of the U. S. Department of Energy  under Contract No. DE-AC02-05CH11231. This work was supported by the  National Research, Development and Innovation office  (Contract No. Ginop-2. 3. 2-15-00002 , to L. G. N. ).
5] [16]  Clinically, however, the functional requirement for dysferlin is most notable in skeletal muscle. At least 416 different pathogenic dysferlin variants are listed in the Universal Mutation Database (UMD-DYSF, http://www. umd. be/DYSF/),  17  most of these lying within one of the 55 exons that are spliced together to form isoform 8 that is critical for muscle function. For approximately 17% of patients, a complete understanding of the genetic lesions underlying their disease is lacking; at least one of their pathogenic mutations has not been identified. It is highly likely that these mutations lie somewhere within dysferlin introns or areas other than exons that regulate dysferlin expression. These gene regions are not examined by standard exonic screening methods. We recently identified one such pathogenic variant deep within dysferlin intron 44i (c.
The dysferlinopathy patients initially screened, JF196 and JF23, are siblings participating in an ongoing international "Clinical Outcome Study for Dysferlinopathy", a collaboration with the Jain Foundation and Newcastle upon Tyne Hospitals. Patient skin fibroblasts were obtained from the Newcastle upon Tyne Hospital Biobank. These patients are heterozygous for one pathogenic dysferlin variant identified by exon sequencing (c. 5698_5699delAG; p. Ser1900GlnfsX14, stop codon in exon 51, DYSF C2G domain), but their other pathogenic allele had not been identified. Similarly, dysferlinopathy patient TDM57 had only one pathogenic allele defined by exon sequencing (c. 2998T>C; p. Ser1000Pro, inner DysF domain, predicted pathogenic, UMD-Predictor algorithm, UMD-DYSF Universal Mutation Database). TDM57 skin biopsy tissue was obtained via the Jain Foundation as part of a diagnostic program at the Centre for Advanced Molecular Diagnostics in Neuromuscular Disorders, Mumbai, Maharashtra, India.
Cells were transfected with each AON (600 nmol/L or other concentrations as indicated) (or TE buffer as control) using Oligofectamine (Life Technologies) and the manufacturer's protocol. After the indicated times, RNA was extracted and evaluated by RT-PCR  18  using primers 16-F and 15-R to amplify either the normal DYSF sequence (88 bp) or the mutant version containing PE50. 1 (268 bp). Proteins were extracted from similar cultures and evaluated on western blots using antibodies against the dysferlin C-terminal region (NCL-Hamlet, Leica, Buffalo Grove, IL, USA, 1/1000) and GAPDH (G9545, Sigma, St. Louis, MO, USA, 1/1000) as described. 18 Protein expression levels were calculated from western blot images using a Li-COR Odyssey infrared imager and Image Studio Software (Li-COR).
1 inclusion in the mRNA transcripts is caused by a novel point mutation (c. 5668-824C>T) deep within intron 50i (Fig. S1 ). As shown in Figure  2B , this point mutation creates a consensus splice donor site that promotes the splicing of the 180 bp PE50. 1 sequence between exons 50 and 51. Additionally, a consensus "YAG" splice acceptor sequence exists immediately upstream of the PE50. 1 sequence, along with a pyrimidine-rich region and potential branch points as predicted by Human Splicing Finder, all of which are important for splicing (Fig. S2 ). We analyzed genomic DNA and differentiated iFDM cell cDNA derived from an unrelated dysferlinopathy patient, TDM57. This patient also had only one known pathogenic dysferlin variant identified (c. 2998T>C). Genomic DNA sequence analysis showed that this patient also carries the c.
5668-824C>T point mutation in intron 50i, and RT-PCR analysis of iFDM cell mRNA showed the aberrant inclusion of PE50. 1 in the mRNA of this patient. Additional sequence variants present within intron 50i of patients JF196, JF23, and TDM57 are summarized in Table  1. Each of these variants are reported in the dbSNP database and have no known pathogenicity.
Discussion Using myogenic cells derived from patient skin fibroblasts, we identified a novel point mutation deep within DYSF intron 50i (c. 5668-824C>T) that causes aberrant dysferlin mRNA splicing and the inclusion of a pathogenic pseudoexon (PE50. 1) in dysferlin mRNA. This is the second such deep intronic pseudoexon-generating point mutation we have identified using this approach; the previous one was identified within DYSF intron 44i (PE44. 1). 18 Initially identified in two siblings with dysferlinopathy (JF196, JF23), we found a total of 23 patients from 17 families that carry this intron 50i mutation, making it one of the more prevalent pathogenic DYSF mutations when compared with those in the Universal Mutation Database (UMD-DYSF, http://www. umd. be/ DYSF/). 17 nown pathogenic variants in genes are typically identified by screening patients' genomic DNA using exon sequencing methods that interrogate the coding regions and intronic sequences near the exon junctions.
Genomic DNA sequence variants in DYSF intron 50i of dysferlinopathy patients JF196, JF23 and TDM57. variations within DYSF intron 50i in patients are listed. The novel mutation c. 5668-824C>T results in PE50. 1 inclusion in mature mRNAs. Other variations listed are reported in the dbSNP database and have not been shown to be pathogenic. Global MAF values: top, 1000 Genomes; bottom, TOPMED. The primer sets used to amplify and sequence these regions are shown. The DYSF reference sequence used: GRCh38. p7; mRNA isoform 8, NM_003494. 3. ª 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
A. Acquisition set-up The data were acquired with a Verasonics research scanner (Verasonics Inc. , Redmond, WA) and a P4-2 phased array probe having 64 elements and a central frequency of 2. 5 MHz. The pulse repetition frequency (PRF) was set to 4500 Hz, the sector size to 90º and the maximum range to 13 cm. There are different ways to compare two methods in a fair way. In this study, as a general principle, we have chosen to adapt the transmission waveform in order to obtain the same total emitted power for both MLT and DW. For MLT, we used an excitation signal which was on during 1/5 of the half cycle and off for the rest of the time. We computed the transmission matrix by overlapping the excitation signals corresponding to all elements and to all simultaneous transmissions. Then, we compared the resulting signals with a threshold in order to obtain a tristate pulse (-1/ 0/ +1) as required by the Verasonics system.
E. In vivo Models In vivo data were acquired in an open-chest pig. The experiments were approved by the Animal Ethical Committee with agreement number A693830501. Parasternal short axis views were examined for both B-mode images and tissue Doppler. The acquisition sequences and settings were similar to those used for the in vitro data. The only difference was the focal point for MLT which was placed at 4 cm, due to the available view. The DW and MLT acquisition sequences were concatenated and the buffers were adapted to receive alternatively sets of DW and MLT frames. Thus, the comparison could be assessed at close cardiac phases within the same cardiac cycle. For B-mode images, an intermediate frame rate of 450 Hz was chosen for both DW and MLT (Table I, third row; headings considered as the first row).
ACKNOWLEDGMENT This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 642612, VPH-CaSE (www. vph-case. eu). This work was performed within the framework of the LABEX PRIMES (ANR-11-LABX-0063) of Université de Lyon, within the program "Investissements d'Avenir" (ANR-11-IDEX-0007) operated by the French National Research Agency (ANR). This work was also supported by LABEX CELYA (ANR-10-LABX-0060). The Verasonics system was cofounded by the FEDER program, Saint-EtienneMetropole (SME) and Conseil General de la Loire (CG42) within the framework of the SonoCardioProtection Project leaded by Dr Pierre Croisille.
Here we draw upon clinical and experimental studies of PPN DBS in patients with PD, in addition to selected insights from experimental work in animals particularly the nonhuman primate, to discuss potential therapeutic mechanisms. However, several limitations of the dataset need to be acknowledged. Firstly, only a few centres have generated the bulk of the published literature regarding PPN DBS. (Ferraye et al. , 2009; Khan et al. , 2012; Moro et al. , 2010; Stefani et al. , 2007; Thevathasan et al. , 2011a)  Secondly, patients with PD implanted with PPN DBS are a selected subgroup where gait freezing and postural instability are the dominant issues. Observations outside of the impact on movement have typically been incidental. Third, whilst the surgical target is the PPN, the impact of DBS may not necessarily reflect modulation of the PPN itself but could arise from its related networks or even from neighbouring regions.