dataesr/scientific-paragraphs-categorization huggingface dataset:
Statistical considerations The incidence of serious adverse events and events of special interest will be documented using two-sided 95% confidence intervals. Analyses will be performed using SAS version 8. 2 or higher. Data will be analyzed annually. Subsets of patients who have been exposed to lomitapide will be compared and incidence rates of events of special interest tabulated. Long-term serum lipid levels in a clinical practice setting will be evaluated. Prescribing patterns of practitioners in a real-world setting will be described.
Discussion LOWER will provide comprehensive real-world data on the clinical use of lomitapide as a treatment for HoFH. The clinical studies already conducted have documented the short-term risk-benefit profile of lomitapide and provided the basis for regulatory approval. LOWER will complement and expand these data by providing long-term safety data and generating information on use in everyday clinical practice. In addition, LOWER is expected to provide valuable information on the clinical and laboratory characteristics of HoFH. As it is a rare disease, there are few published studies on HoFH, and the natural history of the disease is poorly understood in the context of contemporary medical practice. Rare diseases, such as HoFH, are often underdiagnosed and inadequately treated, and the introduction of an effective new therapy may improve awareness and increase motivation for early diagnosis and treatment.
51 o our knowledge, LOWER (together with the mipomersen registry required as a condition of FDA approval) is the first formal HoFH-specific registry. Unlike the registries already mentioned, LOWER is a drug-exposure registry rather than a disease registry. LOWER is expected to provide high-quality information on the clinical characteristics of patients with HoFH taking lomitapide and the impact of lomitapide on the natural history of the disease. A large number of cases will be included and information collected on baseline characteristics, including mutations, diagnostic criteria, previous therapies, and lipid profiles over time. It is anticipated that LOWER will provide robust data on the long-term safety and effectiveness of lomitapide in a patient population that is representative of usual clinical practice and much larger than the population included in the Phase III trial.
These plaque composition analyses will be performed at imaging time points if sufficient data exist with respect to both the size and frequency of the plaques To assess changes in markers of inflammatory and cardiovascular processes at 1, 2, and 5 years of lomitapide treatment compared with baseline and to correlate these changes with the change from baseline in MRI parameters of carotid and aortic atheroma LDL-C, low-density lipoprotein cholesterol; MRI, magnetic resonance imaging. The registry will evaluate the use of lomitapide in conjunction with standard lipid-lowering therapies, including lipoprotein apheresis. LOWER will thus also provide an opportunity to assess the potential of lomitapide to allow a reduction in the frequency or cessation of apheresis while maintaining lipid control.
The overall impact on cardiovascular morbidity and mortality will be recorded through evaluation of MACE. LOWER will also document the effectiveness of the risk minimization strategies that have been implemented in facilitating the use of lomitapide, maximizing benefits for patients and managing risks appropriately. The cardiovascular imaging substudy will provide data on the impact of LDL-C reduction with lomitapide on atherosclerosis. The separate PER will assess the effect of lomitapide exposure on the outcomes of pregnancy in women with HoFH, as well as extending the very limited information available on these patients.
They also exposed the following limitations of the LUT-based HRI method: (1) Using constant NH 3 vertical profiles can introduce potentially large errors  (in Van Damme et al. [2014a] , one fixed profile over land is used which peaks at the surface and one over oceans which peaks around 1400m   , e. g. , Hadji-Lazaro et al. [1999]  and  Turquety et al. [2004]  for earlier satellite retrieval schemes that used NNs). As both rely on a database of training data, a NN can be seen as a generalization of a LUT. However, the important difference is that a LUT needs to store an output value for each combination of its input parameters, and the size of the LUT therefore grows exponentially with the dimension of the table. The great strength of a NN lies in its ability to cope with hundreds of input parameters, thereby offering a lot more flexibility than a two-dimensional LUT, while not requiring the expensive and, in many cases, repetitive calculations of spectral fitting approaches.
Training Set The main idea of the proposed retrieval approach is to map the HRI to NH 3 columns via a NN. As explained in section 1 a NN is built via training. Ideally, the training set should be as large, as accurate, and as extensive as possible, and input data in the training should be representative of the real input data. A description of the principles of operation of a supervised NN for atmospheric remote sensing can be found in Hadji-Lazaro et al. [1999],  Turquety et al. [2004] , and  Blackwell and Chen [2009]. In this section, we explain how the NN training set was built. Since a reference data set of IASI-NH 3 is not available, we built a synthetic training set using forward simulations with the Atmosphit line-by-line radiative transfer model  [Coheur et al. , 2005]. To be representative for IASI observations, background atmospheric conditions were taken from 1year of thermodynamic atmospheric profiles provided by the meteorological Level 2 information from the operational IASI processor  [August et al.
, 2012] ; the  and z 0 parameters describing the shape of the NH 3 vertical profiles; the surface emissivity (); and the viewing angle of the satellite. The temperature, pressure, and humidity profiles are described by 12, 11, and 7 levels, respectively. Surface emissivities over land were taken from the 2014 monthly mean spectral emissivity database provided by  Zhou et al. [2011]. Over sea, emissivities were taken from the  Nalli et al. [2008]  emissivity database. These spectral emissivities were averaged over the range [800-1010; 1065-1200] cm -1. The 1010-1065 cm -1 region was excluded to avoid interferences from the  3 ozone band. The NN output parameter was set as the ratio of the NH 3 total column to the HRI. The relationship between the input and the output parameters can be written as NH 3 column = HRI × f (T, T surf , P, H 2 O, 𝜎, z 0 , 𝜖, angle).
Retrieval, Uncertainty Estimate, and Example For the actual retrieval we first filtered out observations with a cloud fraction inside the IASI field of view above 25%, since our training data did not include clouds. Then for the remaining observations the different input parameters of the NN were gathered. Atmospheric profiles (water vapor, pressure, and temperature) were 10. 1002/2016JD024828 taken from the IASI meteorological L2. Surface emissivities were taken as the mean of the spectral emissivity in the range [800-1010; 1065-1200] cm -1 from the 2014 monthly mean database provided by  Zhou et al. [2011]  (for land measurements) and from the  Nalli et al. [2008]  database for sea measurements. HRIs were calculated following equation (1) (with again angular dependent K, ȳ, and S). In first instance, and to ease comparison with the LUT product, we used fixed values for the  and z 0 input parameters by fitting the single NH 3 profiles used for land and sea in the LUT-based HRI method  [Van Damme et al.
study design As illustrated in Figure  1 , this was a randomized, doubleblind, placebo-controlled, crossover, two-site study (ClinicalTrials. gov, registration number: NCT01655199), wherein eligible patients visited the research facility four times, with a period of 3-7 days within visits. The study protocol and consent form were approved by each institution's Biomedical Research Ethics Board in accordance with the Declaration of Helsinki (IUCPQ, #CER20819; MCI, 12-327-BMA). Written informed consent and medical history were obtained at visit 0 (V0), and inhaled medication was modified, if necessary (details are given in the following section). During visit 1 (V1), complete pre-and post-bronchodilator (200 µg salbutamol) pulmonary function testing was performed, followed by a symptom-limited peak incremental cycle exercise test and then a 3-MST for familiarization purposes.
statistical analysis No pilot data were available to support a formal sample size calculation. The sample size was thus estimated based on the previous work of our research group showing that 40 patients were sufficient to demonstrate the responsiveness of the 3-minute constant rate shuttle walking test to detect the improvement in exertional dyspnea following bronchodilation. 15 Based on this past experience, we estimated that a similar number of patients should be enrolled in the current study. The effects of study medications (ipratropium bromide/salbutamol vs placebo) and measurement time (pre-vs post-dose) on FEV 1 , FVC and FEV 1 / FVC were examined using a two-way repeated measures analysis of variance with correction for multiple comparisons using Bonferroni's post hoc tests (Prism 6; GraphPad Software, La Jolla, CA, USA).
study participants A flowchart of the study is presented in Figure  2. A total of 40 patients with GOLD stage 2 and 3 COPD were recruited between January 2012 and June 2014. Baseline data of the study population are provided in Table  1. On average, patients had static lung hyperinflation, pulmonary gas trapping and low diffusion capacity (D L CO). At symptom-limited, peak incremental cycle exercise, patients reported "severe" to "very severe" dyspnea and leg discomfort and exhibited low peak power output, V ˙O2peak and HR in association with marked dynamic lung hyperinflation (as evidenced by a 0. 70 L IC decrease from rest to peak exercise), ventilatory inefficiency and complete or near-complete erosion of ventilatory reserve and IRV (Table  2 ).
Acknowledgments The authors would like to thank  Marthe Bélanger ,  Marie-Josée Breton ,  Brigitte Jean ,  Josée Picard  and  Jacinthe Baril  in accomplishing this study. They also thank  Julie Milot ,  Yves Lacasse ,  Steeve Provencher ,  Pierre Leblanc ,  Eric Nadreau ,  Alisha Maini  and  Sara Abdallah  for their help with the exercise tests. Dennis Jensen  was supported by a  Chercheurs-boursiers Junior 1 salary award  from the  Fonds de la Recherche Québec-Santé  and by a  William Dawson Research Scholars Award  ( McGill University ). François Maltais holds a  GlaxoSmithKline (GSK) / Canadian Institute of Health Research (CIHR)  Research Chair on COPD at  Université Laval. This work was supported by an unrestricted and investigator-initiated grant from  Boehringer Ingelheim (Canada)  Limited to  François Maltais.
Organisms that have evolved alternative modes of reproduction, complementary to the sexual mode, are found across metazoans. The chordate Botryllus schlosseri is an emerging model for asexual development studies. Botryllus can rebuild its entire body from a portion of adult epithelia in a continuous and stereotyped process called blastogenesis. Anatomy and ontogenies of blastogenesis are well described, however molecular signatures triggering this developmental process are entirely unknown. We isolated tissues at the site of blastogenesis onset and from the same epithelia where this process is never triggered. We linearly amplified an ultra-low amount of mRNA (<10ng) and generated three transcriptome datasets. To provide a conservative landscape of transcripts differentially expressed between blastogenic vs.
non-blastogenic epithelia we compared three different mapping and analysis strategies with a de novo assembled transcriptome and partially assembled genome as references, additionally a self-mapping strategy on the dataset. A subset of differentially expressed genes were analyzed and validated by in situ hybridization. The comparison of different analyses allowed us to isolate stringent sets of target genes, including transcripts with potential involvement in the onset of a non-embryonic developmental pathway. The results provide a good entry point to approach regenerative event in a basal chordate.
The coexistence of two stereotyped ontogenetic pathways within the same species, embryogenesis and blastogenesis, makes B. schlosseri an exceptional chordate model to study and compare different developmental programs within the same species, and even the same individual. Ultimately, allowing us to explore questions related to cell de/trans-differentiation as well as stem cell biology  6, 11, 15  and ageing  16, 17. While extensive literature provides detailed descriptions of morphology, anatomy and ontologies of blastogenic development (Manni et al. )   10  , the molecular mechanisms that trigger blastogenesis, and developmental competences in a differentiated tissue are still unknown. In the present study we surgically isolated blastogenic tissues. Starting from an ultra-low amount of total RNA (< 10 ng) we generated RNA-seq datasets from two early stages of blastogenesis and from non-blastogenic tissues.
In order to obtain a conservative perspective of the genes involved in blastogenesis and to provide a reliable analysis of the transcriptomic landscapes of gene's up-regulation in budding tissues, we compared three approaches to treat the raw data: (1) we took advantage of the recently published genome  18  and performed differential expression (DE) using the TopHat-Cufflink pipeline  19  ; (2) we also mapped our datasets to a reference transcriptome assembly, obtained from multiple developmental stages and genotypes, and proceeded to DE analyses using DEGseq package; (3) finally, we performed DE analyses using de novo assembling obtained after pooling only the blastogenic tissues dataset  20, 21. These three approaches then were compared to identify congruent list of candidate genes. Applying different strategies of assembling and mapping has provided extra-confidence on the identified stage-specific gene expression during blastogenesis.
In the samples at stage "A2" and "B2" the two epithelia (pbe and e) acquired budding capability and present the characteristic morphology, reviewed in Manni et al. 10. approaches of sequence assembly mapping and cross-compared the differential expression data obtained from each approach (Fig. 2 ). Reference-guided method. Starting with the straightforward approach of 'aligning-followed-by-assembling' (methodology 1), reads were first aligned to the partially sequenced reference genome assembly 18 using TopHat2  22  (methodology 1). This resulted in an average 46. 77% (over six samples) of reads mapping (Supplementary Table  S2 ). Mapped reads were assembled into transcripts using Cufflinks  22  , however because of a lower average mapping percentage (less than 50%) and poor DE results, we did not continue with this approach (see Discussion).
De-novo methods. Applying the approach of 'assembling-followed-by-aligning' (methodology 2), a de novo transcriptome of B. schlosseri has been assembled from different ESTs and RNA-seq dataset (See Methods), with a total of 373,374 assembled transcripts, averaging 357 bp in length and an N 50 of 1458 base pairs (Table  1 ). Total RNA-seq reads were then mapped (separately for each sample) to the de novo transcriptome using Bowtie2 which resulted into 58. 06% overall average alignment rate (Supplementary Table  S3 ). Since the reference transcriptome has been assembled from different genotypes, i. e. with high level of polymorphisms, in order to improve the mapping we adopted a third approach (methodology 3) based on a recently published pipeline CORSET  21. Pooling the RNA-seq reads from the six samples, i.
e. the duplicates from stages A2, B2 and Ref (non-blastogenic tissue), were de novo assembled, using Trinity v2. 0. 6, yielding a total number of 230,885 transcripts with average contig length of 346 bp (Supplementary Table  S3 ). This assembly was then used as reference for mapping. Therefore, the reads were self-mapped back to this current reference assembly, using Bowtie2, generating an average alignment rate of 79% (Supplementary Table  S3 ). Conservative DE analyses of linear amplified libraries. Differential expression was tested for all three pairwise comparisons between two blastogenic stages, i. e. A2 vs. B2, and between blastogenic and non-blastogenic (Ref) epithelia: A2 vs. Ref, B2 vs. Ref (Fig. 1c ). By using the two de novo methods (methodology 2 and methodology 3), differential expression was assessed using DEGseq package  23  , by applying the P-value criteria of 0.
001 (default) for contigs to be statistically significant which corresponds to the z-score threshold of + /-3. 3. The total number of identified DEGs along with their up-/down-regulation are summarized in Table  2  and displayed as MA-plots using different color scheme corresponding to the methodology used (Fig. 3a, b ). Other package e. g. DEseq2, which is based on the negative-binomial distribution, has also been tested for DE analysis. DEseq2 has identified 1127 significant genes for A2 vs. Ref that is almost double of those identified by DEGseq package, implying over-sensitivity of DEseq2 for current experimental design. A cross comparison of differentially expressed genes (DEGs) identified under methodology 2 and methodology 3 is presented as Venn diagram illustrating the overlapped DEGs (Fig.
Functional annotation and classification. To gain biological insights into the identified DEGs identified under methodology 2 (de novo method), functional annotations were retrieved using the following programs: BLASTx, BLASTp, InterProScan and enrichment analysis were preformed using Genecodis3 and GSEA (see Methods). All the results obtained from functional and enrichment studies, on the differentially expressed genes, under each pairwise tissue comparisons, were integrated in Supplementary Data S1, S2.
Statistical relevance for each category are reported in Supplementary Data S2, S3, and S4 and graphical representations of the enriched annotations are reported in Supplementary Figs  S5-7. Specifically, comparing the annotations for differentially expressed genes between two blastogenic stages B2 vs. A2 revealed significant overexpression of the following genes at B2 stage: RDH13 (Retinol dehydrogenase 13), ALDH1A2 (Aldehyde dehydrogenase) characterized under GO:0016491 MF oxyreductase activity with FDR of 0. 046 (using SEA, see Methods) and FDR = 0. 022 (using MEA, see Methods). InterPro annotation reported the genes containing the POU3F4 domain (IPR016362, FDR = 0. 0097). While examining B2 vs. Ref, GATA4/5/6 (IPR016357 and IPR00619) was found to be significantly enriched in the B2 stage with an FDR of 0.
The differential expression analysis using Cuffdiff  22  , identified only 75 transcripts with significant differential expression (FDR < 0. 05) in case of A2 vs. Ref, while for the other pairwise comparisons none of the transcripts were found to be statistically significantly differentially expressed. Functionally exploring the significant 75, by using BLASTx against non-redundant database, revealed high homology with the solitary ascidian Ciona intestinalis (proteins dominated with 56%) and only 2% of blast hits matched to published B. schlosseri sequences (Supplementary Fig. S4a ). Since such an approach relies on a robust splice based aligner for genome guided transcriptome reconstruction, its efficacy is integrally limited by the quality of Botryllus genome, which in the current assembly state is not satisfactory.
The datasets here provided are the first tissue specific transcriptomes of asexual development in a chordate, and represent the initial step to characterize, on a large scale, conserved and novel molecular players acting on an epithelium with pluripotent characteristics. The approach adopted, which couples ultra-low input RNA with stringent data analyses, represents a proof of principle that can be successfully applied in further steps, i. e. the collection of additional blastogenic stages, and different reference tissues, not only in B. schlosseri but also in other ascidians and budding metazoans. Whereas vertebrates have limited regenerative capacity, many invertebrate models such as colonial ascidians can rebuild their bodies completely in response to injury  38, 39  or as part of their life cycle  5, 40, 41.
Unlike mammals, where genomic and transcriptomic data are abundant, these models are often poorly annotated due to lack of sequence data  42. The three transcriptomes, together with their DE analyses, provide a tissue specific toolset for the study of the regeneration of complex structures. In order to provide further validation these datasets, more expression (via FISH) and functional testing (i. e. via siRNA) are still required. However, these tools offer the captivating perspective of performing insightful comparisons with vertebrate Functional domain searches were conducted using InterProScan  48  incorporating protein signature from Pfam, SMART, PRINTS, PROSITE, Gene3D, SUPERFAMILY and PANTHER. Single peptide cleavage location and transmembrane helices were predicted using SignalP and TMHMM, respectively.
The extracted annotations involve: GO terms (Biological processes, Molecular Function, Cellular Component)  50  , InterPro 51 motif and Transcription Factors  52  from MSigDB. Further gene set enrichment analysis was also performed using GSEA (Gene Set Enrichment Analysis) software v2. 2. 0 ("Gene Set Enrichment Analysis, www. broadinstitute. org/gsea/index. jsp, 15/06/2015) separately against two a priori defined gene sets collections: C2 (c2. all. v5. 0. symbols), which is a collection of 4725 gene sets from various online pathways (http://www. broadinstitute. org/gsea/msigdb/collection_details. jsp#C2,15/06/2015) and C5 (c5. all. v4. 0. symbols) includes 1454 gene sets based on GO annotations (http://www. broadinstitute. org/gsea/msigdb/collection_details. jsp#C5, 15/06/2015) Other settings for the GSEA run include: (i) collapse dataset to gene symbols = TRUE and (ii) number of gene set permutations were set to 1,000.
Data access. Transcriptome assembly is available at the Octopus database (BioInformatique, http://octopus. obs-vlfr. fr/public/botryllus/blast_botryllus. php, 04/01/2016) hosted by CNRS/UMR7009 and sequences for differentially expressed genes can be retrieved from Octopus: BioDev Bioinformatics Server, http://octopus. obs-vlfr. fr/public/botryllus/fastacmd_riccipaper. html, 28/04/2016) using contig identifier (see Supplementary Data S1) under the sequence identifier section. Fluorescent in situ hybridization. For each gene, couples of forward and reverse primers were designed in order to obtain amplified fragments between 500 and 1200 bp. A T7 promoter sequence was added at the 5′ end of each reverse primer. Fragments of interest were amplified with the Phusion ® High-Fidelity DNA Polymerase (NEB, M0530S) using the forward and modified reverse primers.
Acknowledgements We would like to thank  Mohamed Khamla  for his contribution in drawing sketches of Botryllus blastogenetic buds,  Laurent Gilletta  and  Sophie Collet  for the animal care and the bioinformatics core service ABiMS-EMBRC-Fr. This work was supported by  AFM Telethon  grant (# 16611 ),  IRG Marie Curie grant  (# 276974 ),  ANR  ( ANR-14-CE02-0019-01 ) and IDEX Super (INDIBIO). L. R. was supported by an  UPMC-EMREGENCE  grant and by a  FRM grant  (# FDT20140931163 ). A. C. was supported by a  FRM grant  ( ING 20140129231 ).