dataesr/scientific-paragraphs-categorization huggingface dataset:
The systematic status of echinoids of the Calcaires à Spatangues Fm. was revised so as to update the list of echinoid species reported in the Formation and better assess its remarkable diversity. Of the 54 echinoid species ever described, 26 species are recognized that belong to 16 different families, among which regular (13 species) and irregular (13 species) echinoids are represented in equal proportion. Data resources: the data underpinning analyses of the paper are deposited at GBIF, the Global Biodiversity Information Facility, http://ipt. pensoft. net/ipt/archive. do?r=hauterivian_echinoids_of_the_paris_basin.
Raw data were processed into R/Bioconductor by using the Limma package  (16). To determine genes whose expression increased when IRE1α is inactivated, probe set intensities were obtained by means of Gene Chip Robust Multiarray Averaging and were selected by using a corrected P value threshold of 0. 05 and fold change threshold of | log2(fc)| ≥2. 5 as previously described in ref. 15. The regulated genes are listed in Supplementary Table  S1. Data are accessible on the NCBI Geo portal with the reference number GSE27306.
RNA isolation, reverse transcription PCR, and quantitative PCR analyses Total RNA was prepared using the TRIzol reagent (Invitrogen Corp. ). Semiquantitative analyses were carried out as previously described  (17). The primers used were designed using Primer depot software  (18)  and are listed in Supplementary Table  S4. The PCR products were resolved on 1% to 3% agarose gels. For real-time quantitative PCR (qPCR), RNA was reverse transcribed with Superscript II (Promega). All PCR reactions were carried out with a Stratagene ×4000 thermocycler (Stratagene) and the SYBR Green PCR Core Reagents Kit (Bio-Rad). Experiments were conducted in triplicate for each data point. Each sample was normalized toward the expression of the Rplp0 gene.
5D ). This showed that the absence of/low XBP1s staining significantly correlated with enhanced survival. Together with data obtained with the expression of PER1 mRNA, these results suggested that IRE1α signaling activation in glioblastoma correlated with low patient survival. Finally, we tested the relevance of CXCL3 to glioblastoma outcome using the Rembrandt database  (28). High expression of CXCL3 mRNA seemed to correlate with low patient survival (not shown). Interestingly and as expected, in our cohort of human tumors, expression of CXCL3 mRNA negatively correlated with that of PER1 mRNA (Fig. 6D ). This further reinforced the instrumental role of an IRE1α-dependent pathway in tumor aggressiveness. Taken together, these data further support a specific and important role for IRE1α signaling in human glioblastoma and show that PER1 is a genuine signaling intermediate in glioblastoma progression.
Results were normalized against pCMV-Renilla luciferase (t test, ** P < 0. 05). C, actinomycin D pulse-chase was carried out as described in Materials and Methods. Total mRNA was extracted and quantitative RT-PCR experiments were conducted using PER1 mRNA-specific primer pairs. The experiment was repeated 3 times and data are presented as mean ± SD. Statistical significance was determined using Student t test, * , P < 0. 03. D, empty vector and IRE1_DN cells were transfected with siRNA against XRN1/2 or SKI2. RNA was isolated after 48 hours and was used to amplify different regions of PER1 mRNA. Experiments were carried out in triplicate and the mean ± SD, statistical significance (Student t test) is indicated ( * , P < 0. 05; ** , P < 0. 01). IRE1α-mediated posttranscriptional control of PER1 mRNA in vitro.
Acknowledgments The authors thank  M. Moenner  ( Université Bordeaux 1, Bordeaux, France ) for precious help and fruitful discussions,  S. Manié  ( UMR CNRS 5286 ,  INSERM 1052 ,  Cancer Research Center of Lyon, Lyon, France) , and the  Chevet lab  for critical reading of the manuscript. The authors also thank  Dr S. Gery  ( University of California, Los Angeles, CA ) for the gift of pcDNA3. 1-hPER1expression vector and  Dr U. Albrecht  ( Freiburg, Switzerland ) for providing us with the pPER1-Luc vector.
Grant Support This work was supported by an  Avenir program  (INSERM), grants from the  Institut National du Cancer (INCa) , Ligue contre le cancer, a  Marie Curie International Reintegration Grant  (E. Chevet), a grant from the  Mayo Clinic Cancer Centre (M. E. Fernandez-Zapico) , a grant from  Institut Fédératif de Recherche 66 (O. Pluquet). O. Pluquet was supported by fellowships from  INSERM and Association pour la Recherche contre le Cancer. M. Bouchecareilh  was supported from a fellowship from le  Conseil Régional d'Aquitaine and la Fondation pour la Recherche Française (FRM). Human glioblastoma samples were collected through the  Bordeaux Tumor Bank  ( JP Merlio ,  CHU Bordeaux, France ) funded by the  Cancéropôle Grand Sud-Ouest  and by a  CEREPEG project grant  ( PHRC 2003 ;  H. Loiseau ) or through the  Mayo Clinic Department of Clinical Pathology  and funded by the  Mayo Clinic SPORE in Brain Cancer   P50 CA108961  (Rochester).
interrogans, L. kirschneri, L. borgpetersenii, L. noguchi, and L. santarosai. We also identified L. kmetyi in at least two patients with acute leptospirosis. This is the first time, to our knowledge, that this species has been identified in humans. The most prevalent genotypes were associated with L. interrogans serovars Icterohaemorrhagiae and Copenhageni, L. kirschneri serovar Bogvere, and L. borgpetersenii serovar Arborea. We were unable to identify nine strains at the serovar level and comparison of genotyping results to the MLST database revealed new secY alleles.
Genetic characterization of Leptospira Genomic DNA was extracted from EMJH cultures or from human plasma (see above). DNA was amplified using Taq polymerase (GE Healthcare) under standard conditions. For species identification, the rrs gene was amplified with the primers LA (59-GGCGGCGCGTCTTAAACATG-39) and LB (59-TTCCCCCCATTGAGCAAGATT-39), and when necessary, by nested primers LC (59-CAAGTCAAGCGGAGTAGCAA-39) and RS4 (59-TCTTAACTGCTGCCTCCCGT-39)  [20, 21]. Part of the secY gene was amplified with the primers F (59-ATGCCGAT-CATTTTTGCTTC-39) and R (59-CCGTCCCTTAATTTTA-GACTTCTTC-39)  [22]. Sequencing was performed at the Genotyping of Pathogens and Public Health Platform (Institut Pasteur, Paris, France). All molecular epidemiological data were stored and analysed with Bionumerics software (Version 6.
Other serogroups detected include Mini (9 isolates), Tarassovi (4 isolates), Australis (1 isolate), and Celledoni (1 isolate). Four isolates scored negative (no agglutination) with the antisera raised against the 24 serogroups. A selection of isolates from the serogroup Icterohaemorrhagiae were subsequently typed to serovar level by MAT with monoclonal antibodies (MAbs) against the serovars Icterohaemorrhagiae and Copenhageni: both serovars were present among the clinical isolates (data not shown). Molecular typing was then performed by sequencing the 16S rRNA gene (rrs) in genomic DNA from 110 cultures and 36 acuteblood samples  [20]. All the samples corresponded to one of five pathogenic species: L. interrogans (44 samples), L. kirschneri (36 samples), L. borgpetersenii (38 samples), L. noguchi (3 samples), and L.
The remaining 32 strains were distributed into nine groups (D, E, G, H, I, J, K, L, and M), including six new alleles not found in the database published by Nalam et al. [32]. Thus, there were thirteen groups in total, and most were present on both Guadeloupe and Martinique. However, some genotypes were found only among isolates from Guadeloupe (group G with 9 isolates) or Martinique (groups H with 3 samples, I with 6 samples, and J with 2 isolates). Clusters A and B contained both, clinical and rat isolates.
Serogroups Cynopteri, Tarassovi, Panama, Grippotyphosa and Autumnalis are less common. The sensitivity of MAT is low during the acute stage of disease  [37]  and, because of paradoxical reactions and crossreactions between serogroups, the accuracy of MAT in identifying the infecting serovar or serogroup can also be poor  [38, 39] , limiting its epidemiological value. In this study, MAT serological data from culture-positive patients were reviewed retrospectively, allowing the identification of a total of 36 patients with MAT data for serum samples (data not shown). It was possible to infer the serogroup identity of infecting leptospires from the MAT results for 26 of these 36 patients (72%). Similarly, only a small proportion of PCR-positive samples were correctly identified by MAT (Table  2 ).
A total of thirteen genotypes were found in our study, a large proportion of strains (75%) being of only three genotypes associated with serovars Icterohaemorrhagiae/Copenhageni, Bogvere, and Arborea. The secY sequences from the L. santarosai isolates showed the highest nucleotide diversity. Six genotypes were not found in the MLST database and may therefore be specific to the French West Indies. Further characterization of these isolates should include the use of the CAAT, which requires the preparation of antibodies against the strain of interest, for definitive identification of the serovar. We also detected the appearance of strains related to the pathogenic species L. kmetyi in Martinique in at least two patients, one of which was probably exposed during canyoneering activities in the tropical forest (Hochedez et al.
Introduction In EU countries a rare disease (RD) is any disease affecting fewer than 5 people in 10,000  12  which translates to approximately 425,000 people throughout the EU's 27 member countries. (www. eucerd. eu and Orphanet database www. orpha. net). More than 80% of these diseases are caused by genetic defects. Screening for early diagnosis, followed by suitable care, can improve quality of life and life expectancy. Due to the limited interest of pharmaceutical industry in developing and marketing products, the EU and national governments have prioritised the development of "orphan drugs" for patients with rare diseases. Of the 7,000 rare diseases.
Introduction In EU countries a rare disease (RD) is any disease affecting fewer than 5 people in 10,000  12  which translates to approximately 425,000 people throughout the EU's 27 member countries. (www. eucerd. eu and Orphanet database www. orpha. net). More than 80% of these diseases are caused by genetic defects. Screening for early diagnosis, followed by suitable care, can improve quality of life and life expectancy. Due to the limited interest of pharmaceutical industry in developing and marketing products, the EU and national governments have prioritised the development of "orphan drugs" for patients with rare diseases. Of the 7,000 rare diseases collected in the Online Mendelian Inheritance in Man (OMIM) database (http://www. ncbi. nlm. nih. gov/omim) only 3,000 genes are known, despite the fact that medical genetics has clearly shown that a prerequisite to approaching diagnosis and cure for a RD is to identify the causative mutated gene.
Clinical trials in RDs always involve a limited (and sometimes very limited) number of patients, which can mean offering novel drugs in personalised, mutation specific, experimental treatments. Due to the chronic, progressive nature of DMD and SMA and other NMDs trials should be long enough to be able to show clinical amelioration measured by clinical outcome measures and clinical endpoints 2324. This is why it is highly desirable that trial outcome results are available to other researchers as quickly as possible, in order to inform further work and to minimize wasted efforts  25. There is therefore a need to promote rapid publication of data from clinical trials in RDs, but also to facilitate debate around clinical trial results in order to inform new research strategies. These imperatives will require a culture change both in the attitudes of pharma and the approaches adopted by the academic community.
Broader issues on communication around clinical trials A related point raised at the PEC by parents and patients concerns the perceived lack of openness of pharma with investigators and participants. In many cases trial results are not communicated or at best only aggregate results are released to clinicians and to patient organisations who have helped to fund the research or to set up a particular clinical trial (www. clinicaltrials. gov). This widespread concern is often expressed in terms of the right of those who have a direct interest in gaining access to timely, clear and appropriately detailed information about trial results including individual results where this is appropriate. This point is not new but has probably not been supported by the underpinning ethical arguments that have been elaborated in support of the related rights of research participants.
Overcoming barriers to the organisation of clinical trials: registries Though SMA and DMD are among the more frequently occurring RDs, patients are dispersed across the world, which makes it difficult to organise a clinical trial. RDs are much less likely to benefit from research and healthcare development processes, which are designed with common diseases in mind. Yet in the interests of justice people with rare disease should be given the same opportunity to benefit from health research and treatments as those people with common disorders. Prior to TREAT-NMD, patient organisations often in collaboration with academic centres, had made significant progress in developing and maintaining disease registries with a view to providing feasibility data for clinical trials. However, the effort was often fragmented and in order to facilitate accelerated research and development for RD data needs to be concentrated and standardised.
Patient registries are crucial to achieving this. Patient recruitment through registries for RD clinical trials also raises particular ethical issues requiring good governance, oversight and audit of the registry 30. TREAT-NMD's contribution has been to draw these separate initiatives together into a global disease registry with a validated and standardised approach to data collection, including a record of gene mutations which has become vital data in the current era of personalised, mutation specific therapies 3031. The PEC has proved an invaluable resource to the Global Registry Oversight Committee, the body responsible for the governance and strategic management of the global registry. In addition to some PEC members having dual membership on the Oversight Committee the whole of the PEC has been available as a sounding-board for ethical issues arising out of the establishment and running of the global registry.
Both the PEC and the Oversight Committee drew upon the excellent resources created by Eurordis (http://www. eurordis. org/) giving practical guidance on the creation with investigators and participants. In many cases trial results are not communicated or at best only aggregate results are released to clinicians and to patient organisations who have helped to fund the research or to set up a particular clinical trial (www. clinicaltrials. gov). This widespread concern is often expressed in terms of the right of those who have a direct interest in gaining access to timely, clear and appropriately detailed information about trial results including individual results where this is appropriate. This point is not new but has probably not been supported by the underpinning ethical arguments that have been elaborated in support of the related rights of research participants.
Personalised medicine and mutation specific trials: ensuring genetic molecular diagnosis An important piece of data required by the Global registry pro-forma is the recording of the patient's genetic diagnosis. The need for disease specific mutations is with an eye to the potential benefit from personalised medicine such as exon skipping or premature stop codon drugs for DMD, in which an accurate genetic diagnosis is essential  30. Accurate detection in large genes with high allele heterogeneity is complex and requires specific expertise and equipment. This raises questions regarding the economic aspects of molecular testing as well as further ethical concerns if the aspiration of global treatment is to be realised. The premise that all people with neuromuscular disorders (and other RDs) have a right to treatment and thus a right that appropriate clinical trials happen was the starting point for the PEC's opinion.
Personalised medicine and mutation specific trials: ensuring genetic molecular diagnosis An important piece of data required by the Global registry pro-forma is the recording of the patient's genetic diagnosis. The need for disease specific mutations is with an eye to the potential benefit from personalised medicine such as exon skipping or premature stop codon drugs for DMD, in which an accurate genetic diagnosis is essential  30. Accurate detection in large genes with high allele heterogeneity is complex and requires specific expertise and equipment. This raises questions regarding the economic aspects of molecular testing as well as further ethical concerns if the aspiration of global treatment is to be realised. The premise that all people with neuromuscular disorders (and other RDs The potential availability of therapies for DMD in the near future raised discussions in the PEC about the need to.
Personalised medicine and mutation specific trials: ensuring genetic molecular diagnosis An important piece of data required by the Global registry pro-forma is the recording of the patient's genetic diagnosis. The need for disease specific mutations is with an eye to the potential benefit from personalised medicine such as exon skipping or premature stop codon drugs for DMD, in which an accurate genetic diagnosis is essential  30. Accurate detection in large genes with high allele heterogeneity is complex and requires specific expertise and equipment. This raises questions regarding the economic aspects of molecular testing as well as further ethical concerns if the aspiration of global treatment is to be realised. The premise that all people with neuromuscular disorders (and other RDs The potential availability of therapies for DMD in the near future raised discussions in the PEC about the need to reassess neonatal screening.
e. , in cis or trans) from 1534 in the MRCA data set to 4452 (with <5% FDR). Imputation of 1000 Genomes SNPs further increased the number of eQTLs to 7302. Using the same methods and imputed SNPs in the newly acquired MRCE data set, we identified eQTLs for 9000 genes. The combined results identify strong local and distant effects for transcripts from 14,177 genes. Our eQTL database based on these results is freely available to help define the function of disease-associated variants.
1000genomes. org) aims at developing a comprehensive catalog of human genetic variants of SNP and structure variants with allele frequency down to 1%. One immediate benefit from this project is a deeper and broader reference panel of variants for genotype imputation. Common SNPs that were implicitly tested for association by being tagged by one or more HapMap SNPs may now be directly imputed and tested. In this study we use two large gene expression data sets from nuclear families ascertained through a child with asthma using the Affymetrix Hu133A platform (the MRCA panel)  (Dixon et al. 2007)  or eczema using the Illumina bead array platform (the MRCE panel)  (Morar et al. 2007 ). The study of families allows estimations of heritability for each expression trait. We compare the power of eQTL mapping using imputation of the new reference panel of 8 million SNPs and imputation of HapMap SNPs.
Results The first sample (MRCA) contained 206 siblings of British descent  (Dixon et al. 2007 ). Global gene expression in lymphoblastoid cell lines (LCLs) was measured using Affymetrix HG-U133 Plus 2. 0 chips. All siblings were genotyped using the Illumina Sentrix HumanHap300 BeadChip (ILMN300K), the Illumina Sentrix Human-1 Genotyping BeadChip (ILMN100K), or both. The second sample (MRCE) of 950 individuals from 320 families of British descent was genotyped using the Illumina Sentrix HumanHap300 Genotyping BeadChip. Expression arrays using Illumina Human 6 BeadChips were available on 550 children. As Illumina probe and Affymetrix probesets annotated to the same gene may target different transcripts, we have first analyzed the data as individual transcripts identified by their respective Illumina or Affymetrix identification.
Among the top 3000 eQTLs, the conservativeFDR estimate in the original analysis was ;30% compared with 1% for the PC-adjusted analysis. To further assess the false-discovery rate (FDR) for local and distant eQTLs, we divided the MRCA sample into two independent data sets with approximately 200 subjects per data set. One data set was used for discovery; the other, for replication. For multiple significance thresholds, we calculated the proportion of discovered eQTLs that could be replicated in the second data set with LOD > 3 (P-value of < ;2 3 10 À4 ) (Fig. 2 ). Local and distant syntenic effects had higher replication rates even when using low thresholds for significance, confirming prior observations that local eQTLs are more likely to represent true associations. The PC-adjusted analysis gave higher replication rates for both local and distant eQTLs, indicating that PC-improved analysis helps define reliable distant eQTLs (note that the replication rate here is likely underestimated due to sample size limitation)  (Ding et al.
2010). Encouraged by the low FDR of our PC-adjusted analysis, we used a sequential search to determine the number of PC that maximized power (Supplemental Fig. 1 ;  Liang et al. 2009 ). The number of genes mapped locally (LOD > 6 or P < 1. 5 3 10 À7 , the threshold we previously used to define genome-wide significance in the same data set)  (Dixon et al. 2007 ) was used as an indicator of power. In the MRCA data set, as we gradually included additional PCs in the model, the number of local eQTLs (autosomes plus chromosome X) increased gradually from 2175 (with no PCs) to 6238 (when 69 PCs were used to control for nongenetic variation). Further increases in the number of PCs led to decreases in the number of eQTLs detected (and likely power). This eventual decrease in power may be explained because the later PCs are dominated by contributions from a few transcripts.
Imputation accuracy We used the MaCH program to identify stretches of haplotypes shared between the study samples and the HapMap or 1000G SNPs reference panel and to impute their SNPs into the study sample. In both cases, SNP imputation achieved high estimated imputation accuracy, with 2,492,059 and 7,432,030 SNPs imputed with R 2 > 0. 3, respectively, in the MRCA data set, and 2,429,403 and 7,378,292 SNPs, respectively, in the MRCE data set with R 2 > 0. 3. (The R 2 measure estimates the correlation between imputed and true genotypes, based on the residual uncertainty in estimated genotypes. ) We further assessed the accuracy of genotype imputation by comparing imputed and experimentally derived genotypes on a genomic scale. In the first sample (MRCA), individuals were genotyped on two platforms (Illumina 300K or ILMN300K and Illumina 100K or ILMN100K).
Power gain from genotype imputation The global assessment of mRNA transcript levels includes a variety of traits, each with an unknown genetic architecture. We therefore used our data set as an exemplar to explore the power of different analytical strategies by tallying the number of local signals that reach genome-wide significance levels. We investigated six strategies: traditional and PC-adjusted expression analysis, each combined with three marker panels (Illumina 300K genotype, HapMap2 imputation, and 1000G imputation). For each strategy, we estimated the significance threshold for 5% FDR accounting for the number of all transcript-SNP pairs. We then counted the number of transcripts for which at least one SNP within 1 Mb exceeds that threshold as an indicator of the power of that strategy (Fig.