dataesr/scientific-paragraphs-categorization huggingface dataset:
The polarity of oligonucleotide obtained in such a way and corresponding to the orientation of dT6 in the bacterial Bs-CspB:dT7 structure is referred as standard or direct orientation. In contrast to non-standard or reversed orientation where the strand is oriented upside down. To generate such conformation the atoms of the nucleotide bases were aligned to keep the stacking with the amino acid residues of CSD YB-1 whereas the atoms of sugar and phosphate groups were ignored. Thus, the reversed orientated oligonucleotide preserved the main contacts between nucleotide bases and amino acid residues and only had the flipped polarity of sugarphosphate backbone. Similarly, the CSD YB-1 complexes were generated for ssRNA oligonucleotides. The bacterial numbering scheme of nucleotides bound to the Bs-CspB was used in this work so that the side chains of His29 (His37 in CSD YB-1 ), Phe27 (Phe35 in CSD YB-1 ) and Phe17 (Phe24 in CSD YB-1 ) More recently, an additional 5 th binding site has been identified in two crystals of Bs-CspB in complex with short single-stranded RNA molecules (PDB entries 3PF4 and 3PF5  [28] ).
Molecular dynamics simulations MDS were performed with the Gromacs 4. 5 software  [29]  using the Charmm27 force field  [30, 31]. The starting models of the complexes were placed in an orthogonal water box of 80Å x 60Å x 60Å that contained about 10 000 water molecules of TIP3 type  [32]. The water box was generated in the way to keep at least 15Å of bulk water between the surface of the complex and the edge of the water box. The protonated state for residue was set up as follows: i) the acid functions of acidic residues were deprotonated and carried a -1 charge; ii) the amine functions of basic residues were deprotonated and carried a +1 charge; iii) the phosphate groups of nucleotides were deprotonated and carried a -1 charge. The system was neutralized by the addition of 6 sodium ions to neutralize the -6 charge of the complexes (+3 for the CSD YB-1 and -9 for an oligonucleotide).
MSD trajectory validation To validate the trajectories, the NMR data available at BioMagResBank (entry number 4147  [35] ) were used. The comparison between experimental and calculated chemical shifts was achieved with Sparta software  [36]  using C α -and C β -atoms (S1 Fig). The stereochemical parameters of the models at the different steps of the trajectories were also examined with the Procheck packages  [37]. An example of Ramachandran plot is provided in S2 Fig.
The polar contribution was calculated here by solving the finite-difference Poisson-Boltzmann equation model using the PBEQ module of CHARMM  [40]. The grid spacing was set to 0. 4 Å, and the longest linear dimension of the grid was extended at least 50% beyond the system; the value of the exterior dielectric constant was set to 80, and the solute dielectric constant was set to each of 1, 2 and 4. The non-polar energy ΔG SA was estimated using solvent accessible surface (SAS) as 0. 00542 × SAS + 0. 92 kcal. mol -   [41]. For the calculation of ΔG PB and ΔG SA , 50 snapshots (each 1 ns) evenly extracted from the entire MDS trajectories for each complex (0 to 50 ns) were used. ΔE MM was calculated based on 5000 snapshots from 0 to 50 ns. The conformational entropy change-TΔS was calculated by quasi-harmonic approach using the VIBRAN module of CHARMM  [40].
Specific primers and TaqMan probes (Table  1 ) were defined from porcine sequences using the Primer Express software (Version 3. 0, Applied Biosystems). To avoid amplification of genomic DNA, primers located on different exons were preferred. Expression levels of genes coding for the different MyHC isoforms were quantified by TaqMan technology qPCR, as previously described  (Lefaucheur et al. , 2004). Expression levels of other selected genes were measured using the SybrGreen technology, as previously described  (Gondret et al. , 2013). All reactions were performed on a StepOnePlus TM Real Time PCR system (Applied Biosystems). Specificity of the amplification products was checked by dissociation curves analysis. For each primer pair, the amplification efficiency of qPCR reaction was determined using calibration curves generated with six decreasing concentrations of cDNA from pooled muscle samples (from 12.
Separative gels stained by colloidal Coomassie Brillant Blue G250 were scanned with the ImageQuant LAS 4000 imager and analyzed using the ImageQuant TL 7. 0 image analysis software (GE Healthcare; Vélizy Villacoublay; France). Bands corresponding to the different MyHC isoforms (Figure  1a ) were identified according to  Lefaucheur et al. (2001). The proportion of the different MyHC isoforms was expressed as percentages of the sum of MyHCs within a lane.
Statistics The data for mRNA levels of selected genes and relative protein abundance of MyHC isoforms were submitted to ANOVA using the SAS software (v9. 2; SAS Institute, Cary, NC, USA). The MIXED procedure was used, with fetal weight category (NWT and LWT), maternal nutrition groups (CTL and TRT) and their interaction as main effects, and sow within feeding groups as a random effect. Because there were almost no significant interactions (P > 0. 10) between maternal dietary regimen and fetal weight category for analyzed traits, data are generally presented as the least squares means for the effect of fetal weight categories, and then, the effects of maternal dietary treatments. In the rare occasions where there was a significant interaction, the data are shown for the four experimental groups.
Acknowledgments The authors gratefully acknowledge  C. Tréfeu ,  L. Finot  and  D. Beaudry  for their skillful technical assistance, as well as the staff at the  CRF and COOP Fédérée research farms , especially  I. Cormier  and  A. St-Cyr , and the staff of the  AAFC Swine Complex  for slaughter of the animals. Sincere thanks are extended to  La COOP Fédérée  ( St-Romuald, QC, Canada ) and  INRA  for their financial and technical supports.
T-ALL molecular screening Diagnostic DNA samples from all iT-ALL cases were analysed for the following gene abnormalities: NOTCH1, FBXW7, PTEN, IL7R, KRAS, NRAS, STIL-TAL1 + , TLX3 + and KMT2A-r  (Weng et al, 2004; Mansur et al, 2009 Mansur et al, , 2012;; Zenatti et al, 2011; Emerenciano et al, 2013). T-cell receptor gene rearrangements (TR-r; gamma/TRG, delta/TRD and beta/TRB) were assessed using conditions recommended by the BIOMED-2 Consortium  (van Dongen et al, 2003; Langerak et al, 2012). Clonality was assessed by GeneScan â profiling (Applied Biosystems â , Waltham, MA, USA) followed by cloning of the products and Sanger sequencing. Sequences were analysed using the Ig BLAST (www. ncbi. nlm. nih. gov/igblast/) and the ImMunoGeneTics database (www. imgt. org).
SNP-array and FISH data All diagnostic samples were analysed by SNP-array to identify genomic losses (LOH) and gains (Table  SIII ), although one sample (BR1) had a low contrast quality control (CQC, Table  SIV ). The DNA from this sample was extracted from diagnostic BM slides, from which we were able to identify two alterations: TR monoclonal rearrangements and CDKN2A homozygous deletion. Both results were confirmed using polymerase chain reaction (PCR) and quantitative PCR (Q-PCR) approaches. Among the CNAs identified by SNP-array, we highlight genes considered as 'drivers' of the leukaemic process i. e. those genes already causally implicated in the process of oncogenesis (Table  SIII ). A recurrent 3q25Á32 deletion was observed in three out of 13 cases (BR4, BR6 and BR7; encompassed the entire MLF1 gene.
NGS data Due to the paucity of available DNA from most infants we were unable to perform NGS on all cases and consequently prioritized those cases for which Guthrie Cards were available. Patient BR4 presented an ETP-profile with no typical T-ALL molecular alterations. We performed whole exome sequencing (WES) on DNA isolated from diagnostic material, however this patient did not achieve remission and therefore no germline material was available for matched analyses. In order to uncover somatic alterations acquired by the leukaemic clone, we filtered out mutations listed in the dbSNP and/or 1000genomes databases (http:// www. ncbi. nlm. nih. gov/snp/; http://www. 1000genomes. org/) and identified a total of 832 single nucleotide variations (SNVs) and 872 insertions or deletions (indels) at diagnosis.
e. AIM1, PIK3CB, DTHD1, TIE1, SH3BP2, MLLT4, MZF1, EP300, TLK2, PIDD1, RPL3, KAT6B, BPTF and PDLIM5 (data not shown). For patient BR6 we used a whole genome sequencing (WGS) approach to precisely determine the CNAs breakpoints with the aim of using this data for subsequent blood spot backtracking analyses. We filtered the WGS data by somatic alterations only, somatic P ≤ 0Á05 and exonic areas only and identified 145 mutations (SNVs and indels). Here, we particularly highlight 15 genes that were affected by novel mutations, i. e. mutations not been previously described in reference databases. The genes were: CCDC162P, ADAMTS7, IGSF3, LOC100506990, SPATA31C2, NOS2, ANKRD20A5P, HNRNPCL1, TMEM51-AS1, LOC388692, KCTD18, LOC100506060, MLLT10P1, OLIG1 and NOTCH1 (Fig  3B  and Table  SVI ). Table  II  summarises the main genomic abnormalities observed in our rare series of iT-ALL.
From ten individual Guthrie card DNAs examined for BR6, one was KMT2A-MLLT1 + (Fig 4A  DNAs. Primers 1 and 3 were used for the first PCR reaction and 2 and 3 for the semi-nested one. Sanger sequencing data shows the deletion breakpoint present in both diagnostic (top, BR6 Diagnostic DNA) and also in one of ten Guthrie card DNAs tested (bottom, BR6 Guthrie card DNA-GC5). GRCh37/hg19 was the reference for these analyses. prenatal origin of the NOTCH1 indel detected at diagnosis we also performed a specific semi-nested PCR experiment. In total, we analysed 1200 cloned sequences from the ten blood spot DNAs and identified a single clone with the same NOTCH1-PEST deletion that was present at diagnosis (c. 7280delG). Unexpectedly, this clone also harboured a new mutation found 36 base pairs upstream from c.
Based on these findings we suggest that this gene deletion may have an oncogenic function because TP53 degradation is triggered by E3 ubiquitin ligase activity in the absence of MLF1. Hence, we hypothesize that MLF1 could act as a recurrent tumour suppressor gene in iT-ALL, however functional studies will be needed to elucidate its role in leukaemogenesis. We provide evidence that iT-ALL, in common with infant pro-B ALL  (Ford et al, 1993; Gale et al, 1997)  and at least some cases of T-ALL in childhood  (Ford et al, 1997; Eguchi-Ishimae et al, 2008) , can be initiated in utero. Definitive data was obtained on one patient (BR6). The neonatal blood spots archived for BR6 harboured the clonotypic KMT2A-MLLT1 fusion sequence, as well as the NOTCH1 mutation and the PTEN deletion, albeit at low frequencies.
Acknowledgements The authors would like to thank patients and families that agreed to be involved in the study. Our thanks to the  Brazilian Collaborative Study Group of Infant Acute Leukaemia , especially  Dr. Terezinha Marques Salles ,  Dr. Teresa Cristina Cardoso Fonseca ,  Dr. Isis Quesado Magalhães ,  Dr. Anna Carolina Dias ,  Dr. Imaru ı Costa ,  Dr. Jane de Almeida Dobbin  and  Dr. Renato de Paula Guedes Oliveira  for providing patient samples. The authors also acknowledge staff and services provided by  INCA  and  ICR. This research was funded by the  Partner Fellowship  (# 2011/01 ) awarded to MBM by the  European Hematology Association ; by the  International Award for Research in Leukaemia  awarded to MBM by the  Lady Tata Memorial Trust ;  INCA ,  CNPq  and  FAPERJ (MSPO) ; the  Kay Kendall Leukaemia Fund (FWvD) ; the  Leukaemia & Lymphoma Research (AMF, CLF and MG)  and  The Institute of Cancer Research  (AMF and SMC).
2 ng/ ml), IL-8 (150 ng/ml), TNFα (10 ng/ml), or PDGF-AB (50 ng/ml) at 37 °C. Pictures of scratches were taken again after 14, 18, and/or 22 hours to visualize the wound closure. Scratched surfaces were measured using ImageJ software  [38]  (National Institute of Health, Bethesda, MD, USA). Wound closure surfaces were calculated as the scratch surface at T = 0 minus the scratch surface at T = 22 hours, and results were expressed as percentages of wound closure (wound closure surface/ scratch surface at T = 0)x 100. For inhibitory experiments, before adding neutralizing antibodies, surface uPA was acid-stripped from adherent BM-MSC by incubation of cells with 0. 05 M glycine, 0. 1 M NaCl (pH 3. 0; 2 minutes at room temperature), neutralized with 0. 5 M HEPES, 0. 1 M NaCl (pH 7. 5), and washed with RPMI.
Protein bands were revealed by chemiluminescence using the ECLplus western blotting reagent (GE Healthcare Europe GmbH, Aulnay sous Bois, France) and membranes were analyzed at 430 nm using a camera and the Chemicapt ® software (Vilber Lourmat , Marne la Vallée, France). Bands were quantified by densitometry analysis using ImageJ software (National Institute of Health).
T0, lysate of cells before seeding; Adh. , lysate of cells allowed to adhere for 2 hours on type I dermal collagen. (Right) uPAR blots quantification by densitometry analysis using ImageJ software. Data expressed as the uPAR fold change after PDGF-AB treatment compared with serum-free control medium from three independent experiments (one donor per experiment). c Scratch test assay was performed on BM-MSC isolated from three different donors and seeded in plates coated with type I dermal collagen. Two hours after adherence, cells were grown in serum-free control medium or treated with PDGF-AB, supplemented or not with integrin blocking peptide β1P1 along with the corresponding scrambled control scβ1P1 or anti-uPAR neutralizing antibody. Results are expressed as percentages of wound closure at T = 22 h compared with T = 0.
Acknowledgments This work was supported by a grant from the  7th Framework Program  of the  European Commission :  CASCADE  ( FP7-HEALTH-233236 ). The authors thank  Prof. Jorge Domenech  and  Prof. Alexis Desmoulières  for helpful discussions. They thank the  Microscopy Department of the University François Rabelais , Tours, France where confocal microscopy analysis was performed. The authors thank  Jean-Gérard Descamps ,  Mireille André , and  Mélanie Gadelorge  for MSC characterization. They also thank  Julie-Anne Côté  for English corrections.
Invited health care professionals An invitation with a link to the online questionnaire (Survey Monkey: www. surveymonkey. com) was emailed to 80 health care professionals (HCP) working in the field of PKU from 59 centres in 22 countries in South and Eastern Europe (see Fig. 1  and Appendix). Belarus was not included in this study because no HCP contacts were known. The Russian Federation was not included due to difficulties in accessing health professionals, although many PKU treatment centres exist. The questionnaire was only provided in English. Data were collected from February to August 2014. A maximum of three HCPs per centre were invited to participate. To avoid inconsistencies in responses, all contributing HCPs from the same centre were requested to complete a single questionnaire.
Patients In total, the 31 centres who returned complete questionnaires followed a total of 8573 patients with PKU, of whom approximately 75 % were followed in two countries, Turkey and Poland (Fig. 1 ). Data on patients and the HCPs working in the treatment team at each centre are presented in Table  1. The median number of patients per centre was 102 (range 3-2500), with the largest centres in Turkey and Poland (Fig. 1 ). The median number of new patients followed per year per centre was 6 (range 1-50). A median of 10 % (range 0-100) of patients were late diagnosed, and only two centres had no late diagnosed patients. Across the region, patients were estimated to travel a median of 110 km (range 10-500 km) to their centre.
Screening and confirmatory diagnosis procedures Among the completed questionnaires, only one centre in Malta had no newborn screening programme (Fig. 1 , further information on screening practices presented in Table  2 ; see Sect. "Centres providing demographic data only/e-mail responses" for responses from other countries lacking newborn screening). Seventy-one percent of centres screened at 3 days of age (median 3 days; range 2-7 days), and 77 % saw positively screened newborns within the first 15 days of life (median 10 days; range 3-30 days). The most common upper threshold for a positive newborn screening test was a blood Phe concentration of 120 μmol/L (48. 4 %), followed by 180 μmol/L (25. 8 %). After a positive newborn screening test, diagnosis was confirmed by tandem mass spectrometry (39 %), amino acids chromatography (26 %), and/or a fluorescent, enzymatic or colorimetric method (58 %).
The approach is inspired by the multi-sited approach, particularly the follow the people, follow the thing and follow the life techniques  (Marcus 1995). The data have been collected along the road and biographies have been carried out. Following the goods in commercial areas in town (from main street to inconspicuous interstices), following the rural hawkers from village to village, and using the same means of transport (on foot, moto-taxi, lorry, collective taxi) is a kind of road research: the movement is the vital lead for data collection along the road. It enables one to experience the road and some aspects of the daily life of the hawkers. 54 semi-structured interviews of vendors were used, one third in town with shop managers and shop employees, and two thirds in rural periodic markets with traders which follow the route of the periodic markets.
A volume of 0. 5 ml of CNQX/AP5 was injected into the AcbC 11 with a picoinjector (UC-8 controller, Bioscience tools). BLA-M1 co-stimulations were thus applied and we measured the effect of an infusion of the CNQX/APV mixture into the AcbC on the influence exerted by BLA pre-stimulation over spike probability of aDLS pMSNs in response to M1 stimulation for the specific 100-200-300 ms IsI, those at which the recorded neurons in the aDLS had been shown to be sensitive to BLA stimulation prior to M1 stimulation. Data and statistical analyses. Data are presented as mean±s. e. m. except when individual points are displayed (Fig. 2b ). Analyses were performed using Statsoft STATISTICA 10 software. Assumptions about normality of distribution and homogeneity of variance were assessed using the Kolmogorov-Smirnov and Levene tests, respectively.
In case of violation of at least one of these assumptions, data sets were log-transformed (Fig. 2b, c ). For behavioural studies, lever presses during each 15-min drug-seeking tests were analysed using two-way analyses of variance (ANOVAs) with lever, dose and training level as within-subject factors. For electrophysiological studies, spike probability evoked by M1 stimulation was calculated as the ratio between the number of evoked APs and the number of stimulation cycles. Change in probability of spike discharge evoked by BLA stimulation was calculated by comparing the probability of spike discharge in M1 stimulation-only situation and the spike probability on each pre-stimulation condition. A cluster analysis on average spike probability of pMSNs, obtained for the BLA-M1 IsI of 100, 200 and 300 ms, identified three neuronal populations according to the nature of BLA pre-stimulation influence on the spike probability of discharge evoked by the M1 stimulation.
Acknowledgements This work was supported by the  Fondation pour la Recherche Medicale (FRM) , the  United Kingdom Medical Research Council (MRC)  Grant  9536855  to B. J. E. , the AXA research fund to A. B. -R. , an  INSERM Avenir  and an  Agence Nationale de la Recherche (ANR)  grant  ANR12 SAMA00201  to D. B. Research was conducted within both the  MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute of Cambridge University  and the  Inserm team 'Psychobiology of Compulsive Disorders' , the  University of Poitiers. We thank  Alan Lyon  for his technical assistance,  Laurence Turi  for her help in the animal facility of Poitiers and  Vince McGinty  for his help with extracellular electrophysiology.
Gliomas are a highly heterogeneous group of brain tumours that are refractory to treatment, highly invasive and pro-angiogenic. Glioblastoma patients have an average survival time of less than 15 months. Understanding the molecular basis of different grades of glioma, from well differentiated, low-grade tumours to high-grade tumours, is a key step in defining new therapeutic targets. Here we use a data-driven approach to learn the structure of gene regulatory networks from observational data and use the resulting models to formulate hypothesis on the molecular determinants of glioma stage. Remarkably, integration of available knowledge with functional genomics datasets representing clinical and pre-clinical studies reveals important properties within the regulatory circuits controlling low and high-grade glioma.
The complexity of the factors involved in the biology of gliomas makes it difficult to develop a comprehensive model underlying GBM progression. Here we address this important challenge by integrating functional genomics datasets representing existing knowledge, clinical studies and in vivo and in vitro glioma models. We first show that network modules derived from a comprehensive integration of protein interaction databases and defined by a high density of genes differentially expressed between low and high-grade gliomas are consistent with the hypothesis that Rho GTPases may be part of a key regulatory mechanism controlling hallmarks of high-grade glioma. A key feature of GBM is invasion of tumour cells into the surrounding brain tissue and members of the Rho GTPase family known to control actin cytoskeleton dynamics and cell migration have been implicated in the survival and invasion of tumour cells  [12]   [13] ,  [14].
Modularization of the human proteome identifies a cluster of GTPases with potential regulatory activity in high-grade glioma In order to gain insight in the mechanisms underlying the pathophysiology of human glioma, we first developed an interaction network representing genes differentially expressed between grade II astrocytoma and grade IV glioblastoma. We then applied a modularization procedure to identify sub-networks of highly interconnected proteins, thus capturing important biological networks potentially representative of the differences between low and high-grade glioma. The procedure identified four main modules, with a highly statistically significant functional enrichment profile (Fig  2 ). The entire list of significantly enriched Gene Ontology terms can be found in S1 Dataset.
In order to validate this differential connectivity we used expression data from grade II and grade IV glioma within the Cancer Genome Atlas database. 16 Rho GTPases could be matched between the original data and TCGA grade II and grade IV datasets, of which 13 (81%) showed the same trend as the original analysis (S2 Dataset). Remarkably, Rho GTPases with a higher number of connections in grade IV tumours were correlated to genes in the grade IV networks with a functional profile that included many of the effector functions associated with high-grade glioma (immune response, regulation of apoptosis, regulation of cell proliferation, response to cytokine stimulus, inflammatory response, cell adhesion) (Fig  3C ). On the other hand, in the grade II networks targets of Rho GTPases with a higher proportion of connections in grade II glioma showed a functional profile consistent with glial cells (putative target genes for this group of regulators were enriched with clathrin coated vesicle membrane, dendrite, axonegensis, regulation of exocytosis, neuron development and regulation of synaptic transmission functional terms) (Fig  3C ).