dataesr/scientific-paragraphs-categorization huggingface dataset:
Acknowledgments We thank  V. Girod-David ,  L. Jullien  and  S. Corby , for help with mouse husbandry;  J. P. Chauvin ,  A. Aouane ,  J. Astier ,  K. Minko , and  K Raffaelli  for contributions to histology and  Electron Microscopy ;  C. Castro  for technical help on the CGH arrays,  D. De Petris  for help with qPCRs on human DNA,  S. Cayre  for performing the X-ray imaging;  N. Sibinga  for providing the anti-Fat1 antiserum;  R. Klein  and  R. Sanchez  for the production of additional polyclonal antisera against mouse Fat1;  M. Tessier-Lavigne  for providing the Fat1-lacZ (KST249) mouse line; Genentech for Gdnf-lacZ mice; P. Maire for Pax3-cre mice (with permission of J. Epstein),  T. Fauquier  for Rosa26-YFP mice;  S. Whalen ,  N. Seta  and  C. Fernandez  for human sample collection;  A.
Levy , and through a grant by FSHD global organization to F. Helmbacher. F. Puppo was supported by a fellowship from the  AFM ,  S. Roche , was supported through an  ANR grant  to  F. Magdinier. The contribution of the  Region Provence Alpes Cotes d'Azur and of the Aix-Marseille Universite  ´to the IBDM animal and imaging facilities is also acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The costs, risks and benefits of such approaches remain poorly characterised. However, healthcare cost assessment is necessary for such emerging innovative and expensive targeted therapies, particularly in the context of cost-containment initiatives implemented by health authorities in many countries. For example, in France, the recent Program of Social Security funding emphasised the need for input from economic studies to facilitate the decision process relating to reimbursement of health technologies. Individual current cost data on HER2-positive BC with CNS metastases are limited and published series have mainly reported costs of advanced BC, regardless of their subtype  [15] [16] [17]. Economic data on healthcare costs can be derived from several sources, including analysis of prescription claims databases, observational studies of patient cohorts and modelling approaches.
Patient selection Patients were selected using the disease coding of the ICD 10 (International Classification of Diseases, tenth revision), which is systematically assigned to all patient records in French hospitals. Inpatient stays coded as breast cancer (C50) with brain metastases (C79. 3) were selected. Individual data concerning initial diagnosis, distant and CNS relapses, treatments received and examinations performed, clinical outcomes and complications following the CNS event and admissions were collected. Data were collected retrospectively from the hospital database and all information relating to use of healthcare resources was documented for the two years following the date of diagnosis of CNS metastases, or until death if this occurred within two years.
Identification and allocation of costs Pricing of health services in France is determined at the national level by a Prospective Payment System. Under this system, the income of each hospital is linked directly to the number and type of patients treated, classified in terms of diagnosis-related groups (DRGs). The classification system used in France was inspired by the US Health Care Financing Group classification, but adapted to the French healthcare system. Assignment of patients to DRGs is based on the primary diagnosis. Data on age, length of stay and mode of discharge (death, transfer) are used to define case severity. The DRG prices (tariffs) for each service are set annually based on average costs and are applicable countrywide. In addition, a restricted list of expensive drugs is reimbursed over and above these standard tariffs.
Patient characteristics A total of 218 patients were enrolled in the study and direct medical costs were estimated on 200 patients for whom exhaustive economic data and DRGs were available. The clinical characteristics of the 218 patients enrolled are presented in Table  1. Median age was 51 years at the time of initial diagnosis of BC and 54 years at the time of diagnosis of CNS metastases. The median time to first metastatic relapse at any site was 21. 9 months (0-214. 7). The median interval between BC diagnosis and detection of CNS metastases was 37. 6 months (0-286. 5). The initial metastatic event involved the CNS in 39 patients (17. 4%), this being the unique first metastatic site in 31 patients. Carcinomatous meningitis was present in 28 patients (13%). Prior to diagnosis of CNS metastases, all patients had received trastuzumab-based therapies and 21 had received lapatinib-based therapies.
Data from Sweden also indicate that patients with HER2-positive tumours incur higher cost than HER2negative patients, probably due to the higher cost of targeted therapies, and also to radiotherapy  [16]. Further information on the costs of metastatic BC is available from insurance claims databases. A recent French national database analysis estimated the mean annual cost of BC with brain metastases at €29,995 per patient treated with trastuzumab, and assumed to be HER2-positive  [27]. In a database analysis from the USA, the direct costs of brain metastases secondary to BC, included medication, outpatient care and inpatient admissions were US$60,045 (€50,898) at six months and US$99,899 (€84,681) at 12 months (2006)  [28]. The mean total cost for BC patients with brain metastases was more than twice that of patients without brain metastases at 6 and 12 months.
Although claims database analyses enable broad and exhaustive estimates of cost of illness at a national level to be made relatively rapidly and easily, they are less powerful for comparing sub-groups of populations and for matching economic data to clinical outcomes at the individual patient level. In this respect, observational cohort studies present a number of advantages. Although such studies may be time-consuming and require substantial investment of resources, they provide accurate and detailed information on health care consumption at an individual patient level in both hospital and community settings, and allow the reconstitution of the entire healthcare trajectory of individual patient to be reconstituted. Moreover, cohort analyses provide information on costs in relation to survival and other clinical endpoints.
In particular, the influence of potentially different prognosis between sub-groups on health-care consumption can be assessed. Such data are important to collect in order to refine modelling studies of healthcare costs which are critical to inform decision-making with regard to healthcare resource allocation. In France, the recent commitment to including economic assessments into decision-making relating to the drug reimbursement process makes observational cohort studies particularly relevant. The findings of this study suggest several avenues for future research into the management of BC with CNS metastases in everyday care. These include comparison of costs and outcomes associated with different treatment strategies, which may well not be the same in everyday care than in clinical trials where patients are selected and treatment adherence is optimized.
Acknowledgements We would like to thank the physicians of all medical information departments of the participating centres, who were involved in the preliminary phases of the study:  Dr Patrick Arveux  ( Centre JF Leclerc , Dijon),  Dr Florence Bachelot  ( Institut Curie, Saint Cloud ),  Dr Malgorzata Cucchi  ( Centre Oscar Lambert, Lille ),  Dr Pascal Do  ( Centre François Baclesse, Caen ),  Dr Frederic Gomez  ( Centre Léon Bérard, Lyon ),  Dr Anne Jaffré  ( Institut Bergonié, Bordeaux ),  Dr Sfaya Kouidri-Uzan  ( Institut Sainte Catherine, Avignon ),  Dr Béatrice Le Vu  ( Institut Curie, Paris ),  Dr Agnes Loeb  ( Centre Henri Becquerel, Rouen ) and  Dr Jacques Peltier  ( Centre Gentilly, Nancy ). We are also grateful to  Dr Adam Doble  ( Foxymed, Paris, France ) for his help and advice in finalizing this manuscript.
THP-1 cells were differentiated by treatment, with 200 ng ml Ϫ1 phorbol myristate acetate (PMA). THP1 macrophage monolayers were incubated for 60 min at 37 °C with the bacterial suspensions (multiplicities of infection 100) to allow the bacteria to enter. After washing (time zero of the kinetic analysis), the cells were incubated in fresh culture medium containing gentamicin (10 g ml Ϫ1 ) to kill extracellular bacteria. At several time-points, cells were washed three times in RPMI, macrophages were lysed by addition of water and the titer of viable bacteria released from the cells was determined by spreading preparations on Chocolate agar plates. For each strain and time in an experiment, the assay was performed in triplicate. Each experiment was independently repeated at least three times and the data presented originate from one typical experiment.
Activation type was CID with default settings. LC-MS/MS data were extracted and raw files from the analysis of bands from each independent experiment were merged. For data analysis, peak lists were generated by Proteome Discoverer v1. 2 (Thermo Scientific) and searched against all the concatenated sequences of all the subspecies of F. tularensis (14,148 sequences; available online on http://www. uniprot. org/taxonomy/?query ϭ complete%3Ayesϩcontent%3Afrancisellaϩtularensis&sort ϭ score) from UniProtKB/Swiss-Prot complete proteome database (release 2011_01; 524,420 sequences) using the Mascot search engine (version 2. 2. 07; Matrix Science). Default parameters used were: fixed modification (Carbamidomethyl (C)), and variable modification (Oxidation (M)) were allowed as well as one missed cleavage.
RESULTS In Silico Analyses-We have recently identified a genetic locus, conserved among Francisella genomes, that comprises ten consecutive genes in the same orientation (FTL_0200 to FTL_0209, in F. tularensis LVS). Deletion of gene moxR (FTL_0200) led to a mutant bacterium with increased vulnerability to various stress conditions and a growth defect in infected macrophages  (6). Remarkably, the proximal part of the moxR operon, which is conserved in the genomes of several other pathogenic bacterial species, encodes proteins containing either tetratricopeptide repetition (TPR) or von Willebrand type A (VWA) motifs (Fig. 1 ). Confirming the peculiar characteristics of this genetic region, we identified only a limited number of proteins bearing either TPR or VWA motifs in the F. tularensis genomes currently available in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, us- ing the Superfamily prediction program (available at http:// supfam.
e. 32 repeats in F. tularensis subsp. novicida and 36 repeats in Francisella philomiragia ortholog (as compared with 16 repeats in TPR1 of LVS) (Fig. 1A ). Hence, the protein TPR1 contains both a TPR motif in its proximal part and a NKD repeat region in its central part, suggesting unique structural properties for this protein (Fig. 1B ). In F. tularensis subsp. tularensis SCHU S4, a careful reexamination of the gene designated FTT_0294, which corresponds to the two distinct genes FTL_0204 and FTL_0205 in LVS, revealed it was erroneously annotated as a pseudogene in the KEGG database. In fact, the DNA sequence of FTT_0294 encompasses two consecutive coding sequences with a 10 bp overlap (supplemental Fig. S1A ). The proximal part of FTT_0294 encodes a protein sharing 99. 7% identity with FTL_0204 and the distal part of FTT_0294, a protein sharing 84.
The three recombinant proteins were used individually as baits and their interacting LVS proteins were purified using a two-step elution procedure  (15). In most cases, several bands were specifically eluted by this procedure (Fig. 2C ). In each case, the MS-MS data obtained for each band were combined and analyzed to compact results in a single table for simplification. Experiments were performed in biological replicates. Onedimensional SDS-PAGE protein profiles and MS-MS protein identifications obtained for each experiment were always compared with verify reproducibility. Results issued from triplicate experiments for MoxR-TAP and VWA1-TAP and duplicate experiments for TPR1-TAP are summarized in Tables IA-C. In each table, we chose as a threshold, the protein partners identified with at least two unique peptides and identified in at least two independent experiments.
Pcp, encoded by the distal part of the moxR locus, is in red. This graphical representation was generated by using the Cytoscape software (freely available at http://www. cytoscape. org). ⌬sucAB mutant (lacking OGDH E1 and E2, and thus unable to make succinyl-CoA) was shown to be avirulent in the mouse model  (34). Interestingly, Richardson et al. recently showed that S. typhimurium became auxotroph for methionine and lysine under nitrosative stress, because of reduced succinyl-CoA availability  (35). Our work suggested possible connections between stress response and metabolism in pathogenic F. tularensis. The proteins MoxR, VWA1, TPR1, and possibly other moxR-encoded proteins, might assist multiple enzymatic activities, including the tricarboxylic acid cycle-related PDH and OGDH. Further work will be required to make precise the molecular mechanisms involved in these interactions and their importance for intracellular survival and multiplication of the bacterium.
* This study was supported by  INSERM ,  CNRS , and  Universite Ṕaris Descartes Paris V. Jennifer Dieppedale  and  Gael Gesbert  were funded by a fellowship from the  Delegation Generale al'Armement (DGA)  and  Elodie Ramond  by a fellowship from the  "Region Ile de France. "□ S This article contains supplemental material.
VIMOS Optical integral field unit (IFU) observations of Hydra-A were taken using the VIMOS (Visible Multiobject Spectrograph) instrument on the 8. 2m Very Large Telescope (VLT) in October 2007 (programme ID 080. A-0224(A)). Three 600 second exposures were taken with a pointing dither included between each exposure to minimise the effect of bad pixels. The HR Orange Grism and GG435 filter (spectral resolution of R ∼ ∆λ/λ ∼ 2650 over the wavelength range 5250-7400 Å) were used to observe Hα (λrest = 6562. 8 Å) at the redshift of the cluster. The observations were taken in moderate seeing conditions with a mean seeing of ∼1. 25 ′′. We reduced the raw data using the esorex package. We performed the basic data reduction including bias subtractions, flat fielding and the wavelength and flux calibrations.
IRAM 30m We obtained IRAM 30m data for the CO(1-0) and CO(2-1) lines in Hydra-A in April 2010 at 109. 274 and 218. 545 GHz respectively. The observations were performed simultaneously in exceptional conditions (τ230GHz ∼ 0. 05) with the EMIR receiver using a 4 GHz bandwidth covering each line  (Carter et al. 2012). The observation was of 2 hours duration with wobbler switching with a 90 ′′ throw. The observations reached a noise level of 0. 35 mK and 0. 30 mK in 100 km s -1 channels for CO(1-0) and CO(2-1) respectively. The unusual situation of obtaining a better temperature sensitivity at CO(2-1), combined with a beam of a quarter the size compared to CO(1-0), means that there is a highly significant CO(2-1) detection but at best a marginal one for CO(1-0). Both the WILMA and 4 MHz backends were used to sample the data, but in this paper we present only the CO(2-1) spectrum taken with the WILMA backend as they were the most stable and provide the most reliable CO detection.
Herschel Hydra-A was observed with Herschel as part of an Open Time Key Project to observe a statistical sample of cooling flow clusters (programme OTKP aedge1, PI Edge). We used the PACS instrument to obtain spectral observations of the two principal atomic cooling lines, [OI] (OD:536, OB-SID:1342207793) and [CII] (OD:538, OBSID:1342207817) at 63 and 157 µm respectively. The lines were observed in line spectroscopy mode using the chopping and nodding implementation to account for the background and dark current. These were then analysed using the standard pipeline routines included in the latest release of the Herschel Interactive Processing Environment  (HIPE v. 7. 1. 0). A detailed description of the Herschel data reduction can be found in  Mittal et al. (2011). The full analysis of these spectral data and the additional PACS and SPIRE photometry will be made elsewhere  (Oonk et al.
ACKNOWLEDGEMENTS SLH acknowledges the support received from an  STFC  studentship and the  European Research Council for Advanced   Grant Program num 267399-Momentum. ACE acknowledges support  from  STFC  grant  ST/I001573/1. AMS gratefully acknowledges an  STFC Advanced Fellowship  through grant  ST/H005234/1. Based on observations made with  ESO Telescopes at the La Silla or Paranal Observatories  under programme  ID 080. A-0224  and  082. B-0671 Herschel is an  ESA  space observatory with science instruments provided by European-led Principal Investigator consortia and with important participation from  NASA. Based on observations made with the  NASA/ESA Hubble Space Telescope , obtained from the data archive at the  Space Telescope Institute. STScI is operated by the association of  Universities for Research in Astronomy, Inc.
Patches were excised in 25 mol/liter ATP to prevent run-down. All recordings were monitored, sampled, and analyzed using pCLAMP software (Molecular Devices). K ATP channel activity in membrane patches (inside-out configuration) was calculated relative to activity in the absence of ATP and fitted by the Hill equation (y ϭ [IC 50 ]/([IC 50 ] h ϩ [ATP] h ), where h is the Hill coefficient, [ATP] is the ATP concentration, and [IC 50 ] is the half-maximal inhibitory ATP concentration. Single channel activity was analyzed as previously described  (39). Whole Heart Biotinylation-Hearts were excised from anesthetized mice and retrogradely perfused at 90 mm Hg with Krebs-Henseleit buffer bubbled with 95% O 2 , 5% CO 2 at 37 °C and pH 7. 4. The AV node was mechanically ablated, and hearts were paced at 150 or 100 ms cycle length (i.
1% Triton X-100 (10 min), and blocked with 1% BSA in PBS for 1 h at room temperature. Cells were labeled with Alexa 568-conjugated goat anti-mouse secondary antibody (1:500, Invitrogen) for 1 h at room temperature in a dark chamber. Cells were washed and mounted with vectashield on glass slides for confocal microscopic analysis. Confocal Fluorescence Imaging-Cells were imaged on a Zeiss LSM 510META laser scanning confocal microscope under a 63ϫ oil immersion lens. Middle cuts through cells were analyzed using ImageJ Software (National Institutes of Health, public domain). The ratio of intracellular:total intensity was calculated. Constructs-The Kir6. 2 sequence containing an HA tag and an 11-amino acid linker was used as "WT" Kir6. 2  (30)  and served as a template to generate the following mutant constructs using QuikChange II Site-directed Mutagenesis kit (Stratagene): Kir6.
The coordinates of the four K ϩ ions and the four phosphatidylinositol diphosphate analogues initially present in the x-ray structures of Kir3. 2 were preserved in the Kir6. 2 model. The position of all their non-hydrogen heteroatoms was restrained over all the minimization process. The phosphatidylinositol diphosphate analog was modeled using the CHARMM36 parameters. Analysis of the results was performed with VMD 1. 9. 1. The model of 2 is based on the published structure of 2 co-crystallized with the TGN38 internalization signal peptide DYQRN (PDB code 1BXX). The peptide YQ was superimposed with the YS of YSQKF and 2 positioned by trial and error. The position with the fewest steric conflicts was selected. JANUARY 18, 2013.
* This work was supported by  National Institutes of Health  Grants  HL092286  and  R01HL113089  (to D. H. -Z. ),  HL093368  and  R01DK092412  (to L. Z. ),  R01HL079031 ,  R01HL62494 ,  R01HL70250 , and  R01HL113001  (to M. E. A. ),  HL084583  and  HL083422  (to P. J. M. ), and  HL058812  (to P. M. S). This work was also supported by  VA Merit Review Program  Grant  1I0BX000718  (to L. Z. ), The  Medical Research Council, United Kingdom  Grant  G0802050  (to A. Sivaprasadarao), The  Carver Trust  Grant  01-224  (to D. H. -Z. and L. Z. ), The  Central Society for Clinical Research  (to D. H. -Z. ), The  Fraternal Order of Eagles  (to D. H. -Z. and L. Z. ),  Saving Tiny Hearts Society  (to P. J. M. ), an  American Heart Association Established Investigator Award  (to P. J. M. ),  Agence Nationale de la Recherche  ( ANR-09-PIRI-0010  and  Laboratory of Excellence "Ion Channel Science and Therapeutics" network grant ; to M.
The aevol platform The aevol (artificial evolution) platform was designed to study the evolution of the size and organization of bacterial genomes in various scenarios. It comes as a set of C++ command-line programs, including (i) the main program to perform evolutionary runs and (ii) auxiliary programs to prepare the initial population, visualize the state of an evolved population at a given time, or analyze the mutations on the line of descent of an evolved organism. These programs can be run under Linux or MacOS X, with or without graphical output, depending on whether one wants to get a live impression of the evolution or perform a systematic campaign of experiments on a computer cluster. The source code is available at http://www. aevol. fr.
Genome characteristics of Escherichia coli, Buchnera, Prochlorococcus and simulations. Genomic data (genome size, genes) was obtained from the NCBI database. Coding and non coding bases, gene length and percentage of coding bases are computed using custom Python scripts for Escherichia coli (O157:H7 str. Sakai, 55989, E24377A, O127:H6 str. E2348/69, S88), Buchnera aphidicola (str. APS, Cinara tujafilina, Bp, Sg), non reduced Prochlorococcus (MIT9303, MIT9313), reduced Prochlorococcus (str. AS9601, MIT9211, MIT9215, MIT9301, MIT9312, MIT9515, NATL1A, NATL2A, CCMP1375, CCMP1986.
We also compare the genomes of the original wMelPop strain from Drosophila melanogaster and two sequential derivatives, wMelPop-CLA and wMelPop-PGYP. To develop wMelPop as a novel biocontrol agent, it was first transinfected into and passaged in mosquito cell lines for approximately 3. 5 years, generating wMelPop-CLA. This cell line-passaged strain was then transinfected into Aedes aegypti mosquitoes, creating wMelPop-PGYP, which was sequenced after 4 years in the insect host. We observe a rapid burst of genomic changes during cell line passaging, but no further mutations were detected after transinfection into mosquitoes, indicating either that host preadaptation had occurred in cell lines, that cell lines are a more selectively permissive environment than animal hosts, or both. Our results provide valuable data on the rates of genomic and phenotypic change in Wolbachia associated with host shifts over short time scales.
Here, we describe the draft genome sequences of three sequential variants of popcorn: the original wMelPop strain from w 1118 flies; wMelPop-CLA, the strain produced after 3½ years of serial passage in mosquito cell lines; and wMelPop-PGYP, purified from A. aegypti 4 years after transinfection with wMelPop-CLA (fig. 1 ). We have also obtained genome sequence data of wMelCS. By comparing these genomes, we have determined the evolutionary relationships between wMel, wMelCS, and wMelPop, and identified genomic differences between them. We have also characterized the genetic changes that have occurred during the short period of time during which wMelPop was serially passaged in cell lines and have determined the timings of their origin and fixation.