dataesr/scientific-paragraphs-categorization huggingface dataset:
Retrospective data The "laboratoire de biochimie et génétique moléculaire" (LBGM), Cochin hospital, Paris, is one of the French molecular diagnosis laboratories dedicated to routine molecular diagnosis of dystrophinopathies. It also provides data to the UMD-DMD France database  [23]. This database includes all DMD gene mutations identified in male subjects as well as symptomatic female carriers Table  1  Main selection criteria of Pre-U7 and ULENAP studies from which patients were selected (www. umd. be/DMD/W DMD/index. html). The clinical section of this database includes 200 fields of clinical information on each patient, including age at loss of major motor milestones. For the purpose of the present work, the age at loss of ambulation of DMD patients were extracted from the clinical data when available.
Statistical analysis DMD all-non-53 and DMD del-non-53 patients were precisely age-matched to DMD-53 patients on a patient/patient basis (mean of the difference: 0. 2 and 0. 3 year respectively, maximal difference 0. 9 and 1. 1 year respectively). When several patients were available for matching, the patient with the closest age was selected. The difference in the distribution of ages between compared groups was tested by performing a non-parametric Friedman ANOVA test for paired samples (Fig. 2 ). There were slight differences between the two study protocols, especially the testretest assessment in the first visit of ULENAP and the MRI assessment in Pre-U7 study, which that may induce training or fatigue, respectively. In order to avoid any possible learning and fatigue effect, clinical, strength and function data from ULENAP study were those of the first visit of ULENAP, from test assessment for MyoGrip and MyoPinch and from retest assessment for MoviPlate.
Data from Pre-U7 study were those measured at the second visit. Clinical data, strength and functional data were compared between groups using a non-parametric Wilcoxon test for paired samples. Nominal data were compared using a Chi squared test with Yates's correction for continuity if needed. The limit of statistical significance was set to 0. 05. For retrospective analyses of data from the UMD-DMD-Cochin database, we first performed the Kolmogorov-Smirnov test to assess the normal distribution of the age of ambulation in patients carrying deletions theoretically treatable by exon 44, 45, 50, 51, 52, 53 or 55 skipping. Since the distribution appeared to be non-normal, we used the non-parametric Kruskal-Wallis one-way analysis of variance test and a post-hoc test of Dunn-Bonferroni after verifying the variance's homogeneity between groups by Levene's test.
UMD-DMD-Cochin database Data extracted from the UMD-DMD-Cochin database (Table  6 ) indicated that around 6. 9% were carriers of a deletion theoretically treatable by exon 53 skipping. Kruskal-Wallis one-way analysis of variance was performed to compare ages at loss of ambulation in patients carrying deletions theoretically treatable by skipping of exon 44, 45, 50, 51, 52, 53, or 55. This analysis revealed a significant difference among groups (p = 0. 001). DMD-53 patients   Given the small number of patients in other groups, differences did not reach statistical significance when DMD-53 patients were compared with patients carrying deletions theoretically treatable by exon 50 or 55 skipping (p = 0. 068 and p = 0. 100, respectively), who lost ambulation more than two years later than those theoretically treatable by exon 53 skipping (Fig.
DISCUSSION Using a prospective methodology and standardized evaluations, we demonstrated that non-ambulant DMD patients with a deletion theoretically treatable by exon 53 skipping tend to have a more severe course than age-matched controls with DMD patients who could not be treated by exon 53 skipping whatever are their mutation. This trend is confirmed even by comparing only with DMD patients carrying a deletion. The small number of patients is one of the reason why the level of significance is not reached. Using a retrospective methodology on a large population-based database, we confirmed that patients with a deletion theoretically treatable by exon 53 skipping lost ambulation more than one year earlier than other DMD patients. Selection bias is not a concern with the UMD-DMD-Cochin database since the inclusion of patients is exhaustive within the covered territory  [23].
Nevertheless, as all patients do not have an estimation of the amount of dystrophin on muscle biopsy, we choose to limit the analysis to patients with a DMD phenotype, this being defined only on clinical ground through the age of loss of ambulation. Therefore, patients with an age of loss of ambulation older or equal to fifteen were not retained for analyses due to a phenotype being more like a Becker muscular Dystrophy (BMD) which may introduce a bias in the study. However, the 92 DMD patients carrying a deletion treatable by exon 53 skipping selected from the UMD-DMD-Cochin database represented 6. 9% of the DMD patients whatever is the mutation in this database, which is consistent with previously published data of 7. 7% from the largest DMD database at the Leiden Duchenne Muscular Dystrophy pages which contains 3.
However, the raw data showed that Romanian patients were not particularly different from the mean of the DMD-53 patients. Lastly, even arthrodesis is not a standard of care in Romania, the scoliosis status of Romanian patients did not require arthrodesis surgery. The control group in the prospective study was first constituted on the basis of an age-matching strategy. Assuming that patients carrying a deletion presented a more severe phenotype than patient with duplication or point mutation, we constituted a second control group based on deletion mutation and age-matching strategy. Both control group presented an age at loss of ambulation higher but comparable than the general DMD population of the UMD-DMD Cochin database (10. 4 ± 2. 4 and 10. 7 ± 2. 1 years vs. 10. 0 ± 1. 9, respectively).
This difference would affect not only the statistical powering of the studies but also the selection of control groups for non-placebo-controlled studies. The number of revertant fibers is known to be different between the various sub-groups of patients with genotypes treatable by exon skipping. For instance, patients eligible for exon skipping 44 present more revertant fibers than patients eligible for exon 51 skipping  [8]. This is a possible explanation for differences in the age at loss of ambulation in these patients. Indeed, the classification between groups that can be established from the UMD-DMD-database regarding DMD-53 and DMD-51 patients for which the age at loss of ambulation is lower than DMD-44 patients matches the data available on revertant fiber numbers. This classification of subgroups is also consistent with the North Star data  [27].
It is known that specific subgroups of DMD patients, such as those with deletions of exons 2-7, may present a milder phenotype, but it is unlikely that the inclusion of these subgroups in the general DMD population can account for the difference between DMD-53 and DMD-non-53 patients. Mutations that are theoretically treatable by exon 53 skipping include different genotypes, such as del 52, del 50-52, and del 49-52. Probably any of the existing series include enough patients to determinate whether they present a similar phenotype. In the present dataset, no obvious differences appear between sub-groups, but although we had a very large cohort of patients theoretically treatable by inducing exon 53 skipping, this study was not statistically powered to assess this question. Pooling the data from the different nation-wide databases is required to address this question.
Larger datasets would also be required to assess whether the more severe phenotype of DMD-53 patients could be related to a weaker respond to steroids, which is suggested by the higher percentage of DMD-53 than DMD-non-53 patients in our study who were treated with steroids at the time of the study, despite a more severe phenotype. Studying non-ambulant patients allowed a retrospective overview of the natural history of the disease. It is commonly assumed that in DMD patients the age of occurrence of clinically meaningful endpoints is correlated with lifespan  [30]. Replication of these findings in other large databases or in well conducted prospective studies and further mechanistic studies are required to better understand the specificity of the phenotype of 53-DMD patients. We believe that the present data are important and clinically meaningful in the context of the ongoing exon skipping trials.
ACKNOWLEDGMENTS ULENAP and Pre-U7 studies were funded by  ADNA (Advanced Diagnostics for New Therapeutic Approaches) , a program dedicated to personalized medicine, coordinated by  Institut Merieux  and supported by research and innovation aid from the  French public agency, OSEO. The  UMD-DMD  Cochin database curators wish to thank clinical contributors to the  UMD-DMD  Cochin database regular clinical data updating and the " Association Francaise contre les Myopathies " ( AFM-Telethon ) for its constant support. The contribution of  M. Benali  for patient evaluation is acknowledged.
Statistical analysis Statistical analysis will be conducted on intention to treat (ITT) using Stata software, V. 13 (StataCorp, College Station, Texas, USA). A two-sided p value of less than 0. 05 will be considered to indicate statistical significance (except interim analysis). Baseline characteristics will be presented for each randomised group as the mean±SD or the median (IQR) according to the statistical distribution for continuous data, and as the number of patients and associated percentages for    25  the primary analysis will be completed by an ANCOVA considering the cold pain threshold in the hands 2 weeks after the third cycle of oxaliplatin-based chemotherapy as a dependent variable, and the group and the baseline value of cold pain threshold in the hands as independent parameters.
Data collection and quality management A clinical research technician (BG) is dedicated to the data entry, coding, security and storage. Each included patient and study data are anonymisated. Study data are collected and managed using REDCap electronic data capture tools hosted at University Hospital of Clermont-Ferrand. 27 REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies, providing: (1) an intuitive interface for validated data entry; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for importing data from external sources. A clinical research assistant will be commissioned by the sponsor (University Hospital of Clermont-Ferrand) in order to monitor the progress of the study in accordance with the Standard Operating Procedures implemented in the University Hospital of Clermont-Ferrand, in accordance with the Good Clinical Practice and the current French laws.
Methods This study took place from September 22 th to November 21 th 2014, by all nurses employees in nursing homes in the Rhône-Alpes region (France). This study is based on volunteering with 2 questionnaires available online: one for each institution and one for each nurse. The questionnaire for nurses is self-administered and anonymous. The descriptive analysis of regional data was performed using the software Epi-Info version 6. 04.
Phosphorylation site identification by tandem mass spectrometry. Protein samples were digested with different proteolytic enzymes (chymotrypsin, trypsin and endoproteinase GluC) by incubation overnight at 37°C. The resulting peptides were separated using a nano-HPLC system (Proxeon EasynLC, Thermo) fitted with a reverse-phase column (easy C18 column, 3 µm; 75 µm ID×10 cm; Proxeon, Thermo) eluted with a 0. 1% (v/v) formic acid in a water to acetonitrile gradient (0-35% acetonitrile in 40 min; flow 400 nl/min). Online MS analysis was carried out in the LTQ Velos nano-ESI-linear ion trap instrument (Thermo) in data dependent acquisition mode (full scan followed by MS/MS of the top 5 peaks in each segment, using a dynamic exclusion list). Peptide sequences were assigned using Mascot and Sequest search engines.
An in-house Mascot v. 2. 0 version was used for searching the Swissprot database (20121102) with the following parameters: taxonomy: Mycobacterium tuberculosis complex; peptide tolerance: 1. 5 Da; MS/MS tolerance: 0. 8 Da; methionine oxidation, and Ser/Thr phosphorylation as the allowed variable modifications. The data was filtered using significance threshold p<0. 05 and ion score>30. In addition raw MS/MS spectra were interpreted with the Proteome Discoverer software package (v. 1. 3. 0. 339, Thermo). We considered positive phosphosite identification when more than one spectra for the phosphopeptide was.
It should be noted that only four of these phosphoresidues (Thr21, Ser46, Thr152, Thr224) were visible in the electron density maps of at least one PknA molecule, but they are highly exposed to solvent and possibly do not play a regulatory or structural role. PknA displays an autoinhibited state. The relative position of the two lobes suggests that PknA has been crystallized in a closed state, as observed for PknB in complex with nucleotides or for the ternary complex of human PKA (pdb entry 1atp) (Fig. 2B ), generally considered as the prototype of the active form of Ser/Thr kinases  13. The plasticity of the activation loop and lack of supporting electron density is similar to what is observed for the active conformation of the related M. tuberculosis Ser/Thr kinase PknB, as reported independently by different teams 2.
However, the conformation of PknA corresponds to an inactive state, close to the autoinhibited structure of the kinase domain of Staphylococcus aureus PknB (Fig. 2B ) (pdb entry 4eqm;  14  ). Furthermore, the N-terminus of PknA helix αC is rotated approximately 17° outwards of the active site pocket with respect to the same helix in PknB, hampering formation of the salt bridge Glu61 -Lys42 that is a hallmark of active protein kinases (Fig. 2B ). A similar, but less pronounced tilt of αC was also observed in the inactive conformation of mycobacterial PknE (pdb entry 2h34) (Fig. 2B ). Noteworthy, the conformation of apo PknA represents an example of the wellcharacterized CDK/Src-like inactive conformation, observed in a number of structures of both Ser/Thr and Tyr kinases (reviewed in  15  ).
The known features of this autoinhibited conformation include the closure of the lobes and the swinging out of αC. Furthermore, the N-terminal portion of the activation loop (residues Ile162 to Asp167 in PknA), which immediately follows the DFG motif, assumes a well defined one-turn helical conformation that packs against αC, stabilizing its outward orientation and creating a barrier to the Lys-Glu salt bridge (Fig. 2A ). The presence of such an inhibitory helix (or A-loop helix for activation loop) was first observed in the crystal structures of the human tyrosine kinases c-Src in complex with AMP-PNP (pdb entry 2src;  16  ), as well as Hrc in complex with the pyrazolo-pyrimidine inhibitor PP1 (pdb entry 1qcf;  17  ). In chains B and C of PknA, however, a slightly different autoinhibited conformation is observed, with the traceable residues of the activation loop, despite not forming an α-helix, still hindering the Lys-Glu interaction and the carboxylic group of Glu61 positioned instead to form a salt bridge with the guanidinium of Arg140, part of the HRD motif and adjacent to the strictly conserved Asp141 within the catalytic loop.
However, further experimental evidence is necessary to validate this model or, alternatively, support the recently postulated existence of a hierarchical kinase network in M. tuberculosis, according to which phosphorylation by PknB would be required for PknA activation  9. pdb entry 4eqm,  14  ) and the human cAMP-dependent kinase PKA in ternary complex with MgATP and an inhibitory peptide, shown as the paradigm of the active conformation of a Hanks-type protein kinase (purple; pdb entry 1atp,  13  ). The dashed FIGURE LEGENDS.
Data collection, structure determination and refinement. X-ray diffraction data were collected at 100 K on the beamline ID14-2 at the European Synchrotron Radiation Facility (ESRF) (Grenoble, France). The structure was solved by molecular replacement with Phaser 4 , using the split N-terminal (residues 5-97) and C-terminal (residues 99-276) domains of the STPK PknB from M. tuberculosis (pdb entry 1o6y; 5 ) as separate search models. The molecular replacement solution, composed of three kinase domains per asymmetric unit, was refined with either refmac5 6 or autoBUSTER, applying local structure similarity restraints for NCS 7. The model was validated through the Molprobity server 8. Figures were generated and rendered with PyMOL (The PyMOL Molecular Graphics System, Version 1. 5, Schrödinger, LLC).
ACKNOWLEDGEMENTS We are grateful to  Clément Moroldo  for generating and testing constructs for recombinant protein expression, to  Ahmed Haouz  and  Patrick Weber  for robot-driven crystallization screenings, and to  Gwénaëlle André-Leroux  and  María-Natalia Lisa  for many helpful discussions. The expression plasmid for the TEV protease was a kind gift from  Helena Berglund  ( Karolinska Institute, Stockholm, Sweden ). We also acknowledge the  ESRF (Grenoble, France)  for granting access to its macromolecular crystallography facilities. This work has been funded by grants from the  Institut Pasteur , the  CNRS  and the  European Commission  (contract number  LSHP-CT-2005-018923 ).
Blood sampling was also performed and plasma stored in a subgroup of 64 patients, 5 days after admission for dyspnea. Demographic and biological parameters at admission along with hospital readmission and mortality data at one year of follow-up were recorded in AHF patients. In addition, plasma was also withdrawn from 44 chronic HF patients in stable condition (stable CHF) during an outpatient visit. The study was registered in clinical trials. gov under the identifier NCT01374880. The second population (= the validation cohort) consisted of 711 AHF patients recruited from 2 Leicester hospitals between November, 2006-October, 2012. The diagnosis of AHF was made by 2 physicians, and all patients had evidence of fluid overload (pulmonary oedema or congestion) and oedema. Samples were obtained after 30 minutes bed rest, and plasma was stored at -80°C until thawed for analysis.
To take into account a potential confounding effect of prognostic covariates, adjusted analyses were performed using logistic regression. The association between miR-423-5p and one-year mortality in the validation cohort was assessed using Kaplan Meier analyses. Statistical analyses were performed using the R statistical platform (http://www. r-project. org/) and the SigmaPlot v12 software. A 2-sided p value < 0. 05 was considered statistically significant.
Omitting the primary antibody from the procedure resulted in total absence of labeling. The IG1007 antibody has been used successfully to label glutamatergic neurons in lamprey brains  (Barreiro-Iglesias et al. , 2008; Villar-Cerviño et al. , 2011). According to the supplier data sheet, the polyclonal rabbit antiglutamate antibody was raised against glutamate that has been conjugated to a carrier protein using glutaraldehyde. Its specificity toward glutamate was confirmed by the supplier following tests in monkey, cat, rat, and mouse tissues where the antibody successfully localized glutamate in glutamatergic retinal photoreceptors and cortical pyramidal cells. The dotblots did not yield significant immunoreactions against a variety of amino acid conjugates such as aspartate. Furthermore, western blots revealed no staining of lamprey brain proteins extracts  (Barreiro-Iglesias et al.
The stimulation intensities ranged from 2 to 15 lA for single pulse, and from 1 to 8 lA for train stimulation. Extracellular recordings of the descending RS axons were also performed as described elsewhere (e. g. ,  Ryczko et al. , 2013)  to monitor the activation of the final common descending pathway for locomotion. The tip of a glass micropipette (tip diameter around 5 lm) filled with Ringer's solution was placed on the rostral stump of the cut spinal cord at the level of the first segment. Signals were amplified (bandwidth 100-500 Hz, model 1800, A-M Systems, Everett, WA) and digitized with a Digidata 1200 series interface coupled with Clampex 9. 0 software (Axon Instruments, Burlingame, CA). Stimulation timing was recorded in a separate channel. To provide better visibility of the electrophysiological responses, the stimulus artifacts were removed using Spike2 5.
For each cell, baseline was defined as the averaged fluorescence of the cell body before stimulation. In two experiments, the location of the stimulation site was verified histologically (see ChAT immunofluorescence, below). Data analysis was carried out using Metafluor (Universal Imaging, West Chester, PA), Clampfit (Molecular Devices, Palo Alto, CA) and MatLab (MathWorks, Natick, MA). All quantifications of RS responses were done by calculating the area under the curve from the beginning of the response to the return to baseline using the area calculation script in Clampfit (Molecular Devices). The areas are expressed in DF/F 3 s.
Statistics Data are expressed as mean 6 standard error of the mean (SEM). Statistical analyses were performed using Sigma Plot (Systat, Point Richmond, CA) or MatLab (MathWorks). Statistical differences were assumed to be significant when P < 0. 05. A two-tailed paired Student's t-test was used to compare means between two dependent groups. To compare more than two dependent groups, a parametric one-way analysis of variance (ANOVA) for repeated measures or a nonparametric Friedman ANOVA on ranks for repeated measures were used. Both analyses were followed by a Student-Newman-Keuls post-hoc test. Correlations between variables and their significance as well as 95% confidence intervals were calculated using Sigma Plot (Systat) or the Curve Fitting toolbox (cftool) in MatLab (Math-Works). Figures were made with Adobe Illustrator.
Materials and Methods To prove the hypothesis, we focused on the optimal subset features from the statistical features which are derived from GBM tumors using active GBM portion with high intensity pixels VAT and peritumoral V of GBM with middle intensity pixels. Two Gaussian distributions could clearly be observed in the histogram data of GBM (Figure  1 ). To assist automated recognition of the GBM phenotype based heterogeneity, histogram statistical features and classifier techniques were used for discriminating active tumor parts from edema parts in FLAIR images. Decision tree was considered to recognize the dominant statistical features which represented the foremost characteristic of GBM heterogeneity  [13]. The proposed approach is presented in Figure  2.
Patient Information, Data Acquisition, and Segmentation. After excluding samples with incomplete data, a set of 30 patients was randomly selected from The Cancer Imaging Archive (TCIA, http://www. cancerimagingarchive. net/) publicly available database for a preliminary study. To obtain full imaging sets, 30 other GBM patients' data (age 50-68 years; 15 males, 15 females) were additionally chosen randomly from the TCIA database. Image pixels of the tumor regions were independently normalized on a scale from 0 to 1 (e. g. , Figure  1 (b) where the x-axis represents the normalized tumor pixels). The images were transformed into gray scale (using Matlab 2013 software) before further processing. Only FLAIR sequences were considered in this study. All the images were reconstructed to 512 × 512 matrices by segmenting the appropriate area of GBM by board certified radiologists, using the 3D slicer tool (Figure  3 )  [14].