dataesr/scientific-paragraphs-categorization huggingface dataset:
The functionality of the TH + neurons was assessed using amphetamine-induced rotation. Both groups demonstrated complete functionality without lateral rotational bias after 18 weeks (Figure  6I , n = 3 per group). Importantly, the grafts from the sorted cells were smaller than their counterparts from unsorted cells, and contained a modest total number of TH + neurons  (5, 200, 3, 900, 840). This showed that IAP-sorted cells can function near equipotency of human fetal cells  (Rath et al. , 2013) , as was also previously demonstrated using unsorted hESC-derived DA neurons  (Grealish et al. , 2014; Kirkeby et al. , 2012a). In summary, this dataset demonstrates that d16-sorted IAP + mesDA progenitors survive and mature long term and provide functional recovery in a rodent model of PD.
Single cells were discriminated by FSC-A and FSC-H properties. In the next gate, forward scatter (FSC) was applied against the side scatter (SSC) to mark the population of interest. Propidium iodide was used for discrimination of dead cells only if cells were not permeabilized before. The gates for the fluorescence channel were set according to unstained and isotype controls. Data were acquired using the MACSQuant Analyzer 10 and analyzed with the MACSQuantify Software (Miltenyi Biotec). Antibodies used for flow cytometry and immunocytochemistry are listed in Tables  S1  and S2 , respectively.
05; **p < 0. 005; ***p < 0. 0005). See also Figure S4. (C) IAP + cells sorted on d16 versus IAP + cells sorted on d16 and subsequently differentiated until d50. The color represents log2 intensity values centered to the gene-wise median of all samples; saturation limits are indicated in the green-black-red color bar above the heatmap. The sample groups are depicted by blue color bars above the heatmaps. Shown is a selection of significantly enriched pathways associated with the candidate genes (see color bars on the right-hand side of the heatmaps). (D) The d16 sorted IAP + sample set versus IAP + cells sorted on d16 and subsequently differentiated until d50. The color code corresponds to the log2-fold change values of adult human dopaminergic neurons relative to human embryonic NSCs (GEO: GSE25931) (Marei et al.
ACKNOWLEDGMENTS We would like to acknowledge  Silvia Ru ¨berg ,  Michail Knauel ,  Timon Hick , and  Annett Kurtz  for data processing and technical assistance. This study was supported by grants from the  European Community 's  7th Framework Program through DopaNew (286021) ,  NeuroStemcellRepair  ( 602278 ),  ERC  Grant Agreement ( 309712 ), and the  Swedish Research Council. S. G. was supported by a postdoctoral stipend from the  Swedish Brain Foundation  (Hja ¨rnfonden). M. P. is a  New York Stem Cell Foundation Robertson Investigator. D. L. , A. S. , J. K. , A. B. , and S. K. are employees of  Miltenyi Biotec.
Enzyme residue positions in the combinatorial library for experimental screening of malate kinase activity (Supplementary Table  5 ) are highlighted with green (or cyan) coloured carbon atoms according to whether (or not) direct residue contact can be made with (L)-malate in the model complex. Atoms are otherwise coloured according to element type: other carbon, grey; nitrogen, blue; oxygen, red; and phosphorus, orange. Hydrogen bond interactions are shown as dashed-line vectors connecting donor and acceptor heavy atom positions. The model is overlaid on the X-ray structure of the R-state wild-type enzyme complex with (L)-aspartate and Mg-ADP (PDB code 2j0w) from which it was derived as described in Methods. Diffuse molecular surface representations of the mutant and wild-type enzyme active-sites are respectively shown in green and grey.
An all-atom starting set of co-ordinates was prepared by stepwise energy minimization of the experimental structure (PDB code 2j0w) with harmonic restraints initially placed on all heavy atom positions. Restraining forces on atom subsets comprising the (L)-malate ligand, mutated and neighbouring protein residues and water molecules were then removed before the release of all restraints in the final round of geometry refinement of the mutant enzyme model complexes. Potential energy force field parameter sets used in minimization are described below. Computational re-design of the active-site region in Ec-LysC centred around residue position 119 was performed by the application of 30,000 Monte Carlo rounds of random mutagenesis at nine residue positions (Ser39, Ala40, Thr45, Val115, Glu119, Phe184, Thr195, Ser201 and Thr359) in a modelled binary complex of the E119Q mutant with (L)-malate using RosettaDesign software  67.
All possible exchanges with the 20 native amino-acid side-chains were permitted at each of the nine residue positions. Positions of all atoms in the (L)-malate ligand and in the protein main-chain were held fixed, along with side-chain atom positions in non-mutated residues. A molecular model of the Ec-ASD E241Q mutant complex containing the hemithioacetal malate semialdehyde tetrahedral covalent reaction intermediate presumed to be formed, following phosphate release from malyl-P, by hydride transfer to a thioacyl-enzyme intermediate, was built from the template X-ray crystal structure (PDB code 1gl3) of the Ec-ASD covalent complex formed by reaction of the Cys135 thiol group with the S-methylcysteine sulfoxide substrate analogue inhibitor in the presence of NADP þ (ref. 26). The covalently attached malate semialdehyde substrate derivative was constructed by superposition of a geometry-optimized structure of the model compound (4S)-4-{[(2S)-2-amino-3oxo-propyl] sulfanyl}-L-malate in an analogous conformation to the L-cysteine analogue derivative in the crystallographic structure.
An inorganic phosphate ion was docked into the vacant site occupied by the phosphate group of the malyl-P substrate by superposition of atomic co-ordinates (PDB code 1nx6) from the Haemophilus influenza ASD covalent complex with a hemithioacetal ASA partial reaction substrate derivative  68  at structurally aligned main-chain C a positions. The dimeric structure was then energy minimized in a stage-wise manner with progressive release of harmonic force constraints on heavy atom positions. An initial molecular model of the succinic semialdehyde dehydrogenase from Metallosphaera sedula (Ms-Ssr) was built from its amino-acid sequence (UniProtKB accession number A4YGN0) and the homologous (ADH1) horse liver alcohol dehydrogenase (PDB code 1axe) template structure of the F93W mutant complexed with NAD þ and the inhibitor trifluoroethanol using the I-TASSER web server  69.
The shared sequence identity between Ms-Ssr and the model template was 39%. A NADP þ coenzyme molecule was positioned by superposition at topologically equivalent C a atomic co-ordinate positions of an ADH8 frog (amphibian) vertebrate X-ray crystallographic structure (PDB code 1p0f) with 37% sequence similarity to Ms-Ssr, containing the bound coenzyme, onto those of the model. Determination of the likely substrate binding mode was aided by the superposition of experimental structures of medium-chain dehydrogenase/ reductase (MDR) ADH complexes containing Zn co-ordinated inhibitor or substrate ligands chemically similar to the Ms-Ssr (L)-malate-4-semialdehyde substrate or (L)-2,4-dihydroxybutyrate reduction product (trifluoroethanol, 1axe; glycerol, 1p0f; cyclohexylfluoramide, 1e3i; 2-butanol, 1bxz; 1,4-butanediol, 2 Â aa).
A geometry-optimized structure of the 4-hydroxy-2-oxobutanoic acid alcoholate ion was manually docked into the binding site, guided by the atom positions of the overlaid ligand analogues. The resultant ternary complex was then energy minimized with harmonic positional restraints placed on all of the heavy atoms. A dimeric model structure was generated using the rotation matrix and translation vector for the superposition of the A and B chains in the 1axe co-ordinate data set. A hydrogen-bonded proton relay pathway connecting the active-site with the bulk solvent exists in many MDR-ADHs to facilitate the transfer of the substrate hydroxyl proton to the exterior during the enzyme-catalysed reaction. The archetypal proton shuttle, first identified in the ADH1E (E-isoenzyme) of horse liver alcohol dehydrogenase  70  , is composed of Ser48 and His51 (at the surface), bridged by the 2 0 -hydroxyl of the coenzyme ribose ring (Fig.
4b ). However, His51 in the liver enzyme is replaced by an asparagine residue at the equivalent position (43) in Ms-Ssr. An alternative proton relay system  36  is believed to operate in Ms-Ssr in which the co-enzyme O2' ribosyl hydroxyl oxygen atom instead hydrogen bonds with the side-chain of His39 (Fig. 4b ). Visual inspection of the initial Ms-Ssr model, built using an ADH1 template structure in a 'closed' conformation  71  , showed that the inter-atomic separation distance of 5. 3 Å between the imidazole ring NE atom of His39 and the NADP þ ribose O2' was too long to support the formation of a hydrogen bond. A structurally viable alternative proton relay system is observed in the X-ray structure (PDB code 1e3i) of the P47H mouse ADH2 mutant that exists in a 'semi-open' conformation in a ternary complex with NADH and cyclohexylformamide  37.
Enzyme residue positions in the combinatorial library for experimental screening of malate kinase activity (Supplementary Table5) are highlighted with green (or cyan) coloured carbon atoms according to whether (or not) direct residue contact can be made with (L)-malate in the model complex. Atoms are otherwise coloured according to element type: other carbon, grey; nitrogen, blue; oxygen, red; and phosphorus, orange. Hydrogen bond interactions are shown as dashed-line vectors connecting donor and acceptor heavy atom positions. The model is overlaid on the X-ray structure of the R-state wild-type enzyme complex with (L)-aspartate and Mg-ADP (PDB code 2j0w) from which it was derived as described in Methods. Diffuse molecular surface representations of the mutant and wild-type enzyme active-sites are respectively shown in green and grey.
Acknowledgements This work was supported by the  French National Research Agency  ( ANR   programme d'Investissement d'Avenir , Project  SYNTHACS ,  ANR-10-BTBR-05-01 ) and by  Adisseo. We are grateful to  S. Bozonnet  and  S. Pizzut-Serin  for providing support in using the ICEO high-throughput facility at the LISBP, devoted to the engineering and screening of new and original enzymes, and to  A. Vax ,  H. Serrano-Bataille ,  F. Calvayrac , and  J. Fredonnet  for their technical assistance. This work was granted access to the  HPC resources of the Computing Center of Region Midi-Pyrenees (CALMIP, Toulouse, France ).
V. EXPERIMENT RESULTS Within the MESCAL project 1 , a testbed has been set-up in order to test various functionalities including protocols and algorithms. Note that MQC concept cannot easily be tested because it is a means of classification of l-QCs and its added value could be validated when comparing between the results obtained if this concept is adopted and the ones obtained owing to the use of an alternative method. The conducted experiments within the testbed and simulations aim to validate the inter domain routing behaviours and performance within a MQC plane. Especially, The testbed is used to validate, at the data plane level, the DSCP marking/remarking between ASs in order to signal an inter-domain MQC, to validate the implementation of l-QCs in each domain using Linux traffic control features, to validate the Meta-QoS-Class concept and finally to validate the QoS-inferred inter-domain routing.
Simulation has been used to study scalability issues. The testbed is composed of eight ASs, q-BGP is activated at the boundaries of each domain, and a full mesh q-iBGP is activated within domains that are composed of more than one linux-based router. All routers have DiffServ capabilities for traffic classification, traffic conditioning and various scheduling disciplines. Hierarchical Token Bucket (HTB) scheduling discipline is used rather than Class Based Queuing (CBQ)  [23]  for implementing the classes of service. DSCP ingress re-marking is achieved by using IPFILTER and DSCP egress re-marking is achieved by using DSMARK queuing discipline  [24]. Four l-QCs that belong to four distinct MQCs are configured in each AS. Border routers are represented in each AS by a single Linux-based router, except AS4 that is composed of three routers.
Importantly, treatment of HGPS cells with MG132 improved significantly these cellular phenotypes  (Fig 5H). To further investigate the restoration of normal cellular function of HGPS fibroblasts upon MG132 treatment, we performed RNA-seq experiment (accession number: E-MTAB-5807) and analyzed the expression levels of genes that are misregulated in HGPS fibroblasts. Interestingly, we found an increase in the transcripts levels of genes involved in autophagy activation (p62, ATG4A, ATG4B, ATG4D, ATG3, ATG14, LLK1), proteasome subunits production (PSMC4, PSMB3), splicing (SRSF5), metalloprotease transcripts including MMP3 (whose levels are decreased in HGPS cells), growth factors (EGF, FGF17, FGF22), apoptosis inhibitors (BAG3, BFAR) as well as the improvement of other transcripts involved in inflammation (IkB, SIRT6) (Fig  5I ).
B The percentage of normal nuclei (nuclei with a smooth oval shape) and abnormal nuclei (nuclei with blebs, irregular shape, or multiple folds) was calculated using the Nuclear Irregularity Index (NII) plugin of the ImageJ software (version 1. cellular antiviral defense mechanisms using IFNs. Dramatic linear and rosette PML-NBs lacking substantial SUMO-1, Daxx, and Sp100 have been described as unique to early hESC cultures. These occur primarily between Day 0 and 2 of differentiation and become rare thereafter  (Butler et al, 2009). PML bodies are larger in A-type lamin-deficient fibroblasts compared with their WT counterparts  (Stixova et al, 2012). We also showed that in HGPS patients' nuclei, PML-NBs contained, in addition to progerin, two nuclear envelope proteins: lamin B and emerin; conventional PML protein components were observed as follows: SP100, HP1, DAXX, CBP, and ATRX, while lamin A/C was absent.
Quantitation of abnormal nuclear morphology Fibroblasts from three HGPS patients and three normal individuals were cultured with DMEM medium containing 5 lM MG132, or the same volume of vehicle (DMSO, 0. 025% v/v) for 48 h. Cells stained for lamin A/C or DAPI were examined by fluorescence microscopy with an Axioplan 2 imaging microscope (Carl Zeiss). The percentage of normal nuclei (nuclei with a smooth oval shape) and abnormal nuclei (nuclei with blebs, irregular shape, or multiple folds) was calculated using the Nuclear Irregularity Index (NII) plugin of the ImageJ software (Version 1. 6. 0, NIH, USA). The analysis uses measures of nuclear area and of four parameters of irregularity, named aspect, area/box, radius ratio, and roundness. These four parameters are used to generate a Nuclear Irregularity Index (NII) which, added to area measurement, classify the nuclei in normal or abnormal morphology.
Sequence alignment and quantification of gene expression A subset of 500,000 reads from each Fastq file was aligned to the reference human genome hg38 with TopHat2 to determine insert sizes with Picard. Full Fastq files were aligned to the reference human genome hg38 with TopHat2 (Àp 24 Àr 150 Àg 2 -librarytype fr-firststrand). Reads mapping to multiple locations removed. Gene expression was quantified using two non-overlapping transcriptome annotations: the full Gencode v25 annotation as well as a complementary lncRNA annotation. To obtain this second annotation, exhaustive lncRNA annotations were combined from Cabili et al and Iyer et al and lncRNAs not represented in the Gencode database were selected. HTSeq was used to obtain the number of reads associated to each gene in the Gencode v25 database (restricted to protein-coding genes, antisense and lincRNAs) and to each gene in the additional lncRNA database.
Unsupervised analysis The Bioconductor DESeq package was used to import raw HTSeq counts into R statistical software, to obtain size factors, and to calculate a variance stabilizing transformation (VST) from the fitted dispersion-mean relations to normalize the count data. The normalized expression matrix from the 1,000 most variant genes (based on standard deviation) was used to classify the samples according to their gene expression patterns using principal component analysis (PCA) and hierarchical clustering.
Differential expression analysis The Bioconductor DESeq package was used to import raw HTSeq counts into R statistical software, to obtain size factors and dispersion estimates and to test differential expression. Only genes expressed in at least one sample (FPKM ≥ 0. 1) were tested to improve the statistical power of the analysis. A q-value threshold of ≤ 0. 05 was applied to define differentially expressed genes.
Statistics Statistical analyses were performed with the GraphPad Prism software. Differences between groups were assayed using a two-tailed Student's t-test using GraphPad Prism. In all cases, the experimental data were assumed to fulfill t-test requirements (normal distribution and similar variance); in those cases, where the assumption of the t-test was not valid, a nonparametric statistical method was used (Mann-Whitney test). A P-value less than 0. 05 was considered as significant. Error bars indicate the standard error of the mean.
Scale bar, 40 lm. I Heatmap of RNAseq data (ArrayExpress accession number: E-MTAB-5807) from HGPS fibroblasts treated with DMSO (vehicle control) or with 5 lM MG132 for 6 h. This analysis represents the fold change, in MG132-treated relative to DMSO-treated HGPS fibroblasts, of the most characteristic transcripts of the cellular HGPS phenotype. (n = 2).
Acknowledgements We thank  P. Roubertoux ,  N. Dasilva ,  F. Merono ,  C. Bartoli , and  Anne Laure Egesipe  for their support and assistance. We acknowledge the EMBO Molecular Medicine Vol 9 | No 9 | 2017 ª 2017 The Authors EMBO Molecular Medicine MG132 enhances progerin clearance  Karim Harhouri  et al.
These signal predictions were normalised using the cross-sections of the fiducial regions introduced in Section 7, computed at next-to-leading order (NLO) in α S using the VBFNLO 2. 7. 1  [29] [30] [31] [32]  program and the CT14NLO  [33]  PDF set. The renormalisation and factorisation scales were set to the invariant mass of the triboson system. The WVγ processes that contain τ leptons in their decay are considered as background in this analysis and were simulated like the signal as just described. For cross-checks and for the estimation of systematic uncertainties associated with the event generation, the WVγ signal process was also simulated using the MadGraph 5. 2. 2. 2  [34]  event generator with dynamical renormalisation and factorisation scales. It was interfaced to the PYTHIA 6. 427  [35]  program for the hadronisation and underlying event simulation with the Perugia 2012  [36]  tune and used the CTEQ6L1  [37]  PDF set.
All simulations that used the PYTHIA event generator employed the TAUOLA  [48]  program to compute the τ lepton decays. In samples that do not contain a prompt photon in the final state, the PHOTOS  [49]  program was employed to simulate photon radiation from final-state charged particles. Contributions from additional proton-proton collisions accompanying the hard-scatter interaction, termed pile-up, were simulated using the PYTHIA 8. 160 event generator. The resulting distribution of the mean number of interactions per bunch crossing was corrected to reproduce the distribution measured in data. The level of agreement between simulated and recorded data was further improved by correcting the simulated vertex distribution, object trigger and identification efficiencies, resolution and calibration to agree with the measured values  [50] [51] [52].
For the rejection of Drell-Yan background decaying to τ leptons, the invariant mass of the electron-muon pair is required to be larger than 50 GeV. Finally, events containing any reconstructed jet with p T > 25 GeV are discarded, thereby reducing background contributions from top-quark production. These selection requirements are optimised to yield the best sensitivity to the signal and define the signal region. The expected number of signal events is 12. 2 ± 1. 1, as computed with the VBFNLO program and corrected for acceptance and efficiency effects (described in Section 7 along with the corresponding uncertainties). A total of 26 events are observed. Several processes are backgrounds to the fully leptonic WWγ signal; their contributions in the signal region are summarised in Table  1. The dominant source of background is the production of t tγ events where the top quarks decay to W bosons and b-quarks with a leptonic decay of the W boson (t → Wb → νb).
e. 70 GeV < m j j < 100 GeV. These selection requirements are optimised to yield the best sensitivity to the signal and define the signal region. The expected number of signal events is 14 ± 2 (18 ± 2) in the electron (muon) channel, as computed with the VBFNLO program and corrected for acceptance and efficiency effects (described in Section 7 along with the corresponding uncertainties). A total of 490 (599) events are observed in the electron (muon) channel. The background processes of the semileptonic analysis are listed in Table  2. The dominant contribution arises from Wγ + jets production, as it has the same final state as the signal. The contribution from t tγ, Zγ + jets as well as from WVγ processes containing τ leptons (WVγ → τν j jγ) processes, is estimated using MC simulation. The uncertainties in these background contributions given in Table  2  solely include statistical uncertainties and the uncertainties of the theoretical prediction, that are of the same size.
The expected limits in the absence of a signal are computed using an Asimov data set  [78] , which provides an analytical approximation of the distribution of expected limits based on a χ 2 -distribution of the test statistics. The observed and expected limits are listed in Table  4. The observed limits are between 1. 8 and 4. 1 times larger than the SM cross-section. The observed upper limit on the ν j jγ production cross-section is the most stringent limit reported to date. 4 : Observed and expected cross-section upper limits at 95% CL for the different final states using the CL s method. The expected cross-section limits are computed assuming no signal is present. The last column shows the theory prediction for the signal cross-section (σ theo ) computed with the VBFNLO program and corrected to particle level.
For the determination of the confidence intervals, only one coupling parameter is varied at a time and all others are set to zero. The expected number of events as a function of the varied parameter is described by a quadratic function and the predictions of the VBFNLO program corrected to particle level are used for the determination of this function. Confidence intervals at 95% CL are computed using a maximum profile-likelihood ratio test statistic as done in Ref. [69]. The aQGCs would modify WVγ production at high values of ŝ such that the sensitivity to aQGCs can be improved by raising the threshold of the transverse energy of the photon. As the event count in the signal region decreases with an increasing E γ T threshold, the expected background contribution from the other processes is extrapolated from the results obtained in Sections 5 and 6 with E γ T > 15 GeV.