dataesr/scientific-paragraphs-categorization huggingface dataset:
98718278C > T, c. 1963C > T, and p. Arg655*) was selected as the best candidate given the plausible implication of this factor in the DNA damage response (DDR; Fig. 3 B ). Although this variant was already described in a database (Single Nucleotide Polymorphism database accession no. rs147948835), its overall frequency of 1. 6 × 10 -4 and of 2. 6 × 10 -4 in the European population (The Exome Aggregation Consortium) was low enough to consider it as a possible pathological NSV. Moreover, this NSV had a very high PHR ED score of 49 using combined annotation-dependent depletion  (Kircher et al. , 2014). Sanger resequencing confirmed the appropriate inheritance of the R655X mutation in the patient's family with respect to WGHM results (Fig. 3 C ). The same mutation was initially described by  Tummala et al.
Identification of Hebo Analyzing the assembly of the ERCC6L2 gene in various species through the Ensembl database (Fig. 4  A), we were puzzled by the difference between the longer transcript annotated in the rat (ENS RNOT00000025965) coding for a 1,533-aa protein and the 712-aa human annotated protein, raising the possibility of an error in the automatic annotation of the human counterpart. Blast analysis of the rat ERCC6L2 open reading frame (orf) over the human genomic region spanning the ERCC6L2 gene established that the first 14 exons correspond to the human ERCC6L2-001 annotated transcript, whereas the additional five exons present in the rat matched short alternative human annotated transcripts (ER-CC6L2-006 and ERCC6L2-007) but with a gap of 347 bp within the putative exon 16. Altogether, this suggested the possible expression of a longer ERCC6L2 transcript in humans, comparable with the rat situation but not annotated as such in the Ensembl database.
Functional validation of Hebo mutation As a first mean to corroborate the possible implication of ERCC6L2 in the DDR after DNAdsb's, we disrupted the ERCC6L2 gene in U2OS cells through CRI SPR/Cas9 mutagenesis. Single molecule sequencing of PCR products spanning the guide RNA (gRNA) site from U2OS transfected with the dual spCas9 and gRNA pX330 expression plasmid revealed a level of 82% indels of various sizes (unpublished data). The bulk mutagenized U2OS cells presented increased phleo sensitivity comparable with that of U2OS cells in which DNA ligase IV had been disrupted by CRI SPR/Cas9, well above the sensitivity observed in isogenic WT U2OS cells, attesting for the critical role of ERCC6L2 in DNA repair after phleo-induced DNA damage (Fig. 5 A ). To further validate the R655X mutation in the ER-CC6L2 gene as being responsible for the DNA repair deficiency observed in the patient's cells, we PCR amplified both the ERCC6L2-SF (Ensembl transcript ENST00000288985) and Hebo orf, cloned them into an Ires-GFP lentiviral vector, and transduced the patient's fibroblasts.
Using the limits of this domain for searching sequence databases, we highlighted significant similarities with Hebo homologues in various species (Fig. 6 B ) without, however, identifying this domain in other proteins. No significant similarities were detected with known three-dimensional (3D) structures using threading programs. This suggests that this domain is involved in a specific function of Hebo, likely related to its interaction with putative partners. The domain appears to be made of two distinct subdomains, separated by a variable hinge re- gion. Moreover, highly conserved amino acids are observed in a few positions (Y, H, N, V, G, E, S, P, Q, M, A, A, L, and Y), suggesting that they play key roles in the function and/or structure of this domain. The HEBO domain matches the shorter profile described in the Pfam database (accession no.
We conclude that the recruitment of Hebo at DNA breaks is a very initial event during DDR and is dependent on the presence of NBS1. S1 ). GenBank/NCBI RefSeq accession nos. are NP_064592. 2 (Homo sapiens), AAH91795. 1 (Danio rerio), XP_011663528 (Strongylocentrotus purpuratus), XP_006968442. 1 (Trichoderma reesei), XP_002151909. 1 (Talaromyces marneffei), CDP26308. 1 (Podospora anserina), XP_001391908. 1 (Aspergillus niger), and CAD37001. 1 (Neurospora crassa). (C) Hydrophobic cluster analysis of the C-terminal region of ERCC6L6 reveals a globular domain (boxed), which is conserved in the ERCC6L2 orthologues. The sequences are shown on duplicated α-helical nets, on which hydrophobic amino acids are contoured and form clusters, which mainly correspond to the regular secondary structures forming globular domains.
Hebo presents features of a bona fide DNA repair factor. It is ubiquitously expressed, localized primarily in the nucleus, and rapidly recruited to the site of DNA lesions in an NBS1-dependent manner. Most importantly, the introduction of WT Hebo in the patient's cells rescues their DNA repair defi-    [Thomä et al. , 2005] ; and Sulfolobus solfataricus, Protein Data Bank accession no. 1z63  [Dürr et al. , 2005] ). SWI2/SNF2-specific elements are depicted in magenta (HD1) and green (HD2), whereas the RecA-like helicase domains are blue (lobe1) and red (lobe2). Helicase-specific domains are shown with numbers, and SWI-SNF2-specific elements are depicted with letters  (Thomä et al. , 2005)  ciency as judged by the recovery of a normal sensitivity to the DNAdsb inducer phleo. Whether the ERCC6L2-SF exerts any biological function or represents a nonfunctional alternative transcript remains to be investigated.
ERCC6L2 long form (Hebo) identification and cloning. Based on human (accession no. ENSG00000182150) and rat (accession no. ENS RNOG00000019175) genome annotation in the Ensembl database for the ERCC6L2 gene, primers were designed to amplify a putative transcript linking human transcripts 001, 006, and 007 (Fig. 4 ) as follows: forward exon 12, 5′-TGG ACT AGG CCT CAA TTT TGT CGG TGC-3′; reverse exon 15, 5′-GGC TCT TCA TCA CTG AAG TCA CTG CAG AGA-3′; forward exon 16, 5′-CAA CAG AAG CCA AAG ATG CTG GTT GTG AG-3′; and reverse exon 16, 5′-ACT AGT TGA TTC TTG GTC TGT GGC TCT GT-3′. The expression of a full-length ERCC6L2 long form was further validated by cDNA PCR amplification using the following primers: forward, 5′-TTT GCT GGG ATC CCC CTC CTC CAT CCT-3′; and reverse, 5′-GGC ACT GGA TTC CAC ACT GAT TCT ATT ATC TTG-3′.
ACK NOW LED GME NTS We thank the patient and his parents for participating in this study, the imaging facility of  Institut Imagine  for help with microlaser irradiation, the  Bioinformatic Department of Institut Imagine  for help with WES analysis, and the genomic facility of  Institut Imagine  for single molecule sequencing on the PGM. We thank  Dr. Claudia Lukas  for the pEGFP-NBS1 plasmid and  Dr. Feng Zhang  for the pX330 plasmid. This work was supported by institutional grants from the  Institut National de la Santé et de la Recherche Médicale , the  Institut National du Cancer  ( PLB IO11-151 ),  Imagine Institut  ( ANR-10-IAHU-01 ), the  European Research Council  ( ERC-2009-AdG_20090506 n°FP7-249816 ), and  Ligue Contre le Cancer  ( Equipe Labelisée LA LIG UE ). The authors declare no competing financial interests.
A CPPS has to be aware about the services and functionalities provided by each device and has to orchestrate such services in order to safely execute a high-level global service. In this paper, we introduce a software framework that orchestrates services of the autonomous devices included in a production cell. The framework ensures the real-time monitoring of devices, establishes network connections if requested, deploys new applications onto the devices to offer new functionalities, and checks the correctness of the source code of applications that will be deployed. The framework was experimented on a real use case that connect a SYBOT collaborative robot and a reconfigurable Raspberry-Pi-based camera. The Sybot is a collaborative robot dedicated to different industrial tasks such as polishing.
Design of the Reconfigurable Manufacturing System Using RobotML RobotML (Robot Modeling Language)  7  is based on the Papyrus 1  modeling tool. RobotML intends to facilitate the development of robotics applications and to ease exchanges between roboticists and end users. It allows the specification of a component-based architecture. Low-level details have been hidden behind parametrized and easier to manage abstractions proposed through a graphical interface integrated to Eclipse environment. A sizable amount of low-level programming knowledge has been put into code generation transformations. RobotML generators allow generating source code from models to several target platforms. Our approach to configure the production scene rely on a modeling step within RobotML. At the modeling level, each component properties and ports are configured.
Machine-to-Machine Communication and Orchestration Using OPC UA The OPC Unified Architecture (OPC UA)  8  is an industrial machine to machine communication protocol based on a platform independent service-oriented architecture. In the present application, OPC UA is used as a generic interface and framework for the orchestration of different production components (hardware or software) and their skills and encapsulated methods such as code analysis, network reconfiguration and deployment of new functionalities. Fraunhofer IOSB integrated an open source OPC UA SDK  9  (open62541) written in C99 into the Lua programming language  3. The combined OPC UA server and client called OPC UA orchestration server was designed and developed based on this combination. It can run on a regular computer, as well as on mobile platforms and even on a low-end Raspberry Pi computer.
The OPC UA orchestration server receives the description of the whole production scene from RobotML using an XML representation. This scene description includes information about possible new functionalities and possible reconfigurations of production cells. For example, in this scenario it is possible to ask each production cell to reconfigure its network, to perform source code analysis, to switch the camera from monitoring to detection and to start and stop the robot. Additionally, a visual dashboard has been developed to show an overview of the scene and to display the content of the OPC UA servers for the operator. The dashboard is based on an existing visualization system, ProVis. Visu 4  , which runs on Windows operating system and includes an OPC UA client based on the Unified Automation C++ UA Toolkit  5.
Verification of Parallel Code Using Frama-C/Para-C The verification and the validation layer is included on our software framework to ensure the safety and the compatibility of the software being deployed. The user may need to have some information and calculate some metrics on the software architecture of the new application. Several kinds of analysis tools can be included in this layer depending on the kind of analysis the user wants to perform on its software. In our use case, we choose to use Frama-C [TBD ref] platform and specific plugin Para-C dedicated to parallel applications analysis. A para-C plugin development is an ongoing project dedicated to parallel code analysis. It is developed for two kinds of purpose. The first one is a reengineering purpose, where the parallel code is parsed, then its architecture is generated throughout different graphs (i.
Network Monitoring and Dynamic Reconfiguration Using SDN The SDN architecture defines three interactions level: the infrastructure level, the SDN controller, and high-level services. At the infrastructure level, one retrieves all communicating devices that will support data traffic exchange and generation. These devices could be the robots, cameras, network switches and routers in the factory. To support the SDN architecture, we provides a specific software called NEON. NEON basically establishes and maintains the communication with the SDN controller, collect all devices network interfaces states and capabilities, and is able to interpret and activate commands coming from the SDN controller. The SDN controller is the link between highlevel applications and the infrastructure. Its role is to collect all information from the architecture, to generate an abstracted view of the system to high-level services and to interpret high-level actions into concrete network actions to be pushed to the infrastructure.
However, for this experimentation we use our own ANSI C, Posix Threads implementation because of the strong requirements on source code that are expected by Frama-C/Para-C at this point. We were able to achieve more than 24 frames per second on the Raspberry Pi 2, using the 900MHz ARMv7 quadcore processor and the dedicated 640x480 VGA camera (no use of GPU). Also, the camera reconfiguration time, switching from monitoring to detection with source code analysis, deployment and compilation only takes a few seconds.
CNRM-ESM components 2. 1 The physical core CNRM-ESM1 is based on the physical core of the CNRM-CM5. 1 atmosphere-ocean general circulation model extensively described in  Voldoire et al. (2013) , which accounts for the physical and dynamical interactions occurring between atmosphere, land, ocean and sea ice. The atmospheric component is based on version 6. 1 of the global spectral model ARPEGE-Climat, which corresponds to an updated version of the atmospheric code used in CNRM-CM5. 1. This updated version of the atmospheric code is derived from cycle 37 of the ARPEGE-IFS (integrated forecast system) numerical weather prediction model developed jointly by Météo-France and the European Center for Medium-range Weather Forecast. In CNRM-ESM1, the geometry, parameterizations and dynamics have been chosen to match the choices made for CNRM-CM5.
Land biogeochemical model In CNRM-ESM1, the interactions between climate and vegetation are handled by the ISBA scheme embedded in the SURFEX (Surface Externalisée) model. The land biogeochemical module in ISBA represents land-surface physics, plant physiology, carbon allocation and turnover, and carbon cycling through litter and soil  (Calvet and Soussana, 2001; Calvet et al. , 1998; Gibelin et al. , 2006 Gibelin et al. , , 2008)). The land cover is represented by nine plant functional types (PFT; given in Fig. 1 ) and three non-vegetated surface types that are determined spatially by the ECOCLIMAP physiographic database  (Masson et al. , 2013a). ISBA uses a semi-mechanistic treatment of canopy photosynthesis and mesophyll conductance following the  Jacobs et al. (1996)  and  Goudriaan et al.
Regions CNRM-ESM1 MTE-FluxNet CNRM-ESM1 MTE-FluxNet GPP [Pg C year -1 ] TER [Pg C year -1 ] High-latitude north (> 60  2007), respectively. Furthermore, the geographical structure of cSoil agrees well with Harmonized World Soil Database (JRC, 2012) except in the Northern Hemisphere (Fig. 13 ). Although several processes are missing in ISBA to accurately simulate high-latitude carbon stock (e. g. , permafrost dynamics, bacterial degradation of the litter, fire-induced turnover), a part of cSoil underestimation can be attributed to the summer warm bias in near-surface temperature (Fig. 3b ). This latter tends to enhance heterotrophic respiration of the soil, reducing the soil organic matter (R > 0. 6, Fig. S2 ). Table  2  shows that CNRM-ESM1 overestimates globally terrestrial ecosystem respiration (TER) when compared to the up-scaled measurements of FluxNet-MTE.
, 2012). At the end of the last decades of the historical simulation  (i. e. , 1986-2005) , CNRM-ESM1 overestimates the T 2 m increase, a discrepancy widely shared by other CMIP5 Earth system models  (Huber and Knutti, 2014; Kosaka and Xie, 2013; Meehl et al. , 2011; Watanabe et al. , 2013). The amplitude of the simulated recent IAV is in line with the observations (Table  3 ). In particular, the model simulates strong cooling followed by stronger warming after the 1991 mount Pinatubo eruption. Contrasting with temperature, the simulated SIE poorly agrees with observation-based estimates  (Cavalieri et al. , 1996; Comiso, 1999; Rayner et al. , 2003). Indeed, CNRM-ESM1 underestimates the mean-state SIE by about 2 × 10 6 km 2 and overestimates not only the IAV but Hatching represents the ±2σ estimated from the ensemble deviation between the 100 members of the HadCRUT4 database  (Morice et al.
, 2012)  for near-surface temperature, the standard deviation between two National Snow and Ice Data Center estimates  (Fetterer et al. , 2002; Comiso, 1999)  and Hadisst  (Rayner et al. , 2003)  databases, the pentadal variability of the observed ocean heat content  (Levitus et al. , 2012)  and spread between Global Carbon Project reconstructions for both land and ocean (Le  Quéré et al. , 2014). For both OCS and LCS, positive (negative) fluxes indicate an uptake (outgassing) of CO 2. also the decadal decrease in extent (Table  3 ). Therefore, in terms of Arctic sea ice, the skill of CNRM-ESM1 is similar to CNRM-CM5 as detailed in  Massonnet et al. (2012). A better agreement is found for OHC for which CNRM-ESM1 results agree with observation-based estimates in term of mean-state and decadal trends (Fig.
Summary and conclusions In this article, we evaluate the ability of the Centre National de Recherches Météorologiques Earth system model version 1 (CNRM-ESM1) to reproduce the modern carbon cycle and its prominent physical drivers. CNRM-ESM1 derives from the atmosphere-ocean general circulation model CNRM-CM5  (Voldoire et al. , 2013)  that has contributed to CMIP5 and to the fifth IPCC assessment report. This model employs the same resolution and components as CNRM-CM5 although it uses updated versions of the atmospheric model (ARPEGE-CLIMAT v6. 1), surface scheme (SURFEXv7. 3) and sea-ice model (GELATO6) in addition to a 6 h coupling frequency. Several biophysical coupling processes are enabled in CNRM-ESM1 thanks to the terrestrial carbon cycle module ISBA  (Gibelin et al. , 2008)  and the marine biogeochemistry module PISCES  (Aumont and Bopp, 2006).
Acknowledgements. We thank the two anonymous reviewers for their constructive comments and suggestions of the discussion paper. This work was supported by  Météo-France ,  CNRS  and CERFACS. We particularly acknowledge the support of the team in charge of the CNRM-CM climate model. Supercomputing time was provided by the  Météo-France/DSI  supercomputing center. Data are published thanks to the ESGF and IS-ENES2 projects. Finally, we are grateful to  C. Frauen  for her kind advice on the nuances of the English language. Edited by:  O. Marti.
8 In contrast, families with MUC1 mutations have no other clinical manifestations. 9 ere we describe two families with ADTKD and congenital anemia caused by missense mutations c. 200T>G (p. Val67Gly) and c. 553A>G (p. Thr185Ala) in SEC61A1 (GenBank: NM_013336. 3), encoding the alpha subunit of the integral endoplasmatic reticular membrane translocon SEC61. Taking advantage of its recently reported tertiary structure, we demonstrate that p. Thr185Ala residue lies in the constriction ring of the SEC61 translocon pore and the p. Val67Gly residue is located in the plug domain. Since mutations in SEC61A1 have not been reported, to date, in ADTKD, we transiently expressed both mutant proteins in HEK293 cells. We found that both mutant and wild-type SEC61A1 proteins are localized in the endoplasmic reticulum; however, the mutant was delocalized partly to the Golgi.
Immunohistochemistry of Kidney Biopsies Paraformaldehyde-fixed kidney biopsies of family members 1-II:3 and 1-III:5 were investigated. Immunodetections of UMOD, REN, and MUC1 were performed as previously described. 3, 9, 25 URAT-1 was detected with rabbit polyclonal SLC22A12 antibody (Sigma-Aldrich cat# HPA024575, RRID: AB_1858650) diluted 1:25 in 5% BSA in PBS. SEC61A1 was detected with rabbit recombinant monoclonal SEC61A antibody (EPR14379) (ab183046, Abcam) diluted 1:100 in 5% BSA in PBS. The sections were incubated with primary antibodies overnight at 4 C. Detection of bound primary antibody was achieved using Dako EnVision þ TM Peroxidase Rabbit Kit (DAKO) with 3,3 0 -diaminobenzidine as substrate.
A. 1. 40), 405 nm diode/50 mW DMOD Flexibl, and 488 and 555 laser lines in 470-670 nm 80 MHz pulse continuum WLL2. Images were restored using a classic maximum likelihood restoration algorithm in the Huygens Professional Software (SVI). The colocalization maps employing single pixel overlap coefficient values ranging from 0 to 1 were created in the Huygens Professional Software. The resulting overlap coefficient values are presented as the pseudo color whose scale is shown in the corresponding lookup tables (LUT).
Structural Impact of Identified Mutations Mutations were mapped into the recently resolved 3D structure of Sec61 26 determined in various states, namely, Sec61 complex translating hydrophilic peptide (PDB: 4CG5), translating peptide being inserted into membrane (PDB: 4CG6), and an idle protein complex (PDB: 4CG7). Structural models were visualized with Pymol Viewer (DeLano Scientific).
31 In addition, the variant was absent from the 1000 Genomes Project database,  32     Prediction of the Structural and Functional Impact of the SEC61A1 Mutations SEC61A1 encodes the protein transport protein Sec61 subunit alpha isoform 1 (SEC61a) that assembles with the protein transport protein Sec61 subunit beta (SEC61b) and the protein transport protein Sec61 subunit gamma (SEC61g) to form the heterotrimeric protein-conducting channel SEC61 that is a part of the mammalian ER translocon. The Thr185 residue lies in the transmembrane helix 5 (TM5) that is located in the vicinity of translocated peptides. 33 Residues Ile179 and Ile183 are involved in the formation of the constriction ring within a pore of the SEC61. As such, the mutation p. Thr185Ala is likely to disrupt the intrahelical hydrogen bond between the Thr185 side chain and the carbonyls of Leu181 and Phe182 and thus affects the structural integrity of the channel.
Discussion Here, we present evidence that mutations in SEC61A1 with complete or partial loss of function compared to wild-type can cause autosomal-dominant progressive tubulo-interstitial and glomerulocystic kidney disorder with anemia. Combining linkage analysis with WES in one family, followed by targeted testing and identification of a second family with a similar phenotype, indicated that missense mutations, predicted to affect the pore function of the SEC61 translocon complex, segregate with the disorder and are the likely drivers. Consistent with causality, one of the discovered alleles was absent from 121,410 control alleles, while the second was found only once. Notably, SEC61A1 is evolutionarily conserved and intolerant to deleterious variation in humans. There are no individuals with truncating or nonsense mutations in the ExAC database and most of the 94 identified alleles carrying missense variants represent changes that are structurally predicted to be neutral.
Of note, the phenotype of the family bearing the functionally determined null allele (c. 553A>G [p. Thr185Ala]) appears to have a more severe and more complex phenotype, although caution is obviously warranted in extrapolating genotype-phenotype correlations. The discovery of additional families with SEC61A1 mutations and the functional stratification of new alleles will be necessary to test this hypothesis. Likewise, we speculate that the SEC61A1 alleles probably contribute to some of the additional phenotypes (e. g. , cognitive impairment, neutropenia) found in the two families, though further laboratory investigation will be required to confirm this. In contrast to the phenotype observed in the Sec61a1 Y344H/Y344H (GenBank: NM_016906. 41) ENUinduced mouse homozygous for the mutant allele at codon 344 encoding a histidine-to-tyrosine substitution,  42  we did not observe any glucose homeostasis or hepato-steatosis problems in our affected individuals.