dataesr/scientific-paragraphs-categorization huggingface dataset:
(  11 )-(  14 ). P lm = m z d 3 vf ( v)(v l -V l )(v m -V m ) (13) Q l = m 2 z d 3 vf ( v)(v l -V l )( v -V ) 2 (14) spacecraft prior to computation of fluid parameters characterizing the ambient plasma environment. In addition to those data sets addressed above, the MMS project will produce Level-3 data sets for a limited number of events. The Level-3 data products are intended to be mission-level data products that combine measurements from different MMS spacecraft, and/or from different MMS investigations. Ion fluid moments corrected for the presence of heavy ions using measurements from the HPCA are an example of a possible Level-3 data product.
Descriptions of the Data Sets As indicated in Table  10  all data sets, with the exception of the SITL data, are produced for both the Fast Survey mode of operation and the Slow Survey mode. In the Fast Survey mode, two types of science data are produced by the CIDP. The first type of science data, termed Survey data, is routinely relayed with telemetry to the ground. The second type of science data, called Burst data, is sent to the ground only for selected intervals, due to the high sample rates and telemetry constraints. As described above, the FPI Survey data produced by the IDPU in Fast Survey mode include 4. 5 s survey skymaps, Trigger Terms, and Trigger Data Numbers. The FPI Burst data produced by the IDPU in Fast Survey mode comprise burst skymaps at cadences of 30 ms for DES and 150 ms for DIS.
FPI SITL Data Product Description The parameters provided by FPI for use by the SITL include trigger terms and trigger data numbers, plasma moments, several plasma parameters derived from the plasma moments, and arrays of counts that have been partially summed over directions or energies. These latter quantities are the basis for displays of electron pitch-angle distributions and ion energy spectra. Trigger Terms are semi-log compressed to an un-signed 8 bit value by the IDPU prior to transmission to the CIDP, and therefore are not fully representative of the terms used by the IDPU to compute TDN's. Plasma moments are computed using provisional calibration factors.
FPI Level-2 Data Description The Level-2 data are the basic research data provided for use by MMS instrument teams and the scientific community. They are released 30 days after receipt of data from the spacecraft. They are produced for both the Burst and Survey data. They incorporate updates to calibration factors developed during that 30 day interval. The basic scientific quantities are the phase space densities and the plasma moments. Additionally, uncertainties in these quantities are provided at the one-sigma level. These uncertainties are based entirely on Poisson statistics, i. e. the counting statistics  (Gershman et al. 2015a (Gershman et al. , 2015b)). The Level-2 data product also provides information suitable for producing visualizations of the 3D skymaps in the forms of: (1) Energy-time ion spectrograms (ion flux versus time) for a set of 6 directions (sunward, antisunward, dusk, dawn, and ecliptic north and south).
Summary The MMS Fast Plasma Investigation measures electron and ion differential directional flux distributions on MMS at high temporal resolution. Our approach to conducting these measurements is to use for each species, electrons and ions, eight 180 • top hat spectrometers, packaged as dual spectrometers that we refer to as DES for electrons and DIS for ions. The two sets of four spectrometers on each spacecraft are supported by a single block redundant IDPU that communicates with the Instrument Suite CIDP, controls the spectrometers, and collects data from them. The spectrometers were designed and built with high precision and uniformity, as verified by instrument test and calibration. Extensive ground calibration gave a solid base line for understanding the behavior of the sensors. An extensive program of in-flight calibration is executed for the purpose of maintaining a high standard of instrument calibration for all units.
FAT10 conjugation, a post-translational modification analogous to ubiquitination, specifically requires UBA6 and UBE2Z as its activating (E1) and conjugating (E2) enzymes. Interestingly, these enzymes can also function in ubiquitination. We have determined the crystal structure of UBE2Z and report how the different domains of this E2 enzyme are organized. We further combine our structural data with mutational analyses to understand how specificity is achieved in the FAT10 conjugation pathway. We show that specificity toward UBA6 and UBE2Z lies within the C-terminal CYCI tetrapeptide in FAT10. We also demonstrate that this motif slows down transfer rates for FAT10 from UBA6 onto UBE2Z.
UBE2Z functions as an E2 enzyme downstream of UBA6 in the conjugation of either ubiquitin or FAT10 onto target proteins  (15, 16). It is one of the ϳ35 different ubiquitin conjugating enzymes described so far in humans  (20). E2 enzymes  (21)  are globular proteins that harbor a highly conserved ϳ150-res-idue ellipsoid-shaped core UBC domain, which interacts with the E1 and the E3 ligase at different steps during the conjugation reaction. Whereas most E2 enzymes consist of this UBC core domain only, others also contain N-and/or C-terminal extensions. UBE2Z harbors both N-and C-terminal extensions on top of the UBC core domain, classifying it as a class IV E2 enzyme  (20). The structure and role for such extensions have not been extensively studied. Some of these may be intrinsically disordered  (22) , whereas others have defined structures such as the C-terminal extension of class III E2 UBE2K (also known as E2-25K), which folds as a UBA domain (ubiquitin associated domain) and likely interacts with ubiquitin, or the N-and C-terminal extensions of class IV E2 domain of BIRC6 (baculoviral inhibitor of apoptosis repeat containing 6), whose function is as yet undefined despite the availability of structural data (PDB code 3CEG)  (23).
Timecourse experiments analyzing UBE2Z loading by UBLs also indicate that Cyanine5-labeled UBLs behave in a similar way as unlabeled UBLs. Crystallization-Initial UBE2Z microcrystals were grown using protein concentrated to 12 mg⅐ml Ϫ1 in a crystallization buffer containing 25% (w/v) PEG6000 and 0. 1 M Tris (pH 8. 0). A seed stock was generated from these microcrystals and used in cross-seeding experiments. Diffraction quality crystals grew at room temperature in 8 -25% (w/v) PEG1500, 0. 1 M MMT (D-malic acid-MES-TRIS) buffer at a pH ranging between 5. 0 and 7. 5. Crystals were cryoprotected in mother liquor supplemented with 25% ethylene glycol before they were flash-frozen in liquid nitrogen. Structure Solution and Refinement-Data were collected on beamlines ID23Ϫ1 at European Synchrotron Radiation Facility (France).
UBE2Z crystals were in space group P2 1 2 1 2 and diffracted to a resolution of 2. 1 Å. Data reduction was done using XDS and XSCALE  (28, 29). Molecular replacement trials were performed using PHASER  (30)  with UBE2D3 (PDB code 1X23) as the search model for UBE2Z. The initial model produced was improved upon using phenix. mr_rosetta (31). Experimental phases were further acquired using crystals soaked in methylmercuric chloride. Iterative rounds of refinement were performed using either REFMAC (32) from the CCP4 suite  (33)  or BUSTER  (34)  and were interspersed with manual building in COOT  (35). Both the x-ray weight and B-factor restraint weight in REFMAC were optimized to reduce the R work /R free gap during refinement. Refined structures were optimized using local  (36)  and webserver (37) versions of PDB_REDO and were validated using the Molprobity server  (38).
Structure figures were generated using PyMOL  (39). The UBE2Z structure has been deposited in the Protein Data Bank with accession code 5A4P. Small Angle X-ray Scattering Data Acquisition and Processing-Small angle x-ray scattering measurements on UBE2Z Nter (residues 1-93), prepared in buffer 20 mM HEPES (pH 7. 5), 150 mM NaCl, 10% (w/v) glycerol, and 1 mM TCEP, were performed on beamline BM29 at European Synchrotron Radiation Facility (France). The samples were thawed and centrifuged at high speed for 5 min before data acquisition. Samples were exposed to x-rays in a measuring cell cooled to 4 °C. Data were processed with Primus (40) from the ATSAS software package  (41). The quality of data at low angles was assessed from Guinier plots. E1 and E2 Loading Assays-All loading assays were performed for 30 min at 32 °C in a buffer containing 20 mM HEPES (pH 7.
E2-loading rates were calculated from a gel-based assay. E2-loading reactions were performed with 0. 5 M E1, 5 M Cy5-labeled UBL, 2. 5 mM concentrations each of MgCl 2 and ATP, and 0 -32 M E2 in a buffer composed of 20 mM HEPES (pH 7. 5), 150 mM NaCl, and 10% (w/v) glycerol, with a final reaction volume of 30 l. Reactions were stopped with nonreducing SDS-PAGE buffer after 45 s for reactions including ubiquitin or FAT10 LRLR or after 4 min for reactions including FAT10 or Ub CYCI. Reaction times used were determined based on time-course assays measuring UBL loading on UBE2Z variants. Assay samples were separated on 4 -12% NuPAGE gels (Invitrogen) in MES buffer, and E2ϳUBL bands were quantified using the LAS4000 imager associated with the ImageQuantTL software (GE Healthcare). Quantification was done with data obtained within linear range of exposure.
Initial rates for UBL transfer from the E1 to the E2 enzymes were determined at different E2 concentrations (1-32 M) and were fitted using non-linear regression to the Michaelis-Menten model or to a substrate inhibition effect equation using Prism 6. 05 (Graphpad Software Inc. ). Experiments were performed at least three times using different protein batches. Mean values Ϯ S. E. are plotted. Generating Ubl-loaded UBE2Z variants requires the combined activity of both UBA6 and UBE2Z enzymes. Because the Michaelis-Menten model used in our enzyme characterization assumes that a single enzyme is involved in the reaction, apparent V max and apparent K m values are reported, reflecting the combined activity of the UBA6-UBE2Z couple. A control with the highest E2 concentration for each experimental setup showed that the E2ϳUBL thioester bond was reducible in the presence of 5 mM ␤-mercaptoethanol.
Results UBE2Z Structure: Divergence from UBC Core Domain and Emerging Similarity between Class IV E2 Enzymes-We have solved the structure of UBE2Z to a resolution of 2. 1 Å (Table  1 ) by molecular replacement using the structure of UBE2D3 (also known as UBCH5C) (PDB code 1X23) as a model. UBE2Z is a 354-residue-long atypical ubiquitin conjugating enzyme comprising ϳ100-residue long N-and C-terminal extensions on top of the conserved core UBC domain (Fig. 1,  A-C ), classifying it as a class IV E2 enzyme. The core domain of UBE2Z shares ϳ34% sequence identity with UBE2D3 (Fig. 1B ). Whereas full-length UBE2Z was used in our crystallization trials, our structure lacks the N-terminal 98 residues of the protein corresponding to the UBE2Z N-terminal extension. This region showed poor sequence similarity with class II or class IV E2 enzymes that contain N-terminal extensions (Fig.
1B ) but is well conserved in mammalian UBE2Z orthologs  (15). The amino acid composition of the UBE2Z N-terminal extension was highly biased toward alanine (23%), glycine (20%), proline (12%), and serine (10%) residues (Fig. 1B ), suggesting that this region in UBE2Z is likely to be intrinsically disordered  (42). Kratky plots based on small angle x-ray scattering data acquired on this N-terminal UBE2Z region (residues 1-93) indeed suggest that the N-terminal extension does not acquire a globular fold but is most likely disordered (Fig. 2A ). Residues 327-354 at the C terminus of UBE2Z could also not be built in our structure and are predicted to be unstructured. The rest of our structure (residues 99 -326) is well defined, revealing the UBC core domain and the C-terminal extension of UBE2Z (Figs.
1C  and 2B ). The UBE2Z core domain adopts the characteristic ellipsoid shape of UBC domains (Fig. 1C ) but also harbors two extensions termed loops LA (residues 169 -173) and LB (residues 194 -197) compared with the prototypical class I E2 enzyme UBE2D3 (Fig. 2B ). Interestingly, UBE2Z loop LA is absent in all other E2 enzymes except for class IV E2 BIRC6, and UBE2Z constructs lacking this region yielded insoluble protein. On the other hand, loop regions equivalent to the UBE2Z LB exist in other E2 enzymes such as UBE2T, UBE2G2, or UBE2F, where they adopt different sizes and offer different degrees of closure over the catalytic cysteine of the conjugating enzymes (PDB codes 4CCG, 2CYX, and 3FN1, respectively) (Fig. 2C ). Contrary to those E2 enzymes, UBE2Z and BIRC6 (PDB code 3CEG) display similarly oriented LB loops, which harbor a conserved tryptophan residue (Trp-195 in UBE2Z) that contributes largely in masking the catalytic cysteines in these enzymes (Fig.
This interaction could contribute to orienting UBE2Z such that the transfer of CYCI motif containing FAT10 is favored as opposed to LRLR tetrapeptide containing ubiquitin or FAT10 LRLR. Our structural data show that despite low sequence similarity between C-terminal extensions of class IV E2 enzymes UBE2Z and BIRC6, these adopt a similar double helical arrangement, stacked on the "backside" of the E2 core UBC domain. Lack of structural data on UBE2O, the other member of this class of E2s, prevents us from generalizing on a conserved structural organization of C-terminal extensions in this family of E2 enzymes, but nevertheless, secondary structure predictions suggest that the UBE2O C-terminal extension could also comprise two helices enclosing a large loop region. Interestingly, we find that the CYCI motif in FAT10 hinders both FAT10 activation by the E1 enzyme and its charging on E2 enzymes.
, D. Strachan, P. V. , J. B. W. , G. B. , E. E. , Yun Liu, K. M. R. , S. D. , S. A. K. , D. J. M. , C. P. M. , D. L. , and P. E. analyzed data; C. Liu, S. E. H. , N. K. , J. Luan, K. M. , J. N. , C. S. , R. Schmidt, J. M. S. , A. G. U. , C. V. , V. Data deposition: The database information reported in this paper has been supplied in Datasets S1 and S2. The gene expression profiling data from the Framingham study used herein are available online in dbGaP (www. ncbi. nlm. nih. gov/gap; accession no. phs000007). The full metaanalysis data for the continuous and dichotomous alcohol consumption traits are available online at the dbGaP CHARGE Summary site (accession no. phs000930). Here, we report a genome-wide association study (GWAS) and replication study of over 100,000 individuals of European descent.
Results Association of KLB Gene SNP rs11940694 with Alcohol Drinking in Humans. We carried out a GWAS of quantitative data on alcohol intake in 70,460 individuals (60. 9% women) of European descent from 30 cohorts. We followed up the most significantly associated SNPs (six sentinel SNPs; P < 1. 0 × 10 -6 from independent regions) among up to 35,438 individuals from 14 additional cohorts (SI Appendix and Dataset S1). We analyzed both continuous data on daily alcohol intake in drinkers (as grams per day; log transformed) and a dichotomous variable of heavy vs. light or no drinking (Dataset S1). Average alcohol intake in drinkers across the samples was 14. 0 g/d in men and 6. 0 g/d in women. We performed per-cohort sex-specific and combined sex single-SNP regression analyses under an additive genetic model and conducted metaanalyses across the sex-specific strata and cohorts using an inverse variance weighted fixed effects model.
Results of the primary GWAS for log grams per day alcohol are shown in Fig. 1 , Dataset S2, and Fig. S1. We identified five SNPs for replication at P < 1 × 10 -6 : rs11940694 in the KLB gene, rs197273 in TRAF family member-associated NF-κB (TANK), rs780094 in GCKR, rs350721 in ASB3, and rs10950202 in AUTS2 (Table  1  and Dataset S2). In addition to rs10950202 in AUTS2 (P = 2. 9 × 10 -7 ), we took forward SNP rs6943555 in AUTS2 (P = 1. 4 × 10 -4 ), which was previously reported in relation to alcohol drinking  (7). In both men and women, the SNPs were all significantly associated with log grams per day alcohol at P < 0. 005 (Table  S1 ). When combining discovery and replication data, we observed genome-wide significance for SNP rs11940694 (A/G) in KLB (P = 9. 2 × 10 -12 ) (Table  1  and Fig.
S1 ), for which the minor allele A was associated with reduced drinking. KLB is localized on human chromosome 4p14 and encodes a transmembrane protein, β-Klotho, which is an essential component of receptors for FGF19 and FGF21  (8, 9). rs197273 in the TANK gene narrowly missed reaching genome-wide significance in the combined sample (Table  1 ) (P = 7. 4 × 10 -8 ). In the dichotomous analysis of the primary GWAS, SNP rs12599112 in the Cadherin 13 gene and rs10927848 in the Transmembrane protein 82 gene were significant at P = 2. 3 × 10 -8 and P = 2. 6 × 10 -7 , respectively (Dataset S2, Fig. S2 , and Table  S2 ), but they did not reach genome-wide significance in the combined analysis (Table  S2 ). SNP rs11940694 is localized in intron 1 of the KLB gene. The local linkage disequilibrium (LD) structure of the KLB gene is shown in Fig.
Methods Alcohol Phenotypes. Alcohol intake in grams of alcohol per day was estimated by each cohort based on information about drinking frequency and type of alcohol consumed. For cohorts that collected data in drinks per week, standard ethanol contents in different types of alcohol drinks were provided as guidance to convert the data to grams per week, which was further divided  One SNP with the smallest P value was taken forward per region. Chr, chromosome; EAF, effect allele frequency in the discovery GWAS. by seven to give intake as grams per day. Adjustment was made if cohortspecific drink sizes differed from the standard. For cohorts that collected alcohol use in grams of ethanol per week, the numbers were divided by seven directly into grams per day. Cohorts with only a categorical response to the question for drinks per week used midpoints of each category for the calculation.
Where information was available, current nondrinkers who were former drinkers of >14 drinks per week in men and >7 drinks per week in women as well as current nondrinkers who were former drinkers of unknown amount were excluded, whereas current nondrinkers who were former drinkers of ≤14 for men or ≤7 for women were included. Additional exclusion was made if there were missing data on alcohol consumption or the covariates. The analyses only included participants of European origin and were performed in accordance with the principles expressed in the Declaration of Helsinki. Each cohort's study protocol was reviewed and approved by their respective institutional review board, and informed consent was obtained from all study subjects. Discovery GWAS in the Alcohol Genome-Wide Association (AlcGen) and Cohorts for Heart and Aging Research in Genomic Epidemiology Plus (CHARGE+) Consortia and Replication Analyses.
Genotyping methods are summarized in Dataset S1 B, C, and F. SNPs were excluded if the Hardy-Weinberg equilibrium (HWE) P value was <1 × 10 -6 or based on cohort-specific criteria, minor allele frequency (MAF) was <1%; imputation information score was <0. 5; results were only available from two or fewer cohorts; or total n was <10,000. Population structure was accounted for within cohorts via principal components analysis. LD score regression  (24)  was conducted on the GWAS summary results to examine the degree of inflation in test statistics, and genomic control correction was considered unnecessary (λ GC = 1. 06 and intercept = 1. 00; λ=0. 99-1. 06 for individual cohorts) (Dataset S1 B and C). SNPs were taken forward for replication from discovery GWASs if they passed the above criteria and had P < 1 × 10 -6 [one SNP with the smallest P taken forward in each region, except for AUTS2, for which two SNPs were taken forward based on previous results  (7) ].
For novelty suppression of feeding assays, mice fasted for 12 h were placed in a novel environment, and the time to approach and eat a known food was measured. Statistical Analysis. All data are expressed as means ± SEM. Statistical analysis between the two groups was performed by unpaired two-tailed Student's t test using Excel or GraphPad Prism (GraphPad Software, Inc. ). For multiple comparisons, one-way ANOVA with post hoc Tukey was done using SPSS.
2% polyacrylamide gels which were made in the Bio-Rad mini-Protean II Dual slab cell system. After staining, the gels were scanned and the proportions of the different myosin heavy chain (MyHC) bands were quantified by densitometry with ImageQuant Software 5500 (Amersham Biosciences/GE Healthcare). The quantification of the bands revealed the existence of MyHC-IIb isoform  (Picard & Cassar-Malek 2009)  in only 22 of the 265 animals (BH (8); BA (6); CH (5); AA (2); and Li (1)) with a maximal percentage of 5. 5 %. Consequently MyHC-IIb percentages were totalled with those of MyHC-IIx creating a new variable "MyHC-IIx+b" (fast glycolytic fibres).
Statistical analysis The SAS software  (Version 9. 1, 2002; SAS Institute Inc. )  was used to verify the normality of the data and to conduct ANOVA and principal component analyses (PCA). Pearson correlations, ANCOVA and regression analyses were carried out using XlStat  (Version 2009. 1. 01, Addinsoft ®). Data were normally distributed (Shapiro-Wilk test). ANOVA was used to compare animal types. For these comparisons, the General Linear Model (GLM) procedure fitting animal type as fixed effect, and Tukey test were used to compare LSmeans  (SAS Version 9. 1, 2002; SAS Institute Inc. ). PCA (Pearson) was conducted on all variables using all animal types to produce graphs to illustrate visually the different characteristics of the animal types. An overall Kaiser's Measure of Sampling Adequacy (MSA) was calculated using PROC FACTOR of SAS.
The adjusted r 2 value expressed as a percentage will be referred to as the % of variability explained. The maximal number of explanatory variables was fixed at 3. Variables that were significant but contributed less than 2% in terms of explanatory power (r 2 ) were excluded from the model. The standardised coefficients are reported in the Results section and refer to how many standard deviations the explained variable will change, per standard deviation change in the explanatory variable. Finally, for all variables Z-scores were calculated, removing animal type effects  (Picard et al. 2014). This data set was used to determine associations among variables after removal of breed effects. More specifically, breeds showing a significant correlation between two given variables were combined and an overall r-value was calculated using Z-scores and reported in the "correlation networks.
Acknowledgements This study was conducted within the framework of the  EU  Project  ProSafeBeef  (project no. FOOD-CT-2006-36241 ) with  INRA  Quality Assurance number  AQ284. The authors thank the colleagues of the  Aberystwyth University (UK) ,  FBN ,  Teagasc (Ireland)  and  INRA (France)  for their assistance in data collection, the management and slaughter of animals, muscle sampling, biochemical and sensory analyses. They further thank  Université Frères Mentouri Constantine  and the  INATAA Institute (Algeria)  and the  PROFAS B+ program  for the financial support given to  Dr. Mohammed Gagaoua.