dataesr/scientific-paragraphs-categorization huggingface dataset:
Nrf1 was up-regulated here at the transcript level Fig. 7  -Integration of CsA induced mRNA, protein and metabolites from omic data. Starting from the cellular MTX analysis the pathway was expanded from the available PTX and TCX data. The data shows Nrf2 and ATF4 as major hubs and the interaction between them. The program YEd from the software developers YWorks was used to organize the data. at all time points. However, there were no alterations in Nrf1 cytosolic or nuclear protein levels. Thus it remains unclear if Nrf1 is directly involved in the proteasomal response observed here. Cyclophilins are the primary molecular target of CsA  [47]  and the complex of CsA and cyclophilin leads to calcineurin inhibition and is responsible for the immunosuppressive effects  [48]. Cyclophilins have a peptidyl-prolyl cis-trans isomerase (PPIase) activity and function as molecular chaperones.
However, CyP-B secretion was maximum already at the low CsA concentration. This study demonstrates that in vitro cell culture systems coupled with pharmacokinetics and high content omic approaches can give extremely detailed and quantitative insights into both the pharmacological and toxicological effects of compounds. We also demonstrate the added value of integrating these techniques as illustrated in Fig. 7. In addition, the PTX data did not merely mirror the TCX data, but provided further information on key events, such as CyP-B secretion that is independent from gene transcription. MTX data provided an additional level of information and was particularly useful for assessing mitochondrial perturbations, a common target of xenobiotics. In conclusion, an integrated omic approach combined with stable human-derived in vitro cell culture models has the potential to considerably advance our understanding of chemical induced cellular perturbations and will be an extremely useful approach to drug safety paradigms.
2007 ]. The plate boundary is often indicated as an E-W straight line parallel to the Mediterranean coast, or drawn along the foreland-hinterland limit of the Tertiary fold-and-thrust belt, or inferred from hypothetical tectonic blocks. This is probably due to the low level of seismicity associated with the relatively low convergence rate (3 to 6 mm/yr)  [McKenzie 1972 , Buforn et al. 2004 , Nocquet and Calais 2004] , and to the complex tectonic pattern of the Tertiary contractional orogen [Frizon de  Lamotte et al. 2000 , Faccenna et al. 2004 ]. Recent models using new datasets from bathymetry  [Zitellini et al. 2009 ] and 65 continuous global positioning system (GPS) stations  [Koulali et al. 2011]  have provided new insights along the plate boundary. However, the link between the late Quaternary tectonics and present-day active deformation remains poorly constrained, and a conceptual kinematic model is needed to better explain the transpressive tectonics  [Morel and Meghraoui 1996].
Kinematic analysis of fault populations in the Rif and Tell Atlas indicates two successive shortening directions (NNE and then NNW), which suggests a clockwise block rotation of 15˚ to 25˚, if the main regional stress direction has remained unchanged since the early Quaternary  [Meghraoui et al. 1986 , Rebai et al. 1992 , Morel and Meghraoui 1996 ]. Folded and faulted Quaternary deposits   [Meghraoui 1988 , Rebai et al. 1992 , Morel and Meghraoui 1996]  and P axes (yellow symbols) of all of the events mapped in Figure  2a  for the dataset used in the present study. (c) Recent GPS data for the western Mediterranean with Nubia fixed (black,  Anzidei et al. 2001; red, Fernandes et al. 2007; yellow, Vernant et al. 2010; cyan, Serpelloni et al. 2010). The yellow strip indicates the plate boundary zone in North Africa.
These data were processed from 1996 to 2005 and revealed a clear clockwise rotation of convergence rates from WNW-ESE in northern Spain, to NW-SE in southern Spain, and NNE-SSW in northern Morocco  [Fernandes et al. 2007 ]. This rotation was further confirmed by survey-mode GPS campaigns from 1999 to 2009 in Morocco, which incorporated results from continuous GPS in Spain  [Vernant et al. 2010 , Koulali et al. 2011]. All of the GPS data indicated a 3 mm/yr to 5 mm/yr rate of convergence across the plate boundary between Spain and Algeria-Morocco regions, and 1 mm/yr to 2 mm/yr velocities in southern Spain and the Rif Mountains, and 2 mm/yr to 3 mm/yr across the Tell Atlas in Algeria. The rates of convergence increase to 5-6 mm/yr further east across the plate boundary between Lampedusa, Sicily and Sardinia  [Serpelloni et al.
The strain field distribution along the coastal Rif and Tell mountains has a general consistency with the P axis directions of the focal mechanism solutions, which strike from NW-SE to N-S going eastwards (Figures  1a  and 2b ). To study the pattern of seismic deformation along the plate boundary zone, we use the more recently updated dataset of moment tensors that is available for the last 30 yr in this region (Figure  3 ). Moment tensors are obtained by merging all of the on-line catalogs: (1) the Global Centroid Moment Tensor (GCMT) catalog  [Dziewonski et al. 1983, 2000, and references therein; Ekström et al. 2005a Ekström et al. , 2005b;; www. globalcmt. org ] that includes the seismic moment tensors for all earthquakes worldwide with M ≥5. 5 available, starting from 1977; (2) the European Mediterranean Regional Centroid Moment Tensor (RCMT) catalog  [Pondrelli et al.
2002 [Pondrelli et al. , 2004 [Pondrelli et al. , 2006 [Pondrelli et al. , 2007 ; http://www. bo. ingv. it/RCMT] that includes the moment tensors for all seismic events with M ≥4. 5 in Europe and the Mediterranean region, starting from 1997. When a moment tensor exists in both catalogs, for a given earthquake with M >5. 5, we select the GCMT, while for lower M we use the RCMT solution. As already used for similar datasets by  Pondrelli et al. [2006] , these criteria are associated with the methods used to compute the moment tensors. Indeed, GCMTs have been traditionally computed by inverting for body and mantle seismic waves, which are suitable for large-magnitude events, thus with M >5. 5, while the RCMTs are computed by inverting for surface waves, that when recorded at regional distances are appropriate to determine the seismic moment tensor for moderate magnitude events, with 4.
5 > M > 5. 5. The dataset that we composed and used in the computations included seismic moment tensors for earthquakes of the last 30 years with M >4. 5 (Figure  2 ). We applied the moment tensor summation technique to each box  [Kostrov 1974 , Jackson and McKenzie 1988 , Ekström and England 1989 , Westaway 1990 ], which allowed quantitative evaluation of the strain due to a number N of earthquakes within a rock volume V. V is commonly a layer characterized by a length, width and the thickness of the seismogenic zone, which is here fixed to 15 km (Table  1 ). The  Kostrov [1974]  methodology works starting from the following equation: (1) where µ is the shear modulus, and the sum of the moment tensor elements M ij is taken for each k-earthquake. Already applied in the Mediterranean, this method evolved to determine the average strain rate integrated over time.
The data are shown in Table  1 , where all of the used and obtained parameters are reported for each box. In Figure  3 , the cumulative focal mechanisms obtained by moment tensor summations show that when moving from W to E, the geometry of the seismic deformation is different from what is expected for a pure compressive tectonic boundary. It is evident that the deformation is not simply purely compressive, and that a strike-   [Pondrelli et al. 1995 , Pondrelli 1999 , Pondrelli et al. 2011]. Northwestern Algeria shows a consistent pattern of thrust mechanisms, in agreement with the Tell Atlas thrust-and-fold active belt. The seismic parameters are reported in Table  1. 2 1 V M 1 ij k k N = f n = ij / slip component in most of the boxes prevails or provides a greater contribution, as for the Cheliff region (Figure  1b , CH).
Taking into account the P axes directions of significant earthquakes along the Gibraltar-Sicily plate boundary and the shortening directions from the tectonic data (Figure  2b ), there is good correlation when only the Quaternary thrust structures and the focal mechanisms are involved. A more complex tectonic picture appears for the Alboran-Rif region, which might be due to a rapidly changing deformation zone and the superposition of successive tectonic phases. However, the occurrence of the 1959 (Ms 5. 5) Yussuf earthquake and the 1994 and 2004 (Mw 6. 0, Mw 6. 4, respectively) Al Hoceima earthquakes, and the related Quaternary tectonic  This difference in the convergence directions is the result of an obliquely convergent plate boundary. The regional strain partitioning in North Africa is inferred from the interactions between folds and strike-slip faults in a deforming zone.
Acknowledgements. This work is dedicated to  Renato Funiciello , for his constant support and encouragement. We are grateful to  E. Boschi ,  D. Pantosti ,  P. M. de Martini ,  L. Sagnotti , and  M. Anzidei  for fruitful discussions about the plate boundary in southern Italy and North Africa. We thank  R. M. Fernandes ,  P. Vernant  and  E. Serpelloni  for sharing GPS data. M. M. is thankful to  J. Andrieux ,  J. L. Morel ,  D. F. de Lamotte  and  F. Gomez  for their comments and suggestions on the Atlas Mountains neotectonics. We thank  F. Rossetti  and two anonymous reviewers for their comments. Some of the maps were prepared using the Generic Mapping Tool software [Wessel and Smith 1998].
Results for the QTLMAS example are encouraging but unique and different from those of replicated simulations. At least two reasons may be advanced to explain these different results: the more complicated genetic background and the large family size, a full-sib design, simulated in the QTLMAS data set. But the impact of such factors on predictive ability needs further investigation. Further investigation is also needed on variance component estimation of models including marker and individual effects. Duchemin et al. (2012)  were able to estimate both components of variance from real data using model [3], i. e. , the variance of individual effects and the variance of marker effects. We are currently studying variance components estimation for model  [7] , with infinitesimal effects defined only for the base individuals and variance structure designed to avoid identifiability problems.
Acknowledgments The first author benefits from financial support from  INRA (Animal Genetics Department)  and the  Midi-Pyrenees' Region (France). We thank the computing support of the bio-informatics platform Genotoul (http://bioinfo. genotoul. fr/;Toulouse, France) and financial support from the Cost Action TD1101 of the  European Union. Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
Participants Participants were 256 students, who volunteered to participate in this experiment at the end of different class sessions. The average age was 23. 16 (s. d. = 1. 50) and 55. 6% were female. We followed the recommendations for classroom data collection  (Loyd, Kern, & Thompson, 2005)  and asked participants to individually respond to a package containing the experimental materials using pen and paper. The packages were randomly ordered and distributed in advance based on a 3 (power: high, low, control) by 2 (social influence vs. no social influence) betweensubjects design.
All data reduction procedures followed those previously described in  Bouvier et al. (2003). Additional BVR c I c photometry was obtained on December 23, 2011 using the Cafos focal reducer  (Meisenheimer 1994 ) in direct-imaging mode with CCD SITE1d 15 on the 2. 2m Calar Alto Telescope. Individual BVRI images were bias subtracted and flat-field corrected. Differential photometry was performed between AA Tau and the same comparison stars as at CrAO. The resulting photometry is accurate to about 0. 05 mag. Near-infrared JHK-photometry was obtained on December 13, 17, and 18, 2011 with the Omega2000 camera  (Kovacs et al. 2004 ) mounted on the 3. 5m Calar Alto telescope. The O2000 individual images were first processed using the Alambic EIS-MVM pipeline  (Vandame 2002)  adapted to the characteristics of the instrument.
Finally, the response of the instrument was corrected for using the spectrum of the spectrophotometric standard G191B2b. Medium-resolution spectroscopy was obtained with ESO VLT/XSHOOTER on 25 February 2012. XSHOOTER is a cross-dispersed echelle spectrograph with three arms: UVB (300-590 nm), VIS (550-1020 nm) and NIR (1000-2480 nm)  (D'odorico et al. 2006; Vernet et al. 2011). Slit widths of 1. 3, 0. 7 and 0. 4 were chosen in these arms to deliver a corresponding spectral resolution of 4000, 11000, and 11300 in the respective wavelength domains. The standard steps of data reduction (order extraction, flat-fielding, wavelength calibration) were applied using the XSHOOTER pipeline  (Modigliani et al. 2010). The observations comprised four exposures at alternating offsets along the slit (nodding), allowing for accurate sky subtraction, with a total exposure time of 1000 sec.
8 to V=15, and the maximum brightness level dimmed below V=14. An enlargement of the 2011-2013 seasons is shown in Fig. 1. The deep minimum has continued for more than 500 days. The lowest brightness level (V 16. 5 mag) was registered at the end of September 2012. From 20 November 2012 on (JD≥56251), the average brightness level apparently remained roughly constant at V 14. 8, and the photometric amplitude reached up to 0. 9 mag. Both mid-term change, on a timescale of several weeks (e. g. JD56150-JD56250), and short-term variations, up to 0. 4-0. 6 mag per day, are recorded. In particular, an UX Ori-like smooth and long minimum, with little photometric dispersion, is quite noticeable in the fall of 2012. A search for periodicities in the 2011/12 and 2012/13 photometric datasets, analyzed either separately or combined, did not reveal any significant periodic signal.
Acknowledgements. It is a pleasure to thank  Paula Teixeira  for help in preparing the XSHOOTER observations,  Svetlana Artemenko  for assistance during CrAO observations,  Geoffroy Lesur  and  Christophe Pinte  for discussions about disk instabilities and radiative transfer, respectively. We thank the referee for a prompt and useful report. This research has made use of the SIMBAD database, operated at  CDS, Strasbourg, France. We acknowledge partial funding from  CNRS DERCI  on a  French-Ukrainian collaborative program , as well as funding from  Université Joseph Fourier Grenoble  1 for K. Grankins stay at IPAG. This study was supported in part by the grant  ANR 2011  Blanc  SIMI5-6 020 01  " Toupies: Towards understanding the spin evolution of stars " (http://ipag. osug. fr/Anr_Toupies/).
The lack of long and reliable time series of solar spectral irradiance (SSI) measurements makes an accurate quantification of solar contributions to recent climate change difficult. Whereas earlier SSI observations and models provided a qualitatively consistent picture of the SSI varithe NRLSSI data. Correspondingly, larger UV forcing also leads to a larger surface response. Finally, we discuss the reliability of the available data and we propose additional coordinated work, first to build composite SSI datasets out of scattered observations and to refine 50 current SSI models, and second, to run coordinated CCM experiments.
The large amount of solar flux at the visible and IR bands implies that small flux differences may induce important terrestrial consequences. The impact of the 110 variability of these bands on the Earth's climate is expected Relative contribution of the UV (200-400 nm), visible (400-700 nm), near-IR (700-1000 nm) and IR (1000-2430 nm) ranges to the TSI change over the solar cycle as derived from measurements and models described in Sects. 2 and 3. For SORCE/SIM, only the period between 2004 and 2008 can be considered. For other data and models, the plotted relative differences are between solar maximum an minimum. Within each wavelength bin, from left to right: WR-2002 (light green, only in UV;  Woods and Rottman, 2002) , UARS/SUSIM (green, only in UV;  Morrill et al. , 2011a) , NRLSSI (black), SATIRE-S (blue), COSI (purple), OAR (light blue), SCIAMACHY (brown), SORCE (red), and SORCE re-analysis (orange, only in UV;  Woods, 2012).
Variability out-of-phase with solar activity is indeed predicted by some SSI models in the NIR, but with a sig-135 nificantly lower magnitude than found by SORCE/SIM. Details are provided in the following. The inverse variability observed by SIM in a wide integrated band in the visible was, however, unexpected. It can be interpreted as a result of effects induced by the evolution of surface magnetism 140 in the solar atmosphere (e. g. Harder et al. , 2009). However, other observations and analyses of existing long-term SSI data show results in contrast with those derived from SORCE/SIM  (Wehrli et al. , 2012). When used as solar input to CCM simulations, 145 SORCE/SIM observations lead to significantly larger shortwave (SW) heating rates in the upper stratosphere compared to results obtained by using the commonly utilised NRLSSI model data  (Lean et al.
g. Haigh et al. , 2010; Merkel et al. , 2011) , it should be noted that the SIM measurements employed for the analysis covered less than one solar cycle and required extrapolation over a full cycle, and therefore, added uncertainty  (Garcia, 2010). Also the transition altitude from in-phase (lower and middle stratosphere) to out-of-phase (upper stratosphere) ozone signals with the solar cycle is not consistent among the different models and requires further investigations. Unfortunately, observations of the full solar spectrum will likely have a multi-year gap before the next generation SSI instrument is launched. Based on data presently available, a thorough understanding of the impact of SSI on climate requires verification and validation of existing SSI measurements for internal consistency, calculations of middle atmosphere climate models with different reliable scenarios of SSI variations, and comparison of measurements and model results with climate records, i.
e. a study involving the coordinated work of various research communities, which is part of the COST Action ES1005 1 to which most of the authors of this paper belong. This paper summarises and compares, for the first time, a large number of SSI observations and models, and discusses the impact of these data on Earth's climate. A review in this area was recently published by  Gray et al. (2010) , but their focus was more on different possible forcing mechanisms. Although the Sun affects the climate system in numerous ways, we here focus on radiative forcing only, with particular attention given to the role of the SSI rather than that of the TSI, which is still the sole solar input in many climate models. Since space-based observations of the SSI and of the terrestrial atmosphere conditions are sparse or absent before 1980, we restrict our analysis to the data of the last three decades, i.
Moreover, the values above are relative to annual changes. Therefore, they can be assumed valid for short-term variations, but on longer time scales, the instrument stability could be considerably lower. It is worth mentioning that the SORCE public Level 3 data include the SOLSTICE data up to 308 nm and SIM data above 308 nm. However, the SIM spectra do extend down to about 200 nm. Although the SIM data between 200-308 nm are not publicly available yet, they have been made exploitable for several studies through personal communications. The SORCE data used in our study to estimate the atmospheric response to SSI solar cycle variations are specified in Table  3. They also include data received by personal communications with instrument team members (J. Harder, personal communication, 2012).
The studies have been concentrated on SSI instrument observations, capabilities, and estimated spectral irradiance uncertainties, methods of correcting for degradation, and refinement of estimated uncertainties. It has been understood that all detectors and optics suffer some degradation in space, largely due to exposure to solar light, and also due to hydrocarbon contamination that dominates below 400 nm. Accordingly, new models of degradation based on total dose, rather than just exposure time, are being developed for the SORCE and other instru-ments. Revised data sets, which e. g. will include SIM data down to 240 nm, are expected out in 2013. Besides, degradation trends have also been analyzed by considering the expected invariance of SSI over the solar cycle minimum. The latter method has been developed by  Woods (2012)  and ap-490 plied to data during last solar cycle minimum  (2008) (2009)  to estimate possible degradation trends for SORCE/SIM and SORCE/SOLSTICE.
For the first time Major efforts, however, are still needed in each of the three research areas covered in this study. Resolving differences in existing long-term time series of solar measurements is a 2055 major challenge; forthcoming initiatives for merging these measurements into single homogenous databases will be of invaluable help (see, e. g. http://projects. pmodwrc. ch/solid/). Overcoming inaccuracies of current SSI models is another important challenge that will benefit from the renewed inter-2060 est in the solar radiative output, following the recent solar minimum. Finally, the realistic evaluation by climate models of the solar impact on the Earths climate is an important issue. For example, we focussed on the effect of the solar forcing without quantifying the impacts on amplification and 2065 feedback mechanisms.
Acknowledgements. This work is the outcome of a workshop funded by the  COST Action   ES1005   TOSCA  (http://www. tosca-cost. eu). We thank  J. Lean ,  J. Fontenla ,  2075  and  G. Thuillier  for helpful comments and kind collaboration. The authors are grateful to  W. Ball ,  S. Criscuoli ,  S. Oberländer  and  M. Kunze  for providing updated results of their work, to  F. Hansen  for preparing Figs. 10 to 12, and to  A. Kubin ,  G. Chiodo ,  S. Misios , and  A. Maycock  for their active participation in the workshop of.
0 Cycle Sequencing ready reaction Kit (life Technologies), and 5 % DMSO on the ABI3730Xl capillary genetic analyzer (life Technologies). genotyping assay Two primers (forward primer, 5′-CAg CgC TgC CTg AAA CTC-3′; reverse primer, 5′-gTC CTg CCC CTT CAC CTT C-3′) were designed to amplify a 163-bp product encompassing C228T and C250T hotspot mutations in the TERT promoter-corresponding to the positions 124 and 146 bp, respectively, upstream of the ATg start site. Two fluorogenic lNA probes were designed with different fluorescent dyes to allow single-tube genotyping. One probe was targeted to the WT sequence (TERT 1 3 WT, 5′-5HeX-CCC CTC CCg g-3IABkFQ-3′), and one was targeted to either of the two mutations (TERT mut, 5′-56FAM-CCC CTT CCg g-3IABkFQ). Primer and probes were custom designed by Integrated DNA Technologies (Coralville, Iowa, USA) using internal SNP design software, and sequence homogeneity was confirmed by comparison to all available sequences on the genBank database using BlAST (http://www.
Statistical analysis Survival time according to TERT mutational status was assessed using the Kaplan-Meier estimate and a log-rank test. Comparisons of binary and categorical patient characteristics between subgroups and cohorts were performed using the two-sided Fisher's exact test or Chi-squared test. Continuous variables were analyzed using the Mann-Whitney U test. p values <0. 05 were considered statistically significant. Multivariate Cox proportional hazards regression was used to adjust for additional covariates using the survival r package (v. 2. 36). All other statistical analyses were performed using StataSe 12 (Stata Corp. College Station, TX, USA) and graphpad Prism 5 (la Jolla, CA, USA).