dataesr/scientific-paragraphs-categorization huggingface dataset:
The Cdg language Cdg is an assembly-like DSL. From the programmer's perspective, this represents a major paradigm shift: Cdg expressions describe the instructions that will be generated at runtime instead of the instructions to be executed. Compilettes are implemented by using a mix of ANSI C and Cdg instructions. The C language is used to describe the control part of the compilette that will drive code generation, while Cdg instructions perform code generation. The Cdg instruction set includes a variable length register set, classical arithmetic instructions, load and store instructions. From this high-level instruction set, compilettes map the instructions to machine instructions according to (1) the characteristics of the data to process, (2) the characteristics of the execution context at the time of code generation, (3) the hardware capabilities of the target processor, (4) execution time and/or energy consumption performance criteria.
Main properties of the code generation backend Considering that deGoal targets constrained embedded systems, drastic architecture choices have been made so that code generation can be fast and memory lightweight. At runtime, a compilette performs in this order: register allocation, instruction selection and instruction scheduling. Register allocation. In dynamic compilers, register allocation is usually performed after instruction scheduling: instruction selection and instruction scheduling are performed on a SSA form. The SSA form is later analysed and register allocation is performed, using techniques that provide a reduced runtime computational cost of the register allocation as compared to graph colouring usually used in static compilers  (Kotzmann et al. , 2008). On the contrary, in a compilette register allocation is done first, simply by using greedy algorithm.
g. AES) are easily integrated in the implementation of a compilette. Furthermore, Cdg being a low-level programming language, it is easy to integrate software protections at the instruction level. Limited memory consumption. deGoal compilettes embed only the necessary data to generate the instructions (and algorithmic equivalences in the case of this project) required for the target polymorphic code. For example, we achieved runtime code generation with deGoal on the evaluation board of the MSP430 micro-controller, which includes only 512 bytes of RAM  (Aracil and Couroussé, 2013). Fast runtime code generation. Using deGoal, the current speed of code generation ranges from 10 to 100 cycles per instruction generated in an implementation that is not targeting secure devices  (Couroussé et al.
Conclusion In this paper we advocate the use of code polymorphism as a means to secure the sensitive components of embedded applications such as cryptographic primitives. We assume that code polymorphism can bring improvement to several security issues at the same time. Firstly, it is de facto a mean to obfuscation, hence making reverse engineering more difficult to achieve. Moreover, considering that physical attacks are strongly related to the temporal and spatial behaviour of the target, regularly modifying the target's behaviour will raise the level of security of a component against physical attacks. In the scope of the COGITO project, we plan to implement code polymorphism in secure components thanks to deGoal, a framework for runtime code generation that is applicable to embedded devices even with limited memory and computing resources.
Using GCTA  5  , which approximates a conditional analysis adjusted for the effects of neighbouring SNPs (Extended Data Figure  1  and Supplementary Table  2 ), we identified 123 independent signals for age at menarche at 106 genomic loci, including 11 loci containing multiple independent signals (Extended Data Tables  1 2 3 4 ; plots of all loci are available at www. reprogen. org). Of the 42 previously reported independent signals for age at menarche 4 , all but one (rs2243803, SLC14A2, P=2. 3×10  -6  ) remained genome-wide significant in the expanded dataset. To estimate their overall contribution to the variation in age at menarche, we analysed an additional sample of 8,689 women. 104/123 signals showed directionally-concordant associations or trends with menarche timing (binomial sign test P Sign =2.
The active metabolites of vitamin A, all-trans-RA and 9-cis-RA, have differential effects on GnRH expression and secretion  17. Other possible mechanisms linking RA signaling to pubertal timing include inhibition of embryonic GnRH neuron migration, and enhancement of steroidogenesis and gonadotrophin secretion  18. The relevance of our findings to observations of low circulating vitamin A levels and use of dietary vitamin A in delayed puberty  19  are yet unclear. To identify other mechanisms that regulate pubertal timing, we tested all SNPs genomewide for collective enrichment across any biological pathway defined in publicly available databases. The top ranked pathway reaching study-wise significance (FDR=0. 009) was gamma-aminobutyric acid (GABA B ) receptor II signaling (Extended Data Table  6 ); each of the nine genes in this pathway contained a SNP with sub-genome-wide significant association with menarche (Extended Data Table  7 ).
This array included up to ~25,000 SNPs, or their proxy markers, that showed sub-genome-wide associations (P<0. 0022) with age at menarche in our earlier GWAS  4. SNPs were excluded from individual study datasets if they were poorly imputed or were rare (MAF <1%). Test statistics for each study were adjusted using study-specific genomic control inflation factors and where appropriate individual studies performed additional adjustments for relatedness (Supplementary Table  1 ). Association statistics for each of the 2,441,815 autosomal SNPs that passed QC in at least half of the studies were combined across studies in a fixed effects inverse-variance meta-analysis implemented in METAL  32. On meta-analysis, 3,915 SNPs reached the genome-wide significance threshold (P<5×10 -8 ) for association with age at menarche (Figure  1 ).
Selection of independent signals Given the genome-wide results of the meta-analysis, SNPs showing evidence for association at genome-wide significant P-values were selected and clumped based on a physical (kb) threshold <1 Mb. The lead SNPs of the 105 clumps formed constitute the list of SNPs independently associated with age at menarche (Extended Data Tables  1 2 3 4 ). To augment this list we performed approximate conditional analysis using GCTA software  34  , where the LD between variants was estimated from the Northern Finland Birth Cohort (NFBC66) consisting of 5,402 individuals of European ancestry with GWAS data imputed using CEU haplotypes from Hapmap Phase II. Assuming that the LD correlations between SNPs more than 10 Mb away or on different chromosomes are zero, we performed the GCTA model selection to select SNPs independently associated with age at menarche at genome-wide significant P-values.
This software selected as independently associated with age at menarche 115 SNPs at 98 loci, 11 of which had two or more signals of association (six loci contained two signals, four loci contained three signals, and one locus contained four signals). Plots of all 106 loci are available at www. reprogen. org. SNPs with A/T or C/G alleles were excluded from this analysis to prevent strand issues leading to false-positive results. To summarize the information obtained from the single-SNP and GCTA analyses, the 105 SNPs selected from the uni-variate analysis and the 115 SNPs selected from the GCTA model selection analysis were combined into a single list of signals independently associated with age at menarche (Supplementary Table  2 ), using the following selection process (Extended Data Figure  1 ).
eQTL analyses In order to estimate the potential downstream regulatory effects of age at menarche associated variants, we used publicly available blood eQTL data (downloadable from http:// genenetwork. nl/bloodeqtlbrowser/) from a recently published paper by Westra et al. (2013)  10. Westra et al. conducted cis-eQTL mapping by testing, for a large set of genes, all SNPs (HapMap2 panel) within 250 kb of the transcription start site of the gene for association with total RNA expression level of the gene. The publicly available data contain, for each gene, a list of all SNPs that were found to be significantly associated with gene expression using a False Discovery Rate (FDR) of 5%. For a detailed description of the quality control measures applied to the original data, see Westra et al  10. Their meta-analysis was based on a pooled sample of 5,311 individuals from 7 population-based cohorts with gene expression levels measured from full blood.
We used the software tool SNAP (http:// www. broadinstitute. org/mpg/snap/) to identify variants in close linkage disequilibrium (r 2 ≥ 0. 8) with the trait associated variants. All eQTL effects at FDR 5% and also lists of the strongest SNP effect for all the significant genes are shown in Supplementary Table  7. Index SNPs (or highly correlated proxies) were also interrogated against a collected database of eQTL results from a range of tissues. Blood cell related eQTL studies included fresh lymphocytes  36  , fresh leukocytes  37  , leukocyte samples in individuals with Celiac disease  38  , whole blood samples  [39] [40] [41] [42] [43]  , lymphoblastoid cell lines (LCL) derived from asthmatic children  44, 45  , HapMap LCL from 3 populations  46  , a separate study on HapMap CEU LCL  47  , additional LCL population samples  [48] [49] [50]  (and Mangravite et al.
Parent-of-origin specific associations Evidence for parent-of-origin specific allelic associations at imprinted loci was sought in the deCODE Study, which included 35,377 women with parental origins of alleles determined by a combination of genealogy and long-range phasing as previously described  6. Briefly, using SNP chip data in each proband, genome-wide, long range phasing was applied to overlapping tiles, each 6 cM in length, with 3 cM overlap between consecutive tiles. For each tile, the parental origins of the two phased haplotypes were determined regardless of whether the parents of the proband were chip-typed. Using the Icelandic genealogy database, for each of the two haplotypes of a proband, a search was performed to identify, among those individuals also known to carry the same haplotype, the closest relative on each of the paternal and maternal sides.
Results for the two haplotypes were combined into a robust single-tile score reflecting the relative likelihood of the two possible parental origin assignments. Haplotypes from consecutive tiles were then stitched together based on sharing at the overlapping region. For haplotypes derived by stitching, a contig-score for parental origin was computed by summing the individual single-tile scores. Similarly, parent-oforigin specific allelic associations at imprinted loci were also sought in the deCODE blood cells and adipose tissue expression datasets.
Pathway analyses Meta-Analysis Gene-set Enrichment of variaNT Associations (MAGENTA) was used to explore pathway-based associations in the full GWAS dataset. MAGENTA implements a gene set enrichment analysis (GSEA) based approach, as previously described  76. Briefly, each gene in the genome is mapped to a single index SNP with the lowest P-value within a 110 kb upstream, 40 kb downstream window. This P-value, representing a gene score, is then corrected for confounding factors such as gene size, SNP density and LD-related properties in a regression model. Genes within the HLA-region were excluded from analysis due to difficulties in accounting for gene density and LD patterns. Each mapped gene in the genome is then ranked by its adjusted gene score. At a given significance threshold (95th and 75th percentiles of all gene scores), the observed number of gene scores in a given pathway, with a ranked score above the specified threshold percentile, is calculated.
This observed statistic is then compared to 1,000,000 randomly permuted pathways of identical size. This generates an empirical GSEA P-value for each pathway. Significance was determined when an individual pathway reached a false discovery rate (FDR) <0. 05 in either analysis. In total, 2529 pathways from Gene Ontology, PANTHER, KEGG and Ingenuity were tested for enrichment of multiple modest associations with age at menarche. MAGENTA software was also used for enrichment testing of custom gene sets.
Constructs were submerged in PBS maintained at 37°C for the duration of the experiment. Load-extension data were collected and converted to stress-strain data using the construct dimensions (gauge length and width measurements) determined by digital images of the constructs taken prior to testing (see section 'Construct size measurement'). Stress was calculated by dividing the load by the circular cross-sectional area of each sinew construct, and maximum modulus was calculated from the linear portion of each stress-strain curve. For all tensile tests, each group contained between four and six constructs per group.
Construct size measurement The size of each construct was measured using digital images taken prior to mechanical testing, or after treatment with EDTA and/or SDS. For mechanical testing, once mounted into the sandpaper grips, a digital image was taken of the construct, with a scale included in the image. The scale was used to calibrate the imaging software (Image J; NIH, USA) for each individual image, and measurements were taken of the gauge length (distance between the two sandpaper pieces). Three width measurements were taken (centre and two ends) to obtain an average width along the construct. Following EDTA and SDS treatments, digital images were taken as described above, and the area of each construct was measured (Image J; NIH).
Funding The authors would like to thank  Orthopaedic Research UK  (project #  497 ) and the  Biotechnology and Biological Sciences Research Council  ( BBSRC  project #  BB/G022356/1 ) for funding this work. The Instron microtester used in this research was obtained through  Birmingham Science City: Innovative Uses for Advanced Materials in the Modern World (West Midlands Centre for Advanced Materials Project 2 ), with support from  Advantage West Midlands (AWM ) and part funded by the  European Regional Development Fund (ERDF). C. L. was supported by an internship from the ISIFC.
Materials and methods The Bin1 SH3 domain and the NS5A fragment containing residues 191 to 340 (NS5A(191-340)) were expressed recombinantly as GST-fusions and purified. NMR experiments were performed on Agilent VNMRS 600 MHz and 800 MHz spectrometers equipped with cryogenically cooled triple-resonance (HCN) probes with pulsed z-field gradients. NMR data were processed using NMRPipe and evaluated using CcpNMR. The binding interfaces of NS5A (191-340) and Bin1-SH3 were determined by mapping chemical shift changes upon addition of increasing amounts of Bin1-SH3 to NS5A(191-340). To determine Carbonyl and C α chemical shifts BEST-TROSY HNCO and HNCA experiments were used  [4]. Secondary structure propensities were calculated based on HN, N, Carbonyl and C α secondary chemical shifts of NS5A(191-340) in the free and bound state.
We gathered clinical information about patients' RET genotype, type of treatment for phaeochromocytoma (ie, unilateral or bilateral operations as adrenalectomy or adrenal-sparing surgery, and as open or endoscopic operations), and postoperative outcomes (adrenal function, malignancy, and death). The type of surgery was decided by each investigator and the timing of surgery was patient driven. The primary aim of our analysis was to compare disease-free survival after either adrenal-sparing surgery or adrenalectomy. Findings 1210 patients with multiple endocrine neoplasia type 2 were included in our database, 563 of whom had phaeochromocytoma. Treatment was adrenalectomy in 438 (79%) of 552 operated patients, and adrenal-sparing surgery in 114 (21%). Phaeochromocytoma recurrence occurred in four (3%) of 153 of the operated glands after adrenal-sparing surgery after 6-13 years, compared with 11 (2%) of 717 glands operated by adrenalectomy (p=0•57).
4 e established the EACIMPS database on Nov 1, 2012 and collected data on patients from the records of the participating centres up to a cutoff of Oct 1, 2013. Patients included in the database were enrolled at the participating centres from 1968 to 2013. Patients included in the database had to be diagnosed as carriers of germline pathogenic mutations of the RET gene. Additionally, fi rst-degree relatives with histologically proven medullary thyroid carcinoma and phaeochromocytoma (defi ned by the association of increased urinary or plasma metanephrins and adrenal tumour) were included. Multiple endocrine neoplasia type 2 patients without phaeochromocytoma had to be older than 15 years of age at last follow-up to be included. We gathered demographic, clinical, and molecular genetic data for patients included in the database.
We gathered data on age at diagnosis for phaeo chromocytoma, whether the disease was unilateral or bilateral, if medullary thyroid carcinoma was diagnosed, and if there were any presenting symptoms associated with phaeochromocytoma. For patients with phaeochromocytoma, all centres had performed plasma or urinary metanephrine measurements in symptomatic patients, or in asymptomatic patients every 6-12 months depending on each investigator. Imaging was done systematically when metanephrine concentrations increased and every 3-5 years in patients with normal metanephrine values. These data were also included in our database. Data were collected on whether surgeries were unilateral or bilateral operations, either as adrenalectomy or adrenal-sparing surgery as open or endoscopic operations. In cases of a second or subsequent phaeochromocytoma-related surgery, these data were also recorded accordingly.
All these data were also registered for RET mutation carriers in whom phaeochromocytoma was excluded and who never had an adrenal operation. Additionally, we recorded whether medullary thyroid cancer was diagnosed before, together with, or after phaeochromocytoma, in all carriers of multiple endocrine neoplasia type 2. All patients included in the database were off ered molecular genetic testing for germline mutations of the RET gene. Germline genomic DNA was extracted from ethylenediamine tetra-acetic acid-anticoagulated blood. The analyses were done according to international standards and the manufacturers' instructions in clinical and molecular biology laboratories. Routinely, the analyses included DNA extraction, PCR amplifi cation, and Sanger sequencing of exons 8, 10, 11, and 13-16 of the RET gene.
Statistical analysis We summarised continuous variables as mean (SD), range, and median (IQR). We calculated age-dependent penetrance estimates of phaeochromocytoma with the Kaplan-Meier method. We compared disease-free survival with the log-rank analysis. We did statistical comparisons of quantitative data with Student's t test or ANOVA. For statistical comparisons of dichotomous data, we used the χ² test. All statistical tests were two sided, and p values of less than 0•05 were deemed to indicate statistical signifi cance. All analyses were done with XLStat Software (version 2013. 4. 05).
Systematic review As part of planning for our study, we did a systematic review in which we searched PubMed with the terms "phaeochromocytoma", "multiple endocrine neoplasia", "adrenal sparing surgery", "adrenalectomy", and "endoscopic adrenal surgery", up until Oct 31, 2013. We included only studies published in English. We then assessed each study for the design and quality of the data retrieved, and we compared the published data with our results. Our systematic review showed that no practice guidelines exist for the surgical management of phaeochromocytoma in multiple endocrine neoplasia type 2, and there is a scarcity of large systematic studies to inform such guidelines.
Acknowledgments The study was supported in part by grants from the  European Union  (grant  LSHC-CT-2005-518200 ); the  German Cancer Foundation  (grant  107995  to HPHN); the  Arthur Blank Foundation in Atlanta, GA, USA  (to CE); the  Italian Government project on rare diseases  (grant  10FF11  to MM); the research programme of  Charles University  ( P27/LF1/1 ) and a research grant from the  Czech Ministry of Health  ( NT12336-4/2011 ) (to TZ); the  Key Scientifi c Research Project of Nanjing Military Command, China  ( 09Z038  and  10Z036  to X-PQ); the  National Science Centre Poland  (grant  N401 410639  to KH-L and BJ); the  National Research Council for Scientifi c and Technological Development  grant  401990/2010-9 ; the  State of São Paulo Research Foundation (FAPESP)  grants  2009/11942-1, 11/13518-2 , and  13/01476-9  (to RAT, SPAT, and FLC), and grants  IGA   MH CZ NT/13901-4  and  MH CZ 00023761  (to SD).
Fluorescence microscopy Exponentially growing cells expressing Yap1-GFP under the control of native Yap1 promoter were washed with PBS, resuspended in mounting solution (75% glycerol in PBS) containing 49,6-diamidino-2-phenylindole (DAPI) at concentration of 50 mg/ml, and mounted on a glass slide covered with polylysine (Sigma). Fluorescent images were captured with a Leica microscope (DMRXA) equipped with a cooled CCD camera Micro-MAX (Princeton Instruments) under control of the MetaMorph software (Molecular Devices). Images obtained were processed using ImageJ software.
Acknowledgments We thank  Andrei Chabes  for his generous help in the determination of dNTP levels,  Chris Grant  for his kind gift of anti-Trx1 antibody,  Judith Souphron  for providing TEV protease. We thank  Chitranshu Kumar ,  Marie Dutreix , Dorothee Baı ¨lle,  Pierre-Marie Girard  for helpful discussions.
Statistical analysis Statistical analysis and CI estimations have been run under Bayesian paradigm. Results are given as mean and (95% credible interval). Data were analysed by IC (50/75/90). Group comparisons were based on the mean difference. Normality was assessed with a Shapiro-Wilk test. When required, data transformation was used to reach normality. Each data set was analysed using hierarchical (mixed) model with fixed group effects and random treatment effect as described. 29 The whole data set was analysed using a two-stage hierarchical model, with the fixed group effects and two random effects that were treatment and IC (50/ 75/90), in order to take account of both levels of repeated measurements. Dummy variables, representing the IC studied (50/ 75/90), had also been considered as fixed effects to test differences between CI in each case.
8 Interestingly, combination of different entry inhibitors, including CLDN1-specific mAb and kinase inhibitors, also showed synergy on HCV entry and infection (figure  5A ). While CLDN1-specific antibodies and PKIs both interfere with CD81-CLDN1 coreceptor interactions, PKIs also interfere with glycoprotein-dependent viral fusion. 13 his additional and complementary MOA on membrane fusion of PKIs is most likely responsible for the synergistic effect. This concept is confirmed by the finding that combination of anti-CD81 and anti-CLDN1 mAbs, which target a similar step in the viral entry process, only exhibits an additive effect (figure  5A ). Thus, these results define novel combinations of entry inhibitors for prevention of graft infection. Interestingly, two entry inhibitors erlotinib (targeting EGFR and CD81-CLDN1 co-receptor associations) and ITX-5061 (targeting HCV-SR-BI interactions) have reached clinical development to determine the safety and efficacy in patients with HCV infection (ClinicalTrials.