dataesr/scientific-paragraphs-categorization huggingface dataset:
Data access The following data sets are made available at www. iceandclimate. dk/data and WDC Palaeo: -ECM data sets from NGRIP and NEEM in 1 cm resolution. -NEEM DEP data from 1757 m depth downwards and NGRIP DEP data. -The match points (including the five tephra horizons) used for the timescale transfer. -The NEEM (depth, age) relation in 0. 55 m ("bag") resolution for ice and gas. -age CH 4 tie points and the GI-8-10 δ 15 N data. -Modelled total strain and accumulation in 0. 55 m resolution. -Combined accumulation reconstruction (mean of 4 estimates cf. Sect. 3. 5).
Results and Discussion Our investigations started with the preparation of the novel zwitterionic imidazolium salts 2a-c bearing 3-sulfonatopropyl and 2-pyridyl (2a), 2-picolyl (2b) or 2-pyridylethyl (2c) substituents (Scheme 1). They were synthesized in high yields (73-86%) by reacting the known imidazoles 1a-c 20 with 1,3-propane sultone in acetone, at room temperature, for one week. 21 Analytical and spectroscopic data (IR, and 1 H and 13 C{ 1 H} NMR) obtained for 2a-c were in complete accord with the proposed formulations (details are given in the Experimental Section). The corresponding Au(I)-NHC complexes 4a-c were then synthesized through a silver-carbene transfer method (Scheme 2). Thus, sequential treatment of dichloromethane solutions of 2a-c with Ag 2 O, in the presence of tetrabutylammonium chloride (TBACl), and [AuCl(SMe 2 )] resulted in the major formation of the ionic derivatives 3a-c.
The volatiles were removed under vacuum to yield the corresponding lactone in high yield and purity. When required, lactones were further purified by column chromatography over silica gel using hexane:EtOAc (9:1) as eluent. The identity of the known lactones was assessed by comparison of their 1 H and 13 C{ 1 H} NMR spectroscopic data with those reported in the literature. 12 talyst recycling. The recyclability of complexes 4a-c and 5b-c was investigated using the cycloisomerization of 4-pentynoic acid (7a) to 5-methylenedihydrofuran-2-one (8a) as model reaction. Thus, to a biphasic system composed of 1 mL of toluene and 1 mL of distilled water, 29 mg of 7a (0. 3 mmol) and the appropriate gold complex (0. 0075 mmol; 2. 5 mol%) were added. The resulting mixture was stirred under air at room temperature until complete consumption of 7a was observed by TLC.
In all the cases, data collection was performed with an Oxford Diffraction Xcalibur Nova single crystal diffractometer using Cu-Kα radiation ( = 1. 5418 Å). Images were collected at a fixed crystal-detector distance of 63 mm for 4c, 5c and 6b, and 100 mm for 5b, using the oscillation method with 1º oscillation and 1. 5-2. 5 s variable exposure time per image for 4c, 6-40 s for 5b, and 1. 5 s for 5c and 6b. Data collection strategy was calculated with the program CrysAlis Pro CCD. 46 Data reduction and cell refinement was performed with the program CrysAlis Pro RED. 46 An empirical absorption correction was applied using the SCALE3 ABSPACK algorithm as implemented in the program CrysAlis Pro RED. 46  all the cases the software package WINGX  47  was used for space group determination, structure solution and refinement.
For 4c the structure was solved by direct methods using SIR92,  48  for 5b the structure was solved by direct methods using SIR2004,  49  for 6b the structure was solved by Patterson interpretation and phase expansion using DIRDIF. 50 For 4c, 5b and 6b isotropic least-squares refinement on F 2 using SHELXL97  51  was performed. For 5c the structure was solved, with some difficulty, by direct methods using SIR92, 48 but subsequent refinement was not possible. Therefore, experimental data were examined with the program PLATON  52  which detected pseudo-merohedral twinning. The twin law proposed (1 0 1 / 0 -1 0 / 0 0 -1) is a two-fold axis which belongs to a higher crystal system (orthorhombic) than the structure (monoclinic). Several restraints on displacement parameters were used during the least-squares refinement with SHELXL97  51  to counterbalance the unsatisfactory effective data to parameter ratio caused by twinning.
Files containing read counts from all samples are provided as additional files 3 to 14 (see Methods) in a format that can be readily uploaded into the Integrated Genome Browser IGB  [31]. At low resolution, the obtained histone modification landscapes reproduced the basic properties of previously published profiles, such as absence (H3K4me2, H3K4me3, H3K27me3) and presence (H3K9me2) of specific modifications around centromeres  [32] [33] [34] , and showed no obvious differences between primed and non-primed samples (Additional file 1, Figure  S3 ). However, further analysis of the profiles at high resolution revealed several important differences between primed and non-primed samples, which will be described in the following. Enriched histone modification domains ('islands') were determined with SICER software  [35].
The highest number of islands (around 20,000) was identified for H3K4me2 and H3K4me3, followed by H3K27me3 (around 7,000) and H3K9me2 (around 2,000). Lists specifying the positions of identified islands in all samples are provided as Additional files 17 to 28 for upload into IGB (see Methods). The number of H3K4me2, H3K4me3, and H3K9me2 islands was similar in primed and non-primed plants, but the number of H3K27me3 islands increased from 6,288 in non-primed to 7,687 in primed plants (Figure  3A ). The overall genome coverage with H3K4me2, H3K4me3, and H3K9me2 islands was again similar in primed and non-primed plants but genome coverage with H3K27me3 islands decreased from 19. 3% in non-primed plants to  16. 5% in primed plants despite the higher number of islands (Figure  3B ). Priming induces small but specific changes in histone modification levels CHIPDIFF software  [36]  was used to identify genomic regions that differed in histone modification level between primed and non-primed samples.
Transcription factors are preferred targets of priminginduced changes To investigate which genes were targets of priminginduced changes we identified for all four modifications those islands and differential sites that mapped to genes resulting in gene lists for 'mapped islands' and 'mapped differences'. We then explored enrichment of functional annotations among genes carrying differential sites using the Database for Annotation, Visualization and Integrated Discovery (DAVID  [40] ). To compensate for any priming-independent functional bias among genes associated with certain histone modifications we scored enrichment of gene functions in 'mapped differences' not only over gene functions in the Arabidopsis genome (background 'Arabidopsis') but also over gene functions in the corresponding 'mapped islands' lists (backgrounds 'Islands Primed' and 'Islands Control').
The number of genes containing H3K9me2 islands was too small to extract statistically significant results but a highly significant enrichment of genes encoding transcription factors was found among genes that experienced priminginduced changes in H3K4 and H3K27. The approximately two-fold enrichment of transcription factors was represented by several functional terms extracted from different databases, and was independent of the chosen background or the length of upstream and downstream sequences included in the mapping. An example of gene numbers, enrichment and statistical parameters for the term 'transcriptional regulation' is shown in Table  2. The full dataset is provided as Additional file 2. Our finding that priming-induced differences in H3K27me3 were preferentially seen in transcription factors supports the notion of REF6 involvement because transcription factors were also found to be enriched among REF6binding genes  [39].
For each histone modification the gap length producing the maximal aggregate score of all significant islands was then selected for further calculations. The optimal gap lengths were 0 for H3K4me2 and H3K4me3, 600 bp for H3K9me2, and 400 bp for H3K27me3. SICER scores for each 200-bp window were stored in WIG files (Additional files 3 to 16). The genomic coordinates of the obtained islands were stored in BED files (Additional files 17 to 30). Both file formats can be displayed in modern genome browsers. Identification of sites showing difference in histone modification levels: To identify histone modification sites that differed between primed and non-primed samples we used CHIPDIFF software based on a hidden Markov model approach  [36]. Throughout the calculations we used the same values for effective genome fraction, sample-specific fragment sizes and optimized window sizes as in the SICER-rb calculations (see above).
Applying these parameters required a small change in the software code. For other parameters default values were used  [36]. Separate lists of differences were generated using thresholds of 1. 2, 1. 5, and 2fold changes. The genomic coordinates of the identified differences were stored in BED files. Files containing coordinates of >1. 2-fold differences are provided as additional files for upload into genome browsers (Additional files 31 to 37). A BED file containing coordinates of A. thaliana genes (TAIR9 version) is also provided for upload into genome browser (Additional  File 38). Mapping: The identified islands and differences were mapped onto TAIR9 gene annotations using an inhouse built script. A region was associated with a gene if its genomic coordinates overlapped with those of a gene including up-and downstream sequences of either 100 bp or 1,000 bp (separate lists).
It is accepted that in the adult plexus continuous functional tight junctions between adjacent epithelial cells control access of molecules to the CSF and thence to the brain  [11]. The molecular composition and complexity of these junctions in the developing brain in relation to their ''tightness'' (i. e. permeability properties) have been controversial  [5, 6, 12]. Here we present a transcriptome analysis of embryonic and adult rat choroid plexus, combining RNA sequencing datasets with physiological experiments that demonstrate no paracellular movement of small water-soluble molecules through these junctional complexes. It has been reported recently, based on microarray studies in embryonic mouse choroid plexus  [13]  that many intercellular junction-related and ion transporter and ion channel genes are already expressed in embryonic choroid plexus, including many that are expressed at a higher level or even uniquely in the embryonic choroid plexus.
Illumina next generation RNA sequencing RNA sequencing was performed at the Australian Genome Research Facility (Melbourne, VIC, Australia). A cDNA library was prepared from 10 mg of total RNA using the mRNA-Seq Sample Preparation Kit (Illumina, San Diego, CA, USA) according to standard manufacturer protocol. Quality of the library was verified using a DNA 1000 chip using the Agilent 2100 Bioanalyzer (Agilent) and quantified by fluorimetry. The library was subjected to 100 bp single end read cycles of sequencing on an Illumina HiSeq 2000 sequencer as per manufacturer protocol. Cluster generation was performed on a c-Bot (Illumina) with a single read cluster generation kit. Data analysis. Short reads were trimmed to remove ambiguous bases from the start and segments with low quality scores from the end, as indicated by the ascii character ''B'' in Illumina 1.
Gene ontology descriptions for rat were downloaded from Biomart  [20] , and genes with ''junction'' mentioned in their gene ontology description were selected. Junction genes of interest were then extracted from this list. Similar searches were carried for other functional categories as described in the Results/Discussion below. For initial analysis genes with. 100 sequence reads and age-related fold changes (FC). 2. 0 (log 2 FC. 1. 0) were collated and are summarised in Tables  1, 2 , 3, 4. For more specific analysis of some particular function categories a lower cut-off of 10 sequence reads was used. Illumina RNA sequencing data have been deposited with the Gene Expression Omnibus (http://www. ncbi. nlm. nih. gov/geo/) under accession code GSE44072.
Results and Discussion Sequencing of total RNA samples collected from E15 and adult lateral ventricular choroid plexus was completed using the Illumina platform. A total of 29479 transcripts were mapped, of which 5872 transcripts were enriched at E15 and 4781 enriched in the adult. Over 18000 (approximately 60%) of these genes were already expressed at adult levels in E15 samples, suggesting a great deal of maturity of expression levels in this tissue. Refer to Table  S1  (raw transcript count) and Table  S2  (summarised analysed data) for full dataset.
Slc4a1 Slc4a1 Enzymes and ion transporters known to be involved in CSF secretion. Protein ID from  [72] ; these ion transporters have been shown to be active in adult choroid plexus; as an example the cellular localization of SLC4A1 is shown in Fig. 3C, D. Gene ID and function from NCBI (http://www. ncbi. nlm. nih. gov/gene). Genes in bold were not detected in either RNA-Seq or Affymetrix datasets. Slc4a7 was only identified in Affymetrix. Slc12a2 (NKCC1) has previously been identified in embryonic mouse choroid plexus as has Slc12a4 (KCC1)  [110]  and Slc4a10 (NCBE)  [111]. Genes underlined have not previously been identified in rat choroid plexus (but cf. with mouse choroid plexus  [13] ). A comprehensive list is presented in Table  S2. Most of the genes listed here were identified in both RNA-Seq and Affymetrix datasets.
Following staining for CLIC3 a marked reaction is observed in the entire embryonic plexus (E) in contrast to that in the adult where vasculature is devoid of staining and the cytoplasm of scattered choroid plexus epithelial cells is strongly immunoreactive (F). Scale bars: 100 mm for all. Abbreviation: CSF, cerebrospinal fluid. doi:10. 1371/journal. pone. 0065629. g003 Genes related to synaptic structure and function A surprising finding in the RNA-Seq dataset is a large number of genes related to synaptic structure and function (Table  S5 ). For reasons discussed below they are very likely to be expressed solely in choroid plexus epithelia cells rather than due to contamination from the very small amount of non-epithelial tissue in the whole choroid plexus used for this study. At E15 there were 64 genes defined by their GO categories as synapse-related and expressed at a higher level than in adult plexus (Table  S5 ).
Samples of CSF and plasma were also collected to confirm the presence of the marker in both compartments indicating transfer of the biotinylated marker across the blood-CSF barrier. Following intraperitoneal injection, CSF samples showed biotin reaction product (not shown), while plasma samples taken from animals that received an intrathecal injection showed a positive reaction for biotin (visible in tissue sections in Fig. 4B  and D ). These data suggest that the 3 kDa water soluble marker is transferred through choroid plexus epithelial cells in both a bloodto-CSF and in a CSF-to-blood direction. To ensure no leakage was occurring between cells, functional integrity of the choroid plexus barrier was visualised at the ultrastructural level with a low molecular weight tracer (biotin ethylenediamine, 286 Da) injected directly into the ventricles of E15 and adult rats and plexus tissue was examined by electron microscopy.
Limitations of Study The current study provides an exhaustive analysis at the transcriptome of the rat lateral ventricular choroid plexus of the embryonic and adult rat. The dataset makes available a wealth of information to be mined by researchers from a range of backgrounds including developmental biology, barrier biology and drug delivery. There are three limitations that need to be acknowledged regarding the present study. The first limitation concerns the use of whole choroid plexus tissue. However, the epithelium is the predominant cell type, representing up to 90% of the plexus tissue  [13, 18]. The absence of transcript for Cldn5 (a brain barrier cerebral endothelial-specific claudin family member) in the current dataset suggests that any possible contamination is below detectable limits.
In addition, the immunohistochemical evidence for presence of an ion transporter (SLC4A1) an ion channel (CLIC3) and a carbonic anhydrase (CA8) that were found to be distributed predominantly if not exclusively in epithelial cells but not the endothelium or stroma (Fig. 3 ) reinforces this conclusion. A second limitation concerns the bioinformatics analysis of the RNA sequencing database. The analysis of large RNA sequencing databases is quite new and relies heavily on the accuracy of the annotations for each species being studied. Although the rat genome is well annotated, and the number of unknown genes is extremely low, there is still the possibility that some transcripts are missed. In this study only a very limited number of false negative genes were identified, e. g. Cldn3. Nevertheless, this is a minor concern that can be rectified with future re-analysis if required when new annotations become available -outlining one of the strengths of high throughput RNA sequencing.
SAL, KMD and NRS are supported by the  National Health and Medical Research Council (Australia)  -Grant No. 567205. SAL, KMD, NRS, CJE, HB, H-CB, NS, J-FG-E are supported by the  European Union   Seventh Framework Program  ( FP7) Neurobid  consortium -Agreement No. HEALTH-F2-2009-241778 , KM was an advisor to the consortium. SAL was supported as a Neurological Fellow by the by the  American-Australian Association. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Results Homologous recombination and other DNA repair pathways are a hotspot for negative genetic interactions In order to assess the importance of within-pathway negative interactions we ranked all pathways from the KEGG database  [30]  according to their normalized proportion of negative interactions  [5]  within each KEGG pathway (Figure  2 ). This analysis confirms the previous conclusion  [19]  that only a minority of within-pathway negative interactions can be explained by negative interactions within a complex (Figure  1B3 ). In our analysis only 12% of all negative interactions were of this type (compared to 7% in  [19] ). Interestingly, HR ranks at the top with 27 within-pathway negative interactions between 20 KEGG pathway components (Figure  2 ), of which only a single one affects components of the same protein complex.
Reversibility of the pathway steps in homologous recombination pathway Figure  2. Normalized proportion of negative genetic interactions within one KEGG pathway. The proportion is related to the number of all possible pairwise interactions S(S21)/2, where S is the size of the KEGG pathway. Negative interactions between components of a molecular complex were excluded (compare the fourth and the fifth columns). We counted the normalized number of negative genetic interactions within one pathway using recent data on the genome-wide screening of genetic interactions in yeast from  [5] , using the most stringent filter on the epistasis measure e. Definitions of yeast signaling and metabolic pathways were taken from KEGG database  [30]. Only KEGG pathways with a normalized proportion of $1% are shown.
Acknowledgments We thank  J. Hall ,  M. -H. Stern ,  T. Popova ,  L. Calzone ,  R. Janke ,  S. Ceballos ,  C. Fasching ,  S. Kowalczykowski ,  M. Lichten  and  M. Savageau  for valuable comments on the manuscript. WDH thanks the  Institut Curie  and especially  Dr. Alain Nicolas  for the hospitality during his sabbatical stay.
Patients and Methods All patients provided written informed consent prior to enrolment. The protocol was approved by the Jules Bordet Institute's central ethics committee, and local ethics committees reviewed the protocol at each participating institution. The study was registered with the European Community's Drug Regulatory Authorities Clinical Trial System (EudraCT 2009-015521-36). The protocol for this trial and supporting CONSORT checklist are available as supporting information; see Checklist S1 and Protocol S1. Eligible patients included women with histologically confirmed pT1-pT2 or pT3 operable primary invasive breast cancer with no more than three positive nodes (defined as lymph node metastases >2mm) and absence of distant metastasis. Patients with multifocal tumors were eligible, provided that a sample from each tumor was taken for the GGI test.
Microarray analysis and GGI determination Central pathology review was performed on all tumor samples received at the central laboratory. The H&E slides received had to contain at least 30% of invasive tumor cells for further analysis. RNA was extracted and purified with the RNeasy MiniKit® according to the manufacturer's instructions (Qiagen). RNA was quantified and qualitatively assessed on triplicate samples on a NanoDrop® ND-1000 UV-Vis Spectrophotometer (NanoDrop Technologies, Wilmington, DE, USA) and Agilent 2100 Bioanalyzer (Agilent Technology, Santa Clara, CA). Samples with ≥ 100 ng and a RIN ≥ 7 were qualified for microarray analyses performed on Affymetrix U133 Plus 2. 0 arrays according to MapQuant Dx conditions (GEO accession number GSE43365). GGI was computed using the Ipsogen MapQuant Dx protocol (Table  S1 ), which defines tumors as low GGI (GG-1) or high GGI (GG-3), based on GGI values.
A performance evaluation of the SFSM MIMO system is also carried out considering a zero forcing (ZF) receiver and a semiblind alternating least squares (ALS) receiver that only requires a single pilot symbol per transmitted data stream in order to remove the scaling factor introduced by the estimation process. The remainder of this article is organized as follows. In Section 2, the main building blocks of the SFSM transmitter are detailed and the transmitted signal model is formulated. In Section 3, we present the received signal model and also derive the proposed unifying tensor model and its special cases. A ZF receiver with joint blockdecoding and equalization is formulated in Section 4. Section 5 is dedicated to the problem of joint symbolchannel-code estimation for the unified SFSM MIMO system, where bounds on the required numbers of transmit/receive antennas, subcarriers, spreading length, and the number of symbols per data stream are provided.
SFSM: transmitted signal model We consider the uplink of a single-cell multicarrier multiuser MIMO system with Q active co-channel users transmitting data across the same set of F subcarriers. Each user terminal is equipped with M t transmit antennas and transmits R data streams. The base station is equipped with M r receive antennas. The proposed SFSM transmission structure is composed of three main operations: (i) space spreading, (ii) frequency spreading, and (iii) space-frequency block-coding. Figure  1  depicts the block diagram of the transmitter structure by focusing on the transmission of the nth symbol of the rth data stream. For notational simplicity, we begin by limiting ourselves to a single-user transmission model in order to facilitate the presentation. Later on, we show that the multiuser signal model is readily obtained with minor changes in notation.
Semi-blind ALS receiver The goal of the base station receiver is to separate the co-channel transmissions while recovering the data transmitted by each user. In our proposed SFSM MIMO system, co-channel transmissions are represented by the R data streams accessing simultaneously the space, time, and frequency channel resources. We are interested in a semi-blind receiver that neither requires prior knowledge, or estimation, of channel and antenna array responses, nor relies on statistical independence between the transmitted signals. These properties are distinguishing features of the PARAFAC modeling and constitute the main motivation for using the unified tensor model. Moreover, the proposed receiver is called semi-blind in the sense that it relies only on a single pilot symbol inserted at the beginning of each data stream.