dataesr/scientific-paragraphs-categorization huggingface dataset:
) PCA was repeated for the ON and OFF groups separately. We manually identified clusters based on the projections onto the first three principal components; in this way we identified four functional types, including slow-OFF, fast-OFF, fast-ON, and slow-ON (see Fig. 2B ). Maximum likelihood estimation of linear-nonlinear models. To obtain spatio-temporal receptive fields (STRFs) for both white and exponentially correlated stimuli, we used publicly available code (strflab. berkeley. edu; [24] ) to carry out maximum likelihood estimation. We parameterized the model by a linear filter acting on the stimulus and a logistic nonlinearity, so that firing probability is p(s) = 1/(1 + exp(-g * (s -b))), where s represents the linear filter output, and g and b are gain and offset parameters. Gradient ascent with early stopping was used to compute a maximum likelihood estimate of the linear filter that best fit the data.
We initialized the algorithm for each neuron using the spike-triggered average recorded in response to white noise. Many cells do not yield clear receptive fields when probed with white noise, either because this stimulus does not evoke a sufficiently strong response or because the response is not well modeled as a single linear filter. To avoid potential artifacts that could arise from including such cells in our receptive field and model analyses, we selected cells whose receptive fields had clearly visible centers. This classification of receptive fields as high-quality was done before any other data analysis in order to avoid biasing the selection. In datasets where we obtained receptive fields for both white noise and a correlated stimulus the designations of high-quality agreed between the two stimuli for 98% of cells.
Microarray analysis Microarrays were processed when both the pretreatment and the post-treatment tissue sample had an adequate quality of RNA. We used Agilent long (60 bp) oligonucleotide microarrays and the dual color analysis method in which probes from two specimens are differentially labeled by incorporating Cyanine 5 and Cyanine 3, respectively. For each patient, the paired sample (before treatment and at relapse/progression) was cohybridized on Agilent dual color DNA chips. The results of the microarray analysis have been deposited on array-express (http://www. ebi. ac. uk/arrayexpress/, Experiment name: IGR_CamaraClayette_MCL; ArrayExpress accession: E-MTAB-1090); the details for journal/reviewer access are Username: Reviewer_E-MTAB-1090; and Password: ULK4aVie.
Effect of BMP7 mRNA inhibition on Bortezomib and Cytarabine cytotoxicity Jeko cells were transfected using a transient transfection assay with two BMP7 siRNAs (BMP7-4 and BMP7-3) or a nonsilencing siRNA as a control. At 48h and 72h post transfection with BMP7-4 siRNA, the mRNA levels of BMP-7 were reduced by 55 and 57% respectively and the expression of the protein at 72 hours (Figure  4 ). No direct effect on cell survival was observed neither with the BMP-7 siRNA nor with the nonsilencing siRNA at 48h and 72h after cell transfection. We next treated Jeko cells 24h or 48h after transfection with either Bortezomib (5 ng/ml) or Cytarabine (20 µg/ml) for 24 h. Drugs were given at their IC50 concentration on Jeko cells (data not shown). Apoptotic cells were quantified 48h and 72h Figure  1. Gene expression ratios were calculated for each gene in primary refractory (non-responders) and in responders (secondary resistant).
Background: Dynamic visualisation interfaces are required to explore the multiple microbial genome data now available, especially those obtained by high-throughput sequencinga. k. a. "Next-Generation Sequencing" (NGS)technologies; they would also be useful for "standard" annotated genomes whose chromosome organizations may be compared. Although various software systems are available, few offer an optimal combination of feature-rich capabilities, non-static user interfaces and multi-genome data handling. Results: We developed SynTView, a comparative and interactive viewer for microbial genomes, designed to run as either a web-based tool (Flash technology) or a desktop application (AIR environment). The basis of the program is a generic genome browser with sub-maps holding information about genomic objects (annotations).
The software is characterised by the presentation of syntenic organisations of microbial genomes and the visualisation of polymorphism data (typically Single Nucleotide Polymorphisms -SNPs) along these genomes; these features are accessible to the user in an integrated way. A variety of specialised views are available and are all dynamically inter-connected (including linear and circular multi-genome representations, dot plots, phylogenetic profiles, SNP density maps, and more). SynTView is not linked to any particular database, allowing the user to plug his own data into the system seamlessly, and use external web services for added functionalities. SynTView has now been used in several genome sequencing projects to help biologists make sense out of huge data sets.
Conclusions: The most important assets of SynTView are: (i) the interactivity due to the Flash technology; (ii) the capabilities for dynamic interaction between many specialised views; and (iii) the flexibility allowing various user data sets to be integrated. It can thus be used to investigate massive amounts of information efficiently at the chromosome level. This innovative approach to data exploration could not be achieved with most existing genome browsers, which are more static and/or do not offer multiple views of multiple genomes. Documentation, tutorials and demonstration sites are available at the URL: http://genopole. pasteur. fr/SynTView.
g. , HTML5) or because they are based on native desktop frameworks; however, these applications are mostly limited to the visualisation of one single or few genomes and/or to limited and particular types of data representation. Here, we present a novel software application -SynTViewproviding the user with substantial flexibility for comparative analysis of microbial genome information. Its originality stems from the combination of many features individually available in other applications: it is a web-based and desktop-capable Flash software; it offers highly interactive graphical user interfaces; it is designed for the visualisation, through many complementary perspectives, of both synteny relationships and DNA polymorphism data for multiple bacterial genomes. The SynTView software is therefore ideally suited to the exploration of data obtained in NGS-based population genomic studies.
Implementation The SynTView software was written in ActionScript 3 (AS3) language, using the Apache Software Foundation Flex framework  [30]  and the associated plug-in for the Eclipse™ Integrated Development Environment (IDE). This technology allows Adobe® Flash software to be built, providing dynamic presentations of complex data through either web browsers or desktop clients. Some interactive data visualisations were implemented using the Flare library  [31]. SynTView was built around the following rationale: n genomes should be compared with one reference genome (n can be as large as the computer memory will allow). Depending on the mode of access to the application (see below), genome data can be loaded either by the user using import functions (desktop client) or with the help of a software administrator (web configurationthe only requirement is this case is to place appropriately formatted flat files in the right directory).
These data can include complete annotated genomes and associated comparison files for synteny visualisation, or polymorphism data from NGS data sets. Currently, the accepted file formats are ptt (GenBank) for genome annotation, tabdelimited files for other information (protein correspondence, Single Nucleotide Polymorphisms -SNPs) and the Newick format for phylogenetic trees. The user can access the application in three different ways. First, a stand-alone client can be run using the Adobe desktop application cross-platform runtime AIR (Adobe Integrated Runtime), which will be installed automatically along with SynTView, if required. This allows the users to work with their own locally stored data. Alternatively, web access for multiple users can be implemented; in this configuration, SynTView uses flat files stored on the web server.
Finally, SynTView is available in combination with the GenoList integrated environment  [32] , a multi-genome microbial database accessible on the web, which houses 750 bacterial genomes  [33]. This option can exploit the comparative genome data precomputed in GenoList. Extensive performance tests have shown that the application reached technological limits if more than ten thousand dynamic graphical objects (i. e. , selectable and scalable objects) were used. Drawing strategies were thus developed to ensure that graphical outputs remain below this upper limit, using a mix of static and dynamic objects. For instance, SNP local maps come up with three display modes according to the density of polymorphic positions and the representation scale: (i) in the local view, SNP graphical objects remain interactive (i.
A generic genome browser The SynTView software is built as a generic genome browser including sub-maps that hold information about genomic objects (annotations, in the broad sense). After selecting genomes of interest, users can explore them visually by genomic location, or directly go to specific genes by name (auto-completion feature). Several genomic maps can be stacked on top of each other. The user can dynamically change their respective order, adjust the scale of the maps to use the full area of the screen, and zoom in and out. Organisms can be ordered according to their evolutionary relationships using a phylogenetic tree, whose branches can be graphically flipped. The user can also browse the pivot genome or the content of gene baskets through gene tables, with sorting functionalities and backward access to the graphical view.
Visualisation of synteny relationships The software can display synteny relationships between a reference genome and a set of related genomes. The synteny information is typically computed from the correspondence between proteins of different organisms (e. g. , Bi-Directional Best Hits -BDBHfrom all-against-all BLASTP reports  [34] ) and the conservation of ordering of associated genes along the genomes. Protein associations can be either externally computed by any method yielding compatible files (see Implementation section and the software documentation) or obtained from pre-computed comparative data in GenoList. To represent the synteny information, a colour is randomly assigned to every gene of the reference organism; the related genes in other genomes get the same colour as the reference gene whereas orphan genes remain in black.
Clicking on a gene shows its local synteny: the other genomes shift into alignment with the main sequence and the non-syntenic genes fade away. Protein multiple alignment, when available, can be visualised by clicking on the links between the corresponding genes: this redirects the user either to GenoList or to an external alignment web service. In addition to the local view, three global views are available. The dot plot shows synteny ruptures and chromosome re-arrangements; the matching genes can therefore be selected graphically and exported to a file. The line plot shows the organisation of syntenic groups at the chromosome level. The phylogenetic profile consists of a heat map of BLASTP hits sorted according to a phylogenetic tree. These views sport widgets for filtering the data display dynamically, according to criteria such as keywords, thresholds on BLAST reports, or the content of user-defined gene baskets.
Visualisation of polymorphism information The second specialised module of SynTView is designed to visualise information about polymorphism across a large number of bacterial strains. Such data are typically obtained by population genomics studies involving highthroughput genome (re)sequencing of a collection of isolates. SNPs are the most frequently represented data. They must be determined independently from the SynTView software, and formatted according to the documentation. We have developed our own procedures for computing such data; these procedures allow fine tuning of a large number of parameters for SNP identification, and are available together with the SynTView software. The SNPs are computed and represented using a reference genome, to which n related strains are compared. The SNP maps allow the user to navigate through polymorphism data sets, in which SNPs are mutually linked to cognate genes (e.
Discussion The software features described in this paper illustrate only some of the main capabilities of the SynTView application. A full list of its functionalities is available in Additional file 1. One of the main strengths of SynTView lies in its highly interactive graphical user interface, possible due to the Flash technology used to develop the software. This technology is increasingly exploited by comparative genomics applications  [21, [36] [37] [38]. It allows the development of rich Internet (or client) applications, which escape the limitations faced by standard HTML websites. Flash also provides advantages similar to or greater than those of other technologies (e. g. , JavaScript and SVG): the Flash plug-in is installed out-of-the-box on most computers and it is fully portable across different web browsers.
Although HTML5 is becoming more and more popular on the world-wide web, including for genomics applications (e. g. ,  [39] ), it is currently less crosscompatible among web browsers than Flash and mostly limited to playing videos and animations, rather than rich Internet applications; indeed, development environments and resources are still far more efficient when using Flash/Flex (e. g. , the object serialisation protocol AMF3 in ActionScript/MXML) than using HTML5. In addition, the Flash strategy allows us to propose a web access and a client application (AIR environment) simultaneously. Thus, we have created a versatile solution that offers the best of both worlds: a desktop program that can easily be installed by a non-expert user, providing direct access to his local storage and file systems, without needing an IT infrastructure to deploy complex web architectures; but also, a browser application that may be more intuitive for some users and allows several people to access a single instance of the software, while retaining many of the characteristics of desktop-like programs.
Note that SynTView is not intended for data generation: the software is focused on the dynamic exploration of genome data produced externally. In particular, SynTView is not linked to any particular database, which allows the generation of plain text files that the application will interpret and subsequently represent (thus easily integrating the user's own data) or the exploitation of other sources of information, such as the GenoList environment. SynTView was designed to be extremely fast, and sports a user-friendly interface that is straightforward to use for biologists accustomed to graphical widgets. In particular, data exploration is facilitated by the possibility of connecting several views: indeed, in both the synteny and SNP visualisations, the various representations are interactively linked together, and a user selection (e.
making sense out of large and complex data sets, in a way that is not available in most similar software, even if individual analogous views can be found (see below). For example, interesting areas of the chromosome may be observed (e. g. , recombination, inversion) using the line plot representation; it is possible to zoom in on these regions, then select the corresponding BDBH to export them, or shift with one mouse click to the local view to analyse the region in more detail. The export functionalities offered by SynTView are also appropriate for further analysis, once an initial exploration has identified the data sets to be selected. The images generated by the software can be saved in PNG format and subsequently used in reports or publications. Numerous applications are already available for visualising comparative genomics data from microbial species, but we believe that SynTView fills a gap and is more complete: it is a flexible software package, compatible with various computing environments, and uniquely integrates complementary features present, in isolation, in similar tools.
For instance, the CGAT Java alignment viewer  [28]  and the GSV web package  [23]  are efficient for syntenic visualisations, but are restricted to pairwise genome comparisons. Likewise, MizBee  [19]  implements an innovative multi-scale synteny browser that enables interactive exploration of various kinds of relationships, but only between two multi-chromosome genomes at a time. The Cinteny  [25]  and Genomicus  [18]  web sites are primarily designed for metazoa; Genomicus focuses on ancestral genome reconstruction and Cinteny provides on-the-fly computed, but non-interactive, synteny views. CGView  [14]  and Easyfig  [26]  are highly customisable packages for producing publication-quality, but static-only, figures; the GView  [22]  Java application is more interactive but mainly focused on the display style configuration.
Companion tools to the popular genome browser GBrowse, such as SynBrowse  [20]  and SynView  [29] , also offer interactivity albeit limited. Circos  [17]  and BRIG  [7] , available as desktop applications, are mostly restricted to static (circular) views. GenomeRing  [15]  has an interactive web interface for visualising multiple circular genome alignments, based on an original concept of a common annotation coordinate system. Gobe  [21]  is a web-based Flash application, hence very dynamic, but it is limited to synteny information. Although the Mauve  [11]  and VISTA  [13]  packages come with useful Java visualisation interfaces, they are primarily dedicated to whole genome alignments. The MGV  [16]  and Sybil  [24]  suites are feature-rich web-only applications for the interactive visualisation of microbial genomic contexts, but these software do not include nucleotide polymorphism information.
More recent software were developed especially to handle NGS data sets, although most do not focus on the representation of processed biodiversity information for large collections of microbial strains. They include: IGV  [27]  and Savant  [12]  which are both widely used; and GenomeView  [6]  which is a feature-rich stand-alone genome browser able to cope with dozens of "NGS" genomes, but which lacks integrated circular representations. The latest version of Artemis  [8] , an established annotation tool, in association with ACT  [10]  and DNAPlotter  [9] , provides the user with a large set of comparative views, some of them being dedicated to bacterial population genomics studies. Together, these three Java applications probably come closest to matching the features provided by SynTView.
First, we plan to increase the scope of the software by accommodating other types of data. In particular, SynTView should enable the management of incomplete genomes for synteny representations. For NGS, we also intend to design novel views for RNA-seq data (such as expression levels or transcription start sites) and to improve the SNP representation such that it can handle multiploid organisms. As far as end-user interactions are concerned, improvements will include features such as the ability to save selected views and gene baskets in a permanent way.
Conclusions We have developed software for the dynamic visualisation of microbial genomes, such that both synteny and DNA polymorphism can be displayed. The most important asset of SynTView is its interactivity, inherent to the use of the Flash technology. In addition, several properties of the application facilitate efficient investigation of large data sets at the chromosome scale: for instance, its flexibility for establishing links with various user data sets and the dynamic interactions between the numerous specialised views. This innovative approach to data exploration is not possible with most existing applications, because they are more static and/or do not offer multiple views of multiple genomes. Figure  3  Exploration of bacterial population genomics data. A: SynTView representation of SNP heat maps along 62 genomes of Staphylococcus aureus ordered using a dynamic phylogenetic tree; the colours represent the frequency of SNP occurrence among the strains (from specific to one strain, to shared by all strains).
B: Similar representation using the same data, reproduced from reference  [41]. runtime is pre-installed in most web browsers, the application can run without any further installation. Technical documentation, tutorials and demonstration sites are available at the following URL: <http://genopole. pasteur. fr/ SynTView/documentation>. Project name: SynTView Project home page: http://genopole. pasteur. fr/SynTView Operating system(s): Platform independent Programming language: ActionScript 3 Other requirements: Adobe W Flash Player License: GNU LGPL 3. 0 Any restrictions to use by non-academics: none.
Acknowledgements and funding We thank  Nicolas Beaume ,  Caroline Boursaux-Eude ,  Violette Da Cunha ,  Stéphane Descorps-Declère  and other members of the  Bioanalyse Génomique platform  for testing and making suggestions about the graphical user interface. We are grateful to  Philippe Glaser  for comments on the software and the manuscript, and to  Annie Etienne  for careful proofreading of the manuscript. We thank our fellow biologists who used the application and provided some feedback. This work was supported by  Institut Pasteur  and grants from the  Région Ile-de-France (DIM Malinf) , the  Agence Nationale de la Recherche  ( ANR-08-GENM-027 ) and the  French Government 's  Investissements d'Avenir program  ( Laboratoire d'Excellence "Integrative Biology of Emerging Infectious Diseases " - ANR-10-LABX-62-IBEID ).
Co-immunoprecipitation Cells (2 L) in mid-exponential phase culture (OD 600 = 0. 8) were recovered by centrifugation, suspended in 0. (27)  and analyzed by western blotting. Membranes were probed with mouse 12CA5 anti-HA monoclonal antibodies and rabbit anti-Pol I polyclonal antibodies  (26)  for the detection of Rrn3 and Pol I, respectively. Immunocomplexes were detected with secondary antibodies conjugated to infrared dyes, scanned and analyzed with the Odyssey imaging system and its associated software (Li-Cor).
Interestingly, the same level of repression was observed in the presence of Ag + or Hg 2+ when the PP2A function was altered by disruption of the TPD3 gene (Figure  5A ). This result demonstrates that, WT and ÁTPD3 cells containing a HA-tagged version of Rrn3 were grown in YPD medium to 0. 8 OD 600 at 30 C, then Cd 2+ -treated (50 mM) for 30 min or not. HA-Rrn3 was immunoprecipitated from crude extracts with magnetic beads coated with anti-HA. After washing, bound proteins were eluted and analyzed by western blotting. Membranes were probed with anti-HA and anti-Pol I antibodies for the detection of Rrn3 (upper panel) and Pol I (lower panel), respectively. Immunocomplexes were detected with secondary antibodies conjugated to infrared dyes, scanned and analyzed with the Odyssey imaging system and its associated software (Li-Cor).