dataesr/scientific-paragraphs-categorization huggingface dataset:
, 2010a). This model was toned down by further analyses of the same dataset, which showed that YRE-O were as frequent as YRE-A in the promoters of CgYap1 targets  (Goudot et al. , 2011). Our ChIP-seq data unambiguously suggest that YRE-O is the preferred DNA binding site of CgYap1 and that the co-evolution scenario previously published has to be reconsidered. The discrepancy between these different studies may rely on the size of the genomic sequences which were used for TFBS predictions. Indeed previous ChIP-chip data provided peaks which were as wide as intergenic regions (800 base pairs in  Goudot et al. , 2011)  while the binding regions identified by our ChIP-seq analyses for CgYap1 were 300 base pairs in average, leading to a much more precise identification of the actual binding location of the transcription factor (Supplementary File S4).
Background: Reverse engineeringof gene regulatory networks (GRNs) from gene expression data is a classical challenge in systems biology. Thanks to high-throughput technologies, a massive amount of gene-expression data has been accumulated in the public repositories. Modelling GRNs from multiple experiments (also called integrative analysis) has; therefore, naturally become a standard procedure in modern computational biology. Indeed, such analysis is usually more robust than the traditional approaches, which suffer from experimental biases and the low number of samples by analysing individual datasets. To date, there are mainly two strategies for the problem of interest: the first one ("data merging") merges all datasets together and then infers a GRN whereas the other ("networks ensemble") infers GRNs from every dataset separately and then aggregates them using some ensemble rules (such as ranksum or weightsum).
Unfortunately, a thorough comparison of these two approaches is lacking. Results: In this work, we are going to present another meta-analysis approach for inferring GRNs from multiple studies. Our proposed meta-analysis approach, adapted to methods based on pairwise measures such as correlation or mutual information, consists of two steps: aggregating matrices of the pairwise measures from every dataset followed by extracting the network from the meta-matrix. Afterwards, we evaluate the performance of the two commonly used approaches mentioned above and our presented approach with a systematic set of experiments based on in silico benchmarks.
), Bayesian networks or even ensemble approaches (that combine several different approaches). Among those, mutual information (MI) based algorithms, such as CLR  [4] , ARACNE  [5] , MRNET  [6, 7]  and so on, gather more and more attention owing to their capability to deal with up to several thousands of variables in the presence of a limited number of samples  [7]. Generally, MI-based algorithms start by estimating a pairwise mutual information (i. e. a non-linear dependency measure) between all pairs of genes, resulting in a mutual information matrix (MIM). Afterwards, indirect interactions are eliminated from the MIM by the different approaches and subsequently a GRN is inferred. Since a single dataset has typically a small sample size (usually less than 200 observations) and suffers from potential experimental biases, classical reverse engineering algorithms, which relies only on a standalone dataset, show their limits in unravelling reliably underlying interactions.
By contrast, integrative analysis of multiple studies is able to increase significantly the statistical power and thus is becoming a standard procedure in modern computational biology  [8]. Nevertheless, the question of how to integrate data consistently and efficiently raises new challenges  [9]. In the mean time, meta-analysis strategies have been increasingly used for detecting differentially expressed genes from microarray data  [10]. In the meta-analysis approaches, each single dataset is analysed separately and then the final results are combined  [11]. Several strategies have been proposed in order to perform meta-analysis on expression data. For instance, a meta-analysis of public gene expression data and clinical data was conducted by using the concept of "coexpression" modules to reveal various results of previous gene expression studies in breast cancer  [12, 13].
In another research  [14] , Hong et al. developed a Bioconductor package RankProd that allow researchers to do metaanalysis under two experimental microarray conditions to identify differentially expressed genes. While the problem of detecting differentially expressed genes across several studies has been intensively studied, it is, however, not yet the case when it comes to constructing GRNs. To deal with the challenge of meta-network inference, there have been plenty of proposed methods, which can be divided into two main categories: "data merging" and "network ensemble". In the "data merging" approach, datasets are integrated at the expression level into a unique dataset, from which GRNs are inferred  [15] [16] [17]. However, one of the major problem of this approach is the removal of batch effects.
Indeed, the use of different platforms, and different methodologies by different research groups introduce statistical biases (batch effects) that can lead to incorrect conclusions  [18]. For example, it is known that normalization techniques, such as RMA  [19] , consisting in re-scaling gene expression values at the probe intensity level for Affymetrix data  [20] , is not able to remove batch effects. Consequently, batch removal methods, like COMBAT  [21] , is typically used before merging data  [18]. On the other hand, "ensemble" methods of merging GRNs from different datasets, i. e. by weighting gene-gene interactions according to their average rank in each network  [3] , have emerged as an alternative to the "data merging" approach. This approach rooted in the "wisdoms of crowds" concept, which was first introduced in the DREAM5 challenge and then further developed by  [22]  with the TopkNet algorithms to produce consensus networks.
In this paper, we also introduce a new meta-analysis strategy to build consensus networks. The new strategy consists in aggregating matrices of pairwise mutual information with each being estimated from a gene expression dataset to produce a meta-matrix, from which a GRN is inferred using classical information-theoretic network inference algorithms. Additionally, the paper presents the first thorough experimental comparison of these three "meta" approaches for the reconstruction of networks, namely "data merging", "network ensemble" and "coexpression matrices aggregation". The performances of these three sets of methods are evaluated using synthetic datasets from the standard Bioconductor netbenchmark package.
Data merging -D methods A straightforward approach for performing integrative analysis of multiple studies is combining all datasets together and then analysing the merged dataset. These method, named "data merging" and denoted here with the letter (D), were widely used in  [15] [16] [17]  to reconstruct large-scale GRNs because of their simplicity. However, since high dimensional data often suffers from unwanted biases, a variety of techniques can be used to correct for Fig. 1  Meta-network strategies: assembling datasets, pairwise matrices or networks these non-biological variations. We present in the following two classical scaling methods typically used to assemble datasets, and one batch-effect-removal method.
Normalization: BMC(D1) and z-score (D2) Let X be a matrix X m×n denoting the dataset of gene expression values. In this matrix, columns represent samples and rows represent genes, and x ij represents the expression value of gene i in sample j of dataset X. In  [24] , a normalization technique named BMC (Eq. 3) was applied for merging breast cancer datasets. xij = x ij -xi (3) Similarly, the z-score normalization  [25]  is described by Eq. 4 and was also included for evaluation. xij = x ij -xi σ x i (4).
Batch effects removal: COMBAT(D3) Gene expression datasets mostly come from different platforms and laboratories, causing the so-called batch effects. Consequently, batch removal methods, like COMBAT (also known as Empirical Bayes)  [21] , is often used to detect and remove this inevitable variation. COMBAT, which was shown to outperform other commonly used batch removal methods in some specific scenarios  [26] , uses estimations for the LS (location-scale) parameters (e. x. mean and variance) for each gene independently  [27]. The gene, afterwards, is adjusted to meet the estimated model. In this paper, combining datasets using the COMBAT algorithm will be included for comparison and referred as method D3.
Networks ensemble -N methods As we presented in the previous subsection, one of the difficulties of the data-merging methods is how to handle the batch effects. Consequently, "networks ensemble" method (denoted with the letter (N) in the paper) has been proposed as an alternative approach. In fact, by combining topologies of networks rather than datasets we are able to avoid dealing with batch effects. This method first constructs every single transcriptional networks independently before combining them to produce a so-called community network  [3]. In general, combining networks consists in two distinct steps: transformation and aggregation  [28]. Indeed, before assembling networks, a network-normalization step can be performed because it is common to observe networks that exhibit different distribution of edge weights.
Matrices of coexpression based aggregation approaches -M methods Our new category of meta-analysis approaches (denoted with the letter (M) in this paper) aggregates mutual information matrices rather than data or networks. The idea behind assembling pairwise matrices is that, although expression data typically shows high variability due to differences in technology, samples, labels, etc. , pairwise dependency measures between genes should be much less variant (i. e. dependent variables, such as a regulating variable and its regulated counterpart, should remain dependent in every platform/experiment/dataset even if ranges of values differ greatly). Thus, to infer a network from various expression data, our approach consists in combining mutual information matrices (MIMs) estimated independently from each dataset.
Random-effects model (M1) It should be noted that the problem of combining MIMs across multiple datasets can be framed in the context of a meta-analysis of correlation coefficients  [29]. Hunter and Schmidt  [30]  introduced a single random-effects method based on untransformed correlation coefficients, at which datasets are weighted simply by the sample sizes on which each effect size (the estimated MIM) is based. Our first weighting schema (method M1), described by Eq. 10, utilises this random-effects method, but using MI instead of correlations. ÎRE (X; Y ) = N k=1 n k I(X k ; Y k ) N k=1 n k  (10)  where I(X k ; Y k ) is the MI between two variable X k and Y k in the study k and n k is the number of samples of study k. The idea is simply that effect sizes based on large samples will be more precise than those based on small samples.
Median method (M3) One of the major issue of M1 is that the quality of datasets used in meta-analysis is not explicitly taken into account. Indeed, inclusion of poor quality datasets is likely to weaken statistical power  [10]. Thus, an alternative schema for combining MIMs across heterogeneous studies namely method M3 can be proposed. Method M3 is explained by formula 13, in which the aggregated MI of a gene pair X and Y is the median value of all MI values between them across all studies. ÎM (X, Y ) = median(I(X 1 , Y 1 ), I(X 2 , Y 2 ),. I(X N , Y N )) (13).
Simulated datasets There are two tasks one needs to consider in order to validate networks: 1) defining a "gold standard" -which is a set of true regulations describing the underlying interaction network, 2) selecting quantitative measures to statistically assess the quality of inferred networks. Typically, the first task is addressed by collecting well-known regulations mined from literature with strong supporting evidences. However, those regulations just cover a small part of the underlying network and therefore cannot be an ideal reference network to thoroughly compare methods. Hence the latter approach is often completed by in-silico experiments. In this paper, in silico benchmarks are selected from every one of the 4 biological networks and artificially generated datasets coming from the Netbenchmark Bioconductor package  [31].
The selected datasets are generated by two simulators namely GNW and SynTReN. The GNW simulator generates network structures by extracting parts of known real GRN structures capturing several of their important structural properties while the SynTReN simulator generates the underlying networks by selecting sub-networks from E. coli and Yeast organisms  [31]. The characteristics of the 4 biological networks are presented in more detail in Table  1. In the following step, each large dataset will be split into 6 sub-datasets with a number of experiments ranging between 30 to 300 (a number chosen randomly in order to simulate real case scenario where there is a variety of the number of samples). For example, in Fig. 2 , an original dataset is split into 6 sub-datasets with the following number of samples: 50, 100, 150, 120, 70 and 190.
Network prediction and validation for simulated datasets In order to make the network inference problem more challenging and realistic, noise and transformations of data are added. In particular, we define three levels of data-distortion: i ) Level 1: An independent lognormal noise call "global" noise, with intensity between 20 and 50%, is added to the first 6 datasets. The standard deviation of this noise (σ Global ) is the same for the whole dataset and is a percentage (κ g %) of the mean variance of all the genes in the dataset( σg ). It is defined as follows: σ Global;κ g % = σg U(0. 8κ,1. 2κ) 100. ii ) Level 2: In addition to the global noise, a normally distributed "local" noise with intensity also ranging between 20 and 50%, is added. This is an additive Gaussian noise with zero mean and a standard deviation (σ Local(g) ) that is around a percentage (κ%) of the gene standard deviation (σ g ).
Therefore, the Signal-to-Noise-Ratio(SNR) of each gene is similar. The local noise standard deviation can be formulated as follows: σ Local(g);κ% = σ g U(0. 8κ,1. 2κ) 100 where U(a, b) is a uniform distribution between a and b. iii ) Level 3: In addition to the two previous noises, each sub-dataset can be transformed using a randomly chosen non-linear transformation such as x 2 or log(x). This random data transformation is not really meant to be realistic but rather to allow us to better assess the behaviour of each meta-method when faced with extreme distortion. It is worth emphasizing that the two non-informative studies remain unchanged across all experiments. A flowchart of this process is illustrated in Fig. 2. The schema for network prediction and validation is also illustrated in Fig.
2. Initially, all methods (three D, M and N, totalling nine) are used to construct a consensus GRN from the split datasets. All methods are assessed on 12 challenges (three levels of distortion for four datasets). Finally, the process is repeated for the three information-theoretic inference methods, hence totalling 36 challenges. This is done to make sure that our analysis is not method specific. Given the ground-truth knowledge of the simulated data, traditional statistical error measures, such as F-score, AUCROC (Area Under the Receiver Operating Characteristic curve) or AUPR (Area Under the Precision-Recall curve) can be used to verify the quality of networks at the global-level  [32]. ROC curves, however, can present an overly optimistic view of an algorithm's performance if there is a large skew in the class distribution  [33] , which is generally the case in network inference because of its spareness.
Experimental results In this section, we present the experimental results of all presented methods for reconstructing GRNs from multiple expression datasets (Table  2 ). For the D family of methods, it can be observed that normalization using z-score transformation (D2) is better than BMC (D1). This conclusion is true for all three network inference algorithms used in this paper, namely MRNET, ARACNE and CLR. Another striking feature is that batch effect removal methods like COMBAT (D3) is able to increase significantly the robustness of network inference algorithms. The results reinforce the idea that normalization alone can not remove batch effects, and therefore the removal of batch effects is essential when merging datasets. In the case of method N, N2 and N3 outperform N1 when MRNET or CLR used.
However, in the case of using ARACNE, N1 is as good as N2 while poor results are observed for N3. Interestingly, we can clearly observe that N2 outperforms all three D methods suggesting that assembling networks is better than merging datasets. This could be explained by the fact that gene expression values are very dissimilar in various experiments due to our simulated batch effects (i. e. datasets with different global and local noise). However, the particular combination CLR -D3 offers an exception to this observation. It also should be noted that assembling mutual information matrices (M methods) surpasses the two other well-known strategies (D and N) for all datasets under every different levels of distortion, in particular for MRNET (see Figs. 3  and 4 ) and CLR. Experimental results also show that MRNET benefits the most from meta-analysis and CLR appears to be the most robust.
This suggests that while CLR might be a better strategy for analysing individual datasets, MRNET might be a better choice when multiple datasets are available. Although ARACNE appears to be much worse than the two other techniques, that is mainly due to a bad recall (though not visible with AUPR numbers, its precision remains quite competitive). Finally, in the M family of methods, it appears that combining MIM using random effect model (M1) is better than the two other strategies, the internal quality control index (M2) and the median method (M3).
Conclusion In the present paper, we proposed a framework for evaluating the different strategies for inferring GRNs from multiple expression datasets. To the best of our knowledge, this is the first systematic evaluation of the two state-of-the-art strategies for the problem of interest, namely "data merging" and "networks ensemble". Furthermore, we presented a new, but promising approach for methods based on coexpression matrices. Indeed, our set of experiments strongly suggest that assembling matrices of pairwise dependencies is a better strategy for network inference than the two commonly used ones. However, there exists many different methods of data and network assembly, as well as experimental conditions that have still to be tested in order to gain a complete understanding of the problem of meta-network inference.
Funding The present research benefited from the use of high performance computing resources ("durandal" grid computer) funded by three grants from the  University of Liège : ( SFRD-12/03 ,  SFRD-12/04 ,  C-14/73 ) as well as a  Crédit de Recherche of the FNRS  under award number nr 23678785. GB was supported by  GENGISCAN: GENomic profiling of Gastrointestinal Inflammatory-Sensitive CANcers , [http://mlg. ulb. ac. be/GENGISCAN]Belgian FNRS  PDR  project.
Acknowledgment Sciences ACO wishes to thank its long term partners whose support is essential to the running of the association: the LAL and SOLEIL laboratories; the  Paris-Sud University ; the department (Essonne) and the region (Ile-de-France); the two neighboring cities Bures-sur-Yvette and Orsay; finally, the  CNRS/IN2P3. The association would also like to thank the " Unité démantèlement de l'installation nucléaire de base 106 (LURE)" (UDIL)  for its help and support to run the Sciences ACO museum during the past decade.
Objectives: To review the pathophysiology, co-morbidities, and therapeutic options for psoriasis, psoriatic arthritis and rheumatoid arthritis in order to further understand the similarities and differences in treatment paradigms in the management of each disease. New targets for individualized therapeutic decisions are also identified with the aim of improving therapeutic outcome and reducing toxicity. Search strategy: Using the PubMed database, we searched literature published from 2000 to 2015 using combinations of the key words "psoriasis," "psoriatic arthritis," "rheumatoid arthritis," "pathogenesis," "immunomodulation," and "treatment. " Inclusion and exclusion criteria: This was a non-systematic review and there were no formal inclusion and exclusion criteria. Data extraction: Abstracts identified in the search were screened for relevance and articles considered appropriate evaluated further.
Literature search Using the PubMed database, we reviewed literature pertaining to the role of inflammation in the pathogenesis of psoriasis, psoriatic arthritis, and rheumatoid arthritis. We used different combinations of the key words "psoriasis," "psoriatic arthritis," "rheumatoid arthritis," together with "pathogenesis" or "immunomodulation," and with or without the key word "treatment. " An example of one such combination was (psoriasis OR psoriatic arthritis OR rheumatoid arthritis) AND (pathogenesis OR immunomodulation) together with either (…OR treatment) or (…AND treatment) according to response. Our search covered the period from 2000 to 2015, but the majority of the short-listed articles were published between 2005 and 2014. Abstracts were screened for relevance; as this was not a systematic review, no formal inclusion and exclusion criteria were applied-abstracts were short-listed for full review if the studies were considered well designed and the findings relevant.
Material and methods Studies of micro and macro morphological characters were carried out on field-collected and cultivated material of the newly collected specimens, by eye and with a Zeiss Stemi 2000c dissection microscope equipped with a Zeiss Axiocam MRc 5 digital camera and Zeiss Axio-Vision software (Carl Zeiss, Inc. , Thornwood, NY 10594 U. S. A. ). Preliminary observations suggested that the newly collected specimens were most closely affiliated to Henckelia walkerae. Thus, the newly collected material was compared specifically with herbarium specimens of this taxon. Molecular work followed  Mayer & al. (2003) ,  Möller & al. (2009 Möller & al. ( , 2011)) ,  Weber & al. (2011)  and  Samarakoon & al. (2013)  to obtain sequence data for the nuclear ribo somal internal transcribed spacer (ITS) region constituting ITS1, the 5.
walkerae var. parviflora. As noted by Stafleu & Cowan (1986: 342) the CP numbers of material distributed by Thwaites were not true collection numbers, the material stemming from various locations. We have located seven herbarium sheets in different herbaria bearing the number CP 542. Two sheets at W with the herbarium accession numbers 162356 and 65460, originally annotated as C. walkerae var. β under CP 542, had in 2014 been annotated as isotypes of C. walkerae by J. Walter (annotation numbers W-1889-0162356 and W-1889-0065460, respectively). Although these two specimens do not bear flowers, there are other important characters, such as leaf pubescence, lateral vein number, fruit length and leaf margin characteristics that are comparable with other specimens of CP 542. Hence, these specimens are better referred to C.