Revisiting Date and Party Hubs: Novel Approaches to Role Assignment in Protein Interaction Networks

The idea of 'date' and 'party' hubs has been influential in the study of protein-protein interaction networks. Date hubs display low co-expression with their partners, whilst party hubs have high co-expression. It was proposed that party hubs are local coordinators whereas date hubs are global connectors. Here we show that the reported importance of date hubs to network connectivity can in fact be attributed to a tiny subset of them. Crucially, these few, extremely central, hubs do not display particularly low expression correlation, undermining the idea of a link between this quantity and hub function. The date/party distinction was originally motivated by an approximately bimodal distribution of hub co-expression; we show that this feature is not always robust to methodological changes. Additionally, topological properties of hubs do not in general correlate with co-expression. Thus, we suggest that a date/party dichotomy is not meaningful and it might be more useful to conceive of roles for protein-protein interactions rather than individual proteins. We find significant correlations between interaction centrality and the functional similarity of the interacting proteins.Comment: 27 pages, 5 main figures, 4 supplementary figure

Influence of degree correlations on network structure and stability in protein-protein interaction networks

<p>Abstract</p> <p>Background</p> <p>The existence of negative correlations between degrees of interacting proteins is being discussed since such negative degree correlations were found for the large-scale <it>yeast </it>protein-protein interaction (PPI) network of Ito et al. More recent studies observed no such negative correlations for high-confidence interaction sets. In this article, we analyzed a range of experimentally derived interaction networks to understand the role and prevalence of degree correlations in PPI networks. We investigated how degree correlations influence the structure of networks and their tolerance against perturbations such as the targeted deletion of hubs.</p> <p>Results</p> <p>For each PPI network, we simulated uncorrelated, positively and negatively correlated reference networks. Here, a simple model was developed which can create different types of degree correlations in a network without changing the degree distribution. Differences in static properties associated with degree correlations were compared by analyzing the network characteristics of the original PPI and reference networks. Dynamics were compared by simulating the effect of a selective deletion of hubs in all networks.</p> <p>Conclusion</p> <p>Considerable differences between the network types were found for the number of components in the original networks. Negatively correlated networks are fragmented into significantly less components than observed for positively correlated networks. On the other hand, the selective deletion of hubs showed an increased structural tolerance to these deletions for the positively correlated networks. This results in a lower rate of interaction loss in these networks compared to the negatively correlated networks and a decreased disintegration rate. Interestingly, real PPI networks are most similar to the randomly correlated references with respect to all properties analyzed. Thus, although structural properties of networks can be modified considerably by degree correlations, biological PPI networks do not actually seem to make use of this possibility.</p

GIBA: a clustering tool for detecting protein complexes

Background: During the last years, high throughput experimental methods have been developed which generate large datasets of protein - protein interactions (PPIs). However, due to the experimental methodologies these datasets contain errors mainly in terms of false positive data sets and reducing therefore the quality of any derived information. Typically these datasets can be modeled as graphs, where vertices represent proteins and edges the pairwise PPIs, making it easy to apply automated clustering methods to detect protein complexes or other biological significant functional groupings. Methods: In this paper, a clustering tool, called GIBA (named by the first characters of its developers' nicknames), is presented. GIBA implements a two step procedure to a given dataset of protein-protein interaction data. First, a clustering algorithm is applied to the interaction data, which is then followed by a filtering step to generate the final candidate list of predicted complexes. Results: The efficiency of GIBA is demonstrated through the analysis of 6 different yeast protein interaction datasets in comparison to four other available algorithms. We compared the results of the different methods by applying five different performance measurement metrices. Moreover, the parameters of the methods that constitute the filter have been checked on how they affect the final results. Conclusion: GIBA is an effective and easy to use tool for the detection of protein complexes out of experimentally measured protein - protein interaction networks. The results show that GIBA has superior prediction accuracy than previously published methods

Topological Structure of the Space of Phenotypes: The Case of RNA Neutral Networks

The evolution and adaptation of molecular populations is constrained by the diversity accessible through mutational processes. RNA is a paradigmatic example of biopolymer where genotype (sequence) and phenotype (approximated by the secondary structure fold) are identified in a single molecule. The extreme redundancy of the genotype-phenotype map leads to large ensembles of RNA sequences that fold into the same secondary structure and can be connected through single-point mutations. These ensembles define neutral networks of phenotypes in sequence space. Here we analyze the topological properties of neutral networks formed by 12-nucleotides RNA sequences, obtained through the exhaustive folding of sequence space. A total of 412 sequences fragments into 645 subnetworks that correspond to 57 different secondary structures. The topological analysis reveals that each subnetwork is far from being random: it has a degree distribution with a well-defined average and a small dispersion, a high clustering coefficient, and an average shortest path between nodes close to its minimum possible value, i.e. the Hamming distance between sequences. RNA neutral networks are assortative due to the correlation in the composition of neighboring sequences, a feature that together with the symmetries inherent to the folding process explains the existence of communities. Several topological relationships can be analytically derived attending to structural restrictions and generic properties of the folding process. The average degree of these phenotypic networks grows logarithmically with their size, such that abundant phenotypes have the additional advantage of being more robust to mutations. This property prevents fragmentation of neutral networks and thus enhances the navigability of sequence space. In summary, RNA neutral networks show unique topological properties, unknown to other networks previously described

A randomized, controlled clinical trial: the effect of mindfulness-based cognitive therapy on generalized anxiety disorder among Chinese community patients: protocol for a randomized trial

&lt;b&gt;Background&lt;/b&gt; Research suggests that an eight-week Mindfulness-Based Cognitive Therapy (MBCT) program may be effective in the treatment of generalized anxiety disorders. Our objective is to compare the clinical effectiveness of the MBCT program with a psycho-education programme and usual care in reducing anxiety symptoms in people suffering from generalized anxiety disorder.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods and Design&lt;/b&gt; A three armed randomized, controlled clinical trial including 9-month post-treatment follow-up is proposed. Participants screened positive using the Structure Clinical Interview for DSM-IV (SCID) for general anxiety disorder will be recruited from community-based clinics. 228 participants will be randomly allocated to the MBCT program plus usual care, psycho-education program plus usual care or the usual care group. Validated Chinese version of instruments measuring anxiety and worry symptoms, depression, quality of life and health service utilization will be used. Our primary end point is the change of anxiety and worry score (Beck Anxiety Inventory and Penn State Worry Scale) from baseline to the end of intervention. For primary analyses, treatment outcomes will be assessed by ANCOVA, with change in anxiety score as the baseline variable, while the baseline anxiety score and other baseline characteristics that significantly differ between groups will serve as covariates.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Discussion&lt;/b&gt; This is a first randomized controlled trial that compare the effectiveness of MBCT with an active control, findings will advance current knowledge in the management of GAD and the way that group intervention can be delivered and inform future research

Markov clustering versus affinity propagation for the partitioning of protein interaction graphs

<p>Abstract</p> <p>Background</p> <p>Genome scale data on protein interactions are generally represented as large networks, or graphs, where hundreds or thousands of proteins are linked to one another. Since proteins tend to function in groups, or complexes, an important goal has been to reliably identify protein complexes from these graphs. This task is commonly executed using clustering procedures, which aim at detecting densely connected regions within the interaction graphs. There exists a wealth of clustering algorithms, some of which have been applied to this problem. One of the most successful clustering procedures in this context has been the Markov Cluster algorithm (MCL), which was recently shown to outperform a number of other procedures, some of which were specifically designed for partitioning protein interactions graphs. A novel promising clustering procedure termed Affinity Propagation (AP) was recently shown to be particularly effective, and much faster than other methods for a variety of problems, but has not yet been applied to partition protein interaction graphs.</p> <p>Results</p> <p>In this work we compare the performance of the Affinity Propagation (AP) and Markov Clustering (MCL) procedures. To this end we derive an unweighted network of protein-protein interactions from a set of 408 protein complexes from <it>S. cervisiae </it>hand curated in-house, and evaluate the performance of the two clustering algorithms in recalling the annotated complexes. In doing so the parameter space of each algorithm is sampled in order to select optimal values for these parameters, and the robustness of the algorithms is assessed by quantifying the level of complex recall as interactions are randomly added or removed to the network to simulate noise. To evaluate the performance on a weighted protein interaction graph, we also apply the two algorithms to the consolidated protein interaction network of <it>S. cerevisiae</it>, derived from genome scale purification experiments and to versions of this network in which varying proportions of the links have been randomly shuffled.</p> <p>Conclusion</p> <p>Our analysis shows that the MCL procedure is significantly more tolerant to noise and behaves more robustly than the AP algorithm. The advantage of MCL over AP is dramatic for unweighted protein interaction graphs, as AP displays severe convergence problems on the majority of the unweighted graph versions that we tested, whereas MCL continues to identify meaningful clusters, albeit fewer of them, as the level of noise in the graph increases. MCL thus remains the method of choice for identifying protein complexes from binary interaction networks.</p

Fast Computing Betweenness Centrality with Virtual Nodes on Large Sparse Networks

Betweenness centrality is an essential index for analysis of complex networks. However, the calculation of betweenness centrality is quite time-consuming and the fastest known algorithm uses time and space for weighted networks, where and are the number of nodes and edges in the network, respectively. By inserting virtual nodes into the weighted edges and transforming the shortest path problem into a breadth-first search (BFS) problem, we propose an algorithm that can compute the betweenness centrality in time for integer-weighted networks, where is the average weight of edges and is the average degree in the network. Considerable time can be saved with the proposed algorithm when , indicating that it is suitable for lightly weighted large sparse networks. A similar concept of virtual node transformation can be used to calculate other shortest path based indices such as closeness centrality, graph centrality, stress centrality, and so on. Numerical simulations on various randomly generated networks reveal that it is feasible to use the proposed algorithm in large network analysis

Inferring topology from clustering coefficients in protein-protein interaction networks

BACKGROUND: Although protein-protein interaction networks determined with high-throughput methods are incomplete, they are commonly used to infer the topology of the complete interactome. These partial networks often show a scale-free behavior with only a few proteins having many and the majority having only a few connections. Recently, the possibility was suggested that this scale-free nature may not actually reflect the topology of the complete interactome but could also be due to the error proneness and incompleteness of large-scale experiments. RESULTS: In this paper, we investigate the effect of limited sampling on average clustering coefficients and how this can help to more confidently exclude possible topology models for the complete interactome. Both analytical and simulation results for different network topologies indicate that partial sampling alone lowers the clustering coefficient of all networks tremendously. Furthermore, we extend the original sampling model by also including spurious interactions via a preferential attachment process. Simulations of this extended model show that the effect of wrong interactions on clustering coefficients depends strongly on the skewness of the original topology and on the degree of randomness of clustering coefficients in the corresponding networks. CONCLUSION: Our findings suggest that the complete interactome is either highly skewed such as e.g. in scale-free networks or is at least highly clustered. Although the correct topology of the interactome may not be inferred beyond any reasonable doubt from the interaction networks available, a number of topologies can nevertheless be excluded with high confidence

Unveiling Protein Functions through the Dynamics of the Interaction Network

Protein interaction networks have become a tool to study biological processes, either for predicting molecular functions or for designing proper new drugs to regulate the main biological interactions. Furthermore, such networks are known to be organized in sub-networks of proteins contributing to the same cellular function. However, the protein function prediction is not accurate and each protein has traditionally been assigned to only one function by the network formalism. By considering the network of the physical interactions between proteins of the yeast together with a manual and single functional classification scheme, we introduce a method able to reveal important information on protein function, at both micro- and macro-scale. In particular, the inspection of the properties of oscillatory dynamics on top of the protein interaction network leads to the identification of misclassification problems in protein function assignments, as well as to unveil correct identification of protein functions. We also demonstrate that our approach can give a network representation of the meta-organization of biological processes by unraveling the interactions between different functional classes