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Background: Connecting genes to phenotypes is still a great challenge in genetics. Research related to gene-phenotype associations has made remarkable progress recently due to high-throughput sequencing technology and genome-wide association study (GWAS). However, these genes, which are considered to be significantly associated with a target phenotype according to traditional GWAS, are less precise or subject to greater confounding. Objective: The present study is an attempt to prioritize functional genes for complex phenotypes employing protein-protein interaction (PPI) network-based systems genetics methods on available GWAS results. Methods: In this paper, we calculated the functional gene enrichment ratios of the trait ontology of A. thaliana for three common systems genetics methods (i.e. GeneRank, K-shell and HotNet2). Then, comparison of gene enrichment ratios obtained by PPI network-based methods was performed. Finally, a hybrid model was proposed, integrating GeneRank, comprehensive score algorithm and HotNet diffusion- oriented subnetworks (HotNet2) to prioritize functional genes. Results: These PPI network-based systems genetics methods were indeed useful for prioritizing 775henoltype-associated genes. And functional gene enrichment ratios calculated from the top 20% of GeneRank-identified genes were higher than these ratios of K-shell and these ratios of HotNet2 for most phenotypes. However, the hybrid model can improve the efficiency of functional gene enrichment for A. thaliana (up to 40%). Conclusion: The present study provides a hybrid method integrating GeneRank, comprehensive score algorithm and HotNet2 to prioritize functional genes. The method will contribute to functional genomics in plants. The source data and codes are freely available at http://47.242.161.60/Plant/.

We consider the problem of identifying the induced star with the largest cardinality open neighborhood in a graph. This problem, also known as the star degree centrality (SDC) problem, is shown to be [Formula: see text]-complete. In this work, we first propose a new integer programming (IP) formulation, which has a smaller number of constraints and nonzero coefficients in them than the existing formulation in the literature. We present classes of networks in which the problem is solvable in polynomial time and offer a new proof of [Formula: see text]-completeness that shows the problem remains [Formula: see text]-complete for both bipartite and split graphs. In addition, we propose a decomposition framework that is suitable for both the existing and our formulations. We implement several acceleration techniques in this framework, motivated by techniques used in Benders decomposition. We test our approaches on networks generated based on the Barabási–Albert, Erdös–Rényi, and Watts–Strogatz models. Our decomposition approach outperforms solving the IP formulations in most of the instances in terms of both solution time and quality; this is especially true for larger and denser graphs. We then test the decomposition algorithm on large-scale protein–protein interaction networks, for which SDC is shown to be an important centrality metric. Summary of Contribution: In this study, we first introduce a new integer programming (NIP) formulation for the star degree centrality (SDC) problem in which the goal is to identify the induced star with the largest open neighborhood. We then show that, although the SDC can be efficiently solved in tree graphs, it remains [Formula: see text]-complete in both split and bipartite graphs via a reduction performed from the set cover problem. In addition, we implement a decomposition algorithm motivated by Benders decomposition together with several acceleration techniques to both the NIP formulation and the existing formulation in the literature. Our experimental results indicate that the decomposition implementation on the NIP is the best solution method in terms of both solution time and quality.

Protein–protein interaction (PPI) networks represent complex intra-cellular protein interactions, and the presence or absence of such interactions can lead to biological changes in an organism. Recent network-based approaches have shown that a phenotype’s PPI network’s resilience to environmental perturbations is related to its placement in the tree of life; though we still do not know how or why certain intra-cellular factors can bring about this resilience. Here, we explore the influence of gene expression and network properties on PPI networks’ resilience. We use publicly available data of PPIs for E. coli, S. cerevisiae, and H. sapiens, where we compute changes in network resilience as new nodes (proteins) are added to the networks under three node addition mechanisms—random, degree-based, and gene-expression-based attachments. By calculating the resilience of the resulting networks, we estimate the effectiveness of these node addition mechanisms. We demonstrate that adding nodes with gene-expression-based preferential attachment (as opposed to random or degree-based) preserves and can increase the original resilience of PPI network in all three species, regardless of gene expression distribution or network structure. These findings introduce a general notion of prospective resilience, which highlights the key role of network structures in understanding the evolvability of phenotypic traits., Brennan Klein et al. propose an adapted network resilience measure, the prospective resilience (PR), to explore the resilience of protein–protein interaction networks following addition of new nodes. They apply PR to public datasets and find that resilience of a network is maximized when attachment of new nodes, or proteins, is based on the gene expression levels of the existing proteins in the network.

Protein complexes are one most important kind of functional modules for biological processes in cells. In this regard, their detection is vital for understanding the principle of cell organization and function. A variety of clustering algorithms have been developed to detect protein complexes from protein-protein interaction (PPI) networks. However, most of them are based on a certain clustering criterion. Given the fact that proteins should interact with each other rather than act independently, we reason that clustering upon interactions can better characterize protein complexes than upon proteins, thus improving the detection accuracy. To this end, a link-based clustering algorithm has been proposed in this paper to effectively detect overlapping protein complexes. It first measures the similarity between pairwise interactions from the perspectives of network topology and Gene Ontology. The problem of protein complex detection is then formulated as an optimization problem of link-based clustering, which is resolved by the proposed algorithm. This proposed algorithm explores the intrinsic correlation between protein complexes and interactions for detecting functionally significant protein complexes. Experimental results on five independent PPI datasets demonstrate that compared with state-of-the-art algorithms, the proposed algorithm has significantly improved the detection accuracy for protein complexes

Graphical abstract, Highlights • Provided a family of efficient network algorithms for protein complex identification. • The parameter-free family outperforms existing approaches on different networks. • It exactly recovered ~ 35% of protein complexes in a pan-plant PPI network. • We examined of network perturbations on predicted protein complexes., Identification of protein complexes from protein-protein interaction (PPI) networks is a key problem in PPI mining, solved by parameter-dependent approaches that suffer from small recall rates. Here we introduce GCC-v, a family of efficient, parameter-free algorithms to accurately predict protein complexes using the (weighted) clustering coefficient of proteins in PPI networks. Through comparative analyses with gold standards and PPI networks from Escherichia coli, Saccharomyces cerevisiae, and Homo sapiens, we demonstrate that GCC-v outperforms twelve state-of-the-art approaches for identification of protein complexes with respect to twelve performance measures in at least 85.71% of scenarios. We also show that GCC-v results in the exact recovery of ∼35% of protein complexes in a pan-plant PPI network and discover 144 new protein complexes in Arabidopsis thaliana, with high support from GO semantic similarity. Our results indicate that findings from GCC-v are robust to network perturbations, which has direct implications to assess the impact of the PPI network quality on the predicted protein complexes.

Background: Research has shown that essential proteins play important roles in the development and survival of organisms. Because of the high costs of traditional biological experiments, several computational prediction methods based on known protein-protein interactions (PPIs) have been recently proposed to detect essential proteins. Objective: Here, a novel prediction model called IoMCD is proposed to identify essential proteins by combining known PPIs with a variety of biological information about proteins, including gene expression data and homologous information of proteins. Methods: Compared to the traditional state-of-the-art prediction models, IoMCD involves two kinds of weights that are obtained, respectively, by extracting topological features of proteins from the original known protein–protein interaction (PPI) networks and calculating the Pearson correlation coefficients (PCCs) between the gene expression data of proteins. Based on these two kinds of weights and adopting a cross-entropy method, a unique weight is assigned to each protein. Subsequently, the homologous information of proteins is used to calculate an initial score for each protein. Finally, based on the unique weights and initial score of proteins, an iterative method is designed to measure the essentialities of proteins. Results: Intensive experiments were performed, and simulation results showed that the prediction accuracy of IoMCD, based on the dataset downloaded from the DIP and Gavin databases, was 92.16% and 89.71%, respectively, in the top 1% of the predicted essential proteins. Conclusion: Both simulation results demonstrated that IoMCD can achieve excellent prediction accuracy and could be an effective method for essential protein prediction.

Copy number variation (CNV) is a major type of chromosomal structural variation that play important roles in many diseases including cancers. Due to genome instability, a large number of CNV events can be detected in diseases such as cancer. Therefore, it is important to identify the functionally important CNVs in diseases, which currently still poses a challenge in genomics. One of the critical steps to solve the problem is to define the influence of CNV. In this paper, we provide a topology potential based method, TPQCI, to quantify this kind of influence by integrating statistics, gene regulatory associations, and biological function information. We used this metric to detect functionally enriched genes on genomic segments with CNV in breast cancer and multiple myeloma and discovered biological functions influenced by CNV. Our results demonstrate that, by using our proposed TPQCI metric, we can detect disease-specific genes that are influenced by CNVs. Source codes of TPQCI are provided in Github (https://github.com/usos/TPQCI).

Background Recent advances in simultaneous measurement of RNA and protein abundances at single-cell level provide a unique opportunity to predict protein abundance from scRNA-seq data using machine learning models. However, existing machine learning methods have not considered relationship among the proteins sufficiently. Results We formulate this task in a multi-label prediction framework where multiple proteins are linked to each other at the single-cell level. Then, we propose a novel method for single-cell RNA to protein prediction named PIKE-R2P, which incorporates protein–protein interactions (PPI) and prior knowledge embedding into a graph neural network. Compared with existing methods, PIKE-R2P could significantly improve prediction performance in terms of smaller errors and higher correlations with the gold standard measurements. Conclusion The superior performance of PIKE-R2P indicates that adding the prior knowledge of PPI to graph neural networks can be a powerful strategy for cross-modality prediction of protein abundances at the single-cell level.

Objective: It is a known fact that numerous complex disorders do not happen in isolation indicating the plausible set of shared causes common to several different sicknesses. Hence, analysis of comorbidity can be utilized to explore the association between several disorders. In this study, we have proposed a network-based computational approach, in which genes are organized based on the topological characteristics of the constructed Protein-Protein Interaction Network (PPIN) followed by a network prioritization scheme, to identify distinctive key genes and biological pathways shared among diseases. Methods: The proposed approach is initiated from constructed PPIN of any randomly chosen disease genes in order to infer its associations with other diseases in terms of shared pathways, coexpression, co-occurrence etc. For this, initially, proteins associated to any disease based on random choice were identified. Secondly, PPIN is organized through topological analysis to define hub genes. Finally, using a prioritization algorithm a ranked list of newly predicted multimorbidity-associated proteins is generated. Using Gene Ontology (GO), cellular pathways involved in multimorbidity-associated proteins are mined. Result and Conclusion: : The proposed methodology is tested using three disorders, namely Diabetes, Obesity and blood pressure at an atomic level and the results suggest the comorbidity of other complex diseases that have associations with the proteins included in the disease of present study through shared proteins and pathways. For diabetes, we have obtained key genes like GAPDH, TNF, IL6, AKT1, ALB, TP53, IL10, MAPK3, TLR4 and EGF with key pathways like P53 pathway, VEGF signaling pathway, Ras Pathway, Interleukin signaling pathway, Endothelin signaling pathway, Huntington disease etc. Studies on other disorders such as obesity and blood pressure also revealed promising results.

The analysis of protein-protein interaction networks can transfer the knowledge of well-studied biological functions to functions that are not yet adequately investigated by constructing networks and extracting similar network structures in different species. Multiple network alignment can be used to find similar regions among multiple networks. In this paper, we introduce Accurate Combined Clustering Multiple Network Alignment (ACCMNA), which is a new and accurate multiple network alignment algorithm. It uses both topology and sequence similarity information. First, the importance of all the nodes is calculated according to the network structures. Second, the seed-and-extend framework is used to conduct an iterative search. In each iteration, a clustering method is combined to generate the alignment. Extensive experimental results show that ACCMNA outperformed the state-of-the-art algorithms in producing functionally consistent and topological conservation alignments within an acceptable running time.

Background: Radioresistance remains a significant obstacle in the treatment of prostate cancer (PCa). The mechanisms underlying the radioresistance in PCa remained to be further investigated. Methods: GSE53902 dataset was used in this study to identify radioresistance-related mRNAs. Protein-protein interaction (PPI) network was constructed based on STRING analysis. DAVID system was used to predict the potential roles of radioresistance-related mRNAs. Results: We screened and re-annotated the GSE53902 dataset to identify radioresistance-related mRNAs. A total of 445 up-regulated and 1036 down-regulated mRNAs were identified in radioresistance PCa cells. Three key PPI networks consisting of 81 proteins were further constructed in PCa. Bioinformatics analysis revealed that these genes were involved in regulating MAP kinase activity, response to hypoxia, regulation of the apoptotic process, mitotic nuclear division, and regulation of mRNA stability. Moreover, we observed that radioresistance-related mRNAs, such as PRC1, RAD54L, PIK3R3, ASB2, FBXO32, LPAR1, RNF14, and UBA7, were dysregulated and correlated to the survival time in PCa. Conclusion: We thought this study would be useful to understand the mechanisms underlying radioresistance of PCa and identify novel prognostic markers for PCa.

BackgroundIdentification of genes responsible for anatomical entities is a major requirement in many fields including developmental biology, medicine, and agriculture. Current wet lab techniques used for this purpose, such as gene knockout, are high in resource and time consumption. Protein–protein interaction (PPI) networks are frequently used to predict disease genes for humans and gene candidates for molecular functions, but they are rarely used to predict genes for anatomical entities. Moreover, PPI networks suffer from network quality issues, which can be a limitation for their usage in predicting candidate genes. Therefore, we developed an integrative framework to improve the candidate gene prediction accuracy for anatomical entities by combining existing experimental knowledge about gene-anatomical entity relationships with PPI networks using anatomy ontology annotations. We hypothesized that this integration improves the quality of the PPI networks by reducing the number of false positive and false negative interactions and is better optimized to predict candidate genes for anatomical entities. We used existing Uberon anatomical entity annotations for zebrafish and mouse genes to construct gene networks by calculating semantic similarity between the genes. These anatomy-based gene networks were semantic networks, as they were constructed based on the anatomy ontology annotations that were obtained from the experimental data in the literature. We integrated these anatomy-based gene networks with mouse and zebrafish PPI networks retrieved from the STRING database and compared the performance of their network-based candidate gene predictions.ResultsAccording to evaluations of candidate gene prediction performance tested under four different semantic similarity calculation methods (Lin, Resnik, Schlicker, and Wang), the integrated networks, which were semantically improved PPI networks, showed better performances by having higher area under the curve values for receiver operating characteristic and precision-recall curves than PPI networks for both zebrafish and mouse.ConclusionIntegration of existing experimental knowledge about gene-anatomical entity relationships with PPI networks via anatomy ontology improved the candidate gene prediction accuracy and optimized them for predicting candidate genes for anatomical entities.

Background Infectious diseases are a cruel assassin with millions of victims around the world each year. Understanding infectious mechanism of viruses is indispensable for their inhibition. One of the best ways of unveiling this mechanism is to investigate the host-pathogen protein-protein interaction network. In this paper we try to disclose many properties of this network. We focus on human as host and integrate experimentally 32,859 interaction between human proteins and virus proteins from several databases. We investigate different properties of human proteins targeted by virus proteins and find that most of them have a considerable high centrality scores in human intra protein-protein interaction network. Investigating human proteins network properties which are targeted by different virus proteins can help us to design multipurpose drugs. Results As host-pathogen protein-protein interaction network is a bipartite network and centrality measures for this type of networks are scarce, we proposed seven new centrality measures for analyzing bipartite networks. Applying them to different virus strains reveals unrandomness of attack strategies of virus proteins which could help us in drug design hence elevating the quality of life. They could also be used in detecting host essential proteins. Essential proteins are those whose functions are critical for survival of its host. One of the proposed centralities named diversity of predators, outperforms the other existing centralities in terms of detecting essential proteins and could be used as an optimal essential proteins’ marker. Conclusions Different centralities were applied to analyze human protein-protein interaction network and to detect characteristics of human proteins targeted by virus proteins. Moreover, seven new centralities were proposed to analyze host-pathogen protein-protein interaction network and to detect pathogens’ favorite host protein victims. Comparing different centralities in detecting essential proteins reveals that diversity of predator (one of the proposed centralities) is the best essential protein marker.

Various studies have observed that increased nutrient supply promotes the growth of bloom-forming cyanobacteria, but only a limited number of studies have investigated the influence of increased nutrient supply on bloom-forming cyanobacteria at the proteomic level. We investigated the cellular and proteomic responses ofMicrocystis aeruginosato elevated nitrogen and phosphorus supply. Increased supply of both nutrients significantly promoted the growth ofM. aeruginosaand the synthesis of chlorophylla, protein, and microcystins. The release of microcystins and the synthesis of polysaccharides negatively correlated with the growth ofM. aeruginosaunder high nutrient levels. Overexpressed proteins related to photosynthesis, and amino acid synthesis, were responsible for the stimulatory effects of increased nutrient supply inM. aeruginosa. Increased nitrogen supply directly promoted cyanobacterial growth by inducing the overexpression of the cell division regulatory protein FtsZ. NtcA, that regulates gene transcription related to both nitrogen assimilation and microcystin synthesis, was overexpressed under the high nitrogen condition, which consequently induced overexpression of 2 microcystin synthetases (McyC and McyF) and promoted microcystin synthesis. Elevated nitrogen supply induced the overexpression of proteins involved in gas vesicle organization (GvpC and GvpW), which may increase the buoyancy ofM. aeruginosa. Increased phosphorus level indirectly affected growth and the synthesis of cellular substances inM. aeruginosathrough the mediation of differentially expressed proteins related to carbon and phosphorus metabolism. This study provides a comprehensive description of changes in the proteome ofM. aeruginosain response to an increased supply of 2 key nutrients.

In present study, we constructed the direct protein-protein interaction network of insecticide resistance based on subcellular localization analysis. Totally 177 of 528 resistance proteins were ide...

Retinoblastoma is a common intraocular malignant tumor in children. However, the molecular and genetic mechanisms of retinoblastoma remain unclear. The gene expression dataset GSE110811 was retrieved from Gene Expression Omnibus. After preprocessing, coexpression modules were constructed by weighted gene coexpression network analysis (WGCNA), and modules associated with clinical traits were identified. In addition, functional enrichment analysis was performed for genes in the indicated modules, and protein‑protein interaction (PPI) networks and subnetworks were constructed based on these genes. Eight coexpression modules were constructed through WGCNA. Of these, the yellow module had the highest association with severity and age (r=0.82 and P=3e‑07; r=0.72 and P=3e‑05). The turquoise module had the highest association with months (r=‑0.63 and P=5e‑04). The genes in the two modules participate in multiple pathways of retinoblastoma, and by combining the PPI network and subnetworks; 10 hub genes were identified in the two modules. The present study identified coexpression modules and hub genes associated with clinical traits of retinoblastoma, providing novel insight into retinoblastoma progression.

Research of protein–protein interaction in several model organisms is accumulating since the development of high-throughput experimental technologies and computational methods. The protein–protein interaction network (PPIN) is able to examine biological processes in a systematic manner and has already been used to predict potential disease-related proteins or drug targets. Based on the topological characteristics of the PPIN, we investigated the application of the random forest classification algorithm to predict proteins that may cause neurodegenerative disease, a set of pathological changes featured by protein malfunction. By integrating multiomics data, we further showed the validity of our machine learning model and narrowed down the prediction results to several hub proteins that play essential roles in the PPIN. The novel insights into neurodegeneration pathogenesis brought by this computational study can indicate promising directions for future experimental research.

Protein complexes are key units for studying a cell system. During the past decades, the genome-scale protein–protein interaction (PPI) data have been determined by high-throughput approaches, which enables the identification of protein complexes from PPI networks. However, the high-throughput approaches often produce considerable fraction of false positive and negative samples. In this study, we propose the mutual important interacting partner relation to reflect the co-complex relationship of two proteins based on their interaction neighborhoods. In addition, a new algorithm called idenPC-MIIP is developed to identify protein complexes from weighted PPI networks. The experimental results on two widely used datasets show that idenPC-MIIP outperforms 17 state-of-the-art methods, especially for identification of small protein complexes with only two or three proteins.

Graphical abstract, Pathogen-host protein interactions are fundamental for pathogens to manipulate host signaling pathways and subvert host immune defense. For most pathogens, very few or no experimental studies have been conducted to investigate their signaling cross-talks with host. In this study, we propose a computational framework to validate the biological assumption that human protein–protein interaction (PPI) networks alone are sufficient to infer pathogen-host PPIs via pathogen functional mimicry. Pathogen functional mimicry assumes that a pathogen functionally mimics and substitutes host counterpart proteins in order for the pathogen to get involved in or hijack the host cellular processes. Through pathogen functional mimicry defined via gene ontology (GO) semantic similarity, we first use the known human PPIs as templates to infer pathogen-host PPIs, and the PPIs are further used as training data to build an l2-regularized logistic regression model for novel pathogen-host PPI prediction. Independent tests on the experimental data from human immunodeficiency virus and Francisella tularensis validate the effectiveness of the proposed pathogen functional mimicry technique. Performance comparisons also show that the proposed technique y excels the existing pathogen sequence mimicry approaches and transfer learning methods. The proposed framework provides a new avenue to study the experimentally less-studied pathogens in the worst scenarios that very few or no experimental pathogen-host PPIs are available. As two case studies, we apply the proposed framework to Salmonella typhimurium and Human respiratory syncytial virus to reconstruct the pathogen-host PPI networks and further investigate the interference of these two pathogens with human immune signaling and transcription regulatory system.

Background Glioma is the most lethal nervous system cancer. Recent studies have made great efforts to study the occurrence and development of glioma, but the molecular mechanisms are still unclear. This study was designed to reveal the molecular mechanisms of glioma based on protein-protein interaction network combined with machine learning methods. Key differentially expressed genes (DEGs) were screened and selected by using the protein-protein interaction (PPI) networks. Results As a result, 19 genes between grade I and grade II, 21 genes between grade II and grade III, and 20 genes between grade III and grade IV. Then, five machine learning methods were employed to predict the gliomas stages based on the selected key genes. After comparison, Complement Naive Bayes classifier was employed to build the prediction model for grade II-III with accuracy 72.8%. And Random forest was employed to build the prediction model for grade I-II and grade III-VI with accuracy 97.1% and 83.2%, respectively. Finally, the selected genes were analyzed by PPI networks, Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and the results improve our understanding of the biological functions of select DEGs involved in glioma growth. We expect that the key genes expressed have a guiding significance for the occurrence of gliomas or, at the very least, that they are useful for tumor researchers. Conclusion Machine learning combined with PPI networks, GO and KEGG analyses of selected DEGs improve our understanding of the biological functions involved in glioma growth.

Shortest path length methods are routinely used to validate whether genes of interest are functionally related to each other based on biological network information. However, the methods are computationally intensive, impeding extensive utilization of network information. In addition, non-weighted shortest path length approach, which is more frequently used, often treat all network connections equally without taking into account of confidence levels of the associations. On the other hand, graph-based information diffusion method, which employs both the presence and confidence weights of network edges, can efficiently explore large networks and has previously detected meaningful biological patterns. Therefore, in this study, we hypothesized that the graph-based information diffusion method could prioritize genes with relevant functions more efficiently and accurately than the shortest path length approaches. We demonstrated that the graph-based information diffusion method substantially differentiated not only genes participating in same biological pathways (p << 0.0001) but also genes associated with specific human drug-induced clinical symptoms (p << 0.0001) from random. Furthermore, the diffusion method prioritized these functionally related genes faster and more accurately than the shortest path length approaches (pathways: p = 2.7e-28, clinical symptoms: p = 0.032). These data show the graph-based information diffusion method can be routinely used for robust prioritization of functionally related genes, facilitating efficient network validation and hypothesis generation, especially for human phenotype-specific genes.

Background: Protein-protein interaction (PPI) data is an important type of data used in functional genomics. However, inaccuracies in high-throughput experiments often result in incomplete PPI data. Computational techniques are thus used to infer missing data and to evaluate confidence scores, with link prediction being one such approach that uses the structure of the network of PPIs known so far to find good candidates for missing PPIs. Recently, a new idea called the L3 principle introduced biological motivation into PPI link predictions, yielding predictors that are superior to general-purpose link predictors for complex networks. However, the previously developed L3 principle-based link predictors are only an approximate implementation of the L3 principle. As such, not only is the full potential of the L3 principle not realized, they may even lead to candidate PPIs that otherwise fit the L3 principle being penalized. Result: In this article, we propose a formulation of link predictors without approximation that we call ExactL3 (L3E) by addressing missing elements within L3 predictors in the perspective of network modeling. Through statistical and biological metrics, we show that in general, L3E predictors perform better than the previously proposed methods on seven datasets across two organisms (human and yeast) using a reasonable amount of computation time. In addition to L3E being able to rank the PPIs more accurately, we also found that L3-based predictors, including L3E, predicted a different pool of real PPIs than the general-purpose link predictors. This suggests that different types of PPIs can be predicted based on different topological assumptions and that even better PPI link predictors may be obtained in the future by improved network modeling.

Proteins rarely carry out their cellular functions in isolation. Instead, eukaryotic proteins engage in about six interactions with other proteins on average. The aggregated protein interactome of an organism forms a “hairy ball”-type protein-protein interaction (PPI) network. Yet, in a typical human cell, only about half of all proteins are expressed at a particular time. Hence, it has become common practice to prune the full PPI network to the subset of expressed proteins. If RNAseq data is available, one can further resolve the specific protein isoforms present in a cell or tissue. Here, we review various approaches, software tools and webservices that enable users to construct context-specific or tissue-specific PPI networks and how these are rewired between two cellular conditions. We illustrate their different functionalities on the example of the interactions involving the human TNR6 protein. In an outlook, we describe how PPI networks may be integrated with epigenetic data or with data on the activity of splicing factors.

Background Identifying or prioritizing genes for chronic obstructive pulmonary disease (COPD), one type of complex disease, is particularly important for its prevention and treatment. Methods In this paper, a novel method was proposed to Prioritize genes using Expression information in Protein–protein interaction networks with disease risks transferred between genes (abbreviated as PEP). A weighted COPD PPI network was constructed using expression information and then COPD candidate genes were prioritized based on their corresponding disease risk scores in descending order. Results Further analysis demonstrated that the PEP method was robust in prioritizing disease candidate genes, and superior to other existing prioritization methods exploiting either topological or functional information. Top-ranked COPD candidate genes and their significantly enriched functions were verified to be related to COPD. The top 200 candidate genes might be potential disease genes in the diagnosis and treatment of COPD. Conclusions The proposed method could provide new insights to the research of prioritizing candidate genes of COPD or other complex diseases with expression information from sequencing or microarray data.

This study used established biomarkers of death due to ischemic stroke (IS) and performed network, enrichment, and annotation analysis. Protein-protein interaction (PPI) network analysis revealed that the backbone of the highly connective network of IS death consisted of IL6, ALB, TNF, SERPINE1, VWF, VCAM1, TGFB1, and SELE. Cluster analysis revealed immune and hemostasis subnetworks, which were strongly interconnected through the major switches ALB and VWF. Enrichment analysis revealed that the PPI immune subnetwork of death due to IS was highly associated with TLR2/4, TNF, JAK-STAT, NOD, IL10, IL13, IL4, and TGF-β1/SMAD pathways. The top biological and molecular functions and pathways enriched in the hemostasis network of death due IS were platelet degranulation and activation, the intrinsic pathway of fibrin clot formation, the urokinase-type plasminogen activator pathway, post-translational protein phosphorylation, integrin cell surface interactions, and the proteoglycan-integrin-extra cellular matrix complex (ECM). Regulation Explorer analysis of transcriptional factors shows: a) that NFKB1, RELA and SP1 were the major regulating actors of the PPI network; and b) hsa-mir-26-5p and hsa-16-5p were the major regulating microRNA actors. In conclusion, prevention of death due to IS should consider that current IS treatments may be improved by targeting VWF, VEGFA, proteoglycan-integrin-ECM complex, NFKB/RELA and SP1.

Summary We present PrInCE, an R/Bioconductor package that employs a machine-learning approach to infer protein–protein interaction networks from co-fractionation mass spectrometry (CF-MS) data. Previously distributed as a collection of Matlab scripts, our ground-up rewrite of this software package in an open-source language dramatically improves runtime and memory requirements. We describe several new features in the R implementation, including a test for the detection of co-eluting protein complexes and a method for differential network analysis. PrInCE is extensively documented and fully compatible with Bioconductor classes, ensuring it can fit seamlessly into existing proteomics workflows. Availability and implementation PrInCE is available from Bioconductor (https://www.bioconductor.org/packages/devel/bioc/html/PrInCE.html). Source code is freely available from GitHub under the MIT license (https://github.com/fosterlab/PrInCE). Support is provided via the GitHub issues tracker (https://github.com/fosterlab/PrInCE/issues). Supplementary information Supplementary data are available at Bioinformatics online.

In this paper, we propose a bioinformatics-based method, which introduces thermodynamic measures and topological characteristics aimed to identify potential drug targets for pharmaco-resistant epileptic patients. We apply the Gibbs homology analysis to the protein–protein interaction network characteristic of temporal lobe epilepsy. With the identification of key proteins involved in the disease, particularly a number of ribosomal proteins, an assessment of their inhibitors is the next logical step. The results of our work offer a direction for future development of prospective therapeutic solutions for epilepsy patients, especially those who are not responding to the current standard of care.

There is evidence that schizophrenia is characterized by activation of the immune-inflammatory response (IRS) and compensatory immune-regulatory (CIRS) systems and lowered neuroprotection. Studies performed on antipsychotic-naïve first episode psychosis (AF-FEP) and schizophrenia (FES) patients are important as they may disclose the pathogenesis of the disease. However, the interactome of FEP/FES is not well delineated. The aim of the current study was to delineate the characteristics of the protein-protein interaction (PPI) network of AN-FEP and its transition to FES and the biological functions, pathways, and molecular patterns, which are over-represented in FEP/FES. PPI network analysis shows that FEP and FEP/FES are strongly associated with a response to a bacterium, TNF, NFκB, RELA, SP1, JAK-STAT, death receptor and TLR4 signaling, and tyrosine phosphorylation of STAT proteins. Specific molecular complexes of the peripheral immune response are associated with microglial activation, neuroinflammation and gliogenesis. FEP/FES is accompanied by lowered protection against inflammation in part attributable to dysfunctional miRNA maturation, deficits in neurotrophin/Trk, RTK and Wnt/catenin signaling and adherens junction organization. Lowered neuroprotection due to reduced neurotrophin/Trk and Wnt/catenin signaling, and DISC1 expression and multiple interactions between lowered BDNF, CDH1, CTNNB, and DISC1 expression, increase the vulnerability to the neurotoxic effects of immune products including cytokines and complement factors. All pathways or molecular patterns enriched in the interactome of FEP/FES are directly or indirectly affected by LPS. In summary: FEP appears to be triggered by a biotic stimulus (e.g. Gram-negative bacteria) which may induce neuro-immune toxicity cascades especially when anti-inflammatory and neurotrophic protections are deficient.

Protein-protein interactions (PPIs) are a key component of the subcellular molecular networks which enable cells to function. Due to their importance in homeostasis, alterations to the networks can be detrimental, leading to cellular dysfunction and ultimately disease states. Parkinson's disease (PD) is a progressive neurodegenerative condition with multifactorial aetiology, spanning genetic variation and environmental modifiers. At a molecular and systems level, the characterisation of PD is the focus of extensive research, largely due to an unmet need for disease modifying therapies. PPI network analysis approaches are a valuable strategy to accelerate our understanding of the molecular crosstalk and biological processes underlying PD pathogenesis, especially due to the complex nature of this disease. In this review, we describe the utility of PPI network approaches in modelling complex systems, focusing on previous work in PD research. We discuss four principal strategies for using PPI network approaches: to infer PD related cellular functions, pathways and novel genes; to support genomics studies; to study the interactome of single PD related genes; and to compare the molecular basis of PD to other neurodegenerative disorders. This is an evolving area of research which is likely to further expand as omics data generation and availability increase. These approaches complement and bridge-the-gap between genetics and functional research to inform future investigations. In this review we outline several limitations that require consideration, acknowledging that ongoing challenges in this field continue to be addressed and the refinement of these approaches will facilitate further advances using PPI network analysis for understanding complex diseases.

The entire world is witnessing the coronavirus pandemic (COVID-19), caused by a novel coronavirus (n-CoV) generally distinguished as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). SARS-CoV-2 promotes fatal chronic respiratory disease followed by multiple organ failure, ultimately putting an end to human life. International Committee on Taxonomy of Viruses (ICTV) has reached a consensus that SARS-CoV-2 is highly genetically similar (up to 89%) to the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), which had an outbreak in 2003. With this hypothesis, current work focuses on identifying the spreader nodes in the SARS-CoV-human protein–protein interaction network (PPIN) to find possible lineage with the disease propagation pattern of the current pandemic. Various PPIN characteristics like edge ratio, neighborhood density, and node weight have been explored for defining a new feature spreadability index by which spreader proteins and protein–protein interaction (in the form of network edges) are identified. Top spreader nodes with a high spreadability index have been validated by Susceptible-Infected-Susceptible (SIS) disease model, first using a synthetic PPIN followed by a SARS-CoV-human PPIN. The ranked edges highlight the path of entire disease propagation from SARS-CoV to human PPIN (up to level-2 neighborhood). The developed network attribute, spreadability index, and the generated SIS model, compared with the other network centrality-based methodologies, perform better than the existing state-of-art.

Many computational methods have been proposed to predict essential proteins from protein-protein interaction (PPI) networks. However, it is still challenging to improve the prediction accuracy. In this study, we propose a new method, esPOS (essential proteins Predictor using Order Statistics) to predict essential proteins from PPI networks. Firstly, we refine the networks by using gene expression information and subcellular localization information. Secondly, we design some new features, which combine the protein predicted secondary structure with PPI network. We show that these new features are useful to predict essential proteins. Thirdly, we optimize these features by using a greedy method, and combine the optimized features by order statistic method. Our method achieves the prediction accuracy of 0.76-0.79 on two network datasets. The proposed method is available at https://sourceforge.net/projects/espos/.

Protein complexes are the fundamental units for many cellular processes. Identifying protein complexes accurately is critical for understanding the functions and organizations of cells. With the increment of genome-scale protein–protein interaction (PPI) data for different species, various computational methods focus on identifying protein complexes from PPI networks. In this article, we give a comprehensive and updated review on the state-of-the-art computational methods in the field of protein complex identification, especially focusing on the newly developed approaches. The computational methods are organized into three categories, including cluster-quality-based methods, node-affinity-based methods and ensemble clustering methods. Furthermore, the advantages and disadvantages of different methods are discussed, and then, the performance of 17 state-of-the-art methods is evaluated on two widely used benchmark data sets. Finally, the bottleneck problems and their potential solutions in this important field are discussed.

In this work, we propose a novel centrality metric, referred to as star centrality, which incorporates information from the closed neighborhood of a node, rather than solely from the node itself, when calculating its topological importance. More specifically, we focus on degree centrality and show that in the complex protein–protein interaction networks, it is a naive metric that can lead to misclassifying protein importance. For our extension of degree centrality when considering stars, we derive its computational complexity, provide a mathematical formulation, and propose two approximation algorithms that are shown to be efficient in practice. We portray the success of this new metric in protein–protein interaction networks when predicting protein essentiality in several organisms, including the well-studied Saccharomyces cerevisiae, Helicobacter pylori, and Caenorhabditis elegans, where star centrality is shown to significantly outperform other nodal centrality metrics at detecting essential proteins. We also analyze the average and worst-case performance of the two approximation algorithms in practice and show that they are viable options for computing star centrality in very large-scale protein–protein interaction networks, such as the human proteome, where exact methodologies are bound to be time and memory intensive.

Protein phosphorylation is a kind of important post-translational modification of protein, which plays a critical role in many biological processes of eukaryote. Identifying kinase-substrate interactions is helpful to understand the mechanism of many diseases. Many computational algorithms for kinase-substrate interactions identification have been proposed. However, most of those methods are mainly focused on utilizing protein local sequence information. In this article, we propose a new computational method to predict kinase-substrate interactions based on protein-protein interaction (PPI) network. Different from existing methods, the PPI network is utilized to measure the similarities of kinase-kinase and substrate-substrate, respectively. Then, the pairwise similarities of kinase-kinase and substrate-substrate are adjusted based on the assumption that the similarities of kinase-kinase and substrate-substrate are more reliable if they are in the same cluster. Finally, the bi-random walk is used to predict potential kinase-substrate interactions. The experimental results show that our method outperforms other state-of-the-art algorithms in performance. Furthermore, the case study demonstrates that it is effective in predicting potential kinase-substrate interactions.

The protein-protein interaction (PPI) network of an organism serves as a skeleton for its signaling circuitry, which mediates cellular response to environmental and genetic cues. Understanding this circuitry could improve the prediction of gene function and cellular behavior in response to diverse signals. To realize this potential, one has to comprehensively map PPIs and their directions of signal flow. While the quality and the volume of identified human PPIs improved dramatically over the last decade, the directions of these interactions are still mostly unknown, thus precluding subsequent prediction and modeling efforts. Here we present a systematic approach to orient the human PPI network using drug response and cancer genomic data. We provide a diffusion-based method for the orientation task that significantly outperforms existing methods. The oriented network leads to improved prioritization of cancer driver genes and drug targets compared to the state-of-the-art unoriented network., The directions of most human protein-protein interactions (PPIs) remain unknown. Here, the authors use cancer genomic and drug response data to infer the direction of signal flow in the human PPI network and show that the directed network improves drug target and cancer driver gene prioritization.

An interologous PPI network of tea leaf is designed by developing reference transcriptome assembly and using experimentally validated PPIs in plants. Key regulatory proteins are proposed and potential TFs are predicted. Worldwide, tea (Camellia sinensis) is the most consumed beverage primarily due to the taste, flavour, and aroma of its newly formed leaves; and has been used as an important ingredient in several traditional medicinal systems because of its antioxidant properties. For this medicinally and commercially important plant, design principles of gene-regulatory and protein–protein interaction (PPI) networks at sub-cellular level are largely un-characterized. In this work, we report a tea leaf interologous PPI network (TeaLIPIN) consisting of 11,208 nodes and 197,820 interactions. A reference transcriptome assembly was first developed from all the 44 samples of 6 publicly available leaf transcriptomes (1,567,288,290 raw reads). By inferring the high-confidence interactions among potential proteins coded by these transcripts using known experimental information about PPIs in 14 plants, an interologous PPI network was constructed and its modular architecture was explored. Comparing this network with 10,000 realizations of two types of corresponding random networks (Erdős–Renyi and Barabasi–Albert models) and examining over three network centrality metrics, we predict 2750 bottleneck proteins (having p values

Biclustering is a process of finding groups of genes that behave similarly under a subset of conditions. In this article, we propose an efficient biclustering algorithm, namely RN+, to identify biologically meaningful biclusters in gene expression data. The RN+ algorithm finds biologically meaningful biclusters through a novel gene filtering using protein-protein interaction network, gene searching, gene grouping, and queuing process. It also efficiently removes duplicate biclusters. We tested the proposed RN+ on five real microarray datasets, and compared its performance with seven competitive biclustering algorithms. The experimental results show that RN+ efficiently finds functionally enriched and biologically meaningful biclusters for large gene expression datasets, and outperforms the other tested biclustering algorithms on real datasets.

Hand, foot, and mouth disease (HFMD) is a common infection for children younger than the age of five. HFMD is mainly induced by coxsackievirus A16 and enterovirus 71 (EV71). EV71-associated HFMD often has serious neurological disease complications. The purpose of this study was to reveal the mechanisms of action of EV71 on neurons. SH-SY5Y cells transfected or untransfected with EV71 were sequenced. After data preprocessing, differentially expressed genes (DEGs) were screened using the limma package in R, and clustering analysis was then performed using the ComplexHeatmap package in R. The DAVID tool was used for EDG enrichment analysis. Protein-protein interactions (PPIs) were predicted using the STRING database and PPI networks were then constructed using Cytoscape software. After pathways involved in the key PPI network nodes were enriched, pathway deviation scores were calculated. Clustering analysis was also conducted for these pathways. There were 978 DEGs in the transfected samples. Upregulated

Objectives: Ischemia–reperfusion (I/R) injury can aggravate the dysfunction and structural damage of tissues and organs. This study aimed at investigating the pathogenesis of I/R injury.Met...