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Abstract Biological systems can gain complexity over time. While some of these transitions are likely driven by natural selection, the extent to which they occur without providing an adaptive benefit is unknown. At the molecular level, one example is heteromeric complexes replacing homomeric ones following gene duplication. Here, we build a biophysical model and simulate the evolution of homodimers and heterodimers following gene duplication using distributions of mutational effects inferred from available protein structures. We keep the specific activity of each dimer identical, so their concentrations drift neutrally without new functions. We show that for more than 60% of tested dimer structures, the relative concentration of the heteromer increases over time due to mutational biases that favor the heterodimer. However, allowing mutational effects on synthesis rates and differences in the specific activity of homo- and heterodimers can limit or reverse the observed bias toward heterodimers. Our results show that the accumulation of more complex protein quaternary structures is likely under neutral evolution, and that natural selection would be needed to reverse this tendency.

Multicellular organisms are composed of many tissue types that have distinct morphologies and functions, which are largely driven by specialized proteomes and interactomes. To define the proteome and interactome of a specific type of tissue in an intact animal, we developed a localized proteomics approach called Methionine Analog-based Cell-Specific Proteomics and Interactomics (MACSPI). This method uses the tissue-specific expression of an engineered methionyl-tRNA synthetase to label proteins with a bifunctional amino acid 2-amino-5-diazirinylnonynoic acid in selected cells. We applied MACSPI in Caenorhabditis elegans, a model multicellular organism, to selectively label, capture, and profile the proteomes of the body wall muscle and the nervous system, which led to the identification of tissue-specific proteins. Using the photo-cross-linker, we successfully profiled HSP90 interactors in muscles and neurons and identified tissue-specific interactors and stress-related interactors. Our study demonstrates that MACSPI can be used to profile tissue-specific proteomes and interactomes in intact multicellular organisms. [ABSTRACT FROM AUTHOR]

One of the recent significant but challenging research studies in computational biology and bioinformatics is to unveil protein complexes from protein-protein interaction networks (PPINs). However, the development of a reliable algorithm to detect more complexes with high quality is still ongoing in many studies. The main contribution of this paper is to improve the effectiveness of the well-known modularity density ( ) model when used as a single objective optimization function in the framework of the canonical evolutionary algorithm (EA). To this end, the design of the EA is modified with a gene ontology-based mutation operator, where the aim is to make a positive collaboration between the modularity density model and the proposed gene ontology-based mutation operator. The performance of the proposed EA to have a high quantity and quality of the detected complexes is assessed on two yeast PPINs and compared with two benchmarking gold complex sets. The reported results reveal the ability of modularity density to be more productive in detecting more complexes with high quality when teamed up with a gene ontology-based mutation operator. [ABSTRACT FROM AUTHOR]

Biological systems can gain complexity over time. While some of these transitions are likely driven by natural selection, the extent to which they occur without providing an adaptive benefit is unknown. At the molecular level, one example is heteromeric complexes replacing homomeric ones following gene duplication. Here, we build a biophysical model and simulate the evolution of homodimers and heterodimers following gene duplication using distributions of mutational effects inferred from available protein structures. We keep the specific activity of each dimer identical, so their concentrations drift neutrally without new functions. We show that for more than 60% of tested dimer structures, the relative concentration of the heteromer increases over time due to mutational biases that favor the heterodimer. However, allowing mutational effects on synthesis rates and differences in the specific activity of homo- and heterodimers can limit or reverse the observed bias toward heterodimers. Our results show that the accumulation of more complex protein quaternary structures is likely under neutral evolution, and that natural selection would be needed to reverse this tendency. Synopsis: Duplicated self-interacting proteins can interact with themselves (homomers) or one another (heteromers). To understand whether natural selection is required to keep homomers over heteromers (or vice versa), the evolution of such duplicate proteins is simulated in the absence of new functions. The dynamic equilibrium of homo- and heteromers is given by physical parameters, such as protein folding energy and binding affinities. Simulations of homodimer evolution from actual structures show a trend towards the increase of the relative concentration of the heterodimer, even when there is no inherent advantage of such an increase. The magnitude of the increase in the concentration of heterodimers is associated with mutational biases, that is, an asymmetry with respect to the effects of mutations on homo- and heterodimer binding affinities. The bias towards heterodimers can be counterbalanced by changes in the protein synthesis rates or the specific activities of the dimers. Duplicated self-interacting proteins can interact with themselves (homomers) or one another (heteromers). To understand whether natural selection is required to keep homomers over heteromers (or vice versa), the evolution of such duplicate proteins is simulated in the absence of new functions. [ABSTRACT FROM AUTHOR]

Lung cancer remains a significant health threat with high mortality rates. Using graph theory, we modeled the protein-protein interaction (PPI) network in lung cancer to explore its complex structure. This approach allows for the analysis of network properties and the identification of key proteins driving biological processes. Our analysis revealed RPS27A as a central protein within the network, associated with diverse functions related to ribosome biogenesis, translation, cell growth, apoptosis, and cancer progression. This suggests that RPS27A may have multiple functions in cancer development and progression, including in MAPK signaling pathways. Importantly, our study uniquely identifies RPS27A as a central hub in lung cancer PPI networks, shedding light on its pivotal role in disease pathogenesis. Additionally, we identified a central network zone enriched with proteins involved in key signaling pathways, presenting novel insights into potential therapeutic targets for lung cancer treatment. Pathway enrichment analysis further highlighted functional specialization across network zones, providing a comprehensive understanding of the intricate interplay between biological pathways in lung cancer progression. This study underscores the multifaceted roles of central proteins like RPS27A within lung cancer’s PPI network and the network’s potential for pinpointing therapeutic targets, presenting a novel perspective on the intricate network of molecular interactions driving lung cancer pathogenesis. [ABSTRACT FROM AUTHOR]

Protein structure (and thus function) is dictated by non‐covalent interaction networks. These can be highly evolutionarily conserved across protein families, the members of which can diverge in sequence and evolutionary history. Here we present KIN, a tool to identify and analyze conserved non‐covalent interaction networks across evolutionarily related groups of proteins. KIN is available for download under a GNU General Public License, version 2, from https://www.github.com/kamerlinlab/KIN. KIN can operate on experimentally determined structures, predicted structures, or molecular dynamics trajectories, providing insight into both conserved and missing interactions across evolutionarily related proteins. This provides useful insight both into protein evolution, as well as a tool that can be exploited for protein engineering efforts. As a showcase system, we demonstrate applications of this tool to understanding the evolutionary‐relevant conserved interaction networks across the class A β‐lactamases. [ABSTRACT FROM AUTHOR]

Background Biological networks are often used to describe the relationships between relevant entities, particularly genes and proteins, and are a powerful tool for functional genomics. Many important biological problems can be investigated by comparing biological networks between different conditions or networks obtained with different techniques. Findings We show that contrast subgraphs, a recently introduced technique to identify the most important structural differences between 2 networks, provide a versatile tool for comparing gene and protein networks of diverse origin. We demonstrate the use of contrast subgraphs in the comparison of coexpression networks derived from different subtypes of breast cancer, coexpression networks derived from transcriptomic and proteomic data, and protein–protein interaction networks assayed in different cell lines. Conclusions These examples demonstrate how contrast subgraphs can provide new insight in functional genomics by extracting the gene/protein modules whose connectivity is most altered between 2 conditions or experimental techniques. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme persists to be an enigmatic distress in neuro-oncology. Its untethering capacity to thrive in a confined microenvironment, metastasize intracranially, and remain resistant to the systemic treatments, renders this tumour incurable. The glial cell type specificity in GBM remains exploratory. In our study, we aimed to address this problem by studying the GBM at the cell type level in the brain. The cellular makeup of this tumour is composed of genetically altered glial cells which include astrocyte, microglia, oligodendrocyte precursor cell, newly formed oligodendrocyte and myelinating oligodendrocyte. We extracted cell type-specific solid tumour as well as recurrent solid tumour glioma genes, and studied their functional networks and contribution towards gliomagenesis. We identified the principal transcription factors that are found to be regulating vital tumorigenic processes. We also assessed the protein–protein interaction networks at their domain level to get a more microscopic view of the structural and functional operations that transpire in these cells. This yielded the eminent protein regulators exhibiting their regulation in signaling pathways. Overall, our study unveiled regulatory mechanisms in glioma cell types that can be targeted for a more efficient glioma therapy.

Essential proteins are important participants in various life activities and play a vital role in the survival and reproduction of life. The network-based centrality methods are a common way to identify essential proteins for protein interaction networks. Due to the differences between the existing centrality methods, it is a feasible approach to improve the identification accuracy of essential proteins by combining centrality methods. In this paper, we propose a centrality combination method based on feature selection. First, the measure values of the 14 classical centrality methods are viewed as feature data. Then, a subset of the relevant features is selected according to the importance of features. Finally, the centrality methods corresponding to the selected features are combined by using the geometric mean method for the identification of essential proteins. To verify the effectiveness of the combination method, we apply the combination method on the original static protein interaction network (SPIN), the dynamic protein interaction network (DPIN) and the refined dynamic protein interaction network (RDPIN), and compare the result with those by each single centrality method (LAC, DC, DMNC, NC, TP, CLC, BC, LC, CC, KC, CR, EC, PR, LR). The experimental results on the identification of essential proteins shows that the combination method achieves better results in prediction performance than the 14 centrality mehtods in terms of the prediction precision, sensitivity, specificity, positive predictive value, negative predictive value, F-measure and accuracy rate. It has been illustrated that the proposed method can help to identify essential proteins more accurately.

Ethnopharmacological Relevance: The Yishenjiangya formula (YSJ) is a traditional Chinese medicine (TCM) primarily composed of qi-tonifying components. This classic formula is commonly utilized to treat kidney qi deficiency in elderly patients with hypertension. According to TCM, maintaining a balance between qi and blood is crucial for stable blood pressure. Kidney qi deficiency can disrupt this balance, altering fluid shear force and, ultimately, leading to hypertension, particularly in elderly populations. Despite YSJ's efficacy in treating hypertension, its specific anti-hypertensive mechanisms remain unclear., Aim of the Study: YSJ is commonly prescribed for elderly patients with hypertension. Earlier metabolomics studies demonstrated that YSJ exerts antihypertensive effects by influencing four key pathways: linoleic acid metabolism, glycerol phospholipid metabolism, arginine and proline metabolism, and steroid hormone biosynthesis. This study aims to combine metabolomic and proteomic analyses to thoroughly understand the molecular biological mechanisms responsible for YSJ's anti-hypertensive properties., Methods: Ultra-Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS) metabolomics, combined with Label-Free Quantitation (LFQ) proteomics, was employed to analyze serum samples from elderly individuals with and without hypertension pre- and post-YSJ intervention. Serum levels of candidate proteins were assessed using enzyme-linked immunosorbent assay, and receiver operating characteristic curves were used to evaluate the diagnostic performance of the target proteins., Results: Eight differentially expressed metabolites and three differentially expressed proteins were identified as potential therapeutic targets of YSJ. These substances are primarily involved in unsaturated fatty acid metabolism, fluid shear stress and atherosclerosis pathway, primary bile acid biosynthesis, proline metabolism, apoptosis, and endoplasmic reticulum stress. YSJ exerts its therapeutic effects on hypertension in the elderly by modulating these pathways., Conclusions: YSJ effectively treats senile hypertension. By analyzing the correlation between therapeutic targets and pathways, YSJ's anti-hypertensive effect was achieved by inhibiting lipid peroxidation and matrix degeneration. Combining metabolomics and proteomics provides an effective method for uncovering YSJ's anti-hypertensive mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The modular organization of a cell which can be determined by its interaction network allows us to understand a mesh of cooperation among the functional modules. Therefore, cellular-level identification of functional modules aids in understanding the functional and structural characteristics of the biological network of a cell and also assists in determining or comprehending the evolutionary signal. We develop ProMoCell that performs real-time Web scraping for generating clusters of the cellular level functional units of an organism. ProMoCell constructs the Protein Locality Graphs and clusters the cellular level functional units of an organism by utilizing experimentally verified data from various online sources. Also, we develop ProModb, a database service that houses precomputed whole-cell protein-protein interaction network-based functional modules of an organism using ProMoCell. Our Web service is entirely synchronized with the KEGG pathway database and allows users to generate spatially localized protein modules for any organism belonging to the KEGG genome using its real-time Web scraping characteristics. Hence, the server will host as many organisms as is maintained by the KEGG database. Our Web services provide the users a comprehensive and integrated tool for an efficient browsing and extraction of the spatial locality-based protein locality graph and the functional modules constructed by gathering experimental data from several interaction databases and pathway maps. We believe that our Web services will be beneficial in pharmacological research, where a novel research domain called modular pharmacology has initiated the study on the diagnosis, prevention, and treatment of deadly diseases using functional modules. [ABSTRACT FROM AUTHOR]

Cellular behaviors emerge from layers of molecular interactions: proteins interact to form complexes, pathways, and phenotypes. We show that hierarchical networks of protein interactions can be defined from the statistical pattern of proteome variation measured across thousands of diverse bacteria and that these networks reflect the emergence of complex bacterial phenotypes. Our results are validated through gene-set enrichment analysis and comparison to existing experimentally derived databases. We demonstrate the biological utility of our approach by creating a model of motility in Pseudomonas aeruginosa and using it to identify a protein that affects pilus-mediated motility. Our method, SCALES (Spectral Correlation Analysis of Layered Evolutionary Signals), may be useful for interrogating genotype-phenotype relationships in bacteria.

Autism spectrum disorder (ASD), a heterogeneous neurodevelopmental disorder resulting from both genetic and environmental risk factors, is manifested by deficits in cognitive function. Elucidating the cognitive disorder-relevant biological mechanisms may open up promising therapeutic approaches. In this work, we mined ASD cognitive phenotype proteins to construct and analyze protein–protein and gene–environment interaction networks. Incorporating the protein–protein interaction (PPI), human cognition proteins, and connections of autism-cognition proteins enabled us to generate an autism-cognition network (ACN). With the topological analysis of ACN, important proteins, highly clustered modules, and 3-node motifs were identified. Moreover, the impact of environmental exposures in cognitive impairment was investigated through chemicals that target the cognition-related proteins. Functional enrichment analysis of the ACN-associated modules and chemical targets revealed biological processes involved in the cognitive deficits of ASD. Among the 17 identified hub-bottlenecks in the ACN, PSD-95 was recognized as an important protein through analyzing the module and motif interactions. PSD-95 and its interacting partners constructed a cognitive-specific module. This hub-bottleneck interacted with the 89 cognition-related 3-node motifs. The identification of gene–environment interactions indicated that most of the cognitive-related proteins interact with bisphenol A (BPA) and valproic acid (VPA). Moreover, we detected significant expression changes of 56 cognitive-specific genes using four ASD microarray datasets in the GEO database, including GSE28521, GSE26415, GSE18123 and GSE29691. Our outcomes suggest future endeavors for dissecting the PSD-95 function in ASD and evaluating the various environmental conditions to discover possible mechanisms of the different levels of cognitive impairment. [ABSTRACT FROM AUTHOR]

Intrinsically disordered proteins (IDPs) are proteins that lack rigid structures yet play important roles in myriad biological phenomena. A distinguishing feature of IDPs is that they often mediate specific biological outcomes via multivalent weak cooperative interactions with multiple partners. Here, we show that several proteins specifically associated with processes that were key in the evolution of complex multicellularity in the lineage leading to the multicellular green alga Volvox carteri are IDPs. We suggest that, by rewiring cellular protein interaction networks, IDPs facilitated the co-option of ancestral pathways for specialized multicellular functions, underscoring the importance of IDPs in the early evolution of complex multicellularity. [ABSTRACT FROM AUTHOR]

Abstract Background Basal cell carcinoma (BCC) of the skin is the most common form of human cancer, with more than 90% of tumours presenting with clear genetic activation of the Hedgehog pathway. However, polygenic risk factors affecting mechanisms such as DNA repair and cell cycle checkpoints or which modulate the tumour microenvironment or host immune system play significant roles in determining whether genetic mutations culminate in BCC development. We set out to define background genetic factors that play a role in influencing BCC susceptibility via promoting or suppressing the effects of oncogenic drivers of BCC. Methods We performed genome-wide association studies (GWAS) on 17,416 cases and 375,455 controls. We subsequently performed statistical analysis by integrating data from population-based genetic studies of multi-omics data, including blood- and skin-specific expression quantitative trait loci and methylation quantitative trait loci, thereby defining a list of functionally relevant candidate BCC susceptibility genes from our GWAS loci. We also constructed a local GWAS functional interaction network (consisting of GWAS nearest genes) and another functional interaction network, consisting specifically of candidate BCC susceptibility genes. Results A total of 71 GWAS loci and 46 functional candidate BCC susceptibility genes were identified. Increased risk of BCC was associated with the decreased expression of 26 susceptibility genes and increased expression of 20 susceptibility genes. Pathway analysis of the functional candidate gene regulatory network revealed strong enrichment for cell cycle, cell death, and immune regulation processes, with a global enrichment of genes and proteins linked to TReg cell biology. Conclusions Our genome-wide association analyses and functional interaction network analysis reveal an enrichment of risk variants that function in an immunosuppressive regulatory network, likely hindering cancer immune surveillance and effective antitumour immunity.

Abstract Background In 2017, World Health Organization (WHO) published a catalogue of 12 families of antibiotic-resistant “priority pathogens” that are posing the greatest threats to human health. Six of these dreaded pathogens are known to infect the human gastrointestinal system. In addition to causing gastrointestinal and systemic infections, these pathogens can also affect the composition of other microbes constituting the healthy gut microbiome. Such aberrations in gut microbiome can significantly affect human physiology and immunity. Identifying the virulence mechanisms of these enteric pathogens are likely to help in developing newer therapeutic strategies to counter them. Results Using our previously published in silico approach, we have evaluated (and compared) Host-Pathogen Protein-Protein Interaction (HPI) profiles of four groups of enteric pathogens, namely, different species of Escherichia, Shigella, Salmonella and Vibrio. Results indicate that in spite of genus/ species specific variations, most enteric pathogens possess a common repertoire of HPIs. This core set of HPIs are probably responsible for the survival of these pathogen in the harsh nutrient-limiting environment within the gut. Certain genus/ species specific HPIs were also observed. Conslusions The identified bacterial proteins involved in the core set of HPIs are expected to be helpful in understanding the pathogenesis of these dreaded gut pathogens in greater detail. Possible role of genus/ species specific variations in the HPI profiles in the virulence of these pathogens are also discussed. The obtained results are likely to provide an opportunity for development of novel therapeutic strategies against the most dreaded gut pathogens.

In the post-genomic era, proteomics has achieved significant theoretical and practical advances with the development of high-throughput technologies. Especially the rapid accumulation of protein-protein interactions (PPIs) provides a foundation for constructing protein interaction networks (PINs), which can furnish a new perspective for understanding cellular organizations, processes, and functions at network level. In this paper, we present a comprehensive survey on three main characteristics of PINs: centrality, modularity, and dynamics. 1) Different centrality measures, which are used to calculate the importance of proteins, are summarized based on the structural characteristics of PINs or on the basis of its integrated biological information; 2) Different modularity definitions and various clustering algorithms for predicting protein complexes or identifying functional modules are introduced; 3) The dynamics of proteins, PPIs and sub-networks are discussed, respectively. Finally, the main applications of PINs in the complex diseases are reviewed, and the challenges and future research directions are also discussed. [ABSTRACT FROM AUTHOR]

Network alignment is an important bridge to understanding human protein-protein interactions (PPIs) and functions through model organisms. However, the underlying subgraph isomorphism problem complicates and increases the time required to align protein interaction networks (PINs). Parallel computing technology is an effective solution to the challenge of aligning large-scale networks via sequential computing. In this study, the typical Hungarian-Greedy Algorithm (HGA) is used as an example for PIN alignment. The authors propose a HGA with 2-nearest neighbours (HGA-2N) and implement its graphics processing unit (GPU) acceleration. Numerical experiments demonstrate that HGA-2N can find alignments that are close to those found by HGA while dramatically reducing computing time. The GPU implementation of HGA-2N optimises the parallel pattern, computing mode and storage mode and it improves the computing time ratio between the CPU and GPU compared with HGA when large-scale networks are considered. By using HGA-2N in GPUs, conserved PPIs can be observed, and potential PPIs can be predicted. Among the predictions based on 25 common Gene Ontology terms, 42.8% can be found in the Human Protein Reference Database. Furthermore, a new method of reconstructing phylogenetic trees is introduced, which shows the same relationships among five herpes viruses that are obtained using other methods.

• Liver and lung metastases significantly influenced prostate cancer-specific mortality in visceral metastatic cases. • Genes differentially expressed between liver and lung metastases were associated with respiratory gaseous exchange, pulmonary surfactant metabolism, and fibronectin matrix formation. • SCGB3A1 may contribute to the better survival prognosis of patients with prostate cancer lung metastases compared to those with liver metastases. Prostate cancer patients with visceral metastases often exhibited poor prognoses. Few researches had compared the prognostic impact and gene expression profiles among distinct visceral metastatic sites. Therefore, we conducted a comprehensive study utilizing data from the Surveillance, Epidemiology, and End Results (SEER) database and the Gene Expression Omnibus database. We analyzed the prostate cancer-specific mortality (PCSM) risk for 8,170 patients diagnosed with metastatic prostate cancer (mPCa) between 2000 and 2019, utilizing data from the SEER 17 registry database. Patients with metastatic disease in nonregional lymph nodes, bones, brains, livers, and lungs were identified. Competing risks regression was employed to evaluate the effect of visceral metastatic disease sites on PCSM. Differentially expressed genes (DEGs) between visceral metastases were assessed using data from the GSE6752 dataset. A relative protein-protein interaction (PPI) network was constructed based on STRING analysis. Furthermore, we explored the distribution of DEGs in various normal tissues and tumor tissues using the Human Protein Atlas and GEPIA. Competing risks regression analysis revealed that liver and lung metastases had a substantial impact on PCSM (hazard ratio 2.24, 95% confidence interval 1.70–2.95, P < 0.001; hazard ratio 1.30, 95% confidence interval 1.06–1.59, P = 0.012, respectively). Seven significant DEGs were identified from samples of liver and lung metastases (HERV-FRD, NUDT12, FAM63A, SCGB3A1, CEACAM6, LOC440416, SFTPB) and were associated with respiratory gaseous exchange, pulmonary surfactant metabolism, and fibronectin matrix formation in PPI network analysis. Notably, the expression levels of the three DEGs significantly upregulated in lung metastases were also found to be higher in normal lung tissues compared to normal liver tissues. Patients diagnosed with mPCa and presenting with liver and/or lung metastases exhibit poorer prognoses. SCGB3A1, identified as a tumor suppressor gene, may contribute to the better survival prognosis observed in patients with prostate cancer lung metastases compared to those with liver metastases. The gene expression profiles in these two specific metastatic sites reveal a combination of both heterogeneity and homogeneity. [ABSTRACT FROM AUTHOR]

Abstract Background Protein interaction databases often provide confidence scores for each recorded interaction based on the available experimental evidence. Protein interaction networks (PINs) are then built by thresholding on these scores, so that only interactions of sufficiently high quality are included. These networks are used to identify biologically relevant motifs or nodes using metrics such as degree or betweenness centrality. This type of analysis can be sensitive to the choice of threshold. If a node metric is to be useful for extracting biological signal, it should induce similar node rankings across PINs obtained at different reasonable confidence score thresholds. Results We propose three measures—rank continuity, identifiability, and instability—to evaluate how robust a node metric is to changes in the score threshold. We apply our measures to twenty-five metrics and identify four as the most robust: the number of edges in the step-1 ego network, as well as the leave-one-out differences in average redundancy, average number of edges in the step-1 ego network, and natural connectivity. Our measures show good agreement across PINs from different species and data sources. Analysis of synthetically generated scored networks shows that robustness results are context-specific, and depend both on network topology and on how scores are placed across network edges. Conclusion Due to the uncertainty associated with protein interaction detection, and therefore network structure, for PIN analysis to be reproducible, it should yield similar results across different confidence score thresholds. We demonstrate that while certain node metrics are robust with respect to threshold choice, this is not always the case. Promisingly, our results suggest that there are some metrics that are robust across networks constructed from different databases, and different scoring procedures.

Essential proteins are critical components of living organisms and indispensable to cellular life. Identification of essential proteins plays a critical role in the survival and development of life process and understanding the function of cell machinery. The experimental methods are usually costly and time-consuming. In order to overcome these limitations, many computational methods have been proposed to discover essential proteins based on the topological features of PPI networks and other biological information. In this paper, a new method named NIE is proposed to predict essential proteins based on second-order neighborhood information and information entropy of protein complex and subcellular localization. Firstly, a number of studies have shown that the RNA-Seq data is more advantageous than traditional gene expression data in predicting essential proteins. Meanwhile, the protein essentiality is closely related to the subcellular localization information, protein complex information and protein GO terms through data analysis. A weighted PPI network is constructed to reduce the impact of false positives and false negatives data on the identification of essential proteins, which integrates the GO terms information with Pearson correlation coefficient of RNA-Seq data. Secondly, the information entropy of protein complexes and subcellular localization is calculated to represent the biological characteristics of proteins. Furthermore, an information propagation model is constructed, which combines the biological properties of the proteins with the second-order neighborhood information in the PPI network to measure the essentiality of the proteins. In the experiments section, the proposed method is implemented on three common datasets (DIP, Krogan and MIPS) of Saccharomyces cerevisiae. A comparison study with other commonly used algorithms, including LAC, NC, PeC, WDC, UC, LIDC and LBCC is performed to evaluate the performance of NIE. The results show that the new method NIE has a better performance in predicting essential proteins.

Deciphering the functional impact of genetic variation is required to understand phenotypic diversity and the molecular mechanisms of inherited disease and cancer. While millions of genetic variants are now mapped in genome sequencing projects, distinguishing functional variants remains a major challenge. Protein-coding variation can be interpreted using post-translational modification (PTM) sites that are core components of cellular signaling networks controlling molecular processes and pathways. ActiveDriverDB is an interactive proteo-genomics database that uses more than 260,000 experimentally detected PTM sites to predict the functional impact of genetic variation in disease, cancer and the human population. Using machine learning tools, we prioritize proteins and pathways with enriched PTM-specific amino acid substitutions that potentially rewire signaling networks via induced or disrupted short linear motifs of kinase binding. We then map these effects to site-specific protein interaction networks and drug targets. In the 2021 update, we increased the PTM datasets by nearly 50%, included glycosylation, sumoylation and succinylation as new types of PTMs, and updated the workflows to interpret inherited disease mutations. We added a recent phosphoproteomics dataset reflecting the cellular response to SARS-CoV-2 to predict the impact of human genetic variation on COVID-19 infection and disease course. Overall, we estimate that 16-21% of known amino acid substitutions affect PTM sites among pathogenic disease mutations, somatic mutations in cancer genomes and germline variants in the human population. These data underline the potential of interpreting genetic variation through the lens of PTMs and signaling networks. The open-source database is freely available at www.ActiveDriverDB.org.

Background: Basal cell carcinoma (BCC) of the skin is the most common form of human cancer, with more than 90% of tumours presenting with clear genetic activation of the Hedgehog pathway. However, polygenic risk factors affecting mechanisms such as DNA repair and cell cycle checkpoints or which modulate the tumour microenvironment or host immune system play significant roles in determining whether genetic mutations culminate in BCC development. We set out to define background genetic factors that play a role in influencing BCC susceptibility via promoting or suppressing the effects of oncogenic drivers of BCC. Methods: We performed genome-wide association studies (GWAS) on 17,416 cases and 375,455 controls. We subsequently performed statistical analysis by integrating data from population-based genetic studies of multi-omics data, including blood- and skin-specific expression quantitative trait loci and methylation quantitative trait loci, thereby defining a list of functionally relevant candidate BCC susceptibility genes from our GWAS loci. We also constructed a local GWAS functional interaction network (consisting of GWAS nearest genes) and another functional interaction network, consisting specifically of candidate BCC susceptibility genes. Results: A total of 71 GWAS loci and 46 functional candidate BCC susceptibility genes were identified. Increased risk of BCC was associated with the decreased expression of 26 susceptibility genes and increased expression of 20 susceptibility genes. Pathway analysis of the functional candidate gene regulatory network revealed strong enrichment for cell cycle, cell death, and immune regulation processes, with a global enrichment of genes and proteins linked to TReg cell biology. Conclusions: Our genome-wide association analyses and functional interaction network analysis reveal an enrichment of risk variants that function in an immunosuppressive regulatory network, likely hindering cancer immune surveillance and effective antitumour immunity. [ABSTRACT FROM AUTHOR]

Protein post‐translational modifications and protein interactions are the central research areas in mass‐spectrometry‐based proteomics. Protein post‐translational modifications affect protein structures, stabilities, activities, and all cellular processes are achieved by interactions among proteins and protein complexes. With the continuing advancements of mass spectrometry instrumentations of better sensitivity, speed, and performance, selective enrichment of modifications/interactions of interest from complex cellular matrices during the sample preparation has become the overwhelming bottleneck in the proteomics workflow. Therefore, many strategies have been developed to address this issue by targeting specific modifications/interactions based on their physical properties or chemical reactivities, but only a few have been successfully applied for systematic proteome‐wide study. In this review, we summarized the highlights of recent developments in the affinity enrichment methods focusing mainly on low stoichiometric protein lipidations. Besides, to identify potential glyoxal modified arginines, a small part was added for profiling reactive arginine sites using an enrichment reagent. A detailed section was provided for the enrichment of protein interactions by affinity purification and chemical cross‐linking, to shed light on the potentials of different enrichment strategies, along with the unique challenges in investigating individual protein post‐translational modification or protein interaction network. [ABSTRACT FROM AUTHOR]

Multicellular organisms are composed of many tissue types that have distinct morphologies and functions, which are largely driven by specialized proteomes and interactomes. To define the proteome and interactome of a specific type of tissue in an intact animal, we developed a localized proteomics approach called Methionine Analog-based Cell-Specific Proteomics and Interactomics (MACSPI). This method uses the tissue-specific expression of an engineered methionyl-tRNA synthetase to label proteins with a bifunctional amino acid 2-amino-5-diazirinylnonynoic acid in selected cells. We applied MACSPI in Caenorhabditis elegans, a model multicellular organism, to selectively label, capture, and profile the proteomes of the body wall muscle and the nervous system, which led to the identification of tissue-specific proteins. Using the photo-cross-linker, we successfully profiled HSP90 interactors in muscles and neurons and identified tissue-specific interactors and stress-related interactors. Our study demonstrates that MACSPI can be used to profile tissue-specific proteomes and interactomes in intact multicellular organisms., Competing Interests: Competing interests statement:The authors declare no competing interest.

Protein structure (and thus function) is dictated by non-covalent interaction networks. These can be highly evolutionarily conserved across protein families, the members of which can diverge in sequence and evolutionary history. Here we present KIN, a tool to identify and analyze conserved non-covalent interaction networks across evolutionarily related groups of proteins. KIN is available for download under a GNU General Public License, version 2, from https://www.github.com/kamerlinlab/KIN. KIN can operate on experimentally determined structures, predicted structures, or molecular dynamics trajectories, providing insight into both conserved and missing interactions across evolutionarily related proteins. This provides useful insight both into protein evolution, as well as a tool that can be exploited for protein engineering efforts. As a showcase system, we demonstrate applications of this tool to understanding the evolutionary-relevant conserved interaction networks across the class A β-lactamases., (© 2024 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is accountable for the protracted COVID-19 pandemic. Its high transmission rate and pathogenicity led to health emergencies and economic crisis. Recent studies pertaining to the understanding of the molecular pathogenesis of SARS-CoV-2 infection exhibited the indispensable role of ion channels in viral infection inside the host. Moreover, machine learning (ML)-based algorithms are providing a higher accuracy for host-SARS-CoV-2 protein–protein interactions (PPIs). In this study, PPIs of SARS-CoV-2 proteins with human ion channels (HICs) were trained on the PPI-MetaGO algorithm. PPI networks (PPINs) and a signaling pathway map of HICs with SARS-CoV-2 proteins were generated. Additionally, various U.S. food and drug administration (FDA)-approved drugs interacting with the potential HICs were identified. The PPIs were predicted with 82.71% accuracy, 84.09% precision, 84.09% sensitivity, 0.89 AUC-ROC, 65.17% Matthews correlation coefficient score (MCC) and 84.09% F1 score. Several host pathways were found to be altered, including calcium signaling and taste transduction pathway. Potential HICs could serve as an initial set to the experimentalists for further validation. The study also reinforces the drug repurposing approach for the development of host directed antiviral drugs that may provide a better therapeutic management strategy for infection caused by SARS-CoV-2.

Background: In 2017, World Health Organization (WHO) published a catalogue of 12 families of antibiotic-resistant "priority pathogens" that are posing the greatest threats to human health. Six of these dreaded pathogens are known to infect the human gastrointestinal system. In addition to causing gastrointestinal and systemic infections, these pathogens can also affect the composition of other microbes constituting the healthy gut microbiome. Such aberrations in gut microbiome can significantly affect human physiology and immunity. Identifying the virulence mechanisms of these enteric pathogens are likely to help in developing newer therapeutic strategies to counter them. Results: Using our previously published in silico approach, we have evaluated (and compared) Host-Pathogen Protein-Protein Interaction (HPI) profiles of four groups of enteric pathogens, namely, different species of Escherichia, Shigella, Salmonella and Vibrio. Results indicate that in spite of genus/ species specific variations, most enteric pathogens possess a common repertoire of HPIs. This core set of HPIs are probably responsible for the survival of these pathogen in the harsh nutrient-limiting environment within the gut. Certain genus/ species specific HPIs were also observed. Conslusions: The identified bacterial proteins involved in the core set of HPIs are expected to be helpful in understanding the pathogenesis of these dreaded gut pathogens in greater detail. Possible role of genus/ species specific variations in the HPI profiles in the virulence of these pathogens are also discussed. The obtained results are likely to provide an opportunity for development of novel therapeutic strategies against the most dreaded gut pathogens. [ABSTRACT FROM AUTHOR]

Objective: The human umbilical cord and placenta have been considered as attractive alternative sources for noninvasive isolation of human mesenchymal stem cells (hMSCs). Different sources of MSC may have individual differentiation potential and phenotype. In this study, we compared the genome-wide expression data of umbilical cord and placenta derived hMSCs to identify specific differential expression genes (DEGs) and corresponding functions. Materials and methods: We collected human placental tissues and umbilical cord from healthy full-term placenta (n = 17). The genome-wide gene expression data of hMSCs were used to analyze and compare with that of fibroblasts. We identified the differential expression genes (DEGs) based on the Student's t-test and one-way ANOVA. Results: According to the DEGs of umbilical cord and placenta, we used the Venn diagram to evaluate the consistence and specific genes. There are 390 umbilical cord specific DEGs which functions are related to movement of sub-cellular component. Then, the DEGs derived from placenta have two major clusters (i.e., placenta-specific (AM-CM-specific) and UC-like (UC-CD-specific)). 247 placenta-specific DEGs are down-regulated and involved in cell communication. 278 UC-like genes are up-regulated and are involved in the cell cycle, cell division, and DNA repair process. Finally, we also identified 239 umbilical cord-placenta consistence DEGs. According to the umbilical cord-placenta consistence DEGs, 175 genes are down-regulated and involved in cell death, cell growth, cell developmental processes. Conclusion: We identified the consistence and specific DEGs of human placenta and umbilical cord based on the genome-wide comparison. Our results indicated that hMSCs derived from umbilical cord and placenta have different gene expression patterns, and most of specific genes are involved in the cell cycle, cell division, cell death, and cell developmental processes.

Gene duplication is a driver of the evolution of new functions. The duplication of genes encoding homomeric proteins leads to the formation of homomers and heteromers of paralogs, creating new complexes after a single duplication event. The loss of these heteromers may be required for the two paralogs to evolve independent functions. Using yeast as a model, we find that heteromerization is frequent among duplicated homomers and correlates with functional similarity between paralogs. Using in silico evolution, we show that for homomers and heteromers sharing binding interfaces, mutations in one paralog can have structural pleiotropic effects on both interactions, resulting in highly correlated responses of the complexes to selection. Therefore, heteromerization could be preserved indirectly due to selection for the maintenance of homomers, thus slowing down functional divergence between paralogs. We suggest that paralogs can overcome the obstacle of structural pleiotropy by regulatory evolution at the transcriptional and post-translational levels.

Proteins are the most versatile macromolecules in living systems and perform crucial biological functions. In the advent of the post-genomic era, the next generation sequencing is done routinely at the population scale for a variety of species. The challenging problem is to massively determine the functions of proteins that are yet not characterized by detailed experimental studies. Identification of protein functions experimentally is a laborious and time-consuming task involving many resources. We therefore propose the automated protein function prediction methodology using in silico algorithms trained on carefully curated experimental datasets. We present the improved protein function prediction tool FunPred 3.0, an extended version of our previous methodology FunPred 2, which exploits neighborhood properties in protein–protein interaction network (PPIN) and physicochemical properties of amino acids. Our method is validated using the available functional annotations in the PPIN network of Saccharomyces cerevisiae in the latest Munich information center for protein (MIPS) dataset. The PPIN data of S. cerevisiae in MIPS dataset includes 4,554 unique proteins in 13,528 protein–protein interactions after the elimination of the self-replicating and the self-interacting protein pairs. Using the developed FunPred 3.0 tool, we are able to achieve the mean precision, the recall and the F-score values of 0.55, 0.82 and 0.66, respectively. FunPred 3.0 is then used to predict the functions of unpredicted protein pairs (incomplete and missing functional annotations) in MIPS dataset of S. cerevisiae. The method is also capable of predicting the subcellular localization of proteins along with its corresponding functions. The code and the complete prediction results are available freely at: https://github.com/SovanSaha/FunPred-3.0.git.

Transcriptomic data is a treasure trove in modern molecular biology, as it offers a comprehensive viewpoint into the intricate nuances of gene expression dynamics underlying biological systems. This genetic information must be utilized to infer biomolecular interaction networks that can provide insights into the complex regulatory mechanisms underpinning the dynamic cellular processes. Gene regulatory networks and protein-protein interaction networks are two major classes of such networks. This chapter thoroughly investigates the wide range of methodologies used for distilling insightful revelations from transcriptomic data that include association-based methods (based on correlation among expression vectors), probabilistic models (using Bayesian and Gaussian models), and interologous methods. We reviewed different approaches for evaluating the significance of interactions based on the network topology and biological functions of the interacting molecules and discuss various strategies for the identification of functional modules. The chapter concludes with highlighting network-based techniques of prioritizing key genes, outlining the centrality-based, diffusion- based, and subgraph-based methods. The chapter provides a meticulous framework for investigating transcriptomic data to uncover assembly of complex molecular networks for their adaptable analyses across a broad spectrum of biological domains., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Moonlighting proteins perform multiple unrelated functions without any change in polypeptide sequence. They can coordinate cellular activities, serving as switches between pathways and helping to respond to changes in the cellular environment. Therefore, regulation of the multiple protein activities, in space and time, is likely to be important for the homeostasis of biological systems. Some moonlighting proteins may perform their multiple functions simultaneously while others alternate between functions due to certain triggers. The switch of the moonlighting protein's functions can be regulated by several distinct factors, including the binding of other molecules such as proteins. We here review the approaches used to identify moonlighting proteins and existing repositories. We particularly emphasise the role played by short linear motifs and PTMs as regulatory switches of moonlighting functions. [ABSTRACT FROM AUTHOR]

Biological network figures are ubiquitous in the biology and medical literature. On the one hand, a good network figure can quickly provide information about the nature and degree of interactions between items and enable inferences about the reason for those interactions. On the other hand, good network figures are difficult to create. In this paper, we outline 10 simple rules for creating biological network figures for communication, from choosing layouts, to applying color or other channels to show attributes, to the use of layering and separation. These rules are accompanied by illustrative examples. We also provide a concise set of references and additional resources for each rule. [ABSTRACT FROM AUTHOR]

High-throughput multi-omics studies and corresponding network analyses of multi-omic data have rapidly expanded their impact over the last 10 years. As biological features of different types (e.g. transcripts, proteins, metabolites) interact within cellular systems, the greatest amount of knowledge can be gained from networks that incorporate multiple types of -omic data. However, biological and technical sources of variation diminish the ability to detect cross-type associations, yielding networks dominated by communities comprised of nodes of the same type. We describe here network building methods that can maximize edges between nodes of different data types leading to integrated networks, networks that have a large number of edges that link nodes of different–omic types (transcripts, proteins, lipids etc). We systematically rank several network inference methods and demonstrate that, in many cases, using a random forest method, GENIE3, produces the most integrated networks. This increase in integration does not come at the cost of accuracy as GENIE3 produces networks of approximately the same quality as the other network inference methods tested here. Using GENIE3, we also infer networks representing antibody-mediated Dengue virus cell invasion and receptor-mediated Dengue virus invasion. A number of functional pathways showed centrality differences between the two networks including genes responding to both GM-CSF and IL-4, which had a higher centrality value in an antibody-mediated vs. receptor-mediated Dengue network. Because a biological system involves the interplay of many different types of molecules, incorporating multiple data types into networks will improve their use as models of biological systems. The methods explored here are some of the first to specifically highlight and address the challenges associated with how such multi-omic networks can be assembled and how the greatest number of interactions can be inferred from different data types. The resulting networks can lead to the discovery of new host response patterns and interactions during viral infection, generate new hypotheses of pathogenic mechanisms and confirm mechanisms of disease. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor. Molecular heterogeneity is a hallmark of GBM tumors that is a barrier in developing treatment strategies. In this study, we used the nonsynonymous mutations of GBM tumors deposited in The Cancer Genome Atlas (TCGA) and applied a systems level approach based on biophysical characteristics of mutations and their organization in patient-specific subnetworks to reduce inter-patient heterogeneity and to gain potential clinically relevant insights. Approximately 10% of the mutations are located in “patches” which are defined as the set of residues spatially in close proximity that are mutated across multiple patients. Grouping mutations as 3D patches reduces the heterogeneity across patients. There are multiple patches that are relatively small in oncogenes, whereas there are a small number of very large patches in tumor suppressors. Additionally, different patches in the same protein are often located at different domains that can mediate different functions. We stratified the patients into five groups based on their potentially affected pathways, revealed from the patient-specific subnetworks. These subnetworks were constructed by integrating mutation profiles of the patients with the interactome data. Network-guided clustering showed significant association between each group and patient survival (P-value = 0.0408). Also, each group carries a set of signature 3D mutation patches that affect predominant pathways. We integrated drug sensitivity data of GBM cell lines with the mutation patches and the patient groups to analyze the therapeutic outcome of these patches. We found that Pazopanib might be effective in Group 3 by targeting CSF1R. Additionally, inhibiting ATM that is a mediator of PTEN phosphorylation may be ineffective in Group 2. We believe that from mutations to networks and eventually to clinical and therapeutic data, this study provides a novel perspective in the network-guided precision medicine. [ABSTRACT FROM AUTHOR]

Leishmaniasis is a neglected tropical disease caused by Leishmania parasites and is associated to more than 1.3 million cases annually. Some of the pharmacological options for treating the disease are pentavalent antimonials, pentamidine, miltefosine, and amphotericin B. However, all are associated with a wide range of adverse effects and contraindications, as well as resistance from the parasite. In the present study, we looked for pharmacological alternatives to treat leishmaniasis, with a focus on drug repurposing. This was done by detecting potential homologs between proteins targeted by approved drugs and proteins of the parasite. The proteins were analyzed using an interaction network, and the drugs were subjected to in vitro evaluations and pharmacokinetics simulations to compare probable plasma concentrations with the effective concentrations detected experimentally. This strategy yielded a list of 33 drugs with potential anti-Leishmania activity, and more than 80 possible protein targets in the parasite. From the drugs tested, two reported high in vitro activity (perphenazine EC50 = 1.2 µg/mL and rifabutin EC50 = 8.5 µg/mL). These results allowed us to propose these drugs as candidates for further in vivo studies and evaluations of the effectiveness on their topical forms. [ABSTRACT FROM AUTHOR]

Colorectal cancer is one of the top three causes of cancer-related mortality globally, but no predictive molecular biomarkers are currently available for identifying the disease stage of colorectal cancer patients. Common molecular patterns in the disease, beyond superficial manifestations, can be significant in determining treatment choices. In this study, we used microarray data from colorectal cancer and adjacent normal tissue from the GEO database. These data were categorized into four consensus molecular subtypes based on distinct gene expression signatures. Weighted gene-based protein–protein interaction network analysis was performed for each subtype. NUSAP1, CD44, and COL4A1 modules were found to be statistically significant and present among all the subtypes and displayed though similar but not identical functional enrichment results. Reference of the characteristics of the subtypes to functional modules is necessary since the latter can stay resistant to platform changes and technique noise when compared with other analyses. The CMS4-mesenchymal group, which currently has a poor prognosis, was examined in the study. It is composed mainly of genes involved in immune and stromal expression, with modules focused on ECM dysregulation and chemokine biological processes. Hub genes detection and its’ mapping into the protein–protein interaction network can be indicative of possible targets against specific modules. This approach identified subtypes using enrichment-oriented analysis in functional modules. Proper annotation of functional analysis of modules from different subtypes of CRC might be directive for finding extra options for treatment targets and guiding clinical routines. [ABSTRACT FROM AUTHOR]

The visualization of biological networks is critically important to aid researchers in understanding complex biological systems and arouses interest in designing efficient layout algorithms to draw biological networks according to their topology structures, especially for those networks with potential modules. The algorithms of grid layout series have an advantage in generating compact layouts with overlap-free nodes compared to force-directed; however, extant grid layout algorithms have difficulty in drawing modular networks and often generate layouts of high visual complexity when applied to networks with dense or clustered connectivity structure. To specifically assist the study of modular networks, we propose a grid- and modularity-based layout algorithm (GML) that consists of three stages: network preprocessing, module layout and grid optimization. The algorithm can draw complex biological networks with or without predefined modules based on the grid layout algorithm. It also outperforms other existing grid-based algorithms in the measurement of computation performance, ratio of edge-edge/node-edge crossings, relative edge lengths, and connectivity F-measures. GML helps users to gain insight into the network global characteristics through module layout, as well as to discern network details with grid optimization. GML has been developed as a VisANT plugin () and is freely available to the research community. [ABSTRACT FROM AUTHOR]

Tailored therapy aims to cure cancer patients effectively and safely, based on the complex interactions between patients' genomic features, disease pathology and drug metabolism. Thus, the continual increase in scientific literature drives the need for efficient methods of data mining to improve the extraction of useful information from texts based on patients' genomic features. An important application of text mining to tailored therapy in cancer encompasses the use of mutations and cancer fusion genes as moieties that change patients' cellular networks to develop cancer, and also affect drug metabolism. Fusion proteins, which are derived from the slippage of two parental genes, are produced in cancer by chromosomal aberrations and trans-splicing. Given that the two parental proteins for predicted fusion proteins are known, we used our previously developed method for identifying chimeric protein–protein interactions (ChiPPIs) associated with the fusion proteins. Here, we present a validation approach that receives fusion proteins of interest, predicts their cellular network alterations by ChiPPI and validates them by our new method, ProtFus, using an online literature search. This process resulted in a set of 358 fusion proteins and their corresponding protein interactions, as a training set for a Naïve Bayes classifier, to identify predicted fusion proteins that have reliable evidence in the literature and that were confirmed experimentally. Next, for a test group of 1817 fusion proteins, we were able to identify from the literature 2908 PPIs in total, across 18 cancer types. The described method, ProtFus, can be used for screening the literature to identify unique cases of fusion proteins and their PPIs, as means of studying alterations of protein networks in cancers. Availability: [ABSTRACT FROM AUTHOR]

Acute hepatopancreatic necrosis disease (AHPND), caused by marine bacteria Vibrio Parahaemolyticus, is a huge problem in shrimp farms. The V. parahaemolyticus infecting material is contained in a plasmid which encodes for the lethal toxins PirABVp, whose primary target tissue is the hepatopancreas, causing sloughing of epithelial cells, necrosis, and massive hemocyte infiltration. To get a better understanding of the hepatopancreas response during AHPND, juvenile shrimp Litopenaeus vannamei were infected by immersion with V. parahaemolyticus. We performed transcriptomic mRNA sequencing of infected shrimp hepatopancreas, at 24 hours post-infection, to identify novel differentially expressed genes a total of 174,098 transcripts were examined of which 915 transcripts were found differentially expressed after comparative transcriptomic analysis: 442 up-regulated and 473 down-regulated transcripts. Gene Ontology term enrichment analysis for up-regulated transcripts includes metabolic process, regulation of programmed cell death, carbohydrate metabolic process, and biological adhesion, whereas for down-regulated transcripts include, microtubule-based process, cell activation, and chitin metabolic process. The analysis of protein- protein network between up and down-regulated genes indicates that the first gene interactions are connected to oxidation-processes and sarcomere organization. Additionally, protein-protein networks analysis identified 20-top highly connected hub nodes. Based on their immunological or metabolic function, ten candidate transcripts were selected to measure their mRNA relative expression levels in AHPND infected shrimp hepatopancreas by RT-qPCR. Our results indicate a close connection between the immune and metabolism systems during AHPND infection. Our RNA-Seq and RT-qPCR data provide the possible immunological and physiological scenario as well as the molecular pathways that take place in the shrimp hepatopancreas in response to an infectious disease. [ABSTRACT FROM AUTHOR]