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At least 325 records · Page 18Linked to original sources

SNA--a toolbox for the stoichiometric analysis of metabolic networks.

BACKGROUND: Despite recent algorithmic and conceptual progress, the stoichiometric network analysis of large metabolic models remains a computationally challenging problem. RESULTS: SNA is a interactive, high performance toolbox for analysing the possible steady state behaviour of metabolic networks by computing the generating and elementary vectors of their flux and conversions cones. It also supports analysing the steady states by linear programming. The toolbox is implemented mainly in Mathematica and returns numerically exact results. It is available under an open source license from: http://bioinformatics.org/project/?group_id=546. CONCLUSION: Thanks to its performance and modular design, SNA is demonstrably useful in analysing genome scale metabolic networks. Further, the integration into Mathematica provides a very flexible environment for the subsequent analysis and interpretation of the results.

Algorithms↗

Gene behaviors-based network enrichment analysis and its application to reveal immune disease pathways enriched with COVID-19 severity-specific gene networks.

MOTIVATION: Gene network analysis is essential for understanding the complex mechanisms underlying diseases, which often involve disruptions in molecular networks rather than individual genes. Despite the availability of large-scale omics datasets and computational tools for gene network analysis, interpretation of the biological relevance of these extensive networks remains challenging. RESULTS: We propose a novel computational strategy, gene behaviors-based network enrichment analysis, which systematically identifies functional pathways enriched in phenotype-specific gene networks. Our novel method incorporates comprehensive network characteristics, i.e. gene expression levels, edge strengths, and structural patterns of edges, to rank genes based on activity and assess pathway enrichment, effectively identifying functional pathways enriched within these networks. Through simulation studies, our strategy demonstrated superior performance compared with that of existing methods in identifying enriched pathways. We applied this strategy to whole-blood RNA-seq data from 1102 COVID-19 samples provided by the Japan COVID-19 Task Force. The analysis revealed immune disease pathways enriched with COVID-19 severity-specific gene networks, including "Systemic lupus erythematosus" in asymptomatic and severe samples and "Inflammatory bowel disease," "Primary immunodeficiency," and "Rheumatoid arthritis" in mild samples. Key biomarkers of COVID-19, such as CXCL8, S100A9, and HLA class I genes, have been identified as critical hub genes and the main players within these networks. AVAILABILITY AND IMPLEMENTATION: Code is available in Figshare (https://doi.org/10.6084/m9.figshare.29093648.v3).

COVID-19↗

Computational network biology analysis revealed COVID-19 severity markers: Molecular interplay between HLA-II with CIITA.

COVID-19, severe acute respiratory syndrome coronavirus 2, rapidly spread worldwide. Severe and critical patients are expected to rapidly deteriorate. Although several studies have attempted to uncover the mechanisms underlying COVID-19 severity, most have focused on the perturbations of single genes. However, the complex mechanism of COVID-19 involves numerous perturbed genes in a molecular network rather than a single abnormal gene. Thus, we aimed to identify COVID-19 severity-specific markers in the Japanese population using gene network analysis. In order to reveal the severity-specific molecular interplays, we developed a novel computational network biology strategy that measures dissimilarity between networks based on the comprehensive information of gene network (i.e., expression levels of genes and network structure) by using Kullback-Leibler divergence. Monte Carlo simulations demonstrated the effectiveness of our strategy for differential gene network analysis. We applied this method to publicly available whole blood RNA-seq data from the Japan coronavirus disease 2019 Task Force and identified differentially regulated molecular interplays between 368 severe and 105 non-severe samples. Our analysis suggests the gene network between HLA class II, CIITA, and CD74 as a COVID-19 severity specific molecular marker. Although the association between HLA class II and COVID-19 has been demonstrated, our data analysis revealed that the molecular interplay of HLA class II with its target and/or regulator is a crucial marker for COVID-19 severity. Our findings from computational network biology analysis suggest that suppression and activation of the molecular interplay between HLA class II, CIITA, and CD74 provide crucial clues to uncover the mechanisms of COVID-19 severity.

Humans↗

Biological networks and analysis of experimental data in drug discovery.

Cellular life can be represented and studied as the 'interactome'--a dynamic network of biochemical reactions and signaling interactions between active proteins. Systemic networks analysis can be used for the integration and functional interpretation of high-throughput experimental data, which are abundant in drug discovery but currently poorly utilized. The composition and topology of complex networks are closely associated with vital cellular functions, which have important implications for life science research. Here we outline recent advances in the field, available tools and applications of network analysis in drug discovery.

Computer Simulation↗

A generalized higher-order correlation analysis framework for multi-omics network inference.

Multiple -omics (genomics, proteomics, etc.) profiles are commonly generated to gain insight into a disease or physiological system. Constructing multi-omics networks with respect to the trait(s) of interest provides an opportunity to understand relationships between molecular features but integration is challenging due to multiple data sets with high dimensionality. One approach is to use canonical correlation to integrate one or two omics types and a single trait of interest. However, these types of methods may be limited due to (1) not accounting for higher-order correlations existing among features, (2) computational inefficiency when extending to more than two omics data when using a penalty term-based sparsity method, and (3) lack of flexibility for focusing on specific correlations (e.g., omics-to-phenotype correlation versus omics-to-omics correlations). In this work, we have developed a novel multi-omics network analysis pipeline called Sparse Generalized Tensor Canonical Correlation Analysis Network Inference (SGTCCA-Net) that can effectively overcome these limitations. We also introduce an implementation to improve the summarization of networks for downstream analyses. Simulation and real-data experiments demonstrate the effectiveness of our novel method for inferring omics networks and features of interest.

Genomics↗

Network thermodynamic analysis of vasomotion in a microvascular network.

The modulation of microvascular blood flow by vasomotion in the individual vessels of a simple vascular network was simulated by means of a network thermodynamic model. The flow is driven under a pulsating pressure through two arcades of branching vasoactive arterioles into a passive resistance representing the capillary and venular beds. Each vessel was assumed to have the capability of decreasing rhythmically the local diameter over a short section by a specified fraction of the maximum value and to change the average diameter along its total length in response to alterations in intraluminal pressure. Blood was assumed to exhibit a simple linear viscous flow resistance. Alterations in flow rate and distribution through the network were determined as a function of the magnitude and frequency of vasomotion within the individual arterioles supplying blood to the microvascular bed. Specific cases are shown to illustrate how blood flow can be influenced by the patterns of vasomotion within the network.

Arterioles↗

Quantitative analysis of network architecture, and microhemodynamics in arteriolar vessel trees of the ventilated rabbit lung.

An experimental model has been developed for morphometric and microhemodynamic analysis of discrete arteriolar networks in the ventilated lung. We implanted a transparent window into the right thoracic wall of anesthetized rabbits. Autologous red blood cells were labeled with FITC in vitro. Using a fluorescence video microscopic technique the vessels of superficial arteriolar networks were mapped and classified hierarchically. Networks were investigated under zone 2 conditions (alveolar > left atrial pressure) during continuous monitoring of macrohemodynamics. We comprehensively measured segment length, diameter (D) and branching pattern in the whole network. Microhemodynamic parameters (red blood cell flux (Frbc), red blood cell velocity (Vrbc) and microhematocrit (H mu) were determined in terminal branches. As a result of network analysis the branching rules were found to be similar to those found by cast techniques in human and cat lungs. In terminal arterioles D (21 +/- 4 microns), Frbc (1472 +/- 662 cells/s), Vrbc (863 +/- 250 microns/s) and H mu (0.28 +/- 0.067) were heterogeneously distributed. Geometric, as well as microhemodynamic parameters fitted best to a lognormal distribution. This study represents an example of in vivo analysis of discrete microvascular networks. The measurements in hierarchically equivalent segments of pulmonary arteriolar vessel trees have been shown to be appropriate for estimation of topological, geometrical and microhemodynamic heterogeneity in pulmonary arteriolar networks.

Animals↗

Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target.

Glioblastoma is the most common primary malignant brain tumor of adults and one of the most lethal of all cancers. Patients with this disease have a median survival of 15 months from the time of diagnosis despite surgery, radiation, and chemotherapy. New treatment approaches are needed. Recent works suggest that glioblastoma patients may benefit from molecularly targeted therapies. Here, we address the compelling need for identification of new molecular targets. Leveraging global gene expression data from two independent sets of clinical tumor samples (n = 55 and n = 65), we identify a gene coexpression module in glioblastoma that is also present in breast cancer and significantly overlaps with the "metasignature" for undifferentiated cancer. Studies in an isogenic model system demonstrate that this module is downstream of the mutant epidermal growth factor receptor, EGFRvIII, and that it can be inhibited by the epidermal growth factor receptor tyrosine kinase inhibitor Erlotinib. We identify ASPM (abnormal spindle-like microcephaly associated) as a key gene within this module and demonstrate its overexpression in glioblastoma relative to normal brain (or body tissues). Finally, we show that ASPM inhibition by siRNA-mediated knockdown inhibits tumor cell proliferation and neural stem cell proliferation, supporting ASPM as a potential molecular target in glioblastoma. Our weighted gene coexpression network analysis provides a blueprint for leveraging genomic data to identify key control networks and molecular targets for glioblastoma, and the principle eluted from our work can be applied to other cancers.

Animals↗

The influence of lifestyle on cardiovascular risk factors. Analysis using a neural network.

The cardiovascular pathologies are the most common causes of death in the elderly patient. To single out the main risk factors in order to effectively prevent the onset of the disease, the authors experimented a special computerized tool, the neural network, that works out a mathematical relation that can obtain certain data (defined as output) as a function of other data (defined as input). Data were processed from a sample of 276 subjects of both sexes aged 26-69 years old. The output data were: high/low cholesterolemia, HDL cholesterol, triglyceridemia with respect to an established cut-off; the input data were: sex, age, build, weight, married/single, number of children, number of cigarettes smoked/day, amount of wine and number of cups of coffee. We conclude that: (i) a relationship exists, deduced from a neural network, between a set of input variables and a dichotomous output variable; (ii) this relationship can be expressed as a mathematical function; (iii) a neural network, having learned the data on a sufficiently large population, can provide valid predictive data for a single individual with a high probability (up to 93.33%) that the response it gives is correct. In this study, such a result is found for two of the three cardiovascular risk indicators considered (cholesterol and triglycerides); (iv) the repetition of the neural network analysis of the cases in question after a "pruning" operation provided a somewhat less good performance; (v) a statistical analysis conducted on those same cases has confirmed the existence of a strong relationship between the input and the output variables. Therefore the neural network is a valid instrument for providing predictive in a single subject on cardiovascular pathology risks.

Adult↗

Transcriptome network component analysis with limited microarray data.

UNLABELLED: Network component analysis (NCA) is a method to deduce transcription factor (TF) activities and TF-gene regulation control strengths from gene expression data and a TF-gene binding connectivity network. Previously, this method could analyze a maximum number of regulators equal to the total sample size because of the identifiability limit in data decomposition. As such, the total number of source signal components was limited to the total number of experiments rather than the total number of biological regulators. However, networks that have less transcriptome data points than the number of regulators are of interest. Thus it is imperative to develop a theoretical basis that allows realistic source signal extraction based on relatively few data points. On the other hand, such methods would inherently increase numerical challenges leading to multiple solutions. Therefore, solutions to both the problems are needed. RESULTS: We have improved NCA for transcription factor activity (TFA) estimation, based on the observation that most genes are regulated by only a few TFs. This observation leads to the derivation of a new identifiability criterion which is tested during numerical iteration that allows us to decompose data when the number of TFs is greater than the number of experiments. To show that our method works with real microarray data and has biological utility, we analyze Saccharomyces cerevisiae cell cycle microarray data (73 experiments) using a TF-gene connectivity network (96 TFs) derived from ChIP-chip binding data. We compare the results of NCA analysis with the results obtained from ChIP-chip regression methods, and we show that NCA and regression produce TFAs that are qualitatively similar, but the NCA TFAs outperform regression in statistical tests. We also show that NCA can extract subtle TFA signals that correlate with known cell cycle TF function and cell cycle phase. Overall we determined that 31 TFs have statistically periodic TFAs in one or more experiments, 75% of which are known cell cycle regulators. In addition, we find that the 12 TFAs that are periodic in two or more experiments correspond to well-known cell cycle regulators. We also investigated TFA sensitivity to the choice of connectivity network we constructed two networks using different ChIP-chip p-value cut-offs. AVAILABILITY: The NCA Toolbox for MATLAB is available at http://www.seas.ucla.edu/~liaoj/download.htm.

Algorithms↗

Comprehensive curation and analysis of global interaction networks in Saccharomyces cerevisiae.

BACKGROUND: The study of complex biological networks and prediction of gene function has been enabled by high-throughput (HTP) methods for detection of genetic and protein interactions. Sparse coverage in HTP datasets may, however, distort network properties and confound predictions. Although a vast number of well substantiated interactions are recorded in the scientific literature, these data have not yet been distilled into networks that enable system-level inference. RESULTS: We describe here a comprehensive database of genetic and protein interactions, and associated experimental evidence, for the budding yeast Saccharomyces cerevisiae, as manually curated from over 31,793 abstracts and online publications. This literature-curated (LC) dataset contains 33,311 interactions, on the order of all extant HTP datasets combined. Surprisingly, HTP protein-interaction datasets currently achieve only around 14% coverage of the interactions in the literature. The LC network nevertheless shares attributes with HTP networks, including scale-free connectivity and correlations between interactions, abundance, localization, and expression. We find that essential genes or proteins are enriched for interactions with other essential genes or proteins, suggesting that the global network may be functionally unified. This interconnectivity is supported by a substantial overlap of protein and genetic interactions in the LC dataset. We show that the LC dataset considerably improves the predictive power of network-analysis approaches. The full LC dataset is available at the BioGRID (http://www.thebiogrid.org) and SGD (http://www.yeastgenome.org/) databases. CONCLUSION: Comprehensive datasets of biological interactions derived from the primary literature provide critical benchmarks for HTP methods, augment functional prediction, and reveal system-level attributes of biological networks.

Computational Biology↗

Agent based simulations in healthcare.

Agent Based Simulations (ABS) is a relatively recent computer paradigm. As opposed to "top down" conventional computer simulations, the ABS approach is a "bottom-up" modelling technique where a medium to high number of independent agents is modelled. These agents' interactions sometimes cause unexpected "emergent" system behaviour. ABS is particularly suitable in the social context such as healthcare where a large number of human agents interact and co-operate for common goals. Today ABS in the social context is often used together with the recently introduced network analysis techniques and network visualization tools for modelling and simulating social agents within organisations. At Akdeniz University we are starting a number of projects for applying ABS technology in healthcare. In this paper we present two of the ongoing projects in this field. Firstly we have developed a prototype simulator for the long term monitoring of Chronic Obstructive Pulmonary Disease (COPD) as a major public health problem. We present the COPD simulator, its agents, parameters and working principles. Secondly we want to apply ABS and the network analysis techniques to visualise and explore informal social networks amongst staff at the Akdeniz University Hospital to assess and evaluate properties of the organisation in terms of its ability to innovate and share knowledge. In our applications, we primarily aim to use ABS in a web-based platform to create a virtual environment for discussion, visualising and running what-if scenarios to test out various options for managing healthcare, as well as sharing information and creating a virtual community.

Computer Simulation↗

[Predictive role of diagnostic information in treatment efficacy of rheumatoid arthritis based on neural network model analysis].

OBJECTIVE: To analyze the indications of the therapies for rheumatoid arthritis (RA) with neural network model analysis. METHODS: Three hundred and ninety-seven patients were included in the clinical trial from 9 clinical centers. They were randomly divided into Western medicine (WM) treated group, 194 cases; and traditional Chinese herbal medicine (CM) treated group, 203 cases. A complete physical examination and 18 common clinical manifestations were prepared before the randomization and after the treatment. The WM therapy included voltaren extended action tablet, methotrexate and sulfasalazine. The CM therapy included Glucosidorum Tripterygii Totorum Tablet and syndrome differentiation treatment. The American College of Rheumatology 20 (ACR20) was taken as efficacy evaluation. All data were analyzed on SAS 8.2 statistical package. The relationships between each variable and efficacy were analyzed, and the variables with P<0.2 were included for the data mining analysis with neural network model. All data were classified into training set (75%) and verification set (25%) for further verification on the data-mining model. RESULTS: Eighteen variables in CM and 24 variables in WM were included in the data-mining model. In CM, morning stiffness, swollen joint number, peripheral immunoglobulin M (IgM) level, tenderness joint number, tenderness, rheumatoid factor (RF), C-reactive protein (CRP) and joint pain were positively related to the efficacy, and disease duration and more urination at night negatively related to the efficacy. In WM, erythrocyte sedimentation rate (ESR), weak waist, white fur in tongue, joint pain, joint stiffness and swollen joint were positively related to the efficacy, and yellow fur in tongue, red tongue, white blood negatively related to the efficacy. In the analysis with the neural network model in the patients of verification set, the predictive response rates of 20% patients would be 100% and 90% in the treatment with CM and WM, respectively. CONCLUSION: Neural network model analysis, based on the full clinical trial data with collection of both traditional Chinese medicine and modern medicine diagnostic information, shows a good predictive role for the information in the efficacy in rheumatoid arthritis.

Adult↗

BioNeuralNet: a graph neural network based Multi-Omics network data analysis tool.

SUMMARY: Multi-omics data offer unprecedented insights into complex biological systems, yet their high dimensionality, sparsity, and intricate interactions pose significant analytical challenges. Network-based approaches have advanced multi-omics research by effectively capturing biologically relevant relationships among molecular features (e.g., genes, proteins, metabolites). While these methods are powerful for representing molecular interactions, there remains a need for tools specifically designed to effectively utilize these network representations across diverse downstream analyses. To fulfill this need, we introduce BioNeuralNet, a flexible and modular Python framework tailored for end-to-end network-based multi-omics data analysis. BioNeuralNet leverages Graph Neural Networks (GNNs) to learn biologically meaningful low-dimensional representations from multi-omics networks, converting these complex molecular networks into versatile embeddings. BioNeuralNet supports all major stages of multi-omics network analysis, including several network construction techniques, generation of low-dimensional representations, and a broad range of downstream analytical tasks. Its extensive utilities, including diverse GNN architectures, and compatibility with established Python packages (e.g., scikit-learn, PyTorch, NetworkX), enhance usability and facilitate quick adoption. BioNeuralNet is an open-source, user-friendly, and extensively documented framework designed to support flexible and reproducible multi-omics network analysis in precision medicine. AVAILABILITY AND IMPLEMENTATION: The BioNeuralNet library is available via The Python Package Index (PyPI). Source code, documentation, tutorials, and workflows are hosted at https://bioneuralnet.readthedocs.io. Code archived at https://doi.org/10.5281/zenodo.17503083.

Graph Neural Networks↗

Automatic network coupling analysis for dynamical systems based on detailed kinetic models.

We introduce a numerical complexity reduction method for the automatic identification and analysis of dynamic network decompositions in (bio)chemical kinetics based on error-controlled computation of a minimal model dimension represented by the number of (locally) active dynamical modes. Our algorithm exploits a generalized sensitivity analysis along state trajectories and subsequent singular value decomposition of sensitivity matrices for the identification of these dominant dynamical modes. It allows for a dynamic coupling analysis of (bio)chemical species in kinetic models that can be exploited for the piecewise computation of a minimal model on small time intervals and offers valuable functional insight into highly nonlinear reaction mechanisms and network dynamics. We present results for the identification of network decompositions in a simple oscillatory chemical reaction, time scale separation based model reduction in a Michaelis-Menten enzyme system and network decomposition of a detailed model for the oscillatory peroxidase-oxidase enzyme system.

Algorithms↗

Network neighborhood analysis with the multi-node topological overlap measure.

MOTIVATION: The goal of neighborhood analysis is to find a set of genes (the neighborhood) that is similar to an initial 'seed' set of genes. Neighborhood analysis methods for network data are important in systems biology. If individual network connections are susceptible to noise, it can be advantageous to define neighborhoods on the basis of a robust interconnectedness measure, e.g. the topological overlap measure. Since the use of multiple nodes in the seed set may lead to more informative neighborhoods, it can be advantageous to define multi-node similarity measures. RESULTS: The pairwise topological overlap measure is generalized to multiple network nodes and subsequently used in a recursive neighborhood construction method. A local permutation scheme is used to determine the neighborhood size. Using four network applications and a simulated example, we provide empirical evidence that the resulting neighborhoods are biologically meaningful, e.g. we use neighborhood analysis to identify brain cancer related genes. AVAILABILITY: An executable Windows program and tutorial for multi-node topological overlap measure (MTOM) based analysis can be downloaded from the webpage (http://www.genetics.ucla.edu/labs/horvath/MTOM/).

Algorithms↗

Connecting the dots in Huntington's disease with protein interaction networks.

Analysis of protein-protein interaction networks is becoming important for inferring the function of uncharacterized proteins. A recent study using this approach has identified new proteins and interactions that might be involved in the pathogenesis of the neurodegenerative disorder Huntington's disease, including a GTPase-activating protein that co-localizes with protein aggregates in Huntington's disease patients.

Adaptor Proteins, Signal Transducing↗