Human Interaction Network Research Articles

Deciphering the Molecular Landscape of Dengue Infection: Insights from gene expression profiling and Protein Interactions

Dengue fever (DF) is a viral infection recognized as one of the most rapidly spreading vector-borne diseases among humans. However, the molecular mechanisms underlying disease aetiology and potential therapeutic targets remain unclear. This study presents a thorough examination of differentially expressed genes (DEGs) throughout the spectrum of Dengue infection stages, offering insights into disease mechanisms and therapeutic targets. Through meticulous analysis of DEGs within each infection stage, key genes pertinent to disease progression are identified, highlighting their roles in host-virus interactions. Noteworthy discoveries include the upregulation of IFI27 and USP18 in mild infection, suggesting involvement in viral replication inhibition and host defence, alongside the downregulation of CMTM2, indicating alterations in immune-related functions. Similarly, in severe infection, upregulated genes like IGHV1-69 are linked to illness severity, while downregulated IL-13RA1 signifies disruptions in cytokine signaling. Overlapping DEGs between infection groups unveil shared biological processes, further elucidated through functional enrichment analysis, showcasing coordinated regulation of cellular processes and pathways. Integration of Dengue virus and human interaction network analysis reveals crucial insights into the mechanisms by which the virus mediates the disease progression and offers potential therapeutic opportunities for disease management.

A Simple Modelling of Microscopic Epidemic Process with Two Vaccine Doses on a Synthesized Human Interaction Network

In this study, we illustrate the incorporation of two vaccine doses into a discrete SIR model to aid in the decision-making process for optimal vaccination strategies. We present a basic model of a human interaction network synthesized to depict social contacts within a population, taking into account the number of connections and the level of interaction among individuals. Under a limited number of available vaccine doses, we explore various vaccination scenarios considering factors such as the distribution of vaccines, the proportion of vaccinated individuals, and the timing of vaccination commencement. Our research demonstrates that the most effective vaccination strategy, which focuses on re-characterized hubs or redefining the individual who has high connectivity, will cover fewer individuals and result in the smallest total number of infected individuals.

Abstract IA021: Environmental challenge rewires functional connections among human genes

Abstract A fundamental question in biology is how a limited number of genes combinatorially govern cellular responses to environmental changes. While the prevailing hypothesis is that relationships between genes, processes, and ontologies could be plastic to achieve this adaptability, quantitatively comparing human gene functional connections between specific environmental conditions at scale is very challenging. Therefore, it remains unclear whether and how human genetic interaction networks are rewired in response to changing environmental conditions. Here, we developed a framework for mapping context-specific genetic interactions, enabling us to measure the plasticity of human genetic architecture upon environmental challenge for ∼250,000 interactions, using cell cycle interruption, genotoxic perturbation, and nutrient deprivation as archetypes. We discover large-scale rewiring of human gene relationships across conditions, highlighted by dramatic shifts in the functional connections of epigenetic regulators (TIP60), cell cycle regulators (PP2A), and glycolysis metabolism. Our study demonstrates that upon environmental perturbation, intra-complex genetic rewiring is rare while inter-complex rewiring is common, suggesting a modular and flexible evolutionary genetic strategy that allows a limited number of human genes to enable adaptation to a large number of environmental conditions. Citation Format: Luke Gilbert, Ben Herken. Environmental challenge rewires functional connections among human genes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA021.

GT-CHES: Graph transformation for classification in human evolutionary systems

While increasingly complex algorithms are being developed for graph classification in highly-structured domains, such as image processing and climate forecasting, they often lead to over-fitting and inefficiency when applied to human interaction networks where the confluence of cooperation, conflict, and evolutionary pressures produces chaotic environments. We propose a graph transformation approach for efficient classification in chaotic human systems that is based on game theoretic, network theoretic, and chaos theoretic principles. Graph structural properties are compiled into time-series that are then transposed into the frequency domain to offer a dynamic view of the system for classification. We propose a set of benchmark data sets and show through experiments that the approach is efficient and appropriate for many dynamic networks in which agents both compete and cooperate, such as social media networks, stock markets, political campaigns, legislation, and geopolitical events.

A computational model of epidemic process with three variants on a synthesized human interaction network

Virus mutations give rise to new variants that cause multiple waves of pandemics and escalate the infected number of individuals. In this paper, we develop both a simple random network that we define as a synthesized human interaction network and an epidemiological model based on the microscopic process of disease spreading to describe the epidemic process with three variants in a population with some features of social structure. The features of social structure we take into account in the model are the average number of degrees and the frequency of contacts. This paper shows many computational results from several scenarios both in varying network structures and epidemiological parameters that cannot be obtained numerically by using the compartmental model.

Minor intron-containing genes as an ancient backbone for viral infection?

Minor intron-containing genes (MIGs) account for <2% of all human protein-coding genes and are uniquely dependent on the minor spliceosome for proper excision. Despite their low numbers, we surprisingly found a significant enrichment of MIG-encoded proteins (MIG-Ps) in protein-protein interactomes and host factors of positive-sense RNA viruses, including SARS-CoV-1, SARS-CoV-2, MERS coronavirus, and Zika virus. Similarly, we observed a significant enrichment of MIG-Ps in the interactomes and sets of host factors of negative-sense RNA viruses such as Ebola virus, influenza A virus, and the retrovirus HIV-1. We also found an enrichment of MIG-Ps in double-stranded DNA viruses such as Epstein-Barr virus, human papillomavirus, and herpes simplex viruses. In general, MIG-Ps were highly connected and placed in central positions in a network of human-host protein interactions. Moreover, MIG-Ps that interact with viral proteins were enriched with essential genes. We also provide evidence that viral proteins interact with ancestral MIGs that date back to unicellular organisms and are mainly involved in basic cellular functions such as cell cycle, cell division, and signal transduction. Our results suggest that MIG-Ps form a stable, evolutionarily conserved backbone that viruses putatively tap to invade and propagate in human host cells.

The application of convolutional neural networks in face detection

Face detection is a popular and challenging issue which is widely studied in the past few decades. Its application includes the identity authentication, human machine interaction, security surveillance and social network. To have a better insight of the application of one of the typical deep learning algorithms called Convolutional Neural Network (CNN) in this field, this paper aims to analyze the current literature and progress about the face detection of low image quality and face detection optimization. The literature of Convolutional Neural Network from 2015 was included in this paper. Past research topics of face detection includes the occlusion, scale, small face cluster, speed, precision and multi-task region proposal network. The comparison between various deep learning-based methods in terms of the performance indicated that there is still no high robustness solution to all problems. The future research agendas of face detection based on the Convolutional Neural Network was also summarized.

Total network controllability analysis discovers explainable drugs for Covid-19 treatment

BackgroundThe active pursuit of network medicine for drug repurposing, particularly for combating Covid-19, has stimulated interest in the concept of structural controllability in cellular networks. We sought to extend this theory, focusing on the defense rather than control of the cell against viral infections. Accordingly, we extended structural controllability to total structural controllability and introduced the concept of control hubs. Perturbing any control hub may render the cell uncontrollable by exogenous stimuli like viral infections, so control hubs are ideal drug targets.ResultsWe developed an efficient algorithm to identify all control hubs, applying it to a largest homogeneous network of human protein interactions, including interactions between human and SARS-CoV-2 proteins. Our method recognized 65 druggable control hubs with enriched antiviral functions. Utilizing these hubs, we categorized potential drugs into four groups: antiviral and anti-inflammatory agents, drugs acting on the central nervous system, dietary supplements, and compounds enhancing immunity. An exemplification of our approach’s effectiveness, Fostamatinib, a drug initially developed for chronic immune thrombocytopenia, is now in clinical trials for treating Covid-19. Preclinical trial data demonstrated that Fostamatinib could reduce mortality rates, ICU stay length, and disease severity in Covid-19 patients.ConclusionsOur findings confirm the efficacy of our novel strategy that leverages control hubs as drug targets. This approach provides insights into the molecular mechanisms of potential therapeutics for Covid-19, making it a valuable tool for interpretable drug discovery. Our new approach is general and applicable to repurposing drugs for other diseases.

A spatially defined human Notch receptor interaction network reveals Notch intracellular storage and Ataxin-2-mediated fast recycling

The Notch signaling pathway controls cell growth, differentiation, and fate decisions. Dysregulation of Notch signaling has been linked to various human diseases. Notch receptor resides in multiple cellular compartments, and its translocation plays a central role in pathway activation. However, the spatial regulation of Notch receptor functions remains largely elusive. Using TurboID-based proximity labeling followed by affinity purification and mass spectrometry, we establish a spatially defined human Notch receptor interaction network. Notch receptors interact with different proteins in distinct subcellular compartments to perform specific cellular functions. This spatially defined interaction network also reveals that a large fraction of NOTCH is stored at the endoplasmic reticulum (ER)-Golgi intermediate compartment and recruits Ataxin-2-dependent recycling machinery for rapid recycling, Notch signaling activation, and leukemogenesis. Our work provides insights into dynamic Notch receptor complexes with exquisite spatial resolution, which will help in elucidating the detailed regulation of Notch receptors and highlight potential therapeutic targets for Notch-related pathogenesis.

Multi-scale cross-city community detection of urban agglomeration using signaling big data

ABSTRACT Many existing efforts have taken advantage of large-scale spatial-temporal data to partition cities via constructed human interaction networks. However, few studies focus on communities emerging between adjacent cities in big urban agglomerations, which we call “cross-city” communities. In this study, we introduce a novel framework to detect cross-city communities in urban agglomerations under different scales leveraging a large number of fine-grained mobile signaling data aiming to break the original administrative boundaries. Taking the Pearl River Delta (PRD) urban agglomeration in China as study area, we investigate the existence of potential communities at three scales, i.e. city-group level, city level and sub-city level. The partition results are expected to benefit transportation planning, urban zoning and administrative boundary re-delineation. The results from our study highlight the necessity of considering cross-city communities and their scale effects when examining urban spatial interactions.

Integrating differential expression, co-expression and gene network analysis for the identification of common genes associated with tumor angiogenesis deregulation

Angiogenesis is essential for tumor growth and cancer metastasis. Identifying the molecular pathways involved in this process is the first step in the rational design of new therapeutic strategies to improve cancer treatment. In recent years, RNA-seq data analysis has helped to determine the genetic and molecular factors associated with different types of cancer. In this work we performed integrative analysis using RNA-seq data from human umbilical vein endothelial cells (HUVEC) and patients with angiogenesis-dependent diseases to find genes that serve as potential candidates to improve the prognosis of tumor angiogenesis deregulation and understand how this process is orchestrated at the genetic and molecular level.We downloaded four RNA-seq datasets (including cellular models of tumor angiogenesis and ischaemic heart disease) from the Sequence Read Archive. Our integrative analysis includes a first step to determine differentially and co-expressed genes. For this, we used the ExpHunter Suite, an R package that performs differential expression, co-expression and functional analysis of RNA-seq data. We used both differentially and co-expressed genes to explore the human gene interaction network and determine which genes were found in the different datasets that may be key for the angiogenesis deregulation. Finally, we performed drug repositioning analysis to find potential targets related to angiogenesis inhibition.We found that that among the transcriptional alterations identified, SEMA3D and IL33 genes are deregulated in all datasets. Microenvironment remodeling, cell cycle, lipid metabolism and vesicular transport are the main molecular pathways affected. In addition to this, interacting genes are involved in intracellular signaling pathways, especially in immune system and semaphorins, respiratory electron transport and fatty acid metabolism. The methodology presented here can be used for finding common transcriptional alterations in other genetically-based diseases.

Time tracing the earliest case of local pandemic resurgence

Origin identification of the earliest cases during the pandemic is crucial in containing the transmission of the disease. The high infectiousness of the disease during its incubation period (no symptom yet) and underlying human interaction pattern make it difficult to capture the entire line of the spread. The hidden spreading period is when the disease is silently spreading, for the “silent spreaders” showing no symptoms yet can transmit the infection. Being uncertain of the hidden spreading period would bring a severe challenge to the contact tracing mission. To find the possible hidden spreading period span, we utilized the SEITR (susceptible–exposed–infected–tested positive–recovered) model on networks where the relation between E state and T state can implicitly model the hidden spreading mechanism. We calibrated the model with real local resurgence epidemic data. Through our study, we found that the hidden spreading period span of the possible earliest case of local resurgence could vary according to the people interaction networks. Our modeling results showed the clustering and shortcuts that exist in the human interaction network significantly affect the results in finding the hidden spreading period span. Our study can be a guide for understanding the pandemic and for contact tracing the origin of local resurgence.

Modeling framework unifying contact and social networks.

Temporal networks of face-to-face interactions between individuals are useful proxies of the dynamics of social systems on fast timescales. Several empirical statistical properties of these networks have been shown to be robust across a large variety of contexts. To better grasp the role of various mechanisms of social interactions in the emergence of these properties, models in which schematic implementations of such mechanisms can be carried out have proven useful. Here, we put forward a framework to model temporal networks of human interactions based on the idea of a coevolution and feedback between (i) an observed network of instantaneous interactions and (ii) an underlying unobserved social bond network: Social bonds partially drive interaction opportunities and in turn are reinforced by interactions and weakened or even removed by the lack of interactions. Through this coevolution, we also integrate in the model well-known mechanisms such as triadic closure, but also the impact of shared social context and nonintentional (casual) interactions, with several tunable parameters. We then propose a method to compare the statistical properties of each version of the model with empirical face-to-face interaction data sets to determine which sets of mechanisms lead to realistic social temporal networks within this modeling framework.

Integrated Data Analysis Uncovers New COVID-19 Related Genes and Potential Drug Re-Purposing Candidates.

The COVID-19 pandemic is an acute and rapidly evolving global health crisis. To better understand this disease's molecular basis and design therapeutic strategies, we built upon the recently proposed concept of an integrated cell, iCell, fusing three omics, tissue-specific human molecular interaction networks. We applied this methodology to construct infected and control iCells using gene expression data from patient samples and three cell lines. We found large differences between patient-based and cell line-based iCells (both infected and control), suggesting that cell lines are ill-suited to studying this disease. We compared patient-based infected and control iCells and uncovered genes whose functioning (wiring patterns in iCells) is altered by the disease. We validated in the literature that 18 out of the top 20 of the most rewired genes are indeed COVID-19-related. Since only three of these genes are targets of approved drugs, we applied another data fusion step to predict drugs for re-purposing. We confirmed with molecular docking that the predicted drugs can bind to their predicted targets. Our most interesting prediction is artenimol, an antimalarial agent targeting ZFP62, one of our newly identified COVID-19-related genes. This drug is a derivative of artemisinin drugs that are already under clinical investigation for their potential role in the treatment of COVID-19. Our results demonstrate further applicability of the iCell framework for integrative comparative studies of human diseases.

Drug screening and biomarker gene investigation in cancer therapy through the human transcriptional regulatory network

A complex and vast biological network regulates all biological functions in the human body in a sophisticated manner, and abnormalities in this network can lead to disease and even cancer. The construction of a high-quality human molecular interaction network is possible with the development of experimental techniques that facilitate the interpretation of the mechanisms of drug treatment for cancer. We collected 11 molecular interaction databases based on experimental sources and constructed a human protein-protein interaction (PPI) network and a human transcriptional regulatory network (HTRN). A random walk-based graph embedding method was used to calculate the diffusion profiles of drugs and cancers, and a pipeline was constructed by using five similarity comparison metrics combined with a rank aggregation algorithm, which can be implemented for drug screening and biomarker gene prediction. Taking NSCLC as an example, curcumin was identified as a potentially promising anticancer drug from 5450 natural small molecules, and combined with differentially expressed genes, survival analysis, and topological ranking, we obtained BIRC5 (survivin), which is both a biomarker for NSCLC and a key target for curcumin. Finally, the binding mode of curcumin and survivin was explored using molecular docking. This work has a guiding significance for antitumor drug screening and the identification of tumor markers.

Identifying the temporal dynamics of densification and sparsification in human contact networks

Temporal social networks of human interactions are preponderant in understanding the fundamental patterns of human behavior. In these networks, interactions occur locally between individuals (i.e., nodes) who connect with each other at different times, culminating into a complex system-wide web that has a dynamic composition. Dynamic behavior in networks occurs not only locally but also at the global level, as systems expand or shrink due either to: changes in the size of node population or variations in the chance of a connection between two nodes. Here, we propose a numerical maximum-likelihood method to estimate population size and the probability of two nodes connecting at any given point in time. An advantage of the method is that it relies only on aggregate quantities, which are easy to access and free from privacy issues. Our approach enables us to identify the simultaneous (rather than the asynchronous) contribution of each mechanism in the densification and sparsification of human contacts, providing a better understanding of how humans collectively construct and deconstruct social networks.

Construction of disease-specific cytokine profiles by associating disease genes with immune responses.

The pathogenesis of many inflammatory diseases is a coordinated process involving metabolic dysfunctions and immune response-usually modulated by the production of cytokines and associated inflammatory molecules. In this work, we seek to understand how genes involved in pathogenesis which are often not associated with the immune system in an obvious way communicate with the immune system. We have embedded a network of human protein-protein interactions (PPI) from the STRING database with 14,707 human genes using feature learning that captures high confidence edges. We have found that our predicted Association Scores derived from the features extracted from STRING's high confidence edges are useful for predicting novel connections between genes, thus enabling the construction of a full map of predicted associations for all possible pairs between 14,707 human genes. In particular, we analyzed the pattern of associations for 126 cytokines and found that the six patterns of cytokine interaction with human genes are consistent with their functional classifications. To define the disease-specific roles of cytokines we have collected gene sets for 11,944 diseases from DisGeNET. We used these gene sets to predict disease-specific gene associations with cytokines by calculating the normalized average Association Scores between disease-associated gene sets and the 126 cytokines; this creates a unique profile of inflammatory genes (both known and predicted) for each disease. We validated our predicted cytokine associations by comparing them to known associations for 171 diseases. The predicted cytokine profiles correlate (p-value<0.0003) with the known ones in 95 diseases. We further characterized the profiles of each disease by calculating an "Inflammation Score" that summarizes different modes of immune responses. Finally, by analyzing subnetworks formed between disease-specific pathogenesis genes, hormones, receptors, and cytokines, we identified the key genes responsible for interactions between pathogenesis and inflammatory responses. These genes and the corresponding cytokines used by different immune disorders suggest unique targets for drug discovery.

Retraction Note: Study on mountain landslide distribution characteristics and 3D printing and its performance based on human machine interaction network

Retraction Note: Study on mountain landslide distribution characteristics and 3D printing and its performance based on human machine interaction network

RETRACTED ARTICLE: Study on mountain landslide distribution characteristics and 3D printing and its performance based on human machine interaction network

RETRACTED ARTICLE: Study on mountain landslide distribution characteristics and 3D printing and its performance based on human machine interaction network

Functional assessment of the "two-hit" model for neurodevelopmental defects in Drosophila and X. laevis.

We previously identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental outcomes, where severely affected probands carried an excess of rare pathogenic variants compared to mildly affected carrier parents. We hypothesized that the 16p12.1 deletion sensitizes the genome for disease, while "second-hits" in the genetic background modulate the phenotypic trajectory. To test this model, we examined how neurodevelopmental defects conferred by knockdown of individual 16p12.1 homologs are modulated by simultaneous knockdown of homologs of "second-hit" genes in Drosophila melanogaster and Xenopus laevis. We observed that knockdown of 16p12.1 homologs affect multiple phenotypic domains, leading to delayed developmental timing, seizure susceptibility, brain alterations, abnormal dendrite and axonal morphology, and cellular proliferation defects. Compared to genes within the 16p11.2 deletion, which has higher de novo occurrence, 16p12.1 homologs were less likely to interact with each other in Drosophila models or a human brain-specific interaction network, suggesting that interactions with "second-hit" genes may confer higher impact towards neurodevelopmental phenotypes. Assessment of 212 pairwise interactions in Drosophila between 16p12.1 homologs and 76 homologs of patient-specific "second-hit" genes (such as ARID1B and CACNA1A), genes within neurodevelopmental pathways (such as PTEN and UBE3A), and transcriptomic targets (such as DSCAM and TRRAP) identified genetic interactions in 63% of the tested pairs. In 11 out of 15 families, patient-specific "second-hits" enhanced or suppressed the phenotypic effects of one or many 16p12.1 homologs in 32/96 pairwise combinations tested. In fact, homologs of SETD5 synergistically interacted with homologs of MOSMO in both Drosophila and X. laevis, leading to modified cellular and brain phenotypes, as well as axon outgrowth defects that were not observed with knockdown of either individual homolog. Our results suggest that several 16p12.1 genes sensitize the genome towards neurodevelopmental defects, and complex interactions with "second-hit" genes determine the ultimate phenotypic manifestation.