Breast cancer has the highest diagnosis rate among all cancers. Tumor budding (TB) is recognized as a recent prognostic marker. Identifying genes specific to high-TB samples is crucial for hindering tumor progression and metastasis. In this study, we utilized an RNA sequencing technique, called TempO-Seq, to profile transcriptomic data from breast cancer samples, aiming to identify biomarkers for high-TB cases. Through differential expression analysis and mutual information, we identified seven genes (NOL4, STAR, C8G, NEIL1, SLC46A3, FRMD6, and SCARF2) that are potential biomarkers in breast cancer. To gain more relevant proteins, further investigation based on a protein-protein interaction network and the network diffusion technique revealed enrichment in the Hippo signaling and Wnt signaling pathways, promoting tumor initiation, invasion, and metastasis in several cancer types. In conclusion, these novel genes, recognized as overexpressed in high-TB samples, along with their associated pathways, offer promising therapeutic targets, thus advancing treatment and diagnosis for breast cancer.

The high-throughput genomic and proteomic scanning approaches allow investigators to measure the quantification of genome-wide genes (or gene products) for certain disease conditions, which plays an essential role in promoting the discovery of disease mechanisms. The high-throughput approaches often generate a large gene list of interest (GOIs), such as differentially expressed genes/proteins. However, researchers have to perform manual triage and validation to explore the most promising, biologically plausible linkages between the known disease genes and GOIs (disease signals) for further study. Here, to address this challenge, we proposed a network-based strategy DDK-Linker to facilitate the exploration of disease signals hidden in omics data by linking GOIs to disease knowns genes. Specifically, it reconstructed gene distances in the protein-protein interaction (PPI) network through six network methods (random walk with restart, Deepwalk, Node2Vec, LINE, HOPE, Laplacian) to discover disease signals in omics data that have shorter distances to disease genes. Furthermore, benefiting from the establishment of knowledge base we established, the abundant bioinformatics annotations were provided for each candidate disease signal. To assist in omics data interpretation and facilitate the usage, we have developed this strategy into an application that users can access through a website or download the R package. We believe DDK-Linker will accelerate the exploring of disease genes and drug targets in a variety of omics data, such as genomics, transcriptomics and proteomics data, and provide clues for complex disease mechanism and pharmacological research. DDK-Linker is freely accessible at http://ddklinker.ncpsb.org.cn/.

Single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) data provided new insights into the understanding of epigenetic heterogeneity and transcriptional regulation. With the increasing abundance of dataset resources, there is an urgent need to extract more useful information through high-quality data analysis methods specifically designed for scATAC-seq. However, analyzing scATAC-seq data poses challenges due to its near binarization, high sparsity and ultra-high dimensionality properties. Here, we proposed a novel network diffusion-based computational method to comprehensively analyze scATAC-seq data, named Single-Cell ATAC-seq Analysis via Network Refinement with Peaks Location Information (SCARP). SCARP formulates the Network Refinement diffusion method under the graph theory framework to aggregate information from different network orders, effectively compensating for missing signals in the scATAC-seq data. By incorporating distance information between adjacent peaks on the genome, SCARP also contributes to depicting the co-accessibility of peaks. These two innovations empower SCARP to obtain lower-dimensional representations for both cells and peaks more effectively. We have demonstrated through sufficient experiments that SCARP facilitated superior analyses of scATAC-seq data. Specifically, SCARP exhibited outstanding cell clustering performance, enabling better elucidation of cell heterogeneity and the discovery of new biologically significant cell subpopulations. Additionally, SCARP was also instrumental in portraying co-accessibility relationships of accessible regions and providing new insight into transcriptional regulation. Consequently, SCARP identified genes that were involved in key Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related to diseases and predicted reliable cis-regulatory interactions. To sum up, our studies suggested that SCARP is a promising tool to comprehensively analyze the scATAC-seq data.

Introduction: Connections among neurons form one of the most amazing and effective network in nature. At higher level, also the functional structures of the brain is organized as a network. It is therefore natural to use modern techniques of network analysis to describe the structures of networks in the brain. Many studies have been conducted in this area, showing that the structure of the neuronal network is complex, with a small-world topology, modularity and the presence of hubs. Other studies have been conducted to investigate the dynamical processes occurring in brain networks, analyzing local and large-scale network dynamics. Recently, network diffusion dynamics have been proposed as a model for the progression of brain degenerative diseases and for traumatic brain injuries. Methods: In this paper, the dynamics of network diffusion is re-examined and reaction-diffusion models on networks is introduced in order to better describe the degenerative dynamics in the brain. Results: Numerical simulations of the dynamics of injuries in the brain connectome are presented. Different choices of reaction term and initial condition provide very different phenomenologies, showing how network propagation models are highly flexible. Discussion: The uniqueness of this research lies in the fact that it is the first time that reaction-diffusion dynamics have been applied to the connectome to model the evolution of neurodegenerative diseases or traumatic brain injury. In addition, the generality of these models allows the introduction of non-constant diffusion and different reaction terms with non-constant parameters, allowing a more precise definition of the pathology to be studied.

Drugs targeting genes linked to disease via evidence from human genetics have increased odds of approval. Approaches to prioritize such genes include genome-wide association studies (GWASs), rare variant burden tests in exome sequencing studies (Exome), or integration of a GWAS with expression/protein quantitative trait loci (eQTL/pQTL-GWAS). Here, we compare gene-prioritization approaches on 30 clinically relevant traits and benchmark their ability to recover drug targets. Across traits, prioritized genes were enriched for drug targets with odds ratios (ORs) of 2.17, 2.04, 1.81, and 1.31 for the GWAS, eQTL-GWAS, Exome, and pQTL-GWAS methods, respectively. Adjusting for differences in testable genes and sample sizes, GWAS outperforms e/pQTL-GWAS, but not the Exome approach. Furthermore, performance increased through gene network diffusion, although the node degree, being the best predictor (OR = 8.7), revealed strong bias in literature-curated networks. In conclusion, we systematically assessed strategies to prioritize drug target genes, highlighting the promises and pitfalls of current approaches.

Drug-drug interactions play a vital role in drug research. However, they may also cause adverse reactions in patients, with serious consequences. Manual detection of drug-drug interactions is time-consuming and expensive, so it is urgent to use computer methods to solve the problem. There are two ways for computers to identify drug interactions: one is to identify known drug interactions, and the other is to predict unknown drug interactions. In this paper, we review the research progress of machine learning in predicting unknown drug interactions. Among these methods, the literature-based method is special because it combines the extraction method of DDI and the prediction method of DDI. We first introduce the common databases, then briefly describe each method, and summarize the advantages and disadvantages of some prediction models. Finally, we discuss the challenges and prospects of machine learning methods in predicting drug interactions. This review aims to provide useful guidance for interested researchers to further promote bioinformatics algorithms to predict DDI.

Brain network connections rewire adaptively in response to neural activity. Adaptive rewiring may be understood as a process which, at its every step, is aimed at optimizing the efficiency of signal diffusion. In evolving model networks, this amounts to creating shortcut connections in regions with high diffusion and pruning where diffusion is low. Adaptive rewiring leads over time to topologies akin to brain anatomy: small worlds with rich club and modular or centralized structures. We continue our investigation of adaptive rewiring by focusing on three desiderata: specificity of evolving model network architectures, robustness of dynamically maintained architectures, and flexibility of network evolution to stochastically deviate from specificity and robustness. Our adaptive rewiring model simulations show that specificity and robustness characterize alternative modes of network operation, controlled by a single parameter, the rewiring interval. Small control parameter shifts across a critical transition zone allow switching between the two modes. Adaptive rewiring exhibits greater flexibility for skewed, lognormal connection weight distributions than for normally distributed ones. The results qualify adaptive rewiring as a key principle of self-organized complexity in network architectures, in particular of those that characterize the variety of functional architectures in the brain.

Bridging the gap between symmetric, direct white matter brain connectivity and neural dynamics that are often asymmetric and polysynaptic may offer insights into brain architecture, but this remains an unresolved challenge in neuroscience. Here, we used the graph Laplacian matrix to simulate symmetric and asymmetric high-order diffusion processes akin to particles spreading through white matter pathways. The simulated indirect structural connectivity outperformed direct as well as absent anatomical information in sculpting effective connectivity, a measure of causal and directed brain dynamics. Crucially, an asymmetric diffusion process determined by the sensitivity of the network nodes to their afferents best predicted effective connectivity. The outcome is consistent with brain regions adapting to maintain their sensitivity to inputs within a dynamic range. Asymmetric network communication models offer a promising perspective for understanding the relationship between structural and functional brain connectomes, both in normalcy and neuropsychiatric conditions.

BACKGROUND: Recent cancer genomic studies have generated detailed molecular data on a large number of cancer patients. A key remaining problem in cancer genomics is the identification of driver genes.
RESULTS: We propose BetweenNet, a computational approach that integrates genomic data with a protein-protein interaction network to identify cancer driver genes. BetweenNet utilizes a measure based on betweenness centrality on patient specific networks to identify the so-called outlier genes that correspond to dysregulated genes for each patient. Setting up the relationship between the mutated genes and the outliers through a bipartite graph, it employs a random-walk process on the graph, which provides the final prioritization of the mutated genes. We compare BetweenNet against state-of-the art cancer gene prioritization methods on lung, breast, and pan-cancer datasets.
CONCLUSIONS: Our evaluations show that BetweenNet is better at recovering known cancer genes based on multiple reference databases. Additionally, we show that the GO terms and the reference pathways enriched in BetweenNet ranked genes and those that are enriched in known cancer genes overlap significantly when compared to the overlaps achieved by the rankings of the alternative methods.

Sporadic Creutzfeldt-Jakob disease is a rare fatal rapidly progressive dementia caused by the accumulation and spread of pathologically misfolded prions. Evidence from animal models and in vitro experiments suggests that prion pathology propagates along neural connectivity pathways, with the transmission of misfolded prions initiating a corruptive templating process in newly encountered brain regions. Although particular regional patterns of disease have been recognized in humans, the underlying mechanistic basis of these patterns remains poorly understood. Here, we demonstrate that the spatial pattern of disease derived from publicly available human diffusion-weighted MRI data demonstrates stereotypical features across patient cohorts and can be largely explained by intrinsic connectivity properties of the human structural brain network. Regional diffusion-weighted MRI signal abnormalities are predicted by graph theoretical measures of centrality, with highly affected regions such as cingulate gyrus demonstrating strong structural connectivity to other brain regions. We employ network diffusion modelling to demonstrate that the spatial pattern of disease can be predicted by a diffusion process originating from a single regional pathology seed and operating on the structural connectome. The most likely seeds correspond to the most highly affected brain regions, suggesting that pathological prions could originate in a single brain region and spread throughout the brain to produce the regional distribution of pathology observed on MRI. Further investigation of top seed regions and associated connectivity pathways may be a useful strategy for developing therapeutic approaches.