A weighted network analysis framework for the hourglass effect—And its application in the C. elegans connectome

Understanding hierarchy and modularity in natural as well as technological networks is of utmost importance. A major aspect of such analysis involves identifying the nodes that are crucial to the overall processing structure of the network. More recently, the approach of hourglass analysis has been developed for the purpose of quantitatively analyzing whether only a few intermediate nodes mediate the information processing between a large number of inputs and outputs of a network. We develop a new framework for hourglass analysis that takes network weights into account while identifying the core nodes and the extent of hourglass effect in a given weighted network. We use this framework to study the structural connectome of the C. elegans and identify intermediate neurons that form the core of sensori-motor pathways in the organism. Our results show that the neurons forming the core of the connectome show significant differences across the male and hermaphrodite sexes, with most core nodes in the male concentrated in sex-organs while they are located in the head for the hermaphrodite. Our work demonstrates that taking weights into account for network analysis framework leads to emergence of different network patterns in terms of identification of core nodes and hourglass structure in the network, which otherwise would be missed by unweighted approaches.

A Weighted Network Analysis Framework for the Hourglass Effect — and its Application in the C. Elegans Connectome

ABSTRACTUnderstanding hierarchy and modularity in natural as well as technological networks is of utmost importance. A major aspect of such analysis involves identifying the nodes that are crucial to the overall processing structure of the network. More recently, the approach of hourglass analysis has been developed for the purpose of quantitatively analyzing whether only a few intermediate nodes mediate the information processing between a large number of inputs and outputs of a network. We develop a new framework for hourglass analysis that takes network weights into account while identifying the core nodes and the extent of hourglass effect in a given weighted network. We use this framework to study the structural connectome of theC. elegansand identify intermediate neurons that form the core of sensori-motor pathways in the organism. Our results show that the neurons forming the core of the connectome show significant differences across the male and hermaphrodite sexes, with most core nodes in the male concentrated in sex-organs while they are located in the head for the hermaphrodite. Our work demonstrates that taking weights into account for network analysis framework leads to emergence of different network patterns in terms of identification of core nodes and hourglass structure in the network, which otherwise would be missed by unweighted approaches.

The function annotations of ST3GAL4 in human LAMP1 and Lassa virus GP-C interaction from the perspective of systems virology

Lassa virus (LASV) is a single-stranded RNA virus that has plagued the Sub-Saharan part of Africa, precisely Nigeria where various pathogenic strains with varied genomic isoforms have been identified. The human lysosomal-associated membrane protein 1 (LAMP1) is alternately required for the micropinocytosis of LASV. Therefore, it is of interest to understand the mechanism of action of the host LAMP1 with LASV protein during infection. The role of ST3 beta-galactoside alpha-2, 3-sialyltransferase 4 (ST3GAL4) in the interaction between LASV (glycoprotein) GP-C and the human LAMP1 is relevant in this context. Deposited curated protein sequences of both LAMP1 and LASV GP-C were retrieved for the study. The ST3GAL4 associated data was constructed and analysed from weighted network analysis to infer the function annotations and molecular mediators that characterize the LASV infection. The gene network shows that glycoprotein sialylation, sialyltransferase enzymatic activities and glycosphingolipid biosynthesis are linked with the ST3GAL4 function. However, the physical interaction of FAM 213A, CD8B molecule and proprotein convertase subtilisin/kexin type 1 inhibitor (PCSK1N) with ST3GAL4 is intriguing in this perspective. There are 11 glycosylated asparagine sequons of the human LAMP1 but only nine were assigned a sialylated glycan cap to mediate the LASV GP-C and LAMP1 interaction having exceeded a recommended glycosylation threshold of 0.5. Therefore, the sialylated glycans of the human LAMP1 are a total of nine and these sialylated glycans mediate the molecular recognition between LASV and LAMP1. This study therefore, predicts that there is a cellular interchange between N-linked glycosylation properties of the human LAMP1 and LASV glycoprotein, and sialylation functions of ST3GAL4 in LASV infectivity. Further studies and the clinical trial of this predictive model on the sialylated glycans of LAMP1 will facilitate the understanding of the LASV micropinocytosis process in host cells.

The Function Annotations of ST3GAL4 in Human LAMP1 and Lassa virus GP-C Interaction from the Perspective of Systems Virology

ABSTRACTLassa virus (LASV) is a single-stranded RNA virus that has plagued the Sub-Saharan part of Africa, precisely Nigeria where various pathogenic strains with varied genomic isoforms have been identified. The human lysosomal-associated membrane protein 1 (LAMP1) is alternately required for the micropinocytosis of LASV. Therefore, it is of interest to understand the mechanism of action of the host LAMP1 with LASV protein during infection. The role of ST3 beta-galactoside alpha-2, 3-sialyltransferase 4 (ST3GAL4) in the interaction between LASV (glycoprotein) GP-C and the human LAMP1 is relevant in this context. Deposited curated protein sequences of both LAMP1 and LASV GP-C were retrieved for the study. The ST3GAL4 associated data was constructed and analyzed from weighted network analysis to infer the function annotations and molecular mediators that characterize the LASV infection. The gene network shows that glycoprotein sialylation, sialyltransferase enzymatic activities and glycosphingolipid biosynthesis are linked with the ST3GAL4 function. However, the physical interaction of FAM 213A, CD8B molecule and proprotein convertase subtilisin/kexin type 1 inhibitor (PCSK1N) with ST3GAL4 is intriguing in this perspective. There are eleven glycosylated asparagine sequons of the human LAMP1 but only nine were assigned a sialylated glycan cap to mediate the LASV GP-C and LAMP1 interaction having exceeded a recommended glycosylation threshold of 0.5. Therefore, the sialylated glycans of the human LAMP1 are a total of 9 and these sialylated glycans mediates the molecular recognition between LASV and LAMP1. This study therefore, predicts that there is a cellular interchange between N-linked glycosylation properties of the human LAMP1 and LASV glycoprotein, and sialylation functions of ST3GAL4 in LASV infectivity. Further studies and the clinical trial of this predictive model on the sialylated glycans of LAMP1 will facilitate the understanding of LASV micropinocytosis process in host cell.

A New Model of Identifying Differentially Expressed Genes via Weighted Network Analysis Based on Dimensionality Reduction Method

Background: As a method to identify Differentially Expressed Genes (DEGs), Non- Negative Matrix Factorization (NMF) has been widely praised in bioinformatics. Although NMF can make DEGs to be easily identified, it cannot provide more associated information for these DEGs. Objective: The methods of network analysis can be used to analyze the correlation of genes, but they caused more data redundancy and great complexity in gene association analysis of high dimensions. Dimensionality reduction is worth considering in this condition. Methods: In this paper, we provide a new framework by combining the merits of two: NMF is applied to select DEGs for dimensionality reduction, and then Weighted Gene Co-Expression Network Analysis (WGCNA) is introduced to cluster on DEGs into similar function modules. The combination of NMF and WGCNA as a novel model accomplishes the analysis of DEGs for cholangiocarcinoma (CHOL). Results: Some hub genes from DEGs are highlighted in the co-expression network. Candidate pathways and genes are also discovered in the most relevant module of CHOL. Conclusion: The experiments indicate that our framework is effective and the works also provide some useful clues to the reaches of CHOL.

EPIGENETIC PROFILES OF BIOLOGICAL AGING HALLMARKS

Investigation into the hallmarks of aging point to the existence of shared mechanisms that underlie the biological aging process. While there is a general consensus that hallmarks of aging rarely occur in isolation, little is known in regards to their overlapping networks or how interactions contribute to manifestations at the clinical level. Here, we examine whether shared epigenetic alterations—one of the proposed hallmark of aging—underlies diverse conditions characterized by other hallmarks, including cellular senescence, loss of proteostasis, genomic instability, mitochondrial dysfunction, and inflammation. Using weighted network analysis, we identified consistent overlaps in the methylation profiles across the different traits. For instance, epigenetic modules that were distinct in senescence were also affected in progeroid syndromes (Hutchinson-Gilford Progeria Syndrome and Werner’s Syndrome) and smokers. These CpGs tended to be located in CpG islands, which are notable for their strong association with transcriptional regulation. Overall, our results suggest that epigenetic alterations intersect with various hallmarks of aging. In moving forward, incorporation of this understanding may lead to the development of biomarkers that better capture the biological (rather than chronological) aging process.

Aggregatibacter actinomycetemcomitans colonization and persistence in a primate model

Aggregatibacter actinomycetemcomitans is associated with aggressive periodontitis resulting in premature tooth loss in adolescents. Tooth adherence and biofilm persistence are prerequisites for survival in the oral domain. Here, using a rhesus monkey model, 16S rRNA sequencing, and weighted network analysis, we assessed colonization of A. actinomycetemcomitans variants and ascertained microbial interactions in biofilm communities. Variants in A. actinomycetemcomitans leukotoxin (ltx) were created, labeled, inoculated, and compared with their progenitor strain for in vivo colonization. Samples of tooth-related plaque were assessed for colonization at baseline and after debridement and inoculation of labeled strains. Null, minimal, and hyper-Ltx–producing strains were created and assessed for hydroxyapatite binding and biofilm formation in vitro. Ltx-hyperproducing strains colonized with greater prevalence and at higher levels than wild type or ltx mutants (P = 0.05). Indigenous and inoculated A. actinomycetemcomitans strains that attached were associated with lactate-producing species (i.e., Leptotrichia, Abiotrophia, and Streptoccocci). A. actinomycetemcomitans was found at 0.13% of the total flora at baseline and at 0.05% 4 wk after inoculation. In vivo data were supported by in vitro results. We conclude that hyper-Ltx production affords these strains with an attachment advantage providing a foothold for competition with members of the indigenous microbiota. Increased attachment can be linked to ltx gene expression and up-regulation of adherence-associated genes. Growth of attached A. actinomycetemcomitans in vivo was enhanced by lactate availability due to consorting species. These associations provide A. actinomycetemcomitans with the constituents required for its colonization and survival in the complex and competitive oral environment.