Results from recent clinical studies suggest potential efficacy of immune training (IT)-based approaches for protection against severe lower respiratory tract infections in infants, but underlying ...mechanisms are unclear.
We used systems-level analyses to elucidate IT mechanisms in infants in a clinical trial setting.
Pre- and posttreatment peripheral blood mononuclear cells from a placebo-controlled trial in which winter treatment with the IT agent OM85 reduced infant respiratory infection frequency and/or duration were stimulated for 24 hours with the virus/bacteria mimics polyinosinic:polycytidylic acid/lipopolysaccharide. Transcriptomic profiling via RNA sequencing, pathway and upstream regulator analyses, and systems-level gene coexpression network analyses were used sequentially to elucidate and compare responses in treatment and placebo groups.
In contrast to subtle changes in antivirus-associated polyinosinic:polycytidylic acid response profiles, the bacterial lipopolysaccharide-triggered gene coexpression network responses exhibited OM85 treatment–associated upregulation of IFN signaling. This was accompanied by network rewiring resulting in increased coordination of TLR4 expression with IFN pathway–associated genes (especially master regulator IRF7); segregation of TNF and IFN-γ (which potentially synergize to exaggerate inflammatory sequelae) into separate expression modules; and reduced size/complexity of the main proinflammatory network module (containing, eg, IL-1,IL-6, and CCL3). Finally, we observed a reduced capacity for lipopolysaccharide-induced inflammatory cytokine (eg, IL-6 and TNF) production in the OM85 group.
These changes are consistent with treatment-induced enhancement of bacterial pathogen detection/clearance capabilities concomitant with enhanced capacity to regulate ensuing inflammatory response intensity and duration. We posit that IT agents exemplified by OM85 potentially protect against severe lower respiratory tract infections in infants principally by effects on innate immune responses targeting the bacterial components of the mixed respiratory viral/bacterial infections that are characteristic of this age group.
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Gene coexpression networks are relevant to functional and clinical translation of schizophrenia risk genes. We hypothesized that schizophrenia risk genes converge into coexpression pathways that may ...be associated with gene regulation mechanisms and with response to treatment in patients with schizophrenia.
We identified gene coexpression networks in two prefrontal cortex postmortem RNA sequencing datasets (n = 688) and replicated them in four more datasets (n = 1295). We identified and replicated (p values < .001) a single module enriched for schizophrenia risk loci (13 risk genes in 10 loci). In silico screening of potential regulators of the schizophrenia risk module via bioinformatic analyses identified two transcription factors and three microRNAs associated with the risk module. To translate postmortem information into clinical phenotypes, we identified polymorphisms predicting coexpression and combined them to obtain an index approximating module coexpression (Polygenic Coexpression Index PCI).
The PCI-coexpression association was successfully replicated in two independent brain transcriptome datasets (n = 131; p values < .05). Finally, we tested the association between the PCI and short-term treatment response in two independent samples of patients with schizophrenia treated with olanzapine (n = 167). The PCI was associated with treatment response in the positive symptom domain in both clinical cohorts (p values < .05).
In summary, our findings in 1983 samples of human postmortem prefrontal cortex show that coexpression of a set of genes enriched for schizophrenia risk genes is relevant to treatment response. This coexpression pathway may be coregulated by transcription factors and microRNA associated with it.
Parthenocarpy is the development without fertilization of seedless fruits. In the oil palm industry, the development of parthenocarpic fruits is considered an attractive option to increase palm oil ...production. Previous studies have shown the application of synthetic auxins in
, and interspecific O×G hybrids (
(Kunth) Cortés ×
Jacq.) induces parthenocarpy. The aim of this study was to identify the molecular mechanism through transcriptomics and biology system approach to responding to how the application of NAA induces parthenocarpic fruits in oil palm O×G hybrids. The transcriptome changes were studied in three phenological stages (PS) of the inflorescences: i) PS 603, pre-anthesis III, ii) PS 607, anthesis, and iii) PS 700, fertilized female flower. Each PS was treated with NAA, Pollen, and control (any application). The expression profile was studied at three separate times: five minutes (T0), 24 hours (T1), and 48 h post-treatment (T2). The RNA sequencing (RNA seq) approach was used with 27 oil palm O×G hybrids for a total of 81 raw samples. RNA-Seq showed around 445,920 genes. Numerous differentially expressed genes (DEGs) were involved in pollination, flowering, seed development, hormone biosynthesis, and signal transduction. The expression of the most relevant transcription factors (TF) families was variable and dependent on the stage and time post-treatment. In general, NAA treatment expressed differentially more genes than Pollen. Indeed, the gene co-expression network of Pollen was built with fewer nodes than the NAA treatment. The transcriptional profiles of Auxin-responsive protein and Gibberellin-regulated genes involved in parthenocarpy phenomena agreed with those previously reported in other species. The expression of 13 DEGs was validated by RT-qPCR analysis. This detailed knowledge about the molecular mechanisms involved in parthenocarpy could be used to facilitate the future development of genome editing techniques that enable the production of parthenocarpic O×G hybrid cultivars without growth regulator application.
Tropical forage grasses, particularly those belonging to the
genus, play a crucial role in cattle production and serve as the main food source for animals in tropical and subtropical regions. The ...majority of these species are apomictic and tetraploid, highlighting the significance of
, a sexual diploid species that can be tetraploidized for use in interspecific crosses with apomictic species. As a means to support breeding programs, our study investigates the feasibility of genome-wide family prediction in
families to predict agronomic traits. Fifty half-sibling families were assessed for green matter yield, dry matter yield, regrowth capacity, leaf dry matter, and stem dry matter across different clippings established in contrasting seasons with varying available water capacity. Genotyping was performed using a genotyping-by-sequencing approach based on DNA samples from family pools. In addition to conventional genomic prediction methods, machine learning and feature selection algorithms were employed to reduce the necessary number of markers for prediction and enhance predictive accuracy across phenotypes. To explore the regulation of agronomic traits, our study evaluated the significance of selected markers for prediction using a tree-based approach, potentially linking these regions to quantitative trait loci (QTLs). In a multiomic approach, genes from the species transcriptome were mapped and correlated to those markers. A gene coexpression network was modeled with gene expression estimates from a diverse set of
genotypes, enabling a comprehensive investigation of molecular mechanisms associated with these regions. The heritabilities of the evaluated traits ranged from 0.44 to 0.92. A total of 28,106 filtered SNPs were used to predict phenotypic measurements, achieving a mean predictive ability of 0.762. By employing feature selection techniques, we could reduce the dimensionality of SNP datasets, revealing potential genotype-phenotype associations. The functional annotation of genes near these markers revealed associations with auxin transport and biosynthesis of lignin, flavonol, and folic acid. Further exploration with the gene coexpression network uncovered associations with DNA metabolism, stress response, and circadian rhythm. These genes and regions represent important targets for expanding our understanding of the metabolic regulation of agronomic traits and offer valuable insights applicable to species breeding. Our work represents an innovative contribution to molecular breeding techniques for tropical forages, presenting a viable marker-assisted breeding approach and identifying target regions for future molecular studies on these agronomic traits.
Synchytrium endobioticum
, the causal agent of potato wart disease, poses a major threat to commercial potato production. Understanding the roles of transcriptionally regulated genes following ...pathogen infection is necessary for understanding the system-level host response to pathogen. Although some understanding of defense mechanisms against
S. endobioticum
infection has been gained for incompatible interactions, the genes and signaling pathways involved in the compatible interaction remain unclear. Based on the collection of wart diseased tubers of a susceptible cultivar, we performed phenotypic and dual RNA-Seq analyses of wart lesions in seven stages of disease progression. We totally detected 5,052 differentially expressed genes (DEGs) by comparing the different stages of infection to uninfected controls. The tendency toward differential gene expression was active rather than suppressed under attack by the pathogen. The number of DEGs step-up along with the development of the disease and the first, third and seventh of the disease stages showed substantially increase of DEGs in comparison of the previous stage. The important functional groups identified
via
Gene ontology (GO) and KEGG enrichment were those responsible for plant-pathogen interaction, fatty acid elongation and phenylpropanoid biosynthesis. Gene coexpression networks, composed of 17 distinct gene modules that contained between 25 and 813 genes, revealed high interconnectivity of the induced response and led to the identification of a number of hub genes enriched at different stages of infection. These results provide a comprehensive perspective on the global response of potato to
S. endobioticum
infection and identify a potential transcriptional regulatory network underlying this susceptible response, which contribute to a better understanding of the potato–
S. endobioticum
pathosystem.
The present study sought to identify potential hub genes and pathways of acute coronary syndrome (ACS). We downloaded the dataset (GSE56045) from the Gene Expression Omnibus (GEO) database and ...analyzed weighted gene coexpression networks (WGCNA). Gene Ontology annotation, Disease Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using R software. The protein-protein interaction (PPI) network was constructed using Cytoscape, and the Molecular Complex Detection app was employed to identify significant modules and hub genes. The hub genes were then validated in other microarrays and patients by RT-PCR. Two modules were identified and associated with coronary artery disease (CAD) and included 219 genes. After function and PPI analyses, 24 genes were identified to be potentially associated with CAD. Linear correlation was performed to calculate the relationship between the gene expression levels and coronary artery calcification score and found that
(R = -0.081,
= 0.0065),
(R = -0.075,
= 0.0012),
(R = -0.065,
= 0.029) and
(R = -0.06,
= 0.043) should be validated in other dataset. By comparing the gene expression levels in different groups in GSE23561, GSE34822, GSE59867, GSE60993 and GSE129935, only two genes (
and
) showed significance. The nomogram showed that
showed the risk of ACS. Further analysis in chest patients found
played a key role resulting in ACS. Our WGCNA analysis identified
as a risk factor for ACS, and the potential pathogenesis may be associated with immune inflammation.
• Wood formation was present in early angiosperms, but has been highly modified through evolution to generate the anatomical diversity seen in extant angiosperm lineages. In this project, we modeled ...changes in gene coexpression relationships associated with the evolution of wood formation in a phylogenetic survey of 13 angiosperm tree species.
• Gravitropic stimulation was used as an experimental treatment to alter wood formation and also perturb gene expression. Gene transcript abundances were determined using RNA sequencing of developing wood tissues from upright trees, and from the top (tension wood) and bottom (opposite wood) tissues of gravistimulated trees.
• A network-based approach was employed to align gene coexpression networks across species based on orthologous relationships. A large-scale, multilayer network was modeled that identified both lineage-specific gene coexpression modules and modules conserved across multiple species. Functional annotation and analysis of modules identified specific regulatory processes associated with conserved modules, including regulation of hormones, protein phosphorylation, meristem development and epigenetic processes.
• Our results provide novel insights into the evolution and development of wood formation, and demonstrate the ability to identify biological processes and genes important for the evolution of a foundational trait in nonmodel, undomesticated forest trees.
Abstract
Whereas nonlinear relationships between genes are acknowledged, there exist only a few methods for estimating nonlinear gene coexpression networks or gene regulatory networks (GCNs/GRNs) ...with common deficiencies. These methods often consider only pairwise associations between genes, and are, therefore, poorly capable of identifying higher-order regulatory patterns when multiple genes should be considered simultaneously. Another critical issue in current nonlinear GCN/GRN estimation approaches is that they consider linear and nonlinear dependencies at the same time in confounded form nonparametrically. This severely undermines the possibilities for nonlinear associations to be found, since the power of detecting nonlinear dependencies is lower compared to linear dependencies, and the sparsity-inducing procedures might favor linear relationships over nonlinear ones only due to small sample sizes. In this paper, we propose a method to estimate undirected nonlinear GCNs independently from the linear associations between genes based on a novel semiparametric neighborhood selection procedure capable of identifying complex nonlinear associations between genes. Simulation studies using the common DREAM3 and DREAM9 datasets show that the proposed method compares superiorly to the current nonlinear GCN/GRN estimation methods.
Abstract
Background
Thyroid eye disease (TED) is the most common orbital pathology that occurs in up to 50% of patients with Graves’ disease. Herein, we aimed at discovering the possible hub genes ...and pathways involved in TED based on bioinformatical approaches.
Results
The GSE105149 and GSE58331 datasets were downloaded from the Gene Expression Omnibus (GEO) database and merged for identifying TED-associated modules by weighted gene coexpression network analysis (WGCNA) and local maximal quasi-clique merger (lmQCM) analysis. EdgeR was run to screen differentially expressed genes (DEGs). Transcription factor (TF), microRNA (miR) and drug prediction analyses were performed using ToppGene suite. Function enrichment analysis was used to investigate the biological function of genes. Protein–protein interaction (PPI) analysis was performed based on the intersection between the list of genes obtained by WGCNA, lmQCM and DEGs, and hub genes were identified using the MCODE plugin. Based on the overlap of 497 genes retrieved from the different approaches, a robust TED coexpression network was constructed and 11 genes (ATP6V1A, PTGES3, PSMD12, PSMA4, METAP2, DNAJA1, PSMA1, UBQLN1, CCT2, VBP1 and NAA50) were identified as hub genes. Key TFs regulating genes in the TED-associated coexpression network, including NFRKB, ZNF711, ZNF407 and MORC2, and miRs including hsa-miR-144, hsa-miR-3662, hsa-miR-12136 and hsa-miR-3646, were identified. Genes in the coexpression network were enriched in the biological processes including proteasomal protein catabolic process and proteasome-mediated ubiquitin-dependent protein catabolic process and the pathways of endocytosis and ubiquitin-mediated proteolysis. Drugs perturbing genes in the coexpression network were also predicted and included enzyme inhibitors, chlorodiphenyl and finasteride.
Conclusions
For the first time, TED-associated coexpression network was constructed and key genes and their functions, as well as TFs, miRs and drugs, were predicted. The results of the present work may be relevant in the treatment and diagnosis of TED and may boost molecular studies regarding TED.
Introduction: Aging is the main risk factor for the development of chronic diseases such as cancer, diabetes, Parkinson’s disease, and Alzheimer’s disease. The central nervous system is particularly ...susceptible to progressive functional deterioration associated with age, among the brain regions the prefrontal cortex (PFC) has one of the highest involvements. Transcriptomics studies of this brain region have identified the decrease in synaptic function and activation of neuroglia cells as fundamental characteristics of the aging process. The aim of this study was to identify hub genes in the transcriptomic deregulation in the PFC aging to advance in the knowledge of this process. Materials and methods: A gene co-expression analysis was carried out for 45 people 60 to 80 years old compared with 38 people 20 to 40 years old. The networks were visualized and analyzed using Cytoscape; citoHubba was used to determine which genes had the best topological characteristics in the co-expression networks. Results: Five genes with high topological characteristics were identified. Four of them —hpca, cacng3, ca10, plppr4— were repressed and one was over-expressed —Cryab—. Conclusion: The four repressed genes are expressed preferentially in neurons and regulate the synaptic function and the neuronal plasticity, while the overexpressed gene is typical of glial cells and is expressed as a response to neuronal damage, facilitating myelination and neuronal regeneration.
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