Reverse Engineering of the Pediatric Sepsis Regulatory Network and Identification of Master Regulators

Sepsis remains a leading cause of death in ICUs all over the world, with pediatric sepsis accounting for a high percentage of mortality in pediatric ICUs. Its complexity makes it difficult to establish a consensus on genetic biomarkers and therapeutic targets. A promising strategy is to investigate the regulatory mechanisms involved in sepsis progression, but there are few studies regarding gene regulation in sepsis. This work aimed to reconstruct the sepsis regulatory network and identify transcription factors (TFs) driving transcriptional states, which we refer to here as master regulators. We used public gene expression datasets to infer the co-expression network associated with sepsis in a retrospective study. We identified a set of 15 TFs as potential master regulators of pediatric sepsis, which were divided into two main clusters. The first cluster corresponded to TFs with decreased activity in pediatric sepsis, and GATA3 and RORA, as well as other TFs previously implicated in the context of inflammatory response. The second cluster corresponded to TFs with increased activity in pediatric sepsis and was composed of TRIM25, RFX2, and MEF2A, genes not previously described as acting in a coordinated way in pediatric sepsis. Altogether, these results show how a subset of master regulators TF can drive pathological transcriptional states, with implications for sepsis biology and treatment.

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Identification of transcriptional regulatory network associated with response of host epithelial cells to SARS-CoV-2

Scientific Reports ◽

10.1038/s41598-021-03309-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Chen Su ◽

Simon Rousseau ◽

Amin Emad

Keyword(s):

Gene Expression ◽

Epithelial Cells ◽

Regulatory Network ◽

Transcriptional Regulatory Network ◽

Organ Damage ◽

Host Cells ◽

Regulatory Mechanisms ◽

Transcriptional Regulatory ◽

Transcriptional Regulatory Mechanisms ◽

The Impact

AbstractIdentification of transcriptional regulatory mechanisms and signaling networks involved in the response of host cells to infection by SARS-CoV-2 is a powerful approach that provides a systems biology view of gene expression programs involved in COVID-19 and may enable the identification of novel therapeutic targets and strategies to mitigate the impact of this disease. In this study, our goal was to identify a transcriptional regulatory network that is associated with gene expression changes between samples infected by SARS-CoV-2 and those that are infected by other respiratory viruses to narrow the results on those enriched or specific to SARS-CoV-2. We combined a series of recently developed computational tools to identify transcriptional regulatory mechanisms involved in the response of epithelial cells to infection by SARS-CoV-2, and particularly regulatory mechanisms that are specific to this virus when compared to other viruses. In addition, using network-guided analyses, we identified kinases associated with this network. The results identified pathways associated with regulation of inflammation (MAPK14) and immunity (BTK, MBX) that may contribute to exacerbate organ damage linked with complications of COVID-19. The regulatory network identified herein reflects a combination of known hits and novel candidate pathways supporting the novel computational pipeline presented herein to quickly narrow down promising avenues of investigation when facing an emerging and novel disease such as COVID-19.

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Reverse Engineering of Ewing Sarcoma Regulatory Network Uncovers PAX7 and RUNX3 as Master Regulators Associated with Good Prognosis

Cancers ◽

10.3390/cancers13081860 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1860

Author(s):

Marcel da Câmara Ribeiro-Dantas ◽

Danilo Oliveira Imparato ◽

Matheus Gibeke Siqueira Dalmolin ◽

Caroline Brunetto de Farias ◽

André Tesainer Brunetto ◽

...

Keyword(s):

Transcription Factor ◽

Prognostic Factors ◽

Ewing Sarcoma ◽

Regulatory Network ◽

Chromosomal Translocation ◽

Good Prognosis ◽

Regulatory Mechanisms ◽

Es Cell ◽

Master Regulators ◽

Transcriptional Alterations

Ewing Sarcoma (ES) is a rare malignant tumor occurring most frequently in adolescents and young adults. The ES hallmark is a chromosomal translocation between the chromosomes 11 and 22 that results in an aberrant transcription factor (TF) through the fusion of genes from the FET and ETS families, commonly EWSR1 and FLI1. The regulatory mechanisms behind the ES transcriptional alterations remain poorly understood. Here, we reconstruct the ES regulatory network using public available transcriptional data. Seven TFs were identified as potential MRs and clustered into two groups: one composed by PAX7 and RUNX3, and another composed by ARNT2, CREB3L1, GLI3, MEF2C, and PBX3. The MRs within each cluster act as reciprocal agonists regarding the regulation of shared genes, regulon activity, and implications in clinical outcome, while the clusters counteract each other. The regulons of all the seven MRs were differentially methylated. PAX7 and RUNX3 regulon activity were associated with good prognosis while ARNT2, CREB3L1, GLI3, and PBX3 were associated with bad prognosis. PAX7 and RUNX3 appear as highly expressed in ES biopsies and ES cell lines. This work contributes to the understanding of the ES regulome, identifying candidate MRs, analyzing their methilome and pointing to potential prognostic factors.

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NeTFactor, a framework for identifying transcriptional regulators of gene expression-based biomarkers

Scientific Reports ◽

10.1038/s41598-019-49498-y ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Mehmet Eren Ahsen ◽

Yoojin Chun ◽

Alexander Grishin ◽

Galina Grishina ◽

Gustavo Stolovitzky ◽

...

Keyword(s):

Gene Expression ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Regulatory Mechanisms ◽

Epithelial Cell Line ◽

Specific Gene ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Network Analyses ◽

Gene Regulatory

Abstract Biological and regulatory mechanisms underlying many multi-gene expression-based disease biomarkers are often not readily evident. We describe an innovative framework, NeTFactor, that combines network analyses with gene expression data to identify transcription factors (TFs) that significantly and maximally regulate such a biomarker. NeTFactor uses a computationally-inferred context-specific gene regulatory network and applies topological, statistical, and optimization methods to identify regulator TFs. Application of NeTFactor to a multi-gene expression-based asthma biomarker identified ETS translocation variant 4 (ETV4) and peroxisome proliferator-activated receptor gamma (PPARG) as the biomarker’s most significant TF regulators. siRNA-based knock down of these TFs in an airway epithelial cell line model demonstrated significant reduction of cytokine expression relevant to asthma, validating NeTFactor’s top-scoring findings. While PPARG has been associated with airway inflammation, ETV4 has not yet been implicated in asthma, thus indicating the possibility of novel, disease-relevant discovery by NeTFactor. We also show that NeTFactor’s results are robust when the gene regulatory network and biomarker are derived from independent data. Additionally, our application of NeTFactor to a different disease biomarker identified TF regulators of interest. These results illustrate that the application of NeTFactor to multi-gene expression-based biomarkers could yield valuable insights into regulatory mechanisms and biological processes underlying disease.

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tiRNAs & tRFs Biogenesis and Regulation of Diseases: A Review

Current Medicinal Chemistry ◽

10.2174/0929867326666190124123831 ◽

2019 ◽

Vol 26 (31) ◽

pp. 5849-5861 ◽

Cited By ~ 3

Author(s):

Pan Jiang ◽

Feng Yan

Keyword(s):

Gene Expression ◽

Protein Synthesis ◽

Metabolic Diseases ◽

Viral Infections ◽

Regulatory Mechanisms ◽

Biological Functions ◽

Reverse Transcriptases ◽

Dna Damage Responses ◽

Potential Applications ◽

Viral Reverse Transcriptases

tiRNAs & tRFs are a class of small molecular noncoding tRNA derived from precise processing of mature or precursor tRNAs. Most tiRNAs & tRFs described originate from nucleus-encoded tRNAs, and only a few tiRNAs and tRFs have been reported. They have been suggested to play important roles in inhibiting protein synthesis, regulating gene expression, priming viral reverse transcriptases, and the modulation of DNA damage responses. However, the regulatory mechanisms and potential function of tiRNAs & tRFs remain poorly understood. This review aims to describe tiRNAs & tRFs, including their structure, biological functions and subcellular localization. The regulatory roles of tiRNAs & tRFs in translation, neurodegeneration, metabolic diseases, viral infections, and carcinogenesis are also discussed in detail. Finally, the potential applications of these noncoding tRNAs as biomarkers and gene regulators in different diseases is also highlighted.

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R2R3-MYB transcription factors, StmiR858 and sucrose mediate potato flavonol biosynthesis

Horticulture Research ◽

10.1038/s41438-021-00463-9 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Sen Lin ◽

Rajesh K. Singh ◽

Moehninsi ◽

Duroy A. Navarre

Keyword(s):

Gene Expression ◽

Abiotic Stress ◽

Feedback Loop ◽

Regulatory Mechanisms ◽

Phenylpropanoid Metabolism ◽

Biotic And Abiotic Stress ◽

Health Promoting ◽

Transient Overexpression ◽

R2r3 Myb ◽

R2r3 Myb Transcription Factors

AbstractFlavonols and other phenylpropanoids protect plants from biotic and abiotic stress and are dietarily desirable because of their health-promoting properties. The ability to develop new potatoes (Solanum tuberosum) with optimal types and amounts of phenylpropanoids is limited by lack of knowledge about the regulatory mechanisms. Exogenous sucrose increased flavonols, whereas overexpression of the MYB StAN1 induced sucrolytic gene expression. Heterologous StAN1 protein bound promoter fragments from sucrolytic genes (SUSY1 and INV1). Two additional MYBs and one microRNA were identified that regulated potato flavonols. Overexpression analysis showed MYB12A and C increased amounts of flavonols and other phenylpropanoids. Endogenous flavonol amounts in light-exposed organs were much higher those in the dark. Expression levels of StMYB12A and C were high in flowers but low in tubers. Transient overexpression of miR858 altered potato flavonol metabolism. Endogenous StmiR858 expression was much lower in flowers than leaves and correlated with flavonol amounts in these organs. Collectively, these findings support the hypothesis that sucrose, MYBs, and miRNA control potato phenylpropanoid metabolism in a finely tuned manner that includes a feedback loop between sucrose and StAN1. These findings will aid in the development of potatoes with phenylpropanoid profiles optimized for crop performance and human health.

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Study on the Relationship between the miRNA-centered ceRNA Regulatory Network and Fatigue

Journal of Molecular Neuroscience ◽

10.1007/s12031-021-01845-3 ◽

2021 ◽

Author(s):

Xingzhe Yang ◽

Feng Li ◽

Jie Ma ◽

Yan Liu ◽

Xuejiao Wang ◽

...

Keyword(s):

Gene Expression ◽

Gene Regulatory Network ◽

Regulatory Network ◽

Hot Spot ◽

Genetic Research ◽

Noncoding Rnas ◽

Messenger Rnas ◽

Effective Prevention ◽

Gene Regulatory ◽

The Relationship

AbstractIn recent years, the incidence of fatigue has been increasing, and the effective prevention and treatment of fatigue has become an urgent problem. As a result, the genetic research of fatigue has become a hot spot. Transcriptome-level regulation is the key link in the gene regulatory network. The transcriptome includes messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs). MRNAs are common research targets in gene expression profiling. Noncoding RNAs, including miRNAs, lncRNAs, circRNAs and so on, have been developed rapidly. Studies have shown that miRNAs are closely related to the occurrence and development of fatigue. MiRNAs can regulate the immune inflammatory reaction in the central nervous system (CNS), regulate the transmission of nerve impulses and gene expression, regulate brain development and brain function, and participate in the occurrence and development of fatigue by regulating mitochondrial function and energy metabolism. LncRNAs can regulate dopaminergic neurons to participate in the occurrence and development of fatigue. This has certain value in the diagnosis of chronic fatigue syndrome (CFS). CircRNAs can participate in the occurrence and development of fatigue by regulating the NF-κB pathway, TNF-α and IL-1β. The ceRNA hypothesis posits that in addition to the function of miRNAs in unidirectional regulation, mRNAs, lncRNAs and circRNAs can regulate gene expression by competitive binding with miRNAs, forming a ceRNA regulatory network with miRNAs. Therefore, we suggest that the miRNA-centered ceRNA regulatory network is closely related to fatigue. At present, there are few studies on fatigue-related ncRNA genes, and most of these limited studies are on miRNAs in ncRNAs. However, there are a few studies on the relationship between lncRNAs, cirRNAs and fatigue. Less research is available on the pathogenesis of fatigue based on the ceRNA regulatory network. Therefore, exploring the complex mechanism of fatigue based on the ceRNA regulatory network is of great significance. In this review, we summarize the relationship between miRNAs, lncRNAs and circRNAs in ncRNAs and fatigue, and focus on exploring the regulatory role of the miRNA-centered ceRNA regulatory network in the occurrence and development of fatigue, in order to gain a comprehensive, in-depth and new understanding of the essence of the fatigue gene regulatory network.

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Rapamycin: Drug Repurposing in SARS-CoV-2 Infection

Pharmaceuticals ◽

10.3390/ph14030217 ◽

2021 ◽

Vol 14 (3) ◽

pp. 217

Author(s):

Jiri Patocka ◽

Kamil Kuca ◽

Patrik Oleksak ◽

Eugenie Nepovimova ◽

Martin Valis ◽

...

Keyword(s):

Literature Review ◽

Human Health ◽

World Economy ◽

Web Of Science ◽

Drug Repurposing ◽

Final Analysis ◽

High Rate ◽

Suitable Candidate ◽

Promising Strategy ◽

The World

Since December 2019, SARS-CoV-2 (COVID-19) has been a worldwide pandemic with enormous consequences for human health and the world economy. Remdesivir is the only drug in the world that has been approved for the treating of COVID-19. This drug, as well as vaccination, still has uncertain effectiveness. Drug repurposing could be a promising strategy how to find an appropriate molecule: rapamycin could be one of them. The authors performed a systematic literature review of available studies on the research describing rapamycin in association with COVID-19 infection. Only peer-reviewed English-written articles from the world’s acknowledged databases Web of Science, PubMed, Springer and Scopus were involved. Five articles were eventually included in the final analysis. The findings indicate that rapamycin seems to be a suitable candidate for drug repurposing. In addition, it may represent a better candidate for COVID-19 therapy than commonly tested antivirals. It is also likely that its efficiency will not be reduced by the high rate of viral RNA mutation.

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Increased Emergency Calls during the COVID-19 Pandemic in Saudi Arabia: A National Retrospective Study

Healthcare ◽

10.3390/healthcare9010014 ◽

2020 ◽

Vol 9 (1) ◽

pp. 14

Author(s):

Ahmed Al-Wathinani ◽

Attila J. Hertelendy ◽

Sultana Alhurishi ◽

Abdulmajeed Mobrad ◽

Riyadh Alhazmi ◽

...

Keyword(s):

Saudi Arabia ◽

Retrospective Study ◽

Emergency Medical Services ◽

Indirect Effect ◽

Mobile Application ◽

Healthcare Systems ◽

Emergency Calls ◽

The World ◽

Staffing Patterns ◽

The Impact

The coronavirus 2019 (COVID-19) pandemic has a direct and indirect effect on the different healthcare systems around the world. In this study, we aim to describe the impact on the utilization of emergency medical services (EMS) in Saudi Arabia during the COVID-19 pandemic. We studied cumulative data from emergency calls collected from the SRCA. Data were separated into three periods: before COVID-19 (1 January–29 February 2020), during COVID-19 (1 March–23 April 2020), and during the Holy Month of Ramadan (24 April–23 May 2020). A marked increase of cases was handled during the COVID-19 period compared to the number before pandemic. Increases in all types of cases, except for those related to trauma, occurred during COVID-19, with all regions experiencing increased call volumes during COVID-19 compared with before pandemic. Demand for EMS significantly increased throughout Saudi Arabia during the pandemic period. Use of the mobile application ASAFNY to request an ambulance almost doubled during the pandemic but remained a small fraction of total calls. Altered weekly call patterns and increased call volume during the pandemic indicated not only a need for increased staff but an alteration in staffing patterns.

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