Ace2 and Tmprss2 Expressions Are Regulated by Dhx32 and Influence the Gastrointestinal Symptoms Caused by SARS-CoV-2

Studies showed that the gastrointestinal (GI) tract is one of the most important pathways for SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19). As SARS-CoV-2 cellular entry depends on the ACE2 receptor and TMPRSS2 priming of the spike protein, it is important to understand the molecular mechanisms through which these two proteins and their cognate transcripts interact and influence the pathogenesis of COVID-19. In this study, we quantified the expression, associations, genetic modulators, and molecular pathways for Tmprss2 and Ace2 mRNA expressions in GI tissues using a systems genetics approach and the expanded family of highly diverse BXD mouse strains. The results showed that both Tmprss2 and Ace2 are highly expressed in GI tissues with significant covariation. We identified a significant expression quantitative trait locus on chromosome 7 that controls the expression of both Tmprss2 and Ace2. Dhx32 was found to be the strongest candidate in this interval. Co-expression network analysis demonstrated that both Tmprss2 and Ace2 were located at the same module that is significantly associated with other GI-related traits. Protein–protein interaction analysis indicated that hub genes in this module are linked to circadian rhythms. Collectively, our data suggested that genes with circadian rhythms of expression may have an impact on COVID-19 disease, with implications related to the timing and treatment of COVID-19.

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Large-scale genomic study reveals robust activation of the immune system following advanced Inner Engineering meditation retreat.

10.1101/2021.05.18.444668 ◽

2021 ◽

Author(s):

Vijayendran Chandran ◽

Mei-Ling Bermudez ◽

Mert Koka ◽

Dhanashri Pawale ◽

Ramana Vishnubhotla ◽

...

Keyword(s):

Multiple Sclerosis ◽

Immune Response ◽

Large Scale ◽

Molecular Mechanisms ◽

Positive Impact ◽

Core Network ◽

Protein Protein Interaction ◽

Genomic Study ◽

Meditation Retreat ◽

Significant Expression

The positive impact of meditation on human wellbeing is well documented, yet its molecular mechanisms are incompletely understood. We applied a comprehensive systems biology approach starting with whole blood gene expression profiling combined with multi-level bioinformatic analyses to characterize the co-expression, transcriptional, and protein-protein interaction networks to identify meditation-specific core network after an advanced 8-day Inner Engineering retreat program. We found the response to oxidative stress, detoxification, and cell cycle regulation pathways were downregulated after meditation. Strikingly, 220 genes directly associated with immune response, including 68 genes related to interferon (IFN) signaling were upregulated, with no significant expression changes in the inflammatory genes. This robust meditation-specific immune response network is significantly dysregulated in multiple sclerosis and severe COVID-19 patients. The work provides a foundation for understanding the effect of meditation and potential implications to voluntarily and non-pharmacologically improve the immune response before immunotherapy for many conditions, including multiple sclerosis and COVID-19 vaccination.

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Generation of a Novel Allelic Series of Cryptochrome Mutants via Mutagenesis Reveals Residues Involved in Protein-Protein Interaction and CRY2-Specific Repression

Molecular and Cellular Biology ◽

10.1128/mcb.00641-09 ◽

2009 ◽

Vol 29 (20) ◽

pp. 5465-5476 ◽

Cited By ~ 18

Author(s):

Ellena V. McCarthy ◽

Julie E. Baggs ◽

Jeanne M. Geskes ◽

John B. Hogenesch ◽

Carla B. Green

Keyword(s):

Circadian Rhythms ◽

Molecular Mechanisms ◽

Random Mutagenesis ◽

Single Amino Acid ◽

Allelic Series ◽

Protein Protein Interaction ◽

Binding Function ◽

Depth Analysis ◽

Dose Dependent Decrease ◽

The Many

ABSTRACT CRYPTOCHOME proteins are necessary for mammalian circadian rhythms and have many well-established biochemical roles within the molecular clock. While studies examining the effect of null Cry alleles have been informative, they have failed to dissect out the relative importance of, and the molecular mechanisms behind, the many roles of the CRY1 and CRY2 proteins. To address this, we created an allelic series of Cry mutants through random mutagenesis, followed by a cell-based screen to isolate mutants with aberrant repression of CLOCK-BMAL1. We identified 22 mutants with mutations resulting in single amino acid substitutions which cause a variety of deficiencies in different CRY functions. To illustrate the breadth and value of these new tools, we present an in-depth analysis of two of these mutants, CRY2G354D and CRY2G351D; the former shows deficiency in clock protein binding and is required for repression by both CRYs, while in contrast, the latter displays normal binding function but exhibits a CRY2-specific repression phenotype. Further, while overexpression of CRY2 in NIH 3T3 cells caused a dose-dependent decrease in rhythm amplitude, overexpression of CRY2G351D abolished rhythmicity. In summary, characterization of these unique alleles provides new opportunities for more-sophisticated insight into the multifaceted functions of the CRY proteins in circadian rhythms.

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Proteomics reveals ablation of placental growth factor inhibits the insulin resistance pathways in diabetic mouse retina

10.1101/338368 ◽

2018 ◽

Author(s):

Madhu Sudhana Lennikov ◽

Anton Lennikov ◽

Shibo Tang ◽

Hu Huang

Keyword(s):

Insulin Resistance ◽

Growth Factor ◽

Molecular Mechanisms ◽

Interaction Analysis ◽

Placental Growth Factor ◽

Mouse Retina ◽

Mouse Strains ◽

Neural Function ◽

Label Free ◽

Resistance Pathway

AbstractThe underlying molecular mechanisms that placental growth factor (PlGF) mediates the early complications at non-proliferative diabetic retinopathy (DR) remain largely elusive. The objective of this study is to characterize expression profile due to PlGF ablation in the retina of diabetic mice. The quantitative label-free proteomics was carried out on retinal tissues collected from mouse strains (Akita; PlGF−/− and Akita.PlGF−/−). We have identified 3176 total proteins, and 107 were significantly different between the experimental groups, followed by gene ontology, functional pathways, and protein-protein network interaction analysis. Gnb1, Gnb2, Gnb4, Gnai2, Gnao1, Snap25, Stxbp1, Vamp2 and Gngt1 proteins are involved in insulin resistance pathways, which are down-regulated in PlGF ablation in Akita diabetics (Akita.PlGF−/− vs. Akita), up-regulation in Akita vs. C57, PlGF−/− vs. C57. Prdx6, Prdx5 (up-regulation) are known of antioxidant activity; Map2 is involved in neural protection pathways which are up-regulated in Akita.PlGF−/− vs. Akita. Our results suggest that inhibition of insulin resistance pathway and the enhancement of antioxidant defence and neural function may represent the potential mechanisms of anti-PlGF compounds in the treatment of DR.

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Comprehensive analysis of differentially expressed long noncoding RNAs, miRNAs and mRNAs in breast cancer brain metastasis

Epigenomics ◽

10.2217/epi-2021-0152 ◽

2021 ◽

Author(s):

Meng An ◽

Xiaowen Zang ◽

Jimin Wang ◽

Jie Kang ◽

Xiaoyu Tan ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastasis ◽

Noncoding Rna ◽

Molecular Mechanisms ◽

Interaction Analysis ◽

Expression Profiles ◽

Differentially Expressed ◽

Protein Protein Interaction ◽

Real Time Quantitative Pcr ◽

Breast Cancer Brain Metastasis

Aim: To delineate the transcriptomic landscape and potential molecular mechanisms of breast cancer brain metastasis (BCBM). Materials & methods: Whole-transcriptome sequencing was performed to identify long noncoding RNA (lncRNA), miRNA and mRNA expression profiles associated with BCBM. Results: A total of 739 differentially expressed lncRNAs, 115 differentially expressed miRNAs and 5749 differentially expressed mRNAs were identified in 231-BR cells compared with MDA-MB-231 cells. Real-time quantitative PCR results revealed the expression levels of candidate molecules were consistent with their correspondence RNA-seq data. Protein–protein interaction analysis identified some hub genes associated with BCBM, such as PTBP1, NUP98 and HYOU1. LncRNA-miRNA-mRNA network highlighted a potential mechanism of BCBM in which lncRNA FIRRE and RP11-169F17.1 sponging hsa-miR-501-5p to regulate the expression of MMS19, PTBP1 and NUP98. Conclusion: This study provides a framework for better understanding molecular mechanisms of BCBM.

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Identification of potential molecular mechanisms of radiation pneumonitis development in non-small-cell lung cancer treatment by data mining

Radioprotection ◽

10.1051/radiopro/2020048 ◽

2020 ◽

Vol 55 (3) ◽

pp. 173-178

Author(s):

L. Zhu ◽

J. Zhang ◽

B. Xia ◽

S. Chen ◽

Y. Xu

Keyword(s):

Text Mining ◽

Protein Interaction ◽

Molecular Mechanisms ◽

Radiation Pneumonitis ◽

Interaction Analysis ◽

Interaction Network ◽

Protein Protein Interaction ◽

Gene Sets ◽

Underlying Mechanisms ◽

Unique Genes

Introduction: Radiation pneumonitis (RP) is the most significant dose-limiting toxicity in patients receiving thoracic radiotherapy. The underlying mechanisms of RP are still inconclusive. Our objective was to determine the genes and molecular pathways associated with RP using computational tools and publicly available data. Methods: RP-associated genes were determined by text mining, and the intersection of the two gene sets was selected for Gene Ontology analysis using the GeneCodis program. Protein-protein interaction network analysis was performed using STRINGdb to identify the final genes. Results: Our analysis identified 256 genes related to RP with text mining. The enriched biological process annotations resulted in 47 sets of annotations containing a total of 156 unique genes. KEGG analysis of the enriched pathways identified 24 pathways containing a total of 41 unique genes. The protein-protein interaction analysis yielded 23 genes (mostly the PI3K family). Conclusion: Gene discovery using in silico text mining and pathway analysis tools can facilitate the identification of the underlying mechanisms of RP.

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Abstract 1388: Hdlq14 Gene, A New Gene Regulating HDL Levels

Circulation ◽

10.1161/circ.116.suppl_16.ii_285-a ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Zhiguang Su ◽

Allison Cox ◽

Yuan Shen ◽

Ioannis Stylianou ◽

Beverly Paigen

Keyword(s):

Qtl Analysis ◽

Complex Traits ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Density Lipoprotein ◽

Mouse Strains ◽

F2 Population ◽

New Genes ◽

Trait Locus ◽

Significant Expression

Background . The discovery of new genes responsible for regulation of high-density lipoprotein cholesterol (HDL) has great clinical relevance since increases in HDL can reduce cardiovascular disease risk. Quantitative trait locus (QTL) analysis is a means of finding novel genes that regulate complex traits, such as atherosclerosis and HDL. Hdlq14 and Hdlq15 , two closely linked QTLs for HDL on mouse Chr 1, have been detected by using an intercross between strains C57BL/6 (B6) and 129S1/SvImJ (129). Apoa2 is the gene for Hdlq15 locus, but the gene for Hdlq14 is unknown. Methods: To confirm the Hdlq14 and identify the candidate gene, we performed QTL analysis in a F2 population generated from strains NZB and NZW, which are same at Apoa2 to avoid its strong effect on the nearby QTL. Hdlq14 was further narrowed by several strategies including combining crosses, comparative genomics, and haplotype analysis. The reduced lists of candidate genes were evaluated by their expression or sequence differences between the strains that caused the Hdlq14 . Finally, other HDL crosses, including NZOxNON, B6xC3H, and Pera x D2, were examined to point out the QTL gene. The relationship between the polymorphism at the Hdlq14 gene and HDL was analyzed in 43 genetically diverse mouse strains. Results: Hdlq14 was proved in cross NZBxNZW and the critical interval was reduced from 45 Mb harboring 271 genes to 1.65 Mb containing 15 genes by using bioinformatics tools. Six of these 15 genes have polymorphisms that changed an amino acid; and two genes were found have a significant expression difference between strains B6 and 129. The Hdlq14 gene was further pointed out using HDL QTL identified in crosses including NZOxNON, B6xC3H, and PeraxDBA. In 43 genetically diverse mouse strains, we found that strains with one allele of the Hdlq14 had significantly higher plasma HDL levels than those with the other variant. Conclusions: The Hdlq14 was identified as a new HDL-regulating gene.

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Identification of Ferroptotic Genes in Spinal Cord Injury at Different Time Points: Bioinformatics and Experimental Validation

10.21203/rs.3.rs-1102903/v1 ◽

2021 ◽

Author(s):

Yu Kang ◽

Qiangwei Li ◽

Rui Zhu ◽

Shuang Li ◽

Xin Xu ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Signaling Pathway ◽

Molecular Mechanisms ◽

Interaction Analysis ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Protein Protein Interaction ◽

Cord Injury ◽

Key Genes

Abstract Programmed cell death (PCD) is an important pathologic process after spinal cord injury (SCI), and as a newly type of PCD, ferroptosis is also involved in the secondary SCI, however, the underlying molecular mechanisms remain unclear. Integrating animal experiment and bioinformatics, we validated the ferroptotic phenotype in SCI first, and then bioinformatic analyses, including Gene Ontology enrichment analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis, gene set enrichment analysis and protein-protein interaction analysis were performed to investigate the ferroptotic genes at 1 day, 3 days, 7 days, 14 days and 56 days post-SCI, finally, the ferroptotic genes in SCI were identified and expression of 5 key genes were validated by western blot. The ferroptotic symbols including iron overload, lipid peroxidation, shrunken mitochondria and ROS accumulation were detected in the acute and sub-acute phase of SCI. The outcomes of bioinformatics suggested that mTOR signaling pathway, HIF-1 signaling pathway, VEGF signaling pathway, Protein processing in endoplasmic reticulum were involved in ferroptotic regulation and ATF-3, XBP-1, HO-1, DDIT-3 and CHAC-1 were selected as the ferroptotic key genes in SCI. Besides, response to oxidative stress, amide metabolic process, cation transport and cytokine production were showed as the essential biological process in ferroptosis after SCI. The ferroptotic phenotype following SCI was validated and the ferroptotic genes and signaling pathways were identified. The results contribute to exploring the ferroptotic mechanism underlying secondary SCI and to providing potential target for clinical treatment.

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