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73 Publications visible to you, out of a total of 73
Spaceflight-Associated Changes of snoRNAs in Peripheral Blood Mononuclear Cells and Plasma Exosomes—A Pilot Study

Abstract (Expand)

During spaceflight, astronauts are exposed to various physiological and psychological stressors that have been associated with adverse health effects. Therefore, there is an unmet need to develop novel … diagnostic tools to predict early alterations in astronauts' health. Small nucleolar RNA (snoRNA) is a type of short non-coding RNA (60-300 nucleotides) known to guide 2'-O-methylation (Nm) or pseudouridine (ψ) of ribosomal RNA (rRNA), small nuclear RNA (snRNA), or messenger RNA (mRNA). Emerging evidence suggests that dysregulated snoRNAs may be key players in regulating fundamental cellular mechanisms and in the pathogenesis of cancer, heart, and neurological disease. Therefore, we sought to determine whether the spaceflight-induced snoRNA changes in astronaut's peripheral blood (PB) plasma extracellular vesicles (PB-EV) and peripheral blood mononuclear cells (PBMCs). Using unbiased small RNA sequencing (sRNAseq), we evaluated changes in PB-EV snoRNA content isolated from astronauts (n = 5/group) who underwent median 12-day long Shuttle missions between 1998 and 2001. Using stringent cutoff (fold change > 2 or log2-fold change >1, FDR < 0.05), we detected 21 down-and 9-up-regulated snoRNAs in PB-EVs 3 days after return (R + 3) compared to 10 days before launch (L-10). qPCR validation revealed that SNORA74A was significantly down-regulated at R + 3 compared to L-10. We next determined snoRNA expression levels in astronauts' PBMCs at R + 3 and L-10 (n = 6/group). qPCR analysis further confirmed a significant increase in SNORA19 and SNORA47 in astronauts' PBMCs at R + 3 compared to L-10. Notably, many downregulated snoRNA-guided rRNA modifications, including four Nms and five ψs. Our findings revealed that spaceflight induced changes in PB-EV and PBMCs snoRNA expression, thus suggesting snoRNAs may serve as potential novel biomarkers for monitoring astronauts' health. Keywords: astronaut; biomarker; extracellular vesicles; peripheral blood—mononuclear cells; snoRNA. Copyright © 2022 Rai, Rajan, Bisserier, Brojakowska, Sebastian, Evans, Coleman, Mills, Arakelyan, Uchida, Hadri, Goukassian and Garikipati.

Authors: Amit Kumar Rai, K. Shanmugha Rajan, Malik Bisserier, Agnieszka Brojakowska, Aimy Sebastian, Angela C. Evans, Matthew A. Coleman, Paul J. Mills, Arsen Arakelyan, Shizuka Uchida, Lahouaria Hadri, David A. Goukassian, Venkata Naga Srikanth Garikipati

Date Published: 24th Jun 2022

Publication Type: Journal

Astronauts Plasma-Derived Exosomes Induced Aberrant EZH2-Mediated H3K27me3 Epigenetic Regulation of the Vitamin D Receptor

Abstract (Expand)

There are unique stressors in the spaceflight environment. Exposure to such stressors may be associated with adverse effects on astronauts' health, including increased cancer and cardiovascular … disease risks. Small extracellular vesicles (sEVs, i.e., exosomes) play a vital role in intercellular communication and regulate various biological processes contributing to their role in disease pathogenesis. To assess whether spaceflight alters sEVs transcriptome profile, sEVs were isolated from the blood plasma of 3 astronauts at two different time points: 10 days before launch (L-10) and 3 days after return (R+3) from the Shuttle mission. AC16 cells (human cardiomyocyte cell line) were treated with L-10 and R+3 astronauts-derived exosomes for 24 h. Total RNA was isolated and analyzed for gene expression profiling using Affymetrix microarrays. Enrichment analysis was performed using Enrichr. Transcription factor (TF) enrichment analysis using the ENCODE/ChEA Consensus TF database identified gene sets related to the polycomb repressive complex 2 (PRC2) and Vitamin D receptor (VDR) in AC16 cells treated with R+3 compared to cells treated with L-10 astronauts-derived exosomes. Further analysis of the histone modifications using datasets from the Roadmap Epigenomics Project confirmed enrichment in gene sets related to the H3K27me3 repressive mark. Interestingly, analysis of previously published H3K27me3-chromatin immunoprecipitation sequencing (ChIP-Seq) ENCODE datasets showed enrichment of H3K27me3 in the VDR promoter. Collectively, our results suggest that astronaut-derived sEVs may epigenetically repress the expression of the VDR in human adult cardiomyocytes by promoting the activation of the PRC2 complex and H3K27me3 levels.

Authors: Malik Bisserier, Agnieszka Brojakowska, Nathaniel Saffran, Amit Kumar Rai, Brooke Lee, Matthew Coleman, Aimy Sebastian, Angela Evans, Paul J. Mills, Sankar Addya, Arsen Arakelyan, Venkata Naga Srikanth Garikipati, Lahouaria Hadri, David A. Goukassian

Date Published: 16th Jun 2022

Publication Type: Journal

Space flight associated changes in astronauts’ plasma‐derived small extracellular vesicle microRNA: Biomarker identification

Abstract (Expand)

Dear Editor, This pilot study suggests relatively short (median 12 days long) low-Earth orbit (LEO) spaceflight induces changes in circulating plasma small extracellular vesicle (sEV) microRNA expression. … Normalization of small RNA sequencing (sRNAseq) data and quantitative polymerase chain reaction (qPCR) validation confirmed miR-4732-3p is significantly upregulated up to 3 days post-landing, and enrichment analysis suggests this miRNA is expressed in various central nervous system tissues and hematopoietic cells and may be linked to different organ disorders.

Authors: David Goukassian, Arsen Arakelyan, Agnieszka Brojakowska, Malik Bisserier, Siras Hakobyan, Lahouaria Hadri, Amit Kumar Rai, Angela Evans, Aimy Sebastian, May Truongcao, Carolina Gonzalez, Anamika Bajpai, Zhongjian Cheng, Praveen Kumar Dubey, Sankar Addya, Paul Mills, Kenneth Walsh, Raj Kishore, Matt Coleman, Venkata Naga Srikanth Garikipati

Date Published: 2nd Jun 2022

Publication Type: Journal

Molecular Analysis of SARS-CoV-2 Lineages in Armenia

Abstract (Expand)

The sequencing of SARS-CoV-2 provides essential information on viral evolution, transmission, and epidemiology. In this paper, we performed the whole-genome sequencing of SARS-CoV-2 using nanopore and … Illumina sequencing to describe the circulation of the virus lineages in Armenia. The analysis of 145 full genomes identified six clades (19A, 20A, 20B, 20I, 21J, and 21K) and considerable intra-clade PANGO lineage diversity. Phylodynamic and transmission analysis allowed to attribute specific clades as well as infer their importation routes. Thus, the first two waves of positive case increase were caused by the 20B clade, the third peak caused by the 20I (Alpha), while the last two peaks were caused by the 21J (Delta) and 21K (Omicron) variants. The functional analyses of mutations in sequences largely affected epitopes associated with protective HLA loci and did not cause the loss of the signal in PCR tests targeting ORF1ab and N genes as confirmed by RT-PCR. We also compared the performance of nanopore and Illumina short-read sequencing and showed the utility of nanopore sequencing as an efficient and affordable alternative for large-scale molecular epidemiology research. Thus, our paper describes new data on the genomic diversity of SARS-CoV-2 variants in Armenia in the global context of the virus molecular genomic surveillance.

Authors: Diana Avetyan, Siras Hakobyan, Maria Nikoghosyan, Lilit Ghukasyan, Gisane Khachatryan, Tamara Sirunyan, Nelli Muradyan, Roksana Zakharyan, Andranik Chavushyan, Varduhi Hayrapetyan, Anahit Hovhannisyan, Shah A. Mohamed Bakhash, Keith R. Jerome, Pavitra Roychoudhury, Alexander L. Greninger, Lyudmila Niazyan, Mher Davidyants, Gayane Melik-Andreasyan, Shushan Sargsyan, Lilit Nersisyan, Arsen Arakelyan

Date Published: 17th May 2022

Publication Type: Journal

HLA-C*04:01 Affects HLA Class I Heterozygosity and Predicted Affinity to SARS-CoV-2 Peptides, and in Combination With Age and Sex of Armenian Patients Contributes to COVID-19 Severity

Abstract (Expand)

The novel SARS-CoV-2 coronavirus infection has become a global health concern, causing the COVID-19 pandemic. The disease symptoms and outcomes depend on the host immunity, in which the human leukocyte … antigen (HLA) molecules play a distinct role. The HLA alleles have an inter-population variability, and understanding their link to the COVID-19 in an ethnically distinct population may contribute to personalized medicine. The present study aimed at detecting associations between common HLA alleles and COVID-19 susceptibility and severity in Armenians. In 299 COVID-19 patients (75 asymptomatic, 102 mild/moderate, 122 severe), the association between disease severity and classic HLA-I and II loci was examined. We found that the advanced age, male sex of patients, and sex and age interaction significantly contributed to the severity of the disease. We observed that an age-dependent effect of HLA-B*51:01 carriage [odds ratio (OR)=0.48 (0.28-0.80), Pbonf <0.036] is protective against severe COVID-19. Contrary, the HLA-C*04:01 allele, in a dose-dependent manner, was associated with a significant increase in the disease severity [OR (95% CI) =1.73 (1.20-2.49), Pbonf <0.021] and an advancing age (P<0.013). The link between HLA-C*04:01 and age was secondary to a stronger association between HLA-C*04:01 and disease severity. However, HLA-C*04:01 exerted a sex-dependent differential distribution between clinical subgroups [females: P<0.0012; males: P=0.48]. The comparison of HLA-C*04:01 frequency between subgroups and 2,781 Armenian controls revealed a significant incidence of HLA-C*04:01 deficiency in asymptomatic COVID-19. HLA-C*04:01 homozygous genotype in patients blueprinted a decrease in heterozygosity of HLA-B and HLA class-I loci. In HLA-C*04:01 carriers, these changes translated to the SARS-CoV-2 peptide presentation predicted inefficacy by HLA-C and HLA class-I molecules, simultaneously enhancing the appropriate HLA-B potency. In patients with clinical manifestation, due to the high prevalence of HLA-C*04:01, these effects provided a decrease of the HLA class-I heterozygosity and an ability to recognize SARS-CoV-2 peptides. Based on our observations, we developed a prediction model involving demographic variables and HLA-C*04:01 allele for the identification of potential cases with the risk of hospitalization (the area under the curve (AUC) = 86.2%) or severe COVID-19 (AUC =71%).

Authors: Anahit Hovhannisyan, Vergine Madelian, Sevak Avagyan, Mihran Nazaretyan, Armine Hyussyan, Alina Sirunyan, Rubina Arakelyan, Zorayr Manukyan, Levon Yepiskoposyan, Karine R. Mayilyan, Frieda Jordan

Date Published: 3rd Feb 2022

Publication Type: Journal

Emerging Role of Exosomal Long Non-coding RNAs in Spaceflight-Associated Risks in Astronauts

Abstract (Expand)

During spaceflight, astronauts are exposed to multiple unique environmental factors, particularly microgravity and ionizing radiation, that can cause a range of harmful health consequences. Over the … past decades, increasing evidence demonstrates that the space environment can induce changes in gene expression and RNA processing. Long non-coding RNA (lncRNA) represent an emerging area of focus in molecular biology as they modulate chromatin structure and function, the transcription of neighboring genes, and affect RNA splicing, stability, and translation. They have been implicated in cancer development and associated with diverse cardiovascular conditions and associated risk factors. However, their role on astronauts' health after spaceflight remains poorly understood. In this perspective article, we provide new insights into the potential role of exosomal lncRNA after spaceflight. We analyzed the transcriptional profile of exosomes isolated from peripheral blood plasma of three astronauts who flew on various Shuttle missions between 1998-2001 by RNA-sequencing. Computational analysis of the transcriptome of these exosomes identified 27 differentially expressed lncRNAs with a Log2 fold change, with molecular, cellular, and clinical implications.

Authors: Malik Bisserier, Nathaniel Saffran, Agnieszka Brojakowska, Aimy Sebastian, Angela Clare Evans, Matthew A. Coleman, Kenneth Walsh, Paul J. Mills, Venkata Naga Srikanth Garikipati, Arsen Arakelyan, Lahouaria Hadri, David A. Goukassian

Date Published: 17th Jan 2022

Publication Type: Journal

Cell‐Free Mitochondrial DNA as a Potential Biomarker for Astronauts' Health

Abstract (Expand)

Background: Space travel–associated stressors such as microgravity or radiation exposure have been reported in astronauts after short‐ and long‐duration missions aboard the International Space Station. … Despite risk mitigation strategies, adverse health effects remain a concern. Thus, there is a need to develop new diagnostic tools to facilitate early detection of physiological stress. Methods and Results: We measured the levels of circulating cell‐free mitochondrial DNA in blood plasma of 14 astronauts 10 days before launch, the day of landing, and 3 days after return. Our results revealed a significant increase of cell‐free mitochondrial DNA in the plasma on the day of landing and 3 days after return with vast ~2 to 355‐fold interastronaut variability. In addition, gene expression analysis of peripheral blood mononuclear cells revealed a significant increase in markers of inflammation, oxidative stress, and DNA damage. Conclusions: Our study suggests that cell‐free mitochondrial DNA abundance might be a biomarker of stress or immune response related to microgravity, radiation, and other environmental factors during space flight.

Authors: Malik Bisserier, Santhanam Shanmughapriya, Amit Kumar Rai, Carolina Gonzalez, Agnieszka Brojakowska, Venkata Naga Srikanth Garikipati, Muniswamy Madesh, Paul J. Mills, Kenneth Walsh, Arsen Arakelyan, Raj Kishore, Lahouaria Hadri, David A. Goukassian

Date Published: 2nd Nov 2021

Publication Type: Journal

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