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68 Publications visible to you, out of a total of 68
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

The Evolving Faces of the SARS-CoV-2 Genome

Abstract (Expand)

Surveillance of the evolving SARS-CoV-2 genome combined with epidemiological monitoring and emerging vaccination became paramount tasks to control the pandemic which is rapidly changing in time and … space. Genomic surveillance must combine generation and sharing sequence data with appropriate bioinformatics monitoring and analysis methods. We applied molecular portrayal using self-organizing maps machine learning (SOM portrayal) to characterize the diversity of the virus genomes, their mutual relatedness and development since the beginning of the pandemic. The genetic landscape obtained visualizes the relevant mutations in a lineage-specific fashion and provides developmental paths in genetic state space from early lineages towards the variants of concern alpha, beta, gamma and delta. The different genes of the virus have specific footprints in the landscape reflecting their biological impact. SOM portrayal provides a novel option for ‘bioinformatics surveillance’ of the pandemic, with strong odds regarding visualization, intuitive perception and ‘personalization’ of the mutational patterns of the virus genomes.

Authors: Maria Schmidt, Mamoona Arshad, Stephan H. Bernhart, Siras Hakobyan, Arsen Arakelyan, Henry Loeffler-Wirth, Hans Binder

Date Published: 3rd Sep 2021

Publication Type: Journal

A Transcriptome-Wide Isoform Landscape of Melanocytic Nevi and Primary Melanomas Identifies Gene Isoforms Associated with Malignancy.

Abstract (Expand)

Genetic splice variants have become of central interest in recent years, as they play an important role in different cancers. Little is known about splice variants in melanoma. Here, we analyzed a … genome-wide transcriptomic dataset of benign melanocytic nevi and primary melanomas (<i>n</i> = 80) for the expression of specific splice variants. Using kallisto, a map for differentially expressed splice variants in melanoma vs. benign melanocytic nevi was generated. Among the top genes with differentially expressed splice variants were Ras-related in brain 6B (<i>RAB6B</i>), a member of the RAS family of GTPases, Macrophage Scavenger Receptor 1 (<i>MSR1</i>), Collagen Type XI Alpha 2 Chain (<i>COLL11A2</i>), and LY6/PLAUR Domain Containing 1 (<i>LYPD1</i>). The Gene Ontology terms of differentially expressed splice variants showed no enrichment for functional gene sets of melanoma vs. nevus lesions, but between type 1 (pigmentation type) and type 2 (immune response type) melanocytic lesions. A number of genes such as Checkpoint Kinase 1 (<i>CHEK1</i>) showed an association of mutational patterns and occurrence of splice variants in melanoma. Moreover, mutations in genes of the splicing machinery were common in both benign nevi and melanomas, suggesting a common mechanism starting early in melanoma development. Mutations in some of these genes of the splicing machinery, such as Serine and Arginine Rich Splicing Factor A3 and B3 (<i>SF3A3</i>, <i>SF3B3</i>), were significantly enriched in melanomas as compared to benign nevi. Taken together, a map of splice variants in melanoma is presented that shows a multitude of differentially expressed splice genes between benign nevi and primary melanomas. The underlying mechanisms may involve mutations in genes of the splicing machinery.

Authors: Siras Hakobyan, Henry Loeffler-Wirth, Arsen Arakelyan, Hans Binder, Manfred Kunz

Date Published: 2nd Jul 2021

Publication Type: Journal

High-Resolution Cartography of the Transcriptome and Methylome Landscapes of Diffuse Gliomas

Abstract (Expand)

Molecular mechanisms of lower-grade (II–III) diffuse gliomas (LGG) are still poorly understood, mainly because of their heterogeneity. They split into astrocytoma- (IDH-A) and oligodendroglioma-like … (IDH-O) tumors both carrying mutations(s) at the isocitrate dehydrogenase (IDH) gene and into IDH wild type (IDH-wt) gliomas of glioblastoma resemblance. We generated detailed maps of the transcriptomes and DNA methylomes, revealing that cell functions divided into three major archetypic hallmarks: (i) increased proliferation in IDH-wt and, to a lesser degree, IDH-O; (ii) increased inflammation in IDH-A and IDH-wt; and (iii) the loss of synaptic transmission in all subtypes. Immunogenic properties of IDH-A are diverse, partly resembling signatures observed in grade IV mesenchymal glioblastomas or in grade I pilocytic astrocytomas. We analyzed details of coregulation between gene expression and DNA methylation and of the immunogenic micro-environment presumably driving tumor development and treatment resistance. Our transcriptome and methylome maps support personalized, case-by-case views to decipher the heterogeneity of glioma states in terms of data portraits. Thereby, molecular cartography provides a graphical coordinate system that links gene-level information with glioma subtypes, their phenotypes, and clinical context.

Authors: Edith Willscher, Lydia Hopp, Markus Kreuz, Maria Schmidt, Siras Hakobyan, Arsen Arakelyan, Bettina Hentschel, David T. W. Jones, Stefan M. Pfister, Markus Loeffler, Henry Loeffler-Wirth, Hans Binder

Date Published: 26th Jun 2021

Publication Type: Journal

The radioenhancement potential of Schiff base derived copper (II) compounds against lung carcinoma in vitro.

Abstract (Expand)

For the last years, copper complexes have been intensively implicated in biomedical research as components of cancer treatment. Herewith, we provide highlights of the synthesis, physical measurements, … structural characterization of the newly developed Cu(II) chelates of Schiff Bases, Cu(Picolinyl-L-Tryptopahanate)2, Cu(Picolinyl-L-Tyrosinate)2, Cu(Isonicotinyl-L-Tyrosinate)2, Cu(Picolinyl-L-Phenylalaninate)2, Cu(Nicotinyl-L-Phenylalaninate)2, Cu(Isonicotinyl-L-Phenylalaninate)2, and their radioenhancement capacity at kV and MV ranges of irradiation of human lung carcinoma epithelial cells in vitro. The methods of cell growth, viability and proliferation were used. All compounds exerted very potent radioenhancer capacities in the irradiated lung carcinoma cells at both kV and MV ranges in a 100 μM concentration. At a concentration of 10 μM, only Cu(Picolinyl-L-Tyrosinate)2, Cu(Isonicotinyl-L-Tyrosinate)2, Cu(Picolinyl-L-Phenylalaninate)2 possessed radioenhancer properties at kV and MV ranges. Cu(Picolinyl-L-Tryptophanate)2 showed radioenhancer properties only at kV range. Cu(Nicotinyl-L-Phenylalaninate)2 and Cu(Isonicotinyl-L-Phenylalaninate)2 showed remarkable radioenhancer activity only at MV range. All compounds acted in dose-dependent manner at both tested energy ranges. These copper (II) compounds, in combination with 1 Gy irradiation at either 120 kV or 6 MV, are more efficient at delaying cell growth of lung cancer cells and at reducing cell viability in vitro than the irradiation administered alone. Thus, we have demonstrated that the studied copper compounds have a good potential for radioenhancement.

Authors: Gohar Tsakanova, Ani Stepanyan, Elina Arakelova, Violetta Ayvazyan, Vahan Tonoyan, Arsen Arakelyan, Guido Hildebrandt, Elisabeth Schültke

Date Published: 18th Jun 2021

Publication Type: Journal

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