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73 Publications visible to you, out of a total of 73
Generation of iPSCs from a Patient with the M694V Mutation in the MEFV Gene Associated with Familial Mediterranean Fever and Their Differentiation into Macrophages.

Abstract (Expand)

Familial Mediterranean fever (FMF) is a systemic autoinflammatory disorder caused by inherited mutations in the MEFV (Mediterranean FeVer) gene, located on chromosome 16 (16p13.3) and encoding the pyrin … protein. Despite the existing data on MEFV mutations, the exact mechanism of their effect on the development of the pathological processes leading to the spontaneous and recurrent autoinflammatory attacks observed in FMF, remains unclear. Induced pluripotent stem cells (iPSCs) are considered an important tool to study the molecular genetic mechanisms of various diseases due to their ability to differentiate into any cell type, including macrophages, which contribute to the development of FMF. In this study, we developed iPSCs from an Armenian patient with FMF carrying the M694V, p.(Met694Val) (c.2080A>G, rs61752717) pathogenic mutation in exon 10 of the MEFV gene. As a result of direct differentiation, macrophages expressing CD14 and CD45 surface markers were obtained. We found that the morphology of macrophages derived from iPSCs of a patient with the MEFV mutation significantly differed from that of macrophages derived from iPSCs of a healthy donor carrying the wild-type MEFV gene. Keywords: Familial Mediterranean fever; MEFV gene; differentiation; macrophages; patient-specific induced pluripotent stem cells.

Authors: Elena V Grigor'eva, Lana V Karapetyan, Anastasia A Malakhova, Sergey P Medvedev, Julia M Minina, Varduhi H Hayrapetyan, Valentina S Vardanyan, Suren M Zakian, Arsen Arakelyan, Roksana Zakharyan

Date Published: 2024

Publication Type: Journal

Development of an optimized, non‐stem cell line for intranasal delivery of therapeutic cargo to the central nervous system

Abstract (Expand)

Neural stem cells (NSCs) are considered to be valuable candidates for delivering a variety of anti-cancer agents, including oncolytic viruses, to brain tumors. However, owing to the previously reported … tumorigenic potential of NSC cell lines after intranasal administration (INA), here we identified the human hepatic stellate cell line LX-2 as a cell type capable of longer resistance to replication of oncolytic adenoviruses (OAVs) as a therapeutic cargo, and that is non-tumorigenic after INA. Our data show that LX-2 cells can longer withstand the OAV XVir-N-31 replication and oncolysis than NSCs. By selecting the highly migratory cell population out of LX-2, an offspring cell line with a higher and more stable capability to migrate was generated. Additionally, as a safety backup, we applied genomic herpes simplex virus thymidine kinase (HSV-TK) integration into LX-2, leading to high vulnerability to ganciclovir (GCV). Histopathological analyses confirmed the absence of neoplasia in the respiratory tracts and brains of immuno-compromised mice 3 months after INA of LX-2 cells. Our data suggest that LX-2 is a novel, robust, and safe cell line for delivering anti-cancer and other therapeutic agents to the brain.

Authors: Ali El‐Ayoubi, Arsen Arakelyan, Moritz Klawitter, Luisa Merk, Siras Hakobyan, Irene Gonzalez‐Menendez, Leticia Quintanilla Fend, Per Sonne Holm, Wolfgang Mikulits, Matthias Schwab, Lusine Danielyan, Ulrike Naumann

Date Published: 26th Dec 2023

Publication Type: Journal

Machine learned-based visualization of the diversity of grapevine genomes worldwide and in Armenia using SOMmelier

Abstract (Expand)

In the proposed study three major issues have been addressed: Firstly, the diversity of grapevine accessions worldwide and particularly in Armenia, a small country located in the largely volcanic … Armenian Highlands, is incredibly rich in cultivated and especially wild grapes; secondly, the information hidden in their (whole) genomes, e.g., about the domestication history of grapevine over the last 11,000 years and phenotypic traits such as cultivar utilization and a putative resistance against powdery mildew, and, thirdly machine learning methods to extract and to visualize this information in an easy to percept way. We shortly describe the Self Origanizing Maps (SOM) portrayal method called “SOMmelier” (as the vine-genome “waiter”) and illustrate its power by applying it to whole genome data of hundreds of grapevine accessions. We also give a short outlook on possible future directions of machine learning in grapevine transcriptomics and ampelogaphy.

Authors: Kristina Magaryan, Maria Nikogհosyan, Anush Baloyan, Hripsime Gasoyan, Emma Hovhannisyan, Levon Galstyan, Tomas Konecny, Arsen Arakelyan, Hans Binder

Date Published: 6th Dec 2023

Publication Type: Journal

PSF toolkit: an R package for pathway curation and topology-aware analysis

Abstract (Expand)

Most high throughput genomic data analysis pipelines currently rely on over-representation or gene set enrichment analysis (ORA/GSEA) approaches for functional analysis. In contrast, topology-based … pathway analysis methods, which offer a more biologically informed perspective by incorporating interaction and topology information, have remained underutilized and inaccessible due to various limiting factors. These methods heavily rely on the quality of pathway topologies and often utilize predefined topologies from databases without assessing their correctness. To address these issues and make topology-aware pathway analysis more accessible and flexible, we introduce the PSF (Pathway Signal Flow) toolkit R package. Our toolkit integrates pathway curation and topology-based analysis, providing interactive and command-line tools that facilitate pathway importation, correction, and modification from diverse sources. This enables users to perform topology-based pathway signal flow analysis in both interactive and command-line modes. To showcase the toolkit’s usability, we curated 36 KEGG signaling pathways and conducted several use-case studies, comparing our method with ORA and the topology-based signaling pathway impact analysis (SPIA) method. The results demonstrate that the algorithm can effectively identify ORA enriched pathways while providing more detailed branch-level information. Moreover, in contrast to the SPIA method, it offers the advantage of being cut-off free and less susceptible to the variability caused by selection thresholds. By combining pathway curation and topology-based analysis, the PSF toolkit enhances the quality, flexibility, and accessibility of topology-aware pathway analysis. Researchers can now easily import pathways from various sources, correct and modify them as needed, and perform detailed topology-based pathway signal flow analysis. In summary, our PSF toolkit offers an integrated solution that addresses the limitations of current topology-based pathway analysis methods. By providing interactive and command-line tools for pathway curation and topology-based analysis, we empower researchers to conduct comprehensive pathway analyses across a wide range of applications.

Authors: Siras Hakobyan, Ani Stepanyan, Lilit Nersisyan, Hans Binder, Arsen Arakelyan

Date Published: 23rd Aug 2023

Publication Type: Journal

Generation of three induced pluripotent stem cell lines (RAUi001-A, RAUi001-B and RAUi001-C) from peripheral blood mononuclear cells of a healthy Armenian individual.

Abstract (Expand)

The study of pathological processes in cells carrying mutations should be carried out in comparison with a healthy control group. Familial Mediterranean fever (FMF), which is caused by a mutation in … the MEFV gene, is predominantly found in people of Armenian nationality with the prevalence of 14–100 per 10000. We have obtained induced pluripotent stem cells (iPSCs) from Armenian healthy patient, which will be included as a control group in the study of this disease. iPSCs rapidly proliferate in colonies of cells with a typical pluripotent-like morphology, have a normal karyotype (46,XX). iPSCs express pluripotency markers (OCT4, SOX2, TRA-1–60, NANOG) and are able to give derivatives of three germ layers.

Authors: Elena V. Grigor’eva, Anastasia A. Malakhova, Lilit Ghukasyan, Varduhi Hayrapetyan, Sofi Atshemyan, Valentina Vardanyan, Suren M. Zakian, Roksana Zakharyan, Arsen Arakelyan

Date Published: 17th Jun 2023

Publication Type: Journal

Transcriptional states of CAR-T infusion relate to neurotoxicity – lessons from high-resolution single-cell SOM expression portraying

Abstract (Expand)

Anti-CD19 CAR-T cell immunotherapy is a hopeful treatment option for patients with B cell lymphomas, however it copes with partly severe adverse effects like neurotoxicity. Single-cell resolved molecular … data sets in combination with clinical parametrization allow for comprehensive characterization of cellular subpopulations, their transcriptomic states, and their relation to the adverse effects. We here present a re-analysis of single-cell RNA sequencing data of 24 patients comprising more than 130,000 cells with focus on cellular states and their association to immune cell related neurotoxicity. For this, we developed a single-cell data portraying workflow to disentangle the transcriptional state space with single-cell resolution and its analysis in terms of modularly-composed cellular programs. We demonstrated capabilities of single-cell data portraying to disentangle transcriptional states using intuitive visualization, functional mining, molecular cell stratification, and variability analyses. Our analysis revealed that the T cell composition of the patient's infusion product as well as the spectrum of their transcriptional states of cells derived from patients with low ICANS grade do not markedly differ from those of cells from high ICANS patients, while the relative abundancies, particularly that of cycling cells, of LAG3-mediated exhaustion and of CAR positive cells, vary. Our study provides molecular details of the transcriptomic landscape with possible impact to overcome neurotoxicity. Keywords: CAR-T cell immunotherapy; bioinformatics workflow; data portraying; single-cell transcriptomics; transcriptional states. Copyright © 2022 Loeffler-Wirth, Rade, Arakelyan, Kreuz, Loeffler, Koehl, Reiche and Binder.

Authors: Henry Loeffler-Wirth, Michael Rade, Arsen Arakelyan, Markus Kreuz, Markus Loeffler, Ulrike Koehl, Kristin Reiche, Hans Binder

Date Published: 28th Sep 2022

Publication Type: Journal

Molecular Epidemiology and Virulence of Non-Typhoidal Salmonella in Armenia

Abstract (Expand)

In this work, we analysed human isolates of nontyphoidal Salmonella enterica subsp. enterica (NTS), which were collected from salmonellosis cases in Armenia from 1996 to 2019. This disease became a … leading food-borne bacterial infection in the region, with the younger age groups especially affected. The isolates were characterised by serotyping, Enterobacterial Repetitive Intergenic Consensus (ERIC-PCR) typing, and whole genome sequencing (WGS). The main serotypes were S. Typhimurium, S. Enteritidis, and S. Arizonae. ERIC-PCR indicated a high degree of clonality among S. Typhimurium strains, which were also multidrug-resistant and produced extended spectrum beta-lactamases. During the study period, the frequency of S. Typhimurium and S. Arizonae isolations decreased, but with the increase in S. Enteritidis and other NTS. A total of 42 NTS isolates were subjected to WGS and explored for virulence-related traits and the corresponding genetic elements. Some virulence and genetic factors were shared by all NTS serotypes, while the main differences were attributed to the serotype-specific diversity of virulence genes, SPIs, virulence plasmids, and phages. The results indicated the variability and dynamics in the epidemiology of salmonellosis and a high virulence potential of human NTS isolates circulating in the region.

Authors: Anahit Sedrakyan, Zhanna Ktsoyan, Karine Arakelova, Zaruhi Gevorgyan, Magdalina Zakharyan, Shoghik Hakobyan, Alvard Hovhannisyan, Arsen Arakelyan, Rustam Aminov

Date Published: 18th Aug 2022

Publication Type: Journal

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