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72 Publications visible to you, out of a total of 72
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

Wild grapes of Armenia: unexplored source of genetic diversity and disease resistance.

Abstract (Expand)

The present study is the first in-depth research evaluating the genetic diversity and potential resistance of Armenian wild grapes utilizing DNA-based markers to understand the genetic signature of … this unexplored germplasm. In the proposed research, five geographical regions with known viticultural history were explored. A total of 148 unique wild genotypes were collected and included in the study with 48 wild individuals previously collected as seed. A total of 24 nSSR markers were utilized to establish a fingerprint database to infer information on the population genetic diversity and structure. Three nSSR markers linked to the Ren1 locus were analyzed to identify potential resistance against powdery mildew. According to molecular fingerprinting data, the Armenian V. sylvestris gene pool conserves a high genetic diversity, displaying 292 different alleles with 12.167 allele per loci. The clustering analyses and diversity parameters supported eight genetic groups with 5.6% admixed proportion. The study of genetic polymorphism at the Ren1 locus revealed that 28 wild genotypes carried three R-alleles and 34 wild genotypes carried two R-alleles associated with PM resistance among analyzed 107 wild individuals. This gene pool richness represents an immense reservoir of under-explored genetic diversity and breeding potential. Therefore, continued survey and research efforts are crucial for the conservation, sustainable management, and utilization of Armenian wild grape resources in the face of emerging challenges in viticulture.

Authors: K. Margaryan, R. Topfer, B. Gasparyan, A. Arakelyan, O. Trapp, F. Rockel, E. Maul

Date Published: 25th Dec 2023

Publication Type: Journal

Machine learning extracts marks of thiamine's role in cold acclimation in the transcriptome of Vitis vinifera.

Abstract (Expand)

INTRODUCTION: The escalating challenge of climate change has underscored the critical need to understand cold defense mechanisms in cultivated grapevine Vitis vinifera. Temperature variations can affect … the growth and overall health of vine. METHODS: We used Self Organizing Maps machine learning method to analyze gene expression data from leaves of five Vitis vinifera cultivars each treated by four different temperature conditions. The algorithm generated sample-specific "portraits" of the normalized gene expression data, revealing distinct patterns related to the temperature conditions applied. RESULTS: Our analysis unveiled a connection with vitamin B1 (thiamine) biosynthesis, suggesting a link between temperature regulation and thiamine metabolism, in agreement with thiamine related stress response established in Arabidopsis before. Furthermore, we found that epigenetic mechanisms play a crucial role in regulating the expression of stress-responsive genes at low temperatures in grapevines. DISCUSSION: Application of Self Organizing Maps portrayal to vine transcriptomics identified modules of coregulated genes triggered under cold stress. Our machine learning approach provides a promising option for transcriptomics studies in plants.

Authors: T. Konecny, M. Nikoghosyan, H. Binder

Date Published: 21st 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: S. Hakobyan, A. Stepanyan, L. Nersisyan, H. Binder, A. Arakelyan

Date Published: 8th Sep 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

Long-term environmental metal exposure is associated with hypomethylation of CpG sites in NFKB1 and other genes related to oncogenesis.

Abstract (Expand)

BACKGROUND: Long-term environmental exposure to metals leads to epigenetic changes and may increase risks to human health. The relationship between the type and level of metal exposure and epigenetic … changes in subjects exposed to high concentrations of metals in the environment is not yet clear. The aim of our study is to find the possible association of environmental long-term exposure to metals with DNA methylation changes of genes related to immune response and carcinogenesis. We investigated the association of plasma levels of 21 essential and non-essential metals detected by ICP-MS and the methylation level of 654 CpG sites located on NFKB1, CDKN2A, ESR1, APOA5, IGF2 and H19 genes assessed by targeted bisulfite sequencing in a cohort of 40 subjects living near metal mining area and 40 unexposed subjects. Linear regression was conducted to find differentially methylated positions with adjustment for gender, age, BMI class, smoking and metal concentration. RESULTS: In the metal-exposed group, five CpGs in the NFKB1 promoter region were hypomethylated compared to unexposed group. Four differentially methylated positions (DMPs) were associated with multiple metals, two of them are located on NFKB1 gene, and one each on CDKN2A gene and ESR1 gene. Two DMPs located on NFKB1 (chr4:102500951, associated with Be) and IGF2 (chr11:2134198, associated with U) are associated with specific metal levels. The methylation status of the seven CpGs located on NFKB1 (3), ESR1 (2) and CDKN2A (2) positively correlated with plasma levels of seven metals (As, Sb, Zn, Ni, U, I and Mn). CONCLUSIONS: Our study revealed methylation changes in NFKB1, CDKN2A, IGF2 and ESR1 genes in individuals with long-term human exposure to metals. Further studies are needed to clarify the effect of environmental metal exposure on epigenetic mechanisms and pathways involved.

Authors: A. Stepanyan, A. Petrackova, S. Hakobyan, J. Savara, S. Davitavyan, E. Kriegova, A. Arakelyan

Date Published: 7th Aug 2023

Publication Type: Journal

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