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101 Publications visible to you, out of a total of 101
Transposon DNA sequences facilitate the tissue-specific gene transfer of circulating tumor DNA between human cells

Abstract (Expand)

The exchange of genes between cells is known to play an important physiological and pathological role in many organisms. We show that circulating tumor DNA (ctDNA) facilitates cell-specific gene transfer … between human cancer cells and explain part of the mechanisms behind this phenomenon. As ctDNA migrates into the nucleus, genetic information is transferred. Cell targeting and ctDNA integration require ERVL, SINE or LINE DNA sequences. Chemically manufactured AluSp and MER11C sequences replicated multiple myeloma (MM) ctDNA cell targeting and integration. Additionally, we found that ctDNA may alter the treatment response of MM and pancreatic cancer models. This study shows that retrotransposon DNA sequences promote cancer gene transfer. However, because cell-free DNA has been detected in physiological and other pathological conditions, our findings have a broader impact than just cancer. Furthermore, the discovery that transposon DNA sequences mediate tissue-specific targeting will open up a new avenue for the delivery of genes and therapies.

Authors: Munevver Cinar, Lourdes Martinez-Medina, Pavan K Puvvula, Arsen Arakelyan, Badri N Vardarajan, Neil Anthony, Ganji P Nagaraju, Dongkyoo Park, Lei Feng, Faith Sheff, Marina Mosunjac, Debra Saxe, Steven Flygare, Olatunji B Alese, Jonathan L Kaufman, Sagar Lonial, Juan M Sarmiento, Izidore S Lossos, Paula M Vertino, Jose A Lopez, Bassel El-Rayes, Leon Bernal-Mizrachi

Date Published: 23rd May 2024

Publication Type: Journal

Antiviral screening of natural, anti-inflammatory compound library against African swine fever virus.

Abstract (Expand)

African swine fever virus (ASFV) is a major threat to pig production and the lack of effective vaccines underscores the need to develop robust antiviral countermeasures. Pathologically, a significant … elevation in pro-inflammatory cytokine production is associated with ASFV infection in pigs and there is high interest in identifying dual-acting natural compounds that exhibit antiviral and anti-inflammatory activities.

Authors: Joshua A Jackman, Astghik Hakobyan, Rafayela Grigoryan, Roza Izmailyan, Charles C Elrod, Hovakim Zakaryan

Date Published: 25th Apr 2024

Publication Type: Journal

Temporal changes of gene expression in health, schizophrenia, bipolar disorder, and major depressive disorder

Abstract (Expand)

The molecular events underlying the development, manifestation, and course of schizophrenia, bipolar disorder, and major depressive disorder span from embryonic life to advanced age. However, little … is known about the early dynamics of gene expression in these disorders due to their relatively late manifestation. To address this, we conducted a secondary analysis of post-mortem prefrontal cortex datasets using bioinformatics and machine learning techniques to identify differentially expressed gene modules associated with aging and the diseases, determine their time-perturbation points, and assess enrichment with expression quantitative trait loci (eQTL) genes. Our findings revealed early, mid, and late deregulation of expression of functional gene modules involved in neurodevelopment, plasticity, homeostasis, and immune response. This supports the hypothesis that multiple hits throughout life contribute to disease manifestation rather than a single early-life event. Moreover, the time-perturbed functional gene modules were associated with genetic loci affecting gene expression, highlighting the role of genetic factors in gene expression dynamics and the development of disease phenotypes. Our findings emphasize the importance of investigating time-dependent perturbations in gene expression before the age of onset in elucidating the molecular mechanisms of psychiatric disorders.

Authors: Arsen Arakelyan, Susanna Avagyan, Aleksey Kurnosov, Tigran Mkrtchyan, Gohar Mkrtchyan, Roksana Zakharyan, Karine R. Mayilyan, Hans Binder

Date Published: 17th Feb 2024

Publication Type: Journal

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

Glycerol Monolaurate Inhibits Wild-Type African Swine Fever Virus Infection in Porcine Macrophages.

Abstract (Expand)

Naturally abundant antimicrobial lipids, such as fatty acids and monoglycerides, that disrupt membrane-enveloped viruses are promising mitigants to inhibit African swine fever virus (ASFV). Among … mitigant candidates in this class, glycerol monolaurate (GML) has demonstrated particularly high antiviral activity against laboratory-adapted ASFV strains. However, there is an outstanding need to further determine the effects of GML on wild-type ASFV strains, which can have different virulence levels and sensitivities to membrane-disrupting compounds as compared to laboratory-adapted strains. Herein, we investigated the antiviral effects of GML on a highly virulent strain of a wild-type ASFV isolate (Armenia/07) in an in vitro porcine macrophage model. GML treatment caused a concentration-dependent reduction in viral infectivity, and there was a sharp transition between inactive and active GML concentrations. Low GML concentrations had negligible effect on viral infectivity, whereas sufficiently high GML concentrations caused a >99% decrease in viral infectivity. The concentration onset of antiviral activity matched the critical micelle concentration (CMC) value of GML, reinforcing that GML micelles play a critical role in enabling anti-ASFV activity. These findings validate that GML can potently inhibit wild-type ASFV infection of porcine macrophages and support a biophysical explanation to guide antimicrobial lipid performance optimization for pathogen mitigation applications.

Authors: Joshua A Jackman, Erik Arabyan, Hovakim Zakaryan, Charles C Elrod

Date Published: 25th Sep 2023

Publication Type: Journal

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